bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in the treatment changes and medication persistence of chronic myeloid leukemia in Taiwan from 1997 to 2007: a longitudinal population database analysis
Authors: Chang Chao-Sung , Yang Yi-Hsin , Hsu Chien-Ning , Lin Min-Ting
Published: October 2012

Background

Few studies have examined the longitudinal changes in the patterns, selection, and utilization of treatments for chronic myeloid leukemia (CML) in routine clinical practice since the introduction of imatinib. Therefore, we investigated the trends in CML therapy, including changes, patterns, and persistence to imatinib therapy among patients with newly diagnosed CML.

Methods

We conducted a cross-sectional and longitudinal analysis of 11 years of claims data for patients with newly diagnosed CML included in the Taiwan National Health Insurance program. Pharmacy and diagnosis claims for newly diagnosed CML recorded between 1997 and 2007 year were extracted from the database. Annual overall use, new use of CML therapy, and persistence to imatinib therapy were estimated. The Anatomical Therapeutic Chemical codes for CML therapy [i.e., imatinib and conventional therapy: busulfan, hydroxyurea, interferon-α (IFNα), and cytarabine], and the process code for hematopoietic stem cell transplantation were used to categorize treatment patterns. Associations with patients characteristics were analyzed by multivariate logistic regression.

Results

Overall, the proportion of patients with newly diagnosed CML to all patients with CML increased by approximately 4-fold between 1998 and 2007. There were steady increases in the proportions of all treated patients and those starting therapy from 2003 to 2007. Fewer comorbid conditions and lower severity of CML were associated with treatment initiation. Medication persistence varied according to treatment duration, as 38.7% patients continued imatinib for ≥ 18 months without interruption but only 7.7% continued imatinib for ≥ 5 years. Factors associated with persistence to imatinib therapy were removal of the need for prior authorization for imatinib, and prior use of hydroxyurea and IFNα, whereas having undergone hematopoietic stem cell transplantation led to reduced likelihood of persistence to imatinib therapy.

Conclusion

Treatment decisions for patients with CML changed over time in routine clinical practice. Our findings suggest that clinicians are increasingly adopting the recommendations of international treatment guidelines for CML. However, persistence to imatinib therapy is still substantially below the recommended level based on current evidence for its efficacy. Our study also highlights the need to improve treatment persistence and effectiveness of imatinib over the long term.
Conservation of the three-dimensional structure in non-homologous or unrelated proteins
Authors: Sousounis Konstantinos , Haney Carl E , Cao Jin , Sunchu Bharath , Tsonis Panagiotis A
Published: October 2012

In this review, we examine examples of conservation of protein structural motifs in unrelated or non-homologous proteins. For this, we have selected three DNA-binding motifs: the histone fold, the helix-turn-helix motif, and the zinc finger, as well as the globin-like fold. We show that indeed similar structures exist in unrelated proteins, strengthening the concept that three-dimensional conservation might be more important than the primary amino acid sequence.
Enhanced thermoelectric performance in three-dimensional superlattice of topological insulator thin films
Authors: Fan Zheyong , Zheng Jiansen , Wang Hui-Qiong , Zheng Jin-Cheng
Published: October 2012

We show that certain three-dimensional (3D) superlattice nanostructure based on Bi2Te3 topological insulator thin films has better thermoelectric performance than two-dimensional (2D) thin films. The 3D superlattice shows a predicted peak value of ZT of approximately 6 for gapped surface states at room temperature and retains a high figure of merit ZT of approximately 2.5 for gapless surface states. In contrast, 2D thin films with gapless surface states show no advantage over bulk Bi2Te3. The enhancement of the thermoelectric performance originates from a combination of the reduction of lattice thermal conductivity by phonon-interface scattering, the high mobility of the topologically protected surface states, the enhancement of Seebeck coefficient, and the reduction of electron thermal conductivity by energy filtering. Our study shows that the nanostructure design of topological insulators provides a possible new way of ZT enhancement.
Identification of different lineages of measles virus strains circulating in Uttar Pradesh, North India
Authors: Shakya Akhalesh Kumar , Shukla Vibha , Maan Harjeet Singh , Dhole Tapan N
Published: October 2012

Background

Genetic analysis of measles viruses associated with recent cases and outbreaks has proven to bridge information gaps in routine outbreak investigations and has made a substantial contribution to measles control efforts by helping to identify the transmission pathways of the virus.

Materials and methods

The present study describes the genetic characterization of wild type measles viruses from Uttar Pradesh, India isolated between January 2008 and January 2011. In the study, 526 suspected measles cases from 15 outbreaks were investigated. Blood samples were collected from suspected measles outbreaks and tested for the presence of measles specific IgM; throat swab and urine samples were collected for virus isolation and RT-PCR. Genotyping of circulating measles viruses in Uttar Pradesh was performed by sequencing a 450-bp region encompassing the nucleoprotein hypervariable region and phylogenetic analysis.

Results and conclusion

Based on serological results, all the outbreaks were confirmed as measles. Thirty eight strains were obtained. Genetic analysis of circulating measles strains (n = 38) in Uttar Pradesh from 235 cases of laboratory-confirmed cases from 526 suspected measles cases between 2008 and 2011 showed that all viruses responsible for outbreaks were within clade D and all were genotype D8.

