bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical inactivity in relation to self-rated eyesight: cross-sectional analysis from the English Longitudinal Study of Ageing
Authors: Smith Lee , Timmis Matthew A , Pardhan Shahina , Latham Keziah , Johnstone James , Hamer Mark
Published: January 2017

Background

To assess the cross-sectional association between self-rated eyesight and physical activity behaviour in a large general population sample of older English adults.

Methods

Analyses of data from the English Longitudinal Study of Ageing. Participants provided information on self-rated eyesight (categorised as: excellent/very good/good/fair–poor) and their own physical activity levels (categorised as: inactive/moderate only at least 1/week, vigorous at least 1/week). Associations between self-rated eyesight and physical activity levels were examined using logistic regression.

Results

A total of 6634 participants (mean age 65.0±9.2 years) were included in the analyses. In adjusted logistic regression models, those with fair–poor and good eyesight were significantly more likely to be inactive than those who reported excellent eyesight (OR 2.07, 95% CI 1.58 to 2.72; OR 1.59, 1.27 to 1.99, respectively).

Conclusion

In this sample of older English adults, those with self-rated fair–poor vision were over twice as likely to be physically inactive than those who reported having excellent vision. When consistent data have emerged, interventions to increase physical activity in those who have poor eyesight are needed.
The role of reduced heart rate volatility in predicting disposition from the emergency department
Authors: Mandel-Portnoy Ya-El , Loo George T , Gregoriou Diana , Bansilal Sameer , Richardson Lynne D
Published: December 2016

Objective

Heart rate volatility (HRVO) is a physiological parameter that is believed to reflect the sympathetic activity of the autonomic nervous system. We explored the utility of HRVO as a predictive tool for declining physiological states, hypothesising that patients admitted from the resuscitation area of the ED to a high-dependency unit (HDU) experience low HRVO compared with patients who did not.

Methods

We retrospectively reviewed HR data recordings, medical charts and disposition decisions from the ED of patients who were admitted to the five resuscitation beds in our adult ED between 29 April 2014 and 30 May 2015. HRVO was calculated for each 5 min interval; it was measured as the SD of all HRs within that interval. Logistic regression was used to model the odds of admission to a HDU given low HRVO during ED stay.

Results

HR data from 2051 patients was collected and approximately 7 million HR data points were analysed. 402 patients experienced low HRVO. Patients who experienced low HRVO during their ED stay were twice as likely to be admitted to a HDU from the ED (OR=2.07, 95% CI 1.64 to 2.60; p<0.001).

Conclusions

Our result provides additional evidence supporting previously published data indicating that autonomic nervous system measures such as HRVO could serve as important and useful clinical tools in the early triage of critically ill patients in the ED.
National 10-year trend in road injuries involving school children on the way to and from school in Japan, 2003–2012
Authors: Inada Haruhiko , Tomio Jun , Nakahara Shinji , Xu Xin , Taniguchi Ayako , Ichikawa Masao
Published: December 2016

Objectives

To quantitatively describe the recent longitudinal trend in road injuries involving school children while commuting to and from school in Japan and to identify groups or situations with particularly large or small decreasing trends.

Methods

Data on the number of children aged 6–15 years who sustained road injuries while commuting were obtained, stratified by year, demographic characteristics, mode of transport and other variables. The rates of killed or seriously injured (KSI) children were calculated from the number of KSI cases (the numerator) and the product of population and the proportion of each mode of transport estimated using the Person Trip Survey data (the denominator). We conducted descriptive analyses of the longitudinal trend in KSI rates stratified by the variables, and Poisson regression analyses were employed to quantify the annualised changes in the rates.

Results

During the study period, 166 children were killed and 8484 children were seriously injured; the KSI rate decreased approximately 30%. The KSI rate was almost 10 times higher among cyclists than pedestrians. In cyclists, the decrease in the KSI rate among children aged 12–15 years was smaller in boys than in girls (estimated change −14% vs −30%). The KSI rate of male pedestrians aged 6–7 years was larger than female and older pedestrians, with a large decrease of 48%.

