bluuebunny/crossref_metadata_2025 huggingface dataset:
Basic Characteristics of Adults with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenopathy Syndrome in Comparison with the Typical Pediatric Expression of Disease
Authors: Cattalini Marco , Soliani Martina , Rigante Donato , Lopalco Giuseppe , Iannone Florenzo , Galeazzi Mauro , Cantarini Luca
Published: August 2015

Autoinflammatory diseases are caused by inflammasome dysregulation leading to overproduction of proinflammatory cytokines and a pathological delay in the inflammation switching off. The progress of cellular biology has partially clarified pathogenic mechanisms behind monogenic autoinflammatory diseases, whereas little is known about the polygenic ones. Although the genetic susceptibility of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is still obscure, the presence of overlapping symptoms with monogenic periodic fevers, the recurrence in family members, the important role played by dysregulated interleukin‐ (IL‐) 1β secretion during flares, the overexpression of inflammasome‐associated genes during attacks, and, last but not least, the therapeutic efficacy of IL‐1β blockade strongly indicate a potential genetic involvement in its pathogenesis, probably linked with environmental factors. PFAPA syndrome has a typical inception in the pediatric age, but a delayed onset during adulthood has been described as well. Treatments required as well as effectiveness of tonsillectomy remain controversial, even if the disease seems to have a self‐limited course mostly in children. The purpose of this review is to provide an overview of this complex polygenic/multifactorial autoinflammatory disorder in which the innate immune system undoubtedly plays a basic role.
Skin Abscess due toSerratia marcescensin an Immunocompetent Patient after Receiving a Tattoo
Authors: Diranzo García J. , Villodre Jiménez J. , Zarzuela Sánchez V. , Castillo Ruiperez L. , Bru Pomer A.
Published: August 2015

The incidence of skin infections caused bySerratia marcescensis extremely low and such infections are typically observed in immunocompromised patients. The clinical manifestations of these infections include cellulitis, abscesses, fluctuant nodules, or granulomatous lesions. Infections caused byS. marcescensare very difficult to treat due to their resistance to many antibiotics, which often leads to specific and prolonged treatment. Infections after receiving a tattoo are very rare and are caused by unhygienic conditions or the inexperience of the tattooist. In this paper we present the case of a 32-year-old male with no comorbidity, who presented an abscess caused byS. marcescensin a area that was tattooed one month earlier. The case was resolved with surgery and antimicrobial therapy that was based on the antibiogram. To our knowledge, this is the first reported case of aS. marcescensskin infection following a tattoo, in the absence of immunosuppression.
Spacer Thickness‐Dependent Electron Transport Performance of Titanium Dioxide Thick Film for Dye‐Sensitized Solar Cells
Authors: El-Shater Reda E. , Abdel-Galeil Mohamed M. , Kawamura Go , Matsuda Atsunori
Published: August 2015

A titanium dioxide (P25) film was deposited by cast coating as conductive photoelectrode and subsequently immersed in dye solution (N719) to fabricate the photoanode of dye‐sensitized solar cells (DSSCs). A plastic spacer was used as a separation and sealant layer between the photoanode and the counter electrode. The effect of the thickness of this spacer on the transfer of electrons in the liquid electrolyte of the DSSCs was studied by means of both IV curves and electrochemical impedance. Using a spacer thickness range of 20 μm to 50 μm, efficiency ranges from 3.73% to 7.22%. The highest efficiency of 7.22% was obtained with an optimal spacer thickness of 40 μm.
An Emergency Adaptive Communication Protocol for Driver Health Monitoring in WSN Based Vehicular Environments
Authors: Kim Young-Duk , Kwon Soon , Jung Woo Young , Kim Dongkyun
Published: August 2015

Driver health and activity monitoring is one of the principal design issues for the safety provision in vehicular environments. Recently, the wireless sensor network technology is widely used to address the concerns in such applications. However, only few conventional protocols have dealt with reliable and prompt delivery of emergency packets considering the vehicular specifications. In this paper, we propose an emergency adaptive communication protocol, which treats the data packet in a discriminatory manner by investigating whether it is emergency or not. Hence, the proposed protocol defines an emergency factor for each data packet and exploits it for both route establishment and channel access procedures. In route establishment, the proposed protocol chooses a route with low delay and high reliability among the candidates by periodic calculation of emergency factor. Then, it dynamically adjusts back-off parameters before participating in the channel contention among the neighbors. In addition, an emergency aware queue management scheme and packet drop policy are proposed to improve the reliability of emergency data traffic during transmission. Our simulation results show that the proposed protocol provides a better performance compared with the existing protocol in terms of packet delivery ratio, end-to-end packet delay, and number of dropped packets.
Closed-Form Solutions of the Thomas-Fermi in Heavy Atoms and the Langmuir-Blodgett in Current Flow ODEs in Mathematical Physics
Authors: Theotokoglou Efstathios E. , Zarmpoutis Theodoros I. , Stampouloglou Ioannis H.
Published: August 2015