Analysis of this region showed that it is highly divergent (up to 3.4% divergence in the nucleotide sequence and 4.1% divergence in the amino acid sequence between most distant strains). Considerable genetic heterogeneity was observed in the MV genotype D8 viruses in North India and underscores the need for continued surveillance and in particular increases in vaccination levels to decrease morbidity and mortality attributable to measles.
Expansion of cardiac ischemia/reperfusion injury after instillation of three forms of multi-walled carbon nanotubes
Authors: Urankar Rakhee N , Lust Robert M , Mann Erin , Katwa Pranita , Wang Xiaojia , Podila Ramakrishna , Hilderbrand Susana C , Harrison Benjamin S , Chen Pengyu , Ke Pu Chun , Rao Apparao M , Brown Jared M , Wingard Christopher J
Published: October 2012

Background

The exceptional physical-chemical properties of carbon nanotubes have lead to their use in diverse commercial and biomedical applications. However, their utilization has raised concerns about human exposure that may predispose individuals to adverse health risks. The present study investigated the susceptibility to cardiac ischemic injury following a single exposure to various forms of multi-walled carbon nanotubes (MWCNTs). It was hypothesized that oropharyngeal aspiration of MWCNTs exacerbates myocardial ischemia and reperfusion injury (I/R injury).

Methods

Oropharyngeal aspiration was performed on male C57BL/6J mice with a single amount of MWCNT (0.01 - 100 μg) suspended in 100 μL of a surfactant saline (SS) solution. Three forms of MWCNTs were used in this study: unmodified, commercial grade (C-grade), and functionalized forms that were modified either by acid treatment (carboxylated, COOH) or nitrogenation (N-doped) and a SS vehicle. The pulmonary inflammation, serum cytokine profile and cardiac ischemic/reperfusion (I/R) injury were assessed at 1, 7 and 28 days post-aspiration.

Results

Pulmonary response to MWCNT oropharyngeal aspiration assessed by bronchoalveolar lavage fluid (BALF) revealed modest increases in protein and inflammatory cell recruitment. Lung histology showed modest tissue inflammation as compared to the SS group. Serum levels of eotaxin were significantly elevated in the carboxylated MWCNT aspirated mice 1 day post exposure. Oropharyngeal aspiration of all three forms of MWCNTs resulted in a time and/or dose-dependent exacerbation of myocardial infarction. The severity of myocardial injury varied with the form of MWCNTs used. The N-doped MWCNT produced the greatest expansion of the infarct at any time point and required a log concentration lower to establish a no effect level. The expansion of the I/R injury remained significantly elevated at 28 days following aspiration of the COOH and N-doped forms, but not the C-grade as compared to SS.

Conclusion

Our results suggest that oropharyngeal aspiration of MWCNT promotes increased susceptibility of cardiac tissue to ischemia/reperfusion injury without a significant pulmonary inflammatory response. The cardiac injury effects were observed at low concentrations of MWCNTs and presence of MWCNTs may pose a significant risk to the cardiovascular system.
Surgical trial in traumatic intracerebral hemorrhage (STITCH(Trauma)): study protocol for a randomized controlled trial
Authors: Gregson Barbara A , Rowan Elise N , Mitchell Patrick M , Unterberg Andy , McColl Elaine M , Chambers Iain R , McNamee Paul , Mendelow A David
Published: October 2012

Background

Intracranial hemorrhage occurs in over 60% of severe head injuries in one of three types: extradural (EDH); subdural (SDH); and intraparenchymal (TICH). Prompt surgical removal of significant SDH and EDH is established and widely accepted. However, TICH is more common and is found in more than 40% of severe head injuries. It is associated with a worse outcome but the role for surgical removal remains undefined. Surgical practice in the treatment of TICHs differs widely around the world. The aim of early surgery in TICH removal is to prevent secondary brain injury. There have been trials of surgery for spontaneous ICH (including the STICH II trial), but none so far of surgery for TICH.

Methods/Design

The UK National Institutes of Health Research has funded STITCH(Trauma) to determine whether a policy of early surgery in patients with TICH improves outcome compared to a policy of initial conservative treatment. It will include a health economics component and carry out a subgroup analysis of patients undergoing invasive monitoring. This is an international multicenter pragmatic randomized controlled trial.

Patients are eligible if: they are within 48 h of injury; they have evidence of TICH on CT scan with a confluent volume of attenuation significantly raised above that of the background white and grey matter that has a total volume >10 mL; and their treating neurosurgeon is in equipoise.

Patients will be ineligible if they have: a significant surface hematoma (EDH or SDH) requiring surgery; a hemorrhage/contusion located in the cerebellum; three or more separate hematomas fulfilling inclusion criteria; or severe pre-existing physical or mental disability or severe co-morbidity which would lead to poor outcome even if the patient made a full recovery from the head injury.

Patients will be randomized via an independent service. Patients randomized to surgery receive surgery within 12 h. Both groups will be monitored according to standard neurosurgical practice. All patients have a CT scan at 5 days (+/−2 days) to assess changes in hematoma size. Follow-up is by postal questionnaire at 6 and 12 months. The recruitment target is 840 patients.