Conclusions

Although the overall rate of road injuries among children while commuting was decreasing, cyclists were at a much greater risk than pedestrians, and the improvements for cyclists occurred at a slower pace.
Sports Biostatistician: a critical member of all sports science and medicine teams for injury prevention
Authors: Casals Martí , Finch Caroline F
Published: December 2016

Sports science and medicine need specialists to solve the challenges that arise with injury data. In the sports injury field, it is important to be able to optimise injury data to quantify injury occurrences, understand their aetiology and most importantly, prevent them. One of these specialty professions is that of Sports Biostatistician. The aim of this paper is to describe the emergent field of Sports Biostatistics and its relevance to injury prevention. A number of important issues regarding this profession and the science of sports injury prevention are highlighted. There is a clear need for more multidisciplinary teams that incorporate biostatistics, epidemiology and public health in the sports injury area.
Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study
Authors: Comi Giancarlo , De Stefano Nicola , Freedman Mark S , Barkhof Frederik , Uitdehaag Bernard M J , de Vos Marlieke , Marhardt Kurt , Chen Liang , Issard Delphine , Kappos Ludwig
Published: December 2016

Objective

Early treatment following a first clinical demyelinating event (FCDE) delays further disease activity in patients with multiple sclerosis (MS). This study determined the effects of early versus delayed treatment (DT) with subcutaneous interferon (sc IFN) β-1a 44 μg in patients with an FCDE up to 60 months postrandomisation.

Methods

Patients who completed the 24-month double-blind REFLEX (REbif FLEXible dosing in early MS) study entered an extension (REFLEXION, REbif FLEXible dosing in early MS extensION): patients initially randomised to sc IFN β-1a and not reaching clinically definite MS (clinically definite MS, CDMS (second attack or sustained Expanded Disability Status Scale (EDSS) score increase)) continued original treatment (three times weekly (tiw) or once weekly (qw)); placebo patients switched to tiw (DT); patients with CDMS switched to tiw. Clinical, MRI and adverse event data up to month 60 are reported.

Results

402/517 (77.8%) REFLEX patients entered REFLEXION (DT, n=133; tiw, n=127; qw, n=142). At month 60, cumulative probability of CDMS was: DT 44.6%; qw 40.7% (nominal p=0.084 vs DT); tiw 39.2% (nominal p=0.032 vs DT). Cumulative probability of McDonald MS conversion (CDMS or new MRI activity) at month 60 was also reduced for tiw versus DT (nominal p<0.001). At month 60, mean cumulative numbers of new T2, gadolinium-enhancing and T1 hypointense lesions were lower with sc IFN β-1a qw (nominal p<0.05) and tiw versus DT (nominal p<0.001); T2 and T1 hypointense lesion volume change was lower for sc IFN β-1a tiw versus DT (nominal p<0.01). Treatment was well tolerated; fewer patients receiving tiw versus qw were positive for neutralising or binding antibodies.

Conclusions

Over 5 years in patients presenting with an FCDE, early sc IFN β-1a tiw administration versus DT prolonged time to CDMS and McDonald MS, and reduced overall MRI activity.

Trial registration number

NCT00813709; Results.
SIGLEC1 is a biomarker of disease activity and indicates extraglandular manifestation in primary Sjögren's syndrome
Authors: Rose Thomas , Szelinski Franziska , Lisney Anna , Reiter Karin , Fleischer Sarah J , Burmester Gerd R , Radbruch Andreas , Hiepe Falk , Grützkau Andreas , Biesen Robert , Dörner Thomas
Published: December 2016

Objectives

To evaluate the interferon (IFN) biomarkers sialic acid binding Ig like lectin 1 (SIGLEC1, CD169) and IFN-γ-inducible protein-10 (IP-10) in patients with primary Sjögren's syndrome (pSS).

Methods

31 patients fulfilling the American-European criteria for pSS were included. Disease activity was obtained by EULAR Sjögren's syndrome disease activity index (ESSDAI). SIGLEC1 expression on monocytes was analysed using flow cytometry. IP-10 concentrations were determined using Bioplex human Cytokine 27-plex kit. Spearman rank test (SRT) was used for correlation analysis and Mann-Whitney U (MWU) to test for differences between glandular and extraglandular manifestations.