Two kinds of second-order nonlinear, ordinary differential equations (ODEs) appearing in mathematical physics are analyzed in this paper. The first one concerns the Thomas-Fermi (TF) equation, while the second concerns the Langmuir-Blodgett (LB) equation in current flow. According to a mathematical methodology recently developed, the exact analytic solutions of both TF and LB ODEs are proposed. Both of these are nonlinear of the second order and by a series of admissible functional transformations are reduced to Abel’s equations of the second kind of the normal form. The closed form solutions of the TF and LB equations in the phase and physical plane are given. Finally a new interesting result has been obtained related to the derivative of the TF function at the limit.
Some Applications of Ordinary Differential Operator to Certain Multivalent Functions
Authors: Şan Müfit , Irmak Hüseyin , Şerbetçi Ayhan
Published: August 2015

The aim of this paper is to apply the well-known ordinary differential operator to certain multivalent functions which are analytic in the certain domains of the complex plane and then to determine some criteria concerning analytic and geometric properties of the related complex functions.
Radio Capacity Estimation for Millimeter Wave 5G Cellular Networks Using Narrow Beamwidth Antennas at the Base Stations
Authors: Nassar AlMuthanna Turki , Sulyman Ahmed Iyanda , Alsanie Abdulhameed
Published: August 2015

This paper presents radio frequency (RF) capacity estimation for millimeter wave (mm-wave) based fifth-generation (5G) cellular networks using field-level simulations. It is shown that, by reducing antenna beamwidth from 65° to 30°, we can enhance the capacity of mm-wave cellular networks roughly by 3.0 times at a distance of 220 m from the base station (BS). This enhancement is far much higher than the corresponding enhancement of 1.2 times observed for 900 MHz and 2.6 GHz microwave networks at the same distance from the BS. Thus the use of narrow beamwidth transmitting antennas has more pronounced benefits in mm-wave networks. Deployment trials performed on an LTE TDD site operating on 2.6 GHz show that 6-sector site with 27° antenna beamwidth enhances the quality of service (QoS) roughly by 40% and more than doubles the overall BS throughput (while enhancing the per sector throughput 1.1 times on average) compared to a 3-sector site using 65° antenna beamwidth. This agrees well with our capacity simulations. Since mm-wave 5G networks will use arbitrary number of beams, with beamwidth much less than 30°, the capacity enhancement expected in 5G system when using narrow beamwidth antennas would be much more than three times observed in our simulations.
Neuroprotective Effects of Alpha-Mangostin on MPP+-Induced Apoptotic Cell Death in Neuroblastoma SH-SY5Y Cells
Authors: Janhom Prachya , Dharmasaroja Permphan
Published: August 2015

In vitrostudies have shown that extracts from mangosteen (Garcinia mangostanaLinn.) act as antioxidants and cytoprotective agents against oxidative damage. The protective effect of alpha-mangostin, the major xanthone found in the pericarp of the mangosteen, in cellular models of Parkinson’s disease (PD), has not been investigated. This study aims to investigate whether alpha-mangostin could protect SH-SY5Y neuroblastoma cells from MPP+-induced apoptosis. The effects of alpha-mangostin on MPP+-induced cell death were evaluated with a cell viability assay, staining for nuclear DNA morphology, flow cytometry for apoptotic cells and reactive oxygen species (ROS) production, quantitative real-time PCR for the expression of p53, Bax, and Bcl-2, and western blot analysis for cleaved caspase-3. Concomitant treatment with alpha-mangostin attenuated the effect of MPP+on cell viability and apoptotic cell death. Alpha-mangostin reduced ROS formation induced by MPP+. Bax/Bcl-2 expression ratio and expression of p53 were significantly lower in cells cocultured with alpha-mangostin and MPP+. The cotreated cells showed a significant decrease in activated caspase-3 compared with MPP+treatment alone. Our data suggest that cytoprotection of alpha-mangostin against MPP+-induced apoptosis may be associated with the reduction of ROS production, modulating the balance of pro- and antiapoptotic genes, and suppression of caspase-3 activation.
Classifying Patients with Chronic Pelvic Pain into Levels of Biopsychosocial Dysfunction Using Latent Class Modeling of Patient Reported Outcome Measures
Authors: Fenton Bradford W. , Grey Scott F. , Tossone Krystel , McCarroll Michele , Von Gruenigen Vivian E.
Published: August 2015

Chronic pelvic pain affects multiple aspects of a patient’s physical, social, and emotional functioning. Latent class analysis (LCA) of Patient Reported Outcome Measures Information System (PROMIS) domains has the potential to improve clinical insight into these patients’ pain. Based on the 11 PROMIS domains applied to n=613 patients referred for evaluation in a chronic pelvic pain specialty center, exploratory factor analysis (EFA) was used to identify unidimensional superdomains. Latent profile analysis (LPA) was performed to identify the number of homogeneous classes present and to further define the pain classification system. The EFA combined the 11 PROMIS domains into four unidimensional superdomains of biopsychosocial dysfunction: Pain, Negative Affect, Fatigue, and Social Function. Based on multiple fit criteria, a latent class model revealed four distinct classes of CPP: No dysfunction (3.2%); Low Dysfunction (17.8%); Moderate Dysfunction (53.2%); and High Dysfunction (25.8%). This study is the first description of a novel approach to the complex disease process such as chronic pelvic pain and was validated by demographic, medical, and psychosocial variables. In addition to an essentially normal class, three classes of increasing biopsychosocial dysfunction were identified. The LCA approach has the potential for application to other complex multifactorial disease processes.
A Quantitative System for Studying Metastasis Using Transparent Zebrafish
Authors: Heilmann Silja , Ratnakumar Kajan , Langdon Erin M. , Kansler Emily R. , Kim Isabella S. , Campbell Nathaniel R. , Perry Elizabeth B. , McMahon Amy J. , Kaufman Charles K. , van Rooijen Ellen , Lee William , Iacobuzio-Donahue Christine A. , Hynes Richard O. , Zon Leonard I. , Xavier Joao B. , White Richard M.
Published: August 2015