Trial registration

Current Controlled Trials ISRCTN19321911
Histotype-specific copy-number alterations in ovarian cancer
Authors: Huang Ruby YunJu , Chen Geng Bo , Matsumura Noriomi , Lai Hung-Cheng , Mori Seiichi , Li Jingjing , Wong Meng Kang , Konishi Ikuo , Thiery Jean-Paul , Goh Liang
Published: October 2012

Background

Epithelial ovarian cancer is characterized by multiple genomic alterations; most are passenger alterations which do not confer tumor growth. Like many cancers, it is a heterogeneous disease and can be broadly categorized into 4 main histotypes of clear cell, endometrioid, mucinous, and serous. To date, histotype-specific copy number alterations have been difficult to elucidate. The difficulty lies in having sufficient sample size in each histotype for statistical analyses.

Methods

To dissect the heterogeneity of ovarian cancer and identify histotype-specific alterations, we used an in silico hypothesis-driven approach on multiple datasets of epithelial ovarian cancer.

Results

In concordance with previous studies on global copy number alterations landscape, the study showed similar alterations. However, when the landscape was de-convoluted into histotypes, distinct alterations were observed. We report here significant histotype-specific copy number alterations in ovarian cancer and showed that there is genomic diversity amongst the histotypes. 76 cancer genes were found to be significantly altered with several as potential copy number drivers, including ERBB2 in mucinous, and TPM3 in endometrioid histotypes. ERBB2 was found to have preferential alterations, where it was amplified in mucinous (28.6%) but deleted in serous tumors (15.1%). Validation of ERBB2 expression showed significant correlation with microarray data (p=0.007). There also appeared to be reciprocal relationship between KRAS mutation and copy number alterations. In mucinous tumors where KRAS mutation is common, the gene was not significantly altered. However, KRAS was significantly amplified in serous tumors where mutations are rare in high grade tumors.

Conclusions

The study demonstrates that the copy number landscape is specific to the histotypes and identification of these alterations can pave the way for targeted drug therapy specific to the histotypes.
Child- and family impacts of infants’ oral conditions in Tanzania and Uganda– a cross sectional study
Authors: Masumo Ray , Bardsen Asgeir , Mashoto Kijakazi , Åstrøm Anne Nordrehaug
Published: October 2012

Background

Early childhood dental caries impacts on the quality of life of children and their families. This study set out to assess the psychometric properties of an oral health related quality of life, OHRQoL, measure, based on items emanating from the Child-and Family impact sections of the Early Childhood Oral Health Impact Scale (ECOHIS), in Kiswahili and Luganda speaking communities. It was hypothesized that the Child- and Family impact scores would discriminate between children with and without clinically defined dental problems and reported good and bad oral health.

Method

Kiswahili and Luganda versions of the Child- and Family impact scores were derived through translation in pilot studies. Totals of 1221 and 816 child/caretaker pairs attending health care facilities in Manyara, Tanzania and Kampala, Uganda, were recruited into the study. After caretakers completed the interview, their children underwent oral clinical examination.

Results

Internal consistency reliability (Cronbach’s alpha) was > 0.80 with respect to the Child impact score and 0.79 regarding the Family impact score. Multiple variable logistic- and Poisson regression analyses revealed that the Kiswahili and Luganda versions of the Child- and Family impact score associated in the expected direction with child’s oral diseases as with their reported health and oral health status. In Manyara, multiple logistic regression revealed that the ORs of reporting Child impacts were 1.8 (95% CI 1.0-3.4) and 2.2 (1.3-3.4) among caretakers who confirmed linear hypoplasia and teething symptoms, respectively. In Kampala, the ORs for reporting Child impacts were 2.3 (95% CI 1.3-3.9), 1.7 (95% CI 1.1-2.5), 1.6 (95% CI 1.2-2.3) and 2.7 (95% CI 1.3-5.8) among those who confirmed teeth present, hypoplasia, teething symptoms and tooth bud extractions, respectively. The odds ratios for reporting Family impacts were 2.7 (95% CI 1.5-4.7), 1.5 (95% CI 1.1- 2.1) and 4.6 (95% CI 2.0-10.7) if reporting LEH, teething symptoms and toothbud experience, respectively.

Conclusion

The Child and Family impact scores demonstrated acceptable internal consistency reliability and reproducibility whereas the discriminative validity was more ambiguous. The OHRQoL scores should be developed further and tested among Kiswahili and Luganda speaking caretakers.
Evaluation of recurrent hyphema after trabeculectomy with ultrabiomicroscopy 50-80 MHz: a case report
Authors: Mannino Giuseppe , Verrilli Sara , Calafiore Silvia , Ciarnella Angela , Cutini Alessandro , Mannino Cristina , Perdicchi Andrea , Recupero Santi Maria
Published: October 2012

Background

Hyphema is a complication that can occur after glaucoma filtering surgery. Biomicroscopic examination of the anterior segment is commonly used to diagnose it and gonioscopy may provide a useful support to find the source of the haemorrhage. Unfortunately, when the blood hides the structure of the anterior segment the gonioscopic examination fails. In this case we performed ultrabiomiscroscopy with 50–80 MHz probes to overcome the limits of gonioscopy. The use of this technique to study the anterior segment of the eye has previously been reported in literature, but we illustrates its importance for performing a correct diagnosis in a specific case of hyphema.