Results

An activated IFN system was detected by an upregulation of SIGLEC1 expression in 64.5% and by elevated serum level of IP-10 in 78.9% of our patients with pSS. In a subsequent analysis SIGLEC1 expression was found to be upregulated more frequently in patients with extraglandular manifestations (16/16, 100%) compared to patients with exclusively glandular involvement (4/15, 27%). SIGLEC1 expression could significantly discriminate between these two disease subgroups (p=0.0001, MWU) with a positive predictive value (PPV) of 80% for extraglandular disease. Moreover, the expression correlated with disease activity (p=0.005, r=0.54, SRT). Serum IP-10 levels neither differed significantly between glandular and extraglandular disease nor correlated with ESSDAI.

Conclusions

Our results indicate that increased SIGLEC1 expression characterises patients with systemic involvement and high disease activity. Therefore, SIGLEC1 determination might be of value for subset definition, risk stratification and differential therapeutic considerations in pSS.
Stochastic model for supersymmetric particle branching process
Authors: Zhang Yuanyuan , Chan Aik Hui , Oh Choo Hiap
Published: January 2017

We develop a stochastic branching model to describe the jet evolution of supersymmetric (SUSY) particles. This model is a modified two-phase branching process, or more precisely, a two-phase simple birth process plus Poisson process. Both pure SUSY partons initiated jets and SUSY plus ordinary partons initiated jets scenarios are considered. The stochastic branching equations are established and the Multiplicity Distributions (MDs) are derived for these two scenarios. We also fit the distribution of the general case (SUSY plus ordinary partons initiated jets) with experimental data. The fitting shows the SUSY particles have not participated in branching at current collision energy yet.
Hyper-Damping Behavior of Stiff and Stable Oscillators with Embedded Statically Unstable Stiffness Elements
Authors: Antoniadis Ioannis A. , Kyriakopoulos Konstantinos J. , Papadopoulos Evangelos G.
Published: January 2017

A novel concept of a nonlinear oscillator is proposed, based on a bistable element, which operates around an unstable equilibrium point. Contrary to the Quasi-Zero Stiffness oscillators, a totally different redistribution of the stiffness elements is followed, so that any level required static stiffness for the entire system can be maintained. This oscillator is designed to present the same overall (static) stiffness around the system equilibrium point, the same mass and to use the same damping element as a reference classical linear SDOF oscillator. Once such an oscillator is optimally designed, it is shown to exhibit an extraordinary apparent damping ratio, which is several orders of magnitude higher than that of the original SDOF system, especially in cases where the original damping of the SDOF system is extremely low. This damping behavior is not a result of a novel additional extraordinary energy dissipation mechanism, but a result of the phase difference between the positive and the negative stiffness elastic forces; this is in turn a consequence of the proper redistribution of the stiffness and the damping elements. This fact ensures that an adequate level of elastic forces exists throughout the entire frequency range, able to counteract the inertial and the external excitation forces. Consequently, a resonance phenomenon, which is inherent in the original linear SDOF system, cannot emerge in the proposed oscillator.
Gut microbiota differs between children with Inflammatory Bowel Disease and healthy siblings in taxonomic and functional composition: a metagenomic analysis
Authors: Knoll Rebecca L. , Forslund Kristoffer , Kultima Jens Roat , Meyer Claudius U. , Kullmer Ulrike , Sunagawa Shinichi , Bork Peer , Gehring Stephan
Published: December 2016

Current treatment for pediatric inflammatory bowel disease (IBD) patients is often ineffective, with serious side effects. Manipulating the gut microbiota via fecal microbiota transplantation (FMT) is an emerging treatment approach but remains controversial. We aimed to assess the composition of the fecal microbiome through a comparison of pediatric IBD patients to their healthy siblings, evaluating risks and prospects for FMT in this setting. A case-control (sibling) study was conducted analyzing fecal samples of six children with Crohn’s disease (CD), six children with ulcerative colitis (UC) and 12 healthy siblings by metagenomic sequencing. In addition, lifetime antibiotic intake was retrospectively determined. Species richness and diversity were significantly reduced in UC patients compared with control [Mann-Whitney U-test false discovery rate (MWU FDR) = 0.011]. In UC, bacteria positively influencing gut homeostasis, e.g., Eubacterium rectale and Faecalibacterium prausnitzii, were significantly reduced in abundance (MWU FDR = 0.05). Known pathobionts like Escherichia coli were enriched in UC patients (MWU FDR = 0.084). Moreover, E. coli abundance correlated positively with that of several virulence genes (SCC > 0.65, FDR < 0.1). A shift toward antibiotic-resistant taxa in both IBD groups distinguished them from controls [MWU Benjamini-Hochberg-Yekutieli procedure (BY) FDR = 0.062 in UC, MWU BY FDR = 0.019 in CD). The collected results confirm a microbial dysbiosis in pediatric UC, and to a lesser extent in CD patients, replicating associations found previously using different methods. Taken together, these observations suggest microbiotal remodeling therapy from family donors, at least for children with UC, as a viable option.