Metastasis is the defining feature of advanced malignancy, yet remains challenging to study in laboratory environments. Here, we describe a high-throughput zebrafish system for comprehensive, in vivo assessment of metastatic biology. First, we generated several stable cell lines from melanomas of transgenic mitfa-BRAFV600E;p53−/− fish. We then transplanted the melanoma cells into the transparent casper strain to enable highly quantitative measurement of the metastatic process at single-cell resolution. Using computational image analysis of the resulting metastases, we generated a metastasis score, μ, that can be applied to quantitative comparison of metastatic capacity between experimental conditions. Furthermore, image analysis also provided estimates of the frequency of metastasis-initiating cells (∼1/120,000 cells). Finally, we determined that the degree of pigmentation is a key feature defining cells with metastatic capability. The small size and rapid generation of progeny combined with superior imaging tools make zebrafish ideal for unbiased high-throughput investigations of cell-intrinsic or microenvironmental modifiers of metastasis. The approaches described here are readily applicable to other tumor types and thus serve to complement studies also employing murine and human cell culture systems. Cancer Res; 75(20); 4272–82. ©2015 AACR.
The miR-146b-3p/PAX8/NIS Regulatory Circuit Modulates the Differentiation Phenotype and Function of Thyroid Cells during Carcinogenesis
Authors: Riesco-Eizaguirre Garcilaso , Wert-Lamas León , Perales-Patón Javier , Sastre-Perona Ana , Fernández Lara P. , Santisteban Pilar
Published: August 2015

The presence of differentiated thyroid cells in thyroid cancer is critical for the antitumor response to radioactive iodide treatment, and loss of the differentiated phenotype is a key hallmark of iodide-refractory metastatic disease. The role of microRNAs (miRNA) in fine-tuning gene expression has become a major regulatory mechanism by which developmental and pathologic processes occur. In this study, we performed next-generation sequencing and expression analysis of eight papillary thyroid carcinomas (PTC) to comprehensively characterize miRNAs involved in loss of differentiation. We found that only a small set of abundant miRNAs is differentially expressed between PTC tissue and normal tissue from the same patient. In addition, we integrated computational prediction of potential targets and mRNA sequencing and identified a master miRNA regulatory network involved in essential biologic processes such as thyroid differentiation. Both mature products of mir-146b (miR-146b-5p and -3p) were among the most abundantly expressed miRNAs in tumors. Specifically, we found that miR-146b-3p binds to the 3′-untranslated region of PAX8 and sodium/iodide symporter (NIS), leading to impaired protein translation and a subsequent reduction in iodide uptake. Furthermore, our findings show that miR-146b and PAX8 regulate each other and share common target genes, thus highlighting a novel regulatory circuit that governs the differentiated phenotype of PTC. In conclusion, our study has uncovered the existence of a miR-146b-3p/PAX8/NIS regulatory circuit that may be exploited therapeutically to modulate thyroid cell differentiation and iodide uptake for improved treatment of advanced thyroid cancer. Cancer Res; 75(19); 4119–30. ©2015 AACR.
Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of Glioblastoma Stem-like Cells
Authors: Ahmed Shafiq U. , Carruthers Ross , Gilmour Lesley , Yildirim Salih , Watts Colin , Chalmers Anthony J.
Published: August 2015

Glioblastoma is the most common form of primary brain tumor in adults and is essentially incurable. Despite aggressive treatment regimens centered on radiotherapy, tumor recurrence is inevitable and is thought to be driven by glioblastoma stem-like cells (GSC) that are highly radioresistant. DNA damage response pathways are key determinants of radiosensitivity but the extent to which these overlapping and parallel signaling components contribute to GSC radioresistance is unclear. Using a panel of primary patient-derived glioblastoma cell lines, we confirmed by clonogenic survival assays that GSCs were significantly more radioresistant than paired tumor bulk populations. DNA damage response targets ATM, ATR, CHK1, and PARP1 were upregulated in GSCs, and CHK1 was preferentially activated following irradiation. Consequently, GSCs exhibit rapid G2–M cell-cycle checkpoint activation and enhanced DNA repair. Inhibition of CHK1 or ATR successfully abrogated G2–M checkpoint function, leading to increased mitotic catastrophe and a modest increase in radiation sensitivity. Inhibition of ATM had dual effects on cell-cycle checkpoint regulation and DNA repair that were associated with greater radiosensitizing effects on GSCs than inhibition of CHK1, ATR, or PARP alone. Combined inhibition of PARP and ATR resulted in a profound radiosensitization of GSCs, which was of greater magnitude than in bulk populations and also exceeded the effect of ATM inhibition. These data demonstrate that multiple, parallel DNA damage signaling pathways contribute to GSC radioresistance and that combined inhibition of cell-cycle checkpoint and DNA repair targets provides the most effective means to overcome radioresistance of GSC. Cancer Res; 75(20); 4416–28. ©2015 AACR.
Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition
Authors: Soucheray Margaret , Capelletti Marzia , Pulido Inés , Kuang Yanan , Paweletz Cloud P. , Becker Jeffrey H. , Kikuchi Eiki , Xu Chunxiao , Patel Tarun B. , Al-shahrour Fatima , Carretero Julián , Wong Kwok-Kin , Jänne Pasi A. , Shapiro Geoffrey I. , Shimamura Takeshi
Published: August 2015