Case presentation

We report a case of a sixty-year-old caucasian male with recurrent hyphema in the left eye. The episodes of hyphema were four in two years and the patient came to the hospital for the first time in the last occasion. The past episodes were managed with topical corticosteroids and mydriatic drops. He referred surgical trabeculectomy in both eyes 5 years before the first symptoms and no specific eye trauma before the first episode. The examination of the anterior segment revealed a 2 mm hyphema in the left eye due to blood leakage through the superior iridectomy. Gonioscopy could not identify the source of the haemorrhage. B-scan ultrasound and ultrabiomiscroscopy, with 50–80 MHz probes, were performed. Ultrabiomiscroscopy, mainly with the probe of 80 MHz, provided images of high resolution of the structures of the anterior segment and it allowed the visualization of an abnormal vessel at the inner margin of the trabeculectomy opening, probably responsible of the recurrent hyphema.

Conclusion

Ultrabiomicroscopy proved to be a useful diagnostic technique for identifying the cause of the recurrent hyphema when other examination techniques are not applicable.
Glycodelin A is a prognostic marker to predict poor outcome in advanced stage ovarian cancer patients
Authors: Scholz Christoph , Heublein Sabine , Lenhard Miriam , Friese Klaus , Mayr Doris , Jeschke Udo
Published: October 2012

Background

Glycodelin is a cell surface glycoprotein offering a unique gender specific carbohydrate configuration. Sialylated carbohydrate structures, which are unusual for mammals, characterize Glycodelin isolated from amniotic fluid (Glycodelin A, GdA). Glycodelin in general exerts multiple, partly opposing functions ranging from immunosuppression to cell differentiation. As these markedly influence tumorigenesis, this study aimed to clarify whether expression of different Glycodelin isoforms is related to clinicopathological characteristics and prognosis of ovarian cancer patients. Further the use of Glycodelin as a serum marker in benign and malignant ovarian diseases was evaluated.

Methods

Ovarian cancer specimens (n = 152) were stained for Glycodelin with carbohydrate and peptide specific antibodies. Associations between Glycodelin expression and histological grading, FIGO stage as well as patient’s prognosis were examined. Glycodelin was correlated to expression of gonadotropin receptors and mucin-1, which are discussed as ovarian cancer tissue markers. In addition, Glycodelin serum concentrations were analyzed in patients suffering from benign (n = 73) or malignant (n = 38) ovarian neoplasias.

Results

Glycodelin A was found to be an independent prognostic marker for poor prognosis in advanced ovarian cancer patients. GdA staining correlated with gonadotropin receptor (FSHR and LHCGR) and with hCG expression. Gd expression showed a positive correlation with a tumour-associated epitope of mucin 1 (TA-MUC1). Further, compared to ovarian cancer, serum Gd was increased in patients with benign ovarian tumors.

Conclusion

Glycodelin A might be related to tumor aggressiveness and poor clinical outcome in advanced epithelial ovarian cancer. Glycodelin serum levels found in patients suffering from benign ovarian tumors, might contribute to a more global attenuation during progression of these precursor lesions.
Sulforaphane has opposing effects on TNF-alpha stimulated and unstimulated synoviocytes
Authors: Fragoulis Athanassios , Laufs Jendrik , Müller Susanna , Soppa Ulf , Siegl Stephanie , Reiss Lucy Kathleen , Tohidnezhad Mersedeh , Rosen Christian , Tenbrock Klaus , Varoga Deike , Lippross Sebastian , Pufe Thomas , Wruck Christoph Jan
Published: October 2012

Introduction

Rheumatoid arthritis (RA) is characterized by progressive inflammation associated with rampantly proliferating synoviocytes and joint destruction due to oxidative stress. Recently, we described nuclear factor erythroid 2-related factor 2 (Nrf2) as a major requirement for limiting cartilage destruction. NF-κB and AP-1 are the main transcription factors triggering the inflammatory progression in RA. We used sulforaphane, an isothiocyanate, which is both an Nrf2 inducer and a NF-κB and AP-1 inhibitor.

Methods

Cultured synoviocytes were stimulated with sulforaphane (SFN) with or without TNF-α pre-treatment. NF-κB, AP-1, and Nrf2 activation was investigated via dual luciferase reporter gene assays. Matrix metalloproteinases (MMPs) were measured via zymography and luminex technique. Cytokine levels were detected using ELISA. Cell viability, apoptosis and caspase activity were studied. Cell proliferation was analysed by real-time cell analysis.

Results

SFN treatment decreased inflammation and proliferation dose-dependently in TNF-α-stimulated synoviocytes. SFN did not reduce MMP-3 and MMP-9 activity or expression significantly. Interestingly, we demonstrated that SFN has opposing effects on naïve and TNF-α-stimulated synoviocytes. In naïve cells, SFN activated the cytoprotective transcription factor Nrf2. In marked contrast to this, SFN induced apoptosis in TNF-α-pre-stimulated synoviocytes.