NEW & NOTEWORTHY In this sibling study, prior reports of microbial dysbiosis in IBD patients from 16S rRNA sequencing was verified using deep shotgun sequencing and augmented with insights into the abundance of bacterial virulence genes and bacterial antibiotic resistance determinants, seen against the background of data on the specific antibiotic intake of each of the study participants. The observed dysbiosis, which distinguishes patients from siblings, highlights such siblings as potential donors for microbiotal remodeling therapy in IBD.
Caveolae-specific activation loop between CaMKII and L-type Ca2+channel aggravates cardiac hypertrophy in α1-adrenergic stimulation
Authors: Tonegawa Kota , Otsuka Wataru , Kumagai Shohei , Matsunami Sachi , Hayamizu Nao , Tanaka Shota , Moriwaki Kazumasa , Obana Masanori , Maeda Makiko , Asahi Michio , Kiyonari Hiroshi , Fujio Yasushi , Nakayama Hiroyuki
Published: December 2016

Activation of CaMKII induces a myriad of biological processes and plays dominant roles in cardiac hypertrophy. Caveolar microdomain contains many calcium/calmodulin-dependent kinase II (CaMKII) targets, including L-type Ca2+channel (LTCC) complex, and serves as a signaling platform. The location of CaMKII activation is thought to be critical; however, the roles of CaMKII in caveolae are still elusive due to lack of methodology for the assessment of caveolae-specific activation. Our aim was to develop a novel tool for the specific analysis of CaMKII activation in caveolae and to determine the functional role of caveolar CaMKII in cardiac hypertrophy. To assess the caveolae-specific activation of CaMKII, we generated a fusion protein composed of phospholamban and caveolin-3 (cPLN-Cav3) and GFP fusion protein with caveolin-binding domain fused to CaMKII inhibitory peptide (CBD-GFP-AIP), which inhibits CaMKII activation specifically in caveolae. Caveolae-specific activation of CaMKII was detected using phosphospecific antibody for PLN (Thr17). Furthermore, adenoviral overexpression of LTCC β2a-subunit (β2a) in NRCMs showed its constitutive phosphorylation by CaMKII, which induces hypertrophy, and that both phosphorylation and hypertrophy are abolished by CBD-GFP-AIP expression, indicating that β2aphosphorylation occurs specifically in caveolae. Finally, β2aphosphorylation was observed after phenylephrine stimulation in β2a-overexpressing mice, and attenuation of cardiac hypertrophy after chronic phenylephrine stimulation was observed in nonphosphorylated mutant of β2a-overexpressing mice. We developed novel tools for the evaluation and inhibition of caveolae-specific activation of CaMKII. We demonstrated that phosphorylated β2adominantly localizes to caveolae and induces cardiac hypertrophy after α1-adrenergic stimulation in mice.

NEW & NOTEWORTHY While signaling in caveolae is thought to be important in cardiac hypertrophy, direct evidence is missing due to lack of tools to assess caveolae-specific signaling. This is the first study to demonstrate caveolae-specific activation of CaMKII signaling in cardiac hypertrophy induced by α1-adrenergic stimulation using an originally developed tool.
Long-acting β2-agonists promote glucocorticoid-mediated repression of NF-κB by enhancing expression of the feedback regulator TNFAIP3
Authors: Altonsy Mohammed O. , Mostafa Mahmoud M. , Gerber Anthony N. , Newton Robert
Published: December 2016