Non–small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFβ was sufficient to induce EMT and resistance to EGFR TKI treatment. Furthermore, NSCLC HCC4006 cells with acquired resistance to gefitinib were characterized by a mesenchymal phenotype and displayed a higher prevalence of the EGFR T790M mutated allele. Notably, combined inhibition of EGFR and the TGFβ receptor in HCC4006 cells prevented EMT but was not sufficient to prevent acquired gefitinib resistance because of an increased emergence of the EGFR T790M allele compared with cells treated with gefitinib alone. Conversely, another independent NSCLC cell line, PC9, reproducibly developed EGFR T790M mutations as the primary mechanism underlying EGFR TKI resistance, even though the prevalence of the mutant allele was lower than that in HCC4006 cells. Thus, our findings underscore heterogeneity within NSCLC cells lines harboring EGFR kinase domain mutations that give rise to divergent resistance mechanisms in response to treatment and anticipate the complexity of EMT suppression as a therapeutic strategy. Cancer Res; 75(20); 4372–83. ©2015 AACR.
Enhanced Chemokine Receptor Recycling and Impaired S1P1 Expression Promote Leukemic Cell Infiltration of Lymph Nodes in Chronic Lymphocytic Leukemia
Authors: Patrussi Laura , Capitani Nagaja , Martini Veronica , Pizzi Marco , Trimarco Valentina , Frezzato Federica , Marino Filippo , Semenzato Gianpietro , Trentin Livio , Baldari Cosima T.
Published: August 2015

Lymphocyte trafficking is orchestrated by chemokine and sphingosine 1-phosphate (S1P) receptors that enable homing and egress from secondary lymphoid organs (SLO). These receptors undergo rapid internalization and plasma membrane recycling to calibrate cellular responses to local chemoattractants. Circulating chronic lymphocytic leukemia (CLL) cells display an abnormal increase in the surface levels of the homing receptors CCR7 and CXCR4 concomitant with low S1P receptor 1 (S1P1) expression. In this study, we investigated the role of receptor recycling on CXCR4/CCR7 surface levels in CLL cells and addressed the impact of quantitative alterations of these receptors and S1P1 on the ability of leukemic cells to accumulate in SLOs. We show that recycling accounts, to a major extent, for the high levels of surface CXCR4/CCR7 on CLL cells. In addition, increased expression of these receptors, together with S1P1 deficiency, is detectable not only in circulating leukemic cells, but also in SLOs of CLL patients with lymphoadenopathy. We further provide evidence that ibrutinib, a Btk inhibitor that promotes mobilization of leukemic cells from SLOs, normalizes the imbalance between CXCR4/CCR7 and S1P1. Taken together, our results highlight the relevance of chemokine and S1P receptor recycling in CLL pathogenesis and clinical outcome. Cancer Res; 75(19); 4153–63. ©2015 AACR.
Systematic Review of Tobacco Use after Lung or Head/Neck Cancer Diagnosis: Results and Recommendations for Future Research
Authors: Burris Jessica L. , Studts Jamie L. , DeRosa Antonio P. , Ostroff Jamie S.
Published: August 2015

Tobacco use after cancer diagnosis is associated with adverse cancer outcomes, yet reliable prevalence estimates for this behavior are lacking. We conducted a systematic literature review of the prevalence of current tobacco use among individuals with a history of lung or head/neck cancer (CRD #42012002625). An extensive search of electronic databases (MEDLINE, EMBASE, Cochrane Library, CINAHL, PsycINFO, and Web of Science) identified 7,777 potentially relevant articles published between 1980 and 2014 and 131 of these yielded pertinent information. Aggregating results across heterogeneous study designs and diverse patient samples, the overall mean prevalence rate of current tobacco use (mostly cigarette smoking) was 33.0% (median, 31.0%). Among current tobacco users at cancer diagnosis, the mean prevalence rate of current tobacco use (mostly cigarette smoking) was 53.8% (median, 50.3%). In many cases, an operational definition of “current” tobacco use was absent, and biochemical verification of self-reported smoking status was infrequent. These and other observed methodologic limitations in the assessment and reporting of cancer patients' tobacco use underscore the necessity of uniform tobacco use assessment in future clinical research and cancer care. Cancer Epidemiol Biomarkers Prev; 24(10); 1450–61. ©2015 AACR.
Adherence to Multiple Cancer Screening Tests among Women Living in Appalachia Ohio
Authors: Katz Mira L. , Reiter Paul L. , Young Gregory S. , Pennell Michael L. , Tatum Cathy M. , Paskett Electra D.
Published: August 2015

Background: There is a lack of information about the correlates of completing all three cancer screening tests among women living in Appalachia.