Conclusions

We were able to show that SFN treatment acts contrary on naïve and inflammatory synoviocytes. SFN induces the cytoprotective transcription factor Nrf2 in naïve synoviocytes, whereas it induces apoptosis in inflamed synoviocytes. These findings indicate that the use of sulforaphane might be considered as an adjunctive therapeutic strategy to combat inflammation, pannus formation, and cartilage destruction in RA.
A modified delay-time method for statics estimation with the virtual refraction
Authors: Mikesell T. Dylan , van Wijk Kasper , Ruigrok Elmer , Lamb Andrew , Blum Thomas E.
Published: October 2012

Topography and near-surface heterogeneities lead to traveltime perturbations in surface land-seismic experiments. Usually, these perturbations are estimated and removed prior to further processing of the data. A common technique to estimate these perturbations is the delay-time method. We have developed the “modified delay-time method,” wherein we isolate the arrival times of the virtual refraction and estimate receiver-side delay times. The virtual refraction is a spurious arrival found in wavefields estimated by seismic interferometry. The new method removes the source term from the delay-time equation, is more robust in the presence of noise, and extends the lateral aperture compared to the conventional delay-time method. We tested this in an elastic 2D numerical example, where we estimated the receiver delay-times above a horizontal refractor. Taking advantage of reciprocity of the wave equation and rearranging the common shot gathers into common receiver gathers, isolated source delay times could also be obtained.
Parent-Reported Social Outcomes After Treatment for Pediatric Embryonal Tumors: A Prospective Longitudinal Study
Authors: Brinkman Tara M. , Palmer Shawna L. , Chen Si , Zhang Hui , Evankovich Karen , Swain Michelle A. , Bonner Melanie J. , Janzen Laura , Knight Sarah , Armstrong Carol L. , Boyle Robyn , Gajjar Amar
Published: October 2012

Purpose

To examine longitudinal parent-reported social outcomes for children treated for pediatric embryonal brain tumors.

Patients and Methods

Patients (N = 220) were enrolled onto a multisite clinical treatment protocol. Parents completed the Child Behavior Checklist/6-18 at the time of their child's diagnosis and yearly thereafter. A generalized linear mixed effects model regression approach was used to examine longitudinal changes in parent ratings of social competence, social problems, and withdrawn/depressed behaviors with demographic and treatment factors as covariates.

Results

During the 5-year period following diagnosis and treatment, few patients were reported to have clinically elevated scores on measures of social functioning. Mean scores differed significantly from population norms, yet remained within the average range. Several factors associated with unfavorable patterns of change in social functioning were identified. Patients with high-risk treatment status had a greater increase in parent-reported social problems (P = .001) and withdrawn/depressed behaviors (P = .01) over time compared with average-risk patients. Patients with posterior fossa syndrome had greater parent-reported social problems over time (P = .03). Female patients showed higher withdrawn/depressed scores over time compared with male patients (P < .001). Patient intelligence, age at diagnosis, and parent education level also contributed to parent report of social functioning.

Conclusion

Results of this study largely suggest positive social adjustment several years after diagnosis and treatment of a pediatric embryonal tumor. However, several factors, including treatment risk status and posterior fossa syndrome, may be important precursors of long-term social outcomes. Future research is needed to elucidate the trajectory of social functioning as these patients transition into adulthood.
Methods in Comparative Effectiveness Research
Authors: Armstrong Katrina
Published: October 2012

Comparative effectiveness research (CER) seeks to assist consumers, clinicians, purchasers, and policy makers to make informed decisions to improve health care at both the individual and population levels. CER includes evidence generation and evidence synthesis. Randomized controlled trials are central to CER because of the lack of selection bias, with the recent development of adaptive and pragmatic trials increasing their relevance to real-world decision making. Observational studies comprise a growing proportion of CER because of their efficiency, generalizability to clinical practice, and ability to examine differences in effectiveness across patient subgroups. Concerns about selection bias in observational studies can be mitigated by measuring potential confounders and analytic approaches, including multivariable regression, propensity score analysis, and instrumental variable analysis. Evidence synthesis methods include systematic reviews and decision models. Systematic reviews are a major component of evidence-based medicine and can be adapted to CER by broadening the types of studies included and examining the full range of benefits and harms of alternative interventions. Decision models are particularly suited to CER, because they make quantitative estimates of expected outcomes based on data from a range of sources. These estimates can be tailored to patient characteristics and can include economic outcomes to assess cost effectiveness. The choice of method for CER is driven by the relative weight placed on concerns about selection bias and generalizability, as well as pragmatic concerns related to data availability and timing. Value of information methods can identify priority areas for investigation and inform research methods.
Cost, Coverage, and Comparative Effectiveness Research: The Critical Issues for Oncology
Authors: Pearson Steven D.
Published: October 2012

A new national initiative in comparative effectiveness research (CER) is part of a broad and long-term evolution toward greater reliance on scientific evidence in clinical practice and medical policy. But CER has been controversial because of its high profile in the health care reform effort, its instantiation in a prominent new national research institute, and lingering concerns that the ultimate goal of CER is to empower the government and private insurers to reduce health care costs by restricting access to expensive new medical tests and treatments. This article presents an analysis of the policy development behind CER and focuses on its potential impact on insurance coverage and payment for oncology services. By itself, CER will not solve the tension that exists between the goal of innovative, personalized care and the eroding affordability of cancer treatment in the United States. But CER does offer an important opportunity for progress. Oncologists have taken important first steps in acknowledging their responsibility for addressing cost issues; as a professional society, they should now move forward to assume leadership in the effort to integrate clinical evidence with considerations of cost effectiveness to guide clinical practice and insurer policies.
Publication of Tumor Marker Research Results: The Necessity for Complete and Transparent Reporting
Authors: McShane Lisa M. , Hayes Daniel F.
Published: October 2012