Glucocorticoids, or corticosteroids, are effective treatments for many chronic inflammatory diseases, and in mild/moderate asthma, long-acting β2-adrenoceptor agonists (LABAs) enhance the efficacy of inhaled corticosteroids (ICSs) more than increasing the ICS dose. In human bronchial epithelial, BEAS-2B, cells, expression of TNFα-induced protein-3 (TNFAIP3), or A20, a dual-ubiquitin ligase that provides feedback inhibition of NF-κB, was induced by budesonide, an ICS, and formoterol, a LABA, and was further enhanced by budesonide-formoterol combination. The proinflammatory cytokine TNF induced TNFAIP3 and TNF expression. Whereas subsequent budesonide treatment enhanced TNF-induced TNFAIP3 and reduced TNF expression, formoterol amplified these differential effects. In primary human airway smooth muscle cells, TNFAIP3 expression was induced by TNF. This was largely unaffected by budesonide but was acutely enhanced by budesonide-formoterol combination. In BEAS-2B cells, TNF recruited RELA, the main NF-κB transactivating subunit, to a 3′ region of the TNF gene. RELA binding was reduced by budesonide, was further reduced by formoterol cotreatment, and was associated with reduced RNA polymerase II recruitment to the TNF gene. This is consistent with reduced TNF expression. TNFAIP3 knockdown enhanced TNF expression in the presence of TNF, TNF plus budesonide, and TNF plus budesonide-formoterol combination and confirms feedback inhibition. A luciferase reporter containing the TNF 3′ RELA binding region recapitulated TNF inducibility and was inhibited by an IκB kinase inhibitor and TNFAIP3 overexpression. Repression of reporter activity by budesonide was increased by formoterol and involved TNFAIP3. Thus LABAs may improve the anti-inflammatory properties of ICSs by augmenting TNFAIP3 expression to negatively regulate NF-κB.
Quantitative model of hematologic and plasma volume responses after ascent and acclimation to moderate to high altitudes
Authors: Beidleman Beth A. , Staab Janet E. , Muza Stephen R. , Sawka Michael N.
Published: December 2016

Despite decades of research, the magnitude and time course of hematologic and plasma volume (PV) changes following rapid ascent and acclimation to various altitudes are not precisely described. To develop a quantitative model, we utilized a comprehensive database and general linear mixed models to analyze 1,055 hemoglobin ([Hb]) and hematocrit (Hct) measurements collected at sea level and repeated time points at various altitudes in 393 unacclimatized men ( n = 270) and women ( n = 123) who spent between 2 h and 7 days at 2,500–4,500 m under well-controlled and standardized experimental conditions. The PV change (ΔPV) was calculated from [Hb] and Hct measurements during a time period when erythrocyte volume is stable. The results are 1) ΔPV decreases rapidly (~6%) after the 1st day at 2,500 m and [Hb] and Hct values increase by 0.5 g/dl and 1.5 points, respectively; 2) ΔPV decreases an additional 1%, and [Hb] and Hct increase an additional 0.1 g/dl and 0.2 points every 500-m increase in elevation above 2,500 m after the 1st day; 3) ΔPV continues to decrease over time at altitude, but the magnitude of this decrease and subsequent increase in [Hb] and Hct levels is dependent on elevation and sex; and 4) individuals with high initial levels of [Hb] and Hct and older individuals hemoconcentrate less at higher elevations. This study provides the first quantitative delineation of ΔPV and hematological responses during the first week of exposure over a wide range of altitudes and demonstrates that absolute altitude and time at altitude, as well as initial hematologic status, sex, and age impact the response.
Sequence and functional characterization of hypoxia-inducible factors, HIF1α, HIF2αa, and HIF3α, from the estuarine fish,Fundulus heteroclitus
Authors: Townley Ian K. , Karchner Sibel I. , Skripnikova Elena , Wiese Thomas E. , Hahn Mark E. , Rees Bernard B.
Published: December 2016