Methods: Cross-sectional telephone interviews were conducted (April–September 2013) among women (n = 637) ages 51 to 75 years from 12 Appalachia Ohio counties. Outcomes of within screening guidelines were verified by medical records. Multivariable logistic regression models identified correlates of being within guidelines for all three cancer screening tests.

Results: Screening rates included mammography (32.1%), Pap test (36.1%), and a colorectal cancer test (30.1%). Only 8.6% of women were within guidelines for all tests. Having had a check-up in the past 2 years and having received a screening recommendation were significantly related to being within guidelines for all three tests (P < 0.01). Participants with higher annual household incomes [$60,000+; OR, 3.53; 95% confidence interval (CI), 1.49–8.33] and conditions requiring regular medical visits (OR, 3.16; 95% CI, 1.29–7.74) were more likely to be within guidelines for all three screening tests.

Conclusion: Less than 10% of women had completed screening within guidelines for all three screening tests. Regular contact with the health care system and higher incomes were significant predictors of being within guidelines.

Impact: Within guidelines rates for the three recommended cancer screening tests are low among women in Appalachia Ohio. This finding illustrates the need for innovative interventions to improve rates of multiple cancer screening tests. Cancer Epidemiol Biomarkers Prev; 24(10); 1489–94. ©2015 AACR.
Investigation of Metabolomic Blood Biomarkers for Detection of Adenocarcinoma Lung Cancer
Authors: Fahrmann Johannes F. , Kim Kyoungmi , DeFelice Brian C. , Taylor Sandra L. , Gandara David R. , Yoneda Ken Y. , Cooke David T. , Fiehn Oliver , Kelly Karen , Miyamoto Suzanne
Published: August 2015

Background: Untargeted metabolomics was used in case–control studies of adenocarcinoma (ADC) lung cancer to develop and test metabolite classifiers in serum and plasma as potential biomarkers for diagnosing lung cancer.

Methods: Serum and plasma were collected and used in two independent case–control studies (ADC1 and ADC2). Controls were frequency matched for gender, age, and smoking history. There were 52 adenocarcinoma cases and 31 controls in ADC1 and 43 adenocarcinoma cases and 43 controls in ADC2. Metabolomics was conducted using gas chromatography time-of-flight mass spectrometry. Differential analysis was performed on ADC1 and the top candidates (FDR < 0.05) for serum and plasma used to develop individual and multiplex classifiers that were then tested on an independent set of serum and plasma samples (ADC2).

Results: Aspartate provided the best accuracy (81.4%) for an individual metabolite classifier in serum, whereas pyrophosphate had the best accuracy (77.9%) in plasma when independently tested. Multiplex classifiers of either 2 or 4 serum metabolites had an accuracy of 72.7% when independently tested. For plasma, a multimetabolite classifier consisting of 8 metabolites gave an accuracy of 77.3% when independently tested. Comparison of overall diagnostic performance between the two blood matrices yielded similar performances. However, serum is most ideal given higher sensitivity for low-abundant metabolites.

Conclusion: This study shows the potential of metabolite-based diagnostic tests for detection of lung adenocarcinoma. Further validation in a larger pool of samples is warranted.

Impact: These biomarkers could improve early detection and diagnosis of lung cancer. Cancer Epidemiol Biomarkers Prev; 24(11); 1716–23. ©2015 AACR.
Blinatumomab for the Treatment of Philadelphia Chromosome–Negative, Precursor B-cell Acute Lymphoblastic Leukemia
Authors: Wolach Ofir , Stone Richard M.
Published: August 2015

Blinatumomab is a CD19/CD3 bispescific antibody designed to redirect T cells toward malignant B cells and induce their lysis. It recently gained accelerated approval by the FDA for the treatment of relapsed or refractory Philadelphia chromosome–negative B-cell acute lymphoblastic leukemia (RR-ALL). In the phase II trial that served as the basis for approval, blinatumomab demonstrated significant single-agent activity and induced remission [complete remission (CR) and CR with incomplete recovery of peripheral blood counts (CRh)] in 43% of 189 adult patients with RR-ALL; the majority of responders (82%) also attained negative minimal residual disease (MRD−) status that did not generally translate into long-term remissions in most cases. Additional studies show that blinatumomab can induce high response rates associated with lasting remissions in patients in first remission treated for MRD positivity, suggesting a role for blinatumomab in the upfront, MRD-positive setting. Blinatumomab infusion follows a predictable immunopharmacologic profile, including early cytokine release that can be associated with a clinical syndrome, T-cell expansion, and B-cell depletion. Neurologic toxicities represent a unique toxicity that shares similarities with adverse effects of other T-cell engaging therapies. Further studies are needed to clarify the optimal disease setting and timing for blinatumomab therapy. Additional insights into the pathogenesis, risk factors, and prevention of neurologic toxicities as well as a better understanding of the clinical consequences and biologic pathways that are associated with drug resistance are needed. Clin Cancer Res; 21(19); 4262–9. ©2015 AACR.
Are All Oscillators Created Equal? In vitro Performance Characteristics of Eight High-Frequency Oscillatory Ventilators
Authors: Tingay David G. , John Jubal , Harcourt Edward R. , Black Don , Dargaville Peter A. , Mills John F. , Davis Peter G.
Published: August 2015