Clinical management decisions for patients with cancer are increasingly being guided by prognostic and predictive markers. Use of these markers should be based on a sufficiently comprehensive body of unbiased evidence to establish that benefits to patients outweigh harms and to justify expenditure of health care dollars. Careful assessments of the clinical utility of markers by using comparative effectiveness research methods are urgently needed to more rigorously summarize and evaluate the evidence, but multiple factors have made such assessments difficult. The literature on tumor markers is plagued by nonpublication bias, selective reporting, and incomplete reporting. Several measures to address these problems are discussed, including development of a tumor marker study registry, greater attention to assay analytic performance and specimen quality, use of more rigorous study designs and analysis plans to establish clinical utility, and adherence to higher standards for reporting tumor marker studies. More complete and transparent reporting by adhering to criteria such as BRISQ [Biospecimen Reporting for Improved Study Quality] criteria for reporting details about specimens and REMARK [Reporting Recommendations for Tumor Marker Prognostic Studies] criteria for reporting a multitude of aspects relating to study design, analysis, and results, is essential for reliable assessment of study quality, detection of potential biases, and proper interpretation of study findings. Adopting these measures will improve the quality of the body of evidence available for comparative effectiveness research and enhance the ability to establish the clinical utility of prognostic and predictive tumor markers.
Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Newly Diagnosed Anaplastic Oligodendroglioma: Long-Term Follow-Up of EORTC Brain Tumor Group Study 26951
Authors: van den Bent Martin J. , Brandes Alba A. , Taphoorn Martin J.B. , Kros Johan M. , Kouwenhoven Mathilde C.M. , Delattre Jean-Yves , Bernsen Hans J.J.A. , Frenay Marc , Tijssen Cees C. , Grisold Wolfgang , Sipos László , Enting Roelien H. , French Pim J. , Dinjens Winand N.M. , Vecht Charles J. , Allgeier Anouk , Lacombe Denis , Gorlia Thierry , Hoang-Xuan Khê
Published: October 2012

Purpose

Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT).

Patients and Methods

Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis.

Results

A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance.

Conclusion

The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non–1p/19q-deleted tumors.
Single-Cell Analyses Reveal That KISS1R-Expressing Cells Undergo Sustained Kisspeptin-Induced Signaling That Is Dependent upon An Influx of Extracellular Ca2+
Authors: Babwah Andy V. , Pampillo Macarena , Min Le , Kaiser Ursula B. , Bhattacharya Moshmi
Published: October 2012

The kisspeptin receptor (KISS1R) is a Gαq/11-coupled seven-transmembrane receptor activated by a group of peptides referred to as kisspeptins (Kps). The Kp/KISS1R signaling system is a powerful regulator of GnRH secretion, and inactivating mutations in this system are associated with hypogonadotropic hypogonadism. A recent study revealed that Kp triggers prolonged signaling; not from the inability of the receptor to undergo rapid desensitization, but instead from the maintenance of a dynamic and active pool of KISS1R at the cell surface. To investigate this further, we hypothesized that if a dynamic pool of receptor is maintained at the cell surface for a protracted period, chronic Kp-10 treatment would trigger the sustained activation of Gαq/11 as evidenced through the prolonged activation of phospholipase C, protein kinase C, and prolonged mobilization of intracellular Ca2+. Through single-cell analyses, we tested our hypothesis in human embryonic kidney (HEK) 293 cells and found that was indeed the case. We subsequently determined that prolonged KISS1R signaling was not a phenomenon specific to HEK 293 cells but is likely a conserved property of KISS1R-expressing cells because evidence of sustained KISS1R signaling was also observed in the GT1–7 GnRH neuronal and Chinese hamster ovary cell lines. While exploring the regulation of prolonged KISS1R signaling, we identified a critical role for extracellular Ca2+. We found that although free intracellular Ca2+, primarily derived from intracellular stores, was sufficient to trigger the acute activation of a major KISS1R secondary effector, protein kinase C, it was insufficient to sustain chronic KISS1R signaling; instead extracellular Ca2+ was absolutely required for this.
Na,K-ATPase β-subunit cis homo-oligomerization is necessary for epithelial lumen formation in mammalian cells
Authors: Barwe Sonali P. , Skay Anna , McSpadden Ryan , Huynh Thu P. , Langhans Sigrid A. , Inge Landon J. , Rajasekaran Ayyappan K.
Published: October 2012