The hypoxia-inducible factor (HIF) family of transcription factors plays central roles in the development, physiology, pathology, and environmental adaptation of animals. Because many aquatic habitats are characterized by episodes of low dissolved oxygen, fish represent ideal models to study the roles of HIF in the response to aquatic hypoxia. The estuarine fish Fundulus heteroclitus is found in habitats prone to hypoxia. It responds to low oxygen via behavioral, physiological, and molecular changes, and one member of the HIF family, HIF2α, has been previously described. Herein, cDNA sequencing, phylogenetic analyses, and genomic approaches were used to determine other members of the HIFα family from F. heteroclitus and their relationships to HIFα subunits from other vertebrates. In vitro and cellular approaches demonstrated that full-length forms of HIF1α, HIF2α, and HIF3α independently formed complexes with the β-subunit, aryl hydrocarbon receptor nuclear translocator, to bind to hypoxia response elements and activate reporter gene expression. Quantitative PCR showed that HIFα mRNA abundance varied among organs of normoxic fish in an isoform-specific fashion. Analysis of the F. heteroclitus genome revealed a locus encoding a second HIF2α—HIF2αb—a predicted protein lacking oxygen sensing and transactivation domains. Finally, sequence analyses demonstrated polymorphism in the coding sequence of each F. heteroclitus HIFα subunit, suggesting that genetic variation in these transcription factors may play a role in the variation in hypoxia responses among individuals or populations.
Limited potential of genetic predisposition scores to predict muscle mass and strength performance in Flemish Caucasians between 19 and 73 years of age
Authors: Charlier Ruben , Caspers Maarten , Knaeps Sara , Mertens Evelien , Lambrechts Diether , Lefevre Johan , Thomis Martine
Published: December 2016

Since both muscle mass and strength performance are polygenic in nature, the current study compared four genetic predisposition scores (GPS) in their ability to predict these phenotypes. Data were gathered within the framework of the first-generation Flemish Policy Research Centre “Sport, Physical Activity and Health” (2002–2004). Results are based on muscle characteristics data of 565 Flemish Caucasians (19–73 yr, 365 men). Skeletal muscle mass was determined from bioelectrical impedance. The Biodex dynamometer was used to measure isometric (PTstatic120°) and isokinetic strength (PTdynamic60° and PTdynamic240°), ballistic movement speed (S20%), and muscular endurance (Work) of the knee extensors. Genotyping was done for 153 gene variants, selected on the basis of a literature search and the expression quantitative trait loci of selected genes. Four GPS were designed: a total GPS (based on the sum of all 153 variants, each favorable allele = score 1), a data-driven and weighted GPS [respectively, the sum of favorable alleles of those variants with significant b-coefficients in stepwise regression (GPSdd), and the sum of these variants weighted with their respective partial r2 (GPSw)], and an elastic net GPS (based on the variants that were selected by an elastic net regularization; GPSen). It was found that four different models for a GPS were able to significantly predict up to ~7% of the variance in strength performance. GPSen made the best prediction of SMM and Work. However, this was not the case for the remaining strength performance parameters, where best predictions were made by GPSdd and GPSw.
Inflammation and vascular smooth muscle cell dedifferentiation following carotid artery ligation
Authors: Herring B. Paul , Hoggatt April M. , Griffith Sarah L. , McClintick Jeanette N. , Gallagher Patricia J.
Published: December 2016

Following vascular injury medial smooth muscle cells dedifferentiate and migrate through the internal elastic lamina where they form a neointima. The goal of the current study was to identify changes in gene expression that occur before the development of neointima and are associated with the early response to injury. Vascular injury was induced in C57BL/6 mice and in Myh11-creER(T2) mTmG reporter mice by complete ligation of the left carotid artery. Reporter mice were used to visualize cellular changes in the injured vessels. Total RNA was isolated from control carotid arteries or from carotid arteries 3 days following ligation of C57BL/6 mice and analyzed by Affymetrix microarray and quantitative RT-PCR. This analysis revealed decreased expression of mRNAs encoding smooth muscle-specific contractile proteins that was accompanied by a marked increase in a host of mRNAs encoding inflammatory cytokines following injury. There was also marked decrease in molecules associated with BMP, Wnt, and Hedgehog signaling and an increase in those associated with B cell, T cell, and macrophage signaling. Expression of a number of noncoding RNAs were also altered following injury with microRNAs 143/145 being dramatically downregulated and microRNAs 1949 and 142 upregulated. Several long noncoding RNAs showed altered expression that mirrored the expression of their nearest coding genes. These data demonstrate that following carotid artery ligation an inflammatory cascade is initiated that is associated with the downregulation of coding and noncoding RNAs that are normally required to maintain smooth muscle cells in a differentiated state.
Molecular Pathways: Mucins and Drug Delivery in Cancer
Authors: Rao Chinthalapally V. , Janakiram Naveena B. , Mohammed Altaf
Published: December 2016