Background: The mode of waveform generation and circuit characteristics differ between high-frequency oscillators. It is unknown if this influences performance. Objectives: To describe the relationships between set and delivered pressure amplitude (ΔP), and the interaction with frequency and endotracheal tube (ETT) diameter, in eight high-frequency oscillators. Methods: Oscillators were evaluated using a 70-ml test lung at 1.0 and 2.0 ml/cm H2O compliance, with mean airway pressures (PAW) of 10 and 20 cm H2O, frequencies of 5, 10 and 15 Hz, and an ETT diameter of 2.5 and 3.5 mm. At each permutation of PAW, frequency and ETT, the set ΔP was sequentially increased from 15 to 50 cm H2O, or from 20 to 100% maximum amplitude (10% increments) depending on the oscillator design. The ΔP at the ventilator (ΔPVENT), airway opening (ΔPAO) and within the test lung (ΔPTRACH), and tidal volume (VT) at the airway opening were determined at each set ΔP. Results: In two oscillators the relationships between set and delivered ΔP were non-linear, with a plateau in ΔP thresholds noted at all frequencies (Dräger Babylog 8000) or ≥10 Hz (Dräger VN500). In all other devices there was a linear relationship between ΔPVENT, ΔPAO and ΔPTRACH (all r2 >0.93), with differing attenuation of the pressure wave. Delivered VT at the different settings tested varied between devices, with some unable to deliver VT >3 ml at 15 Hz, and others generating VT >20 ml at 5 Hz and a 1:1 inspiratory-to-expiratory time ratio. Conclusions: Clinicians should be aware that modern high-frequency oscillators exhibit important differences in the delivered ΔP and VT.
How Effective Is First-Trimester Screening for Trisomy 21 Based on Ultrasound Only?
Authors: Wiechec Marcin , Knafel Anna , Nocun Agnieszka , Matyszkiewicz Anna , Juszczak Magdalena , Wiercinska Ewa , Latała Emilia
Published: August 2015

Objective: To evaluate the most common first-trimester ultrasound features of fetuses with trisomy 21 (T21) and to examine the screening performance for Down syndrome (DS) using only ultrasound-based protocols. To investigate whether maternal age (MA) has an impact on the efficacy of the ultrasound-based screening methods. Methods: In a prospective study, 6,265 patients were examined. Two ultrasound-based risk calculation protocols were applied: ‘NT' (based on nuchal translucency) and ‘NT+' (based on NT and secondary markers). Results: A total of 5,696 patients were enrolled for analysis; 84 subjects with T21 were identified. Combinations of abnormal ultrasound markers were observed in only 1.2% of euploid fetuses compared to 71.5% of fetuses with T21. Among 17.9% of DS cases with cardiac anomaly, 14.3% comprised atrioventricular septal defects. For a false-positive rate of 3%, the detection rates of T21 were 73.8 and 91.7% for the ‘NT' and ‘NT+' protocols, respectively. The efficacy of both methods was affected by MA. Conclusions: Most of the fetuses with DS demonstrate a combination of ultrasound markers of aneuploidy in the first trimester. The ‘NT+' protocol is efficient and provides comparable performance as a combined screening test. It is a valuable method, especially when the access to biochemical analysis is restricted.
Heart Rate, Life Expectancy and the Cardiovascular System: Therapeutic Considerations
Authors: Boudoulas Konstantinos Dean , Borer Jeffrey S. , Boudoulas Harisios
Published: August 2015

It has long been known that life span is inversely related to resting heart rate in most organisms. This association between heart rate and survival has been attributed to the metabolic rate, which is greater in smaller animals and is directly associated with heart rate. Studies have shown that heart rate is related to survival in apparently healthy individuals and in patients with different underlying cardiovascular diseases. A decrease in heart rate due to therapeutic interventions may result in an increase in survival. However, there are many factors regulating heart rate, and it is quite plausible that these may independently affect life expectancy. Nonetheless, a fast heart rate itself affects the cardiovascular system in multiple ways (it increases ventricular work, myocardial oxygen consumption, endothelial stress, aortic/arterial stiffness, decreases myocardial oxygen supply, other) which, in turn, may affect survival. In this brief review, the effects of heart rate on the heart, arterial system and survival will be discussed.
Looking Beyond Chronological Age: Current Knowledge and Future Directions in the Study of Subjective Age
Authors: Kotter-Grühn Dana , Kornadt Anna E. , Stephan Yannick
Published: August 2015