Na,K-ATPase is a hetero-oligomer of an α- and a β-subunit. The α-subunit (Na,K-α) possesses the catalytic function, whereas the β-subunit (Na,K-β) has cell-cell adhesion function and is localized to the apical junctional complex in polarized epithelial cells. Earlier, we identified two distinct conserved motifs on the Na,K-β1 transmembrane domain that mediate protein-protein interactions: a glycine zipper motif involved in the cis homo-oligomerization of Na,K-β1 and a heptad repeat motif that is involved in the hetero-oligomeric interaction with Na,K-α1. We now provide evidence that knockdown of Na,K-β1 prevents lumen formation and induces activation of extracellular regulated kinases 1 and 2 (ERK1/2) mediated by phosphatidylinositol 3-kinase in MDCK cells grown in three-dimensional collagen cultures. These cells sustained cell proliferation in an ERK1/2-dependent manner and did not show contact inhibition at high cell densities, as revealed by parental MDCK cells. This phenotype could be rescued by wild-type Na,K-β1 or heptad repeat motif mutant of Na,K-β1, but not by the glycine zipper motif mutant that abrogates Na,K-β1 cis homo-oligomerization. These studies suggest that Na,K-β1 cis homo-oligomerization rather than hetero-oligomerization with Na,K-α1 is involved in epithelial lumen formation. The relevance of these findings to pre-neoplastic lumen filling in epithelial cancer is discussed.
Nuclear Na,K-ATPase plays an active role in Nucleoplasmic Calcium Homeostasis*
Authors: Galva Charitha , Artigas Pablo , Gatto Craig
Published: October 2012

Na,K-ATPase, an integral membrane protein, has been studied for over a half century with respect to its transporter function in the plasma membrane where it expels 3 Na+ ions from the cell in exchange for two K+ ions. In this study, we demonstrate a functioning Na,K-ATPase within HEK 293 cell nuclei. This subcellular localization was confirmed by western blotting, ouabain-sensitive ATPase activity of the nuclear membrane fraction, immunocytochemistry, and delivery of fluorescently-tagged Na,K-ATPase α- and β- subunits. In addition, we observed an overlap between nuclear Na,K-ATPase and Na/Ca-exchanger (NCX) when nuclei were immunostained with commercially available Na,K-ATPase and NCX antibodies suggesting a concerted physiological coupling between these transporters. In keeping with this, we observed an ATP-dependent, strophanthidin-sensitive Na+ flux into the nuclear envelope (NE) lumen loaded with the Na-sensitive dye, CoroNa-Green. Analogous experiments using Fluo-5N, a low affinity Ca2+ indicator, demonstrated a similar ATP-dependent and strophanthidin-sensitive Ca2+ flux into the NE lumen. Our results reveal an intracellular physiological role for the coordinated efforts of the Na,K-ATPase and NCX to actively remove Ca2+ from the nucleoplasm into the NE lumen (i.e. the nucleoplasmic reticulum).
Evolution and the arts of civilisation
Authors: Room Graham
Published: October 2012

There have been many attempts to apply evolutionary models to social change. This article takes Darwin’s account of artificial – as well as natural – selection as its starting point. It thereby brings together human intention and learning – the arts of civilisation – and the unintended processes of change with which evolutionary models are more usually concerned. It argues that policy science should be an evolutionary science, studying endogenous processes of technological and institutional transformation; but that it must be more than this, articulating political goals and policy trade-offs and illuminating the arts of civilisation as applied to society as a whole.
Social security expenditures in Ireland, 1981–2007: an analysis of welfare state change
Authors: McCashin Anthony
Published: October 2012

The analysis of welfare state change is bedevilled by controversy about how to define and measure change, and about the role of expenditure data in quantifying change. Using social security in Ireland as an illustration, this article shows that national-level expenditure data, properly decomposed and disaggregated, can identify patterns of change that are masked in highly aggregated, comparative data. Social security in Ireland, when examined through the lens of detailed, national data, has experienced quite varied patterns of change that combine expansion, retrenchment and extension, substantiating the emerging findings that small states are not necessarily prone to general retrenchment.
ELISA System for Human Endothelial Lipase
Authors: Ishida Tatsuro , Miyashita Kazuya , Shimizu Mamoru , Kinoshita Noriaki , Mori Kenta , Sun Li , Yasuda Tomoyuki , Imamura Shigeyuki , Nakajima Katsuyuki , Stanhope Kimber L , Havel Peter J , Hirata Ken-ichi
Published: October 2012

BACKGROUND

Endothelial lipase (EL) regulates the metabolism of HDL cholesterol (HDL-C). However, the role of EL in regulating plasma HDL-C concentrations and EL's potential involvement in atherosclerosis in humans has not been fully investigated due to the lack of reliable assays for EL mass. We developed an ELISA system for serum EL mass.

METHODS

Human recombinant EL proteins, purified from cultured media of human EL–transfected Chinese hamster ovary cells, were used as antigen and calibrator. Two specific monoclonal antibodies were generated in mice against recombinant EL protein for a sandwich ELISA. We measured EL mass in human serum using EL recombinant protein as a calibration standard.

RESULTS

The EL antibodies did not cross-react with lipoprotein lipase and hepatic triglyceride lipase. The detection limit of the ELISA was 20 pg/mL, which is approximately 10 times lower than that of previous ELISA systems. Recovery of spiked EL in serum was 90%–105%. Assay linearity was intact with a >4-fold dilution of serum. Intra- and interassay CVs were <5%. The serum EL mass in 645 human subjects was [mean (SE)] 344.4 (7.7) pg/mL (range 55.2–1387.7 pg/mL). Interestingly, serum EL mass was increased in patients with diagnosed cardiovascular disease and inversely correlated with serum HDL-C concentrations. There was no difference in EL mass between pre- and postheparin plasma samples.

CONCLUSIONS

This ELISA should be useful for clarifying the impact of EL on HDL metabolism and EL's potential role in atherosclerosis.
What Drives Managerial Use of Marketing and Financial Metrics and Does Metric Use Affect Performance of Marketing-Mix Activities?
Authors: Mintz Ofer , Currim Imran S.
Published: October 2012

To increase marketing's accountability, Journal of Marketing, Marketing Science Institute, and the Institute for the Study of Business Markets have advocated development of marketing metrics and linking marketing-mix activities with financial metrics. Although the marketing field has made progress, researchers have paid less attention to what drives managerial use of marketing and financial metrics and whether metric use is associated with marketing-mix performance. The authors propose a conceptual model that links firm strategy, metric orientation, type of marketing-mix activity, and managerial, firm, and environmental characteristics to marketing and financial metric use, which in turn are linked to performance of marketing-mix activities. An analysis of 1287 marketing-mix activities reported by 439 U.S. managers reveals that firm strategy, metric orientation, type of marketing-mix activity, and firm and environmental characteristics are more useful than managerial characteristics in explaining use of marketing and financial metrics and that use of metrics is positively associated with marketing-mix performance. The results help identify conditions under which managers use fewer metrics and how metric use can be increased to improve marketing-mix performance.
A Comprehensive Small Interfering RNA Screen Identifies Signaling Pathways Required for Gephyrin Clustering
Authors: Wuchter Jennifer , Beuter Simone , Treindl Fridolin , Herrmann Thoralf , Zeck Günther , Templin Markus F. , Volkmer Hansjürgen
Published: October 2012

The postsynaptic scaffold protein gephyrin is clustered at inhibitory synapses and serves for the stabilization of GABAAreceptors. Here, a comprehensive kinome-wide siRNA screen in a human HeLa cell-based model for gephyrin clustering was used to identify candidate protein kinases implicated in the stabilization of gephyrin clusters. As a result, 12 hits were identified including FGFR1 (FGF receptor 1), TrkB, and TrkC as well as components of the MAPK and mammalian target of rapamycin (mTOR) pathways. For confirmation, the impact of these hits on gephyrin clustering was analyzed in rat primary hippocampal neurons. We found that brain-derived neurotrophic factor (BDNF) acts on gephyrin clustering through MAPK signaling, and this process may be controlled by the MAPK signaling antagonist sprouty2. BDNF signaling through phosphatidylinositol 3-kinase (PI3K)–Akt also activates mTOR and represses GSK3β, which was previously shown to reduce gephyrin clustering. Gephyrin is associated with inactive mTOR and becomes released upon BDNF-dependent mTOR activation. In primary neurons, a reduction in the number of gephyrin clusters due to manipulation of the BDNF–mTOR signaling is associated with reduced GABAAreceptor clustering, suggesting functional impairment of GABA signaling. Accordingly, application of the mTOR antagonist rapamycin leads to disinhibition of neuronal networks as measured on microelectrode arrays. In conclusion, we provide evidence that BDNF regulates gephyrin clustering via MAPK as well as PI3K–Akt–mTOR signaling.
Integration of Taste and Calorie Sensing inDrosophila
Authors: Stafford Jeffrey W. , Lynd Kaylea M. , Jung Aera Y. , Gordon Michael D.
Published: October 2012

Animals use gustatory information to assess the suitability of potential food sources and make critical decisions on what to consume. For example, the taste of sugar generally signals a potent dietary source of carbohydrates. However, the intensity of the sensory response to a particular sugar, or “sweetness,” is not always a faithful reporter of its nutritional value, and recent evidence suggests that animals can sense the caloric content of food independently of taste. Here, we demonstrate that the vinegar flyDrosophila melanogasteruses both taste and calorie sensing to determine feeding choices, and that the relative contribution of each changes over time. Using the capillary feeder assay, we allowed flies to choose between sources of sugars that varied in their ratio of sweetness to caloric value. We found that flies initially consume sugars according to taste. However, over several hours their preference shifts toward the food source with higher caloric content. This behavioral shift occurs more rapidly following food deprivation and is modulated by cAMP and insulin signaling within neurons. Our results are consistent with the existence of a taste-independent calorie sensor in flies, and suggest that calorie-based reward modifies long-term feeding preferences.
Hilferufe aus dem besetzten Polen
Authors: Löw Andrea
Published: October 2012

Vorspann

Der große bittere Streit um die Judenräte, den Hannah Arendt 1963 mit ihrem Buch „Eichmann in Jerusalem“ auslöste, zeichnete sich schon 1939/40 ab. Damals waren knapp 1.600 Juden aus Wien in das Generalgouvernement deportiert worden, wo nichts, aber auch gar nichts vorbereitet gewesen war. In ihrer Not und Verzweiflung fühlten sie sich auch von ihrer Heimatgemeinde im Stich gelassen, die harte Worte der Kritik einstecken musste, im Rahmen ihrer Möglichkeiten aber alles tat, um ihren Glaubensbrüdern zu helfen. Andrea Löw, Mitarbeiterin am Institut für Zeitgeschichte München-Berlin und im großen Dokumentationsprojekt „Die Verfolgung und Ermordung der europäischen Juden durch das nationalsozialistische Deutschland 1933-1945“, präsentiert eindrucksvolle Briefe, in denen sich das bedrückende Schicksal dieser Deportierten ebenso spiegelt wie die Ohnmacht der jüdischen Kultusgemeinde Wien.