The notion of the heterogeneity of aging goes along with the awareness that every person experiences aging differently. Over the past years, scholars have emphasized that the assessment of these subjective experiences of aging contributes to our understanding of a range of psychological and physiological processes and outcomes among older adults. One construct frequently used in this context is subjective age, that is, how old or young a person feels. Subjective age has been shown to be an important correlate as well as a predictor of markers of successful aging such as well-being, health, and longevity. However, less is known about the antecedents of subjective age and the mechanisms underlying the relationship between feeling younger and positive developmental outcomes. This article briefly summarizes and critically evaluates the empirical evidence on this topic and makes suggestions on how to address and potentially overcome currently existing theoretical, methodological, and psychometric challenges. Based on the discussion of these challenges, the paper provides directions for future research by outlining underexplored topics such as intraindividual variability and determinants of subjective age, the match between objective age indicators and subjective age, and how subjective age maps on behavior and functioning.
Recognition and Management of Oral Mucosal Injury Caused by Mammalian Target of Rapamycin Inhibitors: A Case Series
Authors: Meiller Timothy F. , Varlotta Sharon , Weikel Dianna
Published: August 2015

The mammalian target of rapamycin inhibitors (mTORIs) everolimus and temsirolimus are approved by the US Food and Drug Administration (FDA) for the treatment of various forms of advanced cancer, and the mTORI sirolimus is approved as an immunosuppressive agent for the prophylaxis of organ rejection in patients receiving renal transplants. The oral lesions associated with mTORI toxicity are distinct from the well-documented chemotherapy- and radiotherapy-induced mucositis, but they may often be misdiagnosed by medical oncologists or transplant physicians, potentially resulting in inappropriate management of this complication. mTORI-associated oral mucosal injury appears to be dose related, and its onset is consistently earlier than conventional mucositis associated with chemotherapy or radiation therapy. Although the lesions appear to resolve within approximately 2 weeks and do not seem to recur as severely with subsequent courses of therapy, the reduction in a patient's quality of life as a result of oral pain that affects the intake of nutritional foods should be taken into consideration. We report three cases that illustrate the complexity involved in the early assessment, referral, and appropriate management of mTORI-associated oral mucosal injury. Corticosteroids appear to be very useful in managing and perhaps preventing these lesions, whereas this approach has never shown efficacy in conventional chemotherapy-related mucositis. Early intervention to reduce the mTORI-associated oral mucosal injury is important to diminish the need for dose alterations of mTORIs and, therefore, to improve patient outcomes.
Significance of the Splenic Vein and Its Branches in Pancreatoduodenectomy with Resection of the Portal Vein System
Authors: Hattori Masashi , Fujii Tsutomu , Yamada Suguru , Inokawa Yoshikuni , Suenaga Masaya , Takami Hideki , Kanda Mitsuro , Sugimoto Hiroyuki , Nomoto Shuji , Murotani Kenta , Nakao Akimasa , Kodera Yasuhiro
Published: August 2015

Background/Aims: Pancreatic head carcinoma frequently invades the superior mesenteric vein (SMV) and/or portal vein (PV). We aimed to evaluate the outcome of transection of the splenic vein (SV) and inferior mesenteric vein (IMV) in pancreatoduodenectomy (PD) with SMV and/or PV resection. Methods: We retrospectively analyzed the records of 660 patients who had undergone pancreatectomy at our institution from January 2004 to October 2013, and selected 141 consecutive patients who had undergone PD with concurrent SMV/PV resection. Postoperative hypersplenism and the presence of remnant branches were evaluated. Results: The SV had been transected in 81 patients and preserved in 60. Postoperative complications and white blood cell counts were similar between the groups. The postoperative splenic volume was not significantly associated with the status of the SV or IMV on the transected SV. The platelet count was significantly lower, and the incidence of collateral veins was higher after SV transection than after SV preservation until 6 months after surgery; these variables were similar in the long term. Conclusion: SV reconstruction might be unnecessary when SV transection is required. Preservation of the IMV on the remnant SV might not prevent sinistral portal hypertension.
Leiomyosarcoma of the Mesenteric Root: A Strategic Location of a Rare Tumor
Authors: Kluger Yoram , Ben-Ishay Offir
Published: August 2015

High mesenteric root sarcomas are difficult to manage due to their proximity to the superior mesenteric vessels. Resection of these tumors along with the blood vessels may lead to a complicated and protracted convalescence for the patient. Resection remains the main treatment modality for these tumors. During operation on high mesenteric root sarcomas, sound clinical judgment is needed for the decision not to sacrifice vital blood vessels.
Clinical Effects of Phosphodiesterase 3A Mutations in Inherited Hypertension With Brachydactyly
Authors: Toka Okan , Tank Jens , Schächterle Carolin , Aydin Atakan , Maass Philipp G. , Elitok Saban , Bartels-Klein Eireen , Hollfinger Irene , Lindschau Carsten , Mai Knut , Boschmann Michael , Rahn Gabriele , Movsesian Matthew A. , Müller Thomas , Doescher Andrea , Gnoth Simone , Mühl Astrid , Toka Hakan R. , Wefeld-Neuenfeld Yvette , Utz Wolfgang , Töpper Agnieszka , Jordan Jens , Schulz-Menger Jeanette , Klussmann Enno , Bähring Sylvia , Luft Friedrich C.
Published: August 2015

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A–mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population.
Effects of Transcranial Direct Current Stimulation over Left Dorsolateral pFC on the Attentional Blink Depend on Individual Baseline Performance
Authors: London Raquel E. , Slagter Heleen A.
Published: August 2015

Selection mechanisms that dynamically gate only relevant perceptual information for further processing and sustained representation in working memory are critical for goal-directed behavior. We examined whether this gating process can be modulated by anodal transcranial direct current stimulation (tDCS) over left dorsolateral pFC (DLPFC)—a region known to play a key role in working memory and conscious access. Specifically, we examined the effects of tDCS on the magnitude of the so-called “attentional blink” (AB), a deficit in identifying the second of two targets presented in rapid succession. Thirty-four participants performed a standard AB task before (baseline), during, and after 20 min of 1-mA anodal and cathodal tDCS in two separate sessions. On the basis of previous reports linking individual differences in AB magnitude to individual differences in DLPFC activity and on suggestions that effects of tDCS depend on baseline brain activity levels, we hypothesized that anodal tDCS over left DLPFC would modulate the magnitude of the AB as a function of individual baseline AB magnitude. Indeed, individual differences analyses revealed that anodal tDCS decreased the AB in participants with a large baseline AB but increased the AB in participants with a small baseline AB. This effect was only observed during (but not after) stimulation, was not found for cathodal tDCS, and could not be explained by regression to the mean. Notably, the effects of tDCS were not apparent at the group level, highlighting the importance of taking individual variability in performance into account when evaluating the effectiveness of tDCS. These findings support the idea that left DLPFC plays a critical role in the AB and in conscious access more generally. They are also in line with the notion that there is an optimal level of prefrontal activity for cognitive function, with both too little and too much activity hurting performance.
Early recognition and response to predator, heterospecific, and conspecific visual cues by multiple species of poeciliid fry
Authors: Culumber Zachary W.
Published: August 2015

Recognition and response to cues from conspecific and heterospecific individuals is critical to survival and reproduction and therefore should be learned early in life. Young fry of two live-bearing fishes, Poecilia mexicana and Xiphophorus birchmanni, were exposed to visual cues of three different species in order to measure shoal tightening, an antipredator defence. Both species responded to a putative predator with shoal tightening, but response to a con- and hetero-specific poeciliid did not differ, though inter-fry distances became larger in the presence of both species compared to distances prior to exposure. There were also size-dependent effects on the pairwise distance between fry. These results suggest that fry are able to learn to distinguish among species based on visual cues alone at an early age, that A. mexicanus is perceived as a threat, but that adult poeciliids are likely not perceived as a predator by fry as some studies have posited.
Genetic evidence for mixed broods and extra-pair matings in a socially monogamous biparental cichlid fish
Authors: Lee-Jenkins Stacey S.Y. , Smith Myron L. , Wisenden Brian D. , Wong Alex , Godin Jean-Guy J.
Published: August 2015

Mobile young under parental care have a high potential for intermixing with other broods, which potentially increases the costs to the foster parents. Here, we examined for the first time the genetic composition of wild-caught broods of the convict cichlid (Amatitlania siquia), a socially monogamous biparental fish, for evidence of brood mixing and adoption. Our microsatellite genotyping data revealed that 79% of broods contained adopted young. Moreover, 25% of broods contained adopted sibsets likely arising from extra-pair matings, a phenomenon hitherto not documented for this species. Overall, adopted foreign fry and host fry in mixed broods were generally different in body length, as would be expected if they have different parents. However, fry from possible extra-pair matings were similar in body length to host fry, suggesting that they are of similar age. Our results are important because they reveal a very high prevalence and degree of brood mixing, and indicate that social monogamy does not necessarily lead to genetic monogamy in the convict cichlid in nature. These findings raise questions about potential brood-mixing mechanisms and the reproductive ecology (especially opportunities for polygamy in nature) of this important model species in the study of animal behaviour.
Public information use by foraging ninespine sticklebacks: Social learning or an unlearned social influence on travel direction?
Authors: Webster M.M. , Laland K.N.
Published: August 2015

If we are to understand the cognitive basis and evolutionary origins of a particular behaviour, it is necessary to identify its underlying mechanism. Ninespine sticklebacks (Pungitius pungitius) can identify the richer of two prey patches by observing other foragers’ success. This may be due to social learning, or an unlearned social effect on travel direction, brought about by the fish being more likely to face and subsequently travel towards areas where they have observed more feeding activity. Here we show that observer orientation does not predict patch choice, and that fish are still more likely to spend more time in richer patches even if they have to take an indirect route to reach them. This suggests that sticklebacks can learn the location of the richer patch through observation, and viewed in conjunction with other published findings, suggests that learned local enhancement lies behind public information use in this species.
Domestic dogs match human male voices to faces, but not for females
Authors: Yong Min Hooi , Ruffman Ted
Published: August 2015

Dogs can match human genders when viewing a live person with vocal playback in a cross-modal discrimination task. In addition, dogs behave differently towards a live human male, with more defensive aggression shown towards human males compared to females. We investigated whether domestic dogs could gender-match a human male or female voice to a still face presented on a computer monitor. Forty-five dogs were presented pairs of male and female faces displaying neutral expressions, while listening to either a male or female voice uttering a sentence in a neutral voice. We measured their looking time at the matching and non-matching faces. While dogs showed some evidence of matching male faces to voices, this was not the case for female stimuli. Our findings support previous studies that dogs are more vigilant with males than females.