Over the past few decades, clinical and preclinical studies have clearly demonstrated the role of mucins in tumor development. It is well established that mucins form a barrier impeding drug access to target sites, leading to cancer chemoresistance. Recently gained knowledge regarding core enzyme synthesis has opened avenues to explore the possibility of disrupting mucin synthesis to improve drug efficacy. Cancer cells exploit aberrant mucin synthesis to efficiently mask the epithelial cells and ensure survival under hostile tumor microenvironment conditions. However, O-glycan synthesis enzyme core 2 beta 1,6 N-acetylglucosaminyltransferase (GCNT3/C2GnT-2) is overexpressed in Kras-driven mouse and human cancer, and inhibition of GCNT3 has been shown to disrupt mucin synthesis. This previously unrecognized developmental pathway might be responsible for aberrant mucin biosynthesis and chemoresistance. In this Molecular Pathways article, we briefly discuss the potential role of mucin synthesis in cancers, ways to improve drug delivery and disrupt mucin mesh to overcome chemoresistance by targeting mucin synthesis, and the unique opportunity to target the GCNT3 pathway for the prevention and treatment of cancers. Clin Cancer Res; 23(6); 1373–8. ©2016 AACR.
Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo
Authors: Cecil Denise L. , Slota Meredith , O'Meara Megan M. , Curtis Benjamin C. , Gad Ekram , Dang Yushe , Herendeen Daniel , Rastetter Lauren , Disis Mary L.
Published: December 2016

Purpose: Triple-negative breast cancer (TNBC) represents a cancer stem cell–enriched phenotype. Hypoxia-inducible factor-1α (HIF-1α) induces the expression of proteins associated with stemness and is highly upregulated in TNBC. We questioned whether HIF-1α was immunogenic and whether vaccination targeting HIF-1α would impact the growth of basal-like mammary tumors in transgenic mice.

Experimental Design: We evaluated HIF-1α–specific IgG in sera from controls and patients with breast cancer. Class II epitopes derived from the HIF-1α protein sequence were validated by ELISPOT. To assess therapeutic efficacy, we immunized Tg-MMTVneu and C3(1)Tag mice with HIF-1α Th1-inducing peptides. Stem cells were isolated via magnetic bead separation. Levels of HIF-1α and stem cells in the tumor were quantitated by Western blotting and flow cytometry.

Results: The magnitude (P < 0.001) and incidence (P < 0.001) of HIF-1α–specific IgG were elevated in TNBC patients compared with controls. Both breast cancer patients and donors showed evidence of HIF-1α–specific Th1 and Th2 immunity. Three HIF-1α–specific Th1 class II restricted epitopes that were highly homologous between species elicited type I immunity in mice. After HIF-1α vaccination, mammary tumor growth was significantly inhibited in only C3(1)Tag (basal-like/stem cellhigh; P < 0.001) not TgMMTV-neu (luminal/neu/stem celllow; P = 0.859) murine models. Vaccination increased type I T cells in the tumor (P = 0.001) and decreased cells expressing the stem cell marker, Sca-1, compared with controls (P = 0.004).

Conclusions: An HIF-1α vaccine may be uniquely effective in limiting tumor growth in TNBC. Inhibiting outgrowth of breast cancer stem cells via active immunization in the adjuvant setting may impact disease recurrence. Clin Cancer Res; 23(13); 3396–404. ©2016 AACR.
Potent Anti-leukemia Activities of Chimeric Antigen Receptor–Modified T Cells against CD19 in Chinese Patients with Relapsed/Refractory Acute Lymphocytic Leukemia
Authors: Hu Yongxian , Wu Zhao , Luo Yi , Shi Jimin , Yu Jian , Pu Chengfei , Liang Zuyu , Wei Guoqing , Cui Qu , Sun Jie , Jiang Jing , Xie Jue , Tan Yamin , Ni Wanmao , Tu Jifang , Wang Jinping , Jin Aiyun , Zhang Hao , Cai Zhen , Xiao Lei , Huang He
Published: December 2016

Purpose: Patients with relapsed/refractory acute lymphocytic leukemia (R/R ALL) have a poor prognosis. Chimeric antigen receptor–modified T cells against CD19 (CART19) have displayed anti-leukemia activities. However, data from systemic trials in Chinese patients are limited.

Experimental Design: T cells transduced with CD19-directed CAR lentiviral vectors were infused in patients with R/R ALL under fludarabine- and cyclophosphamide-based lymphodepletion. The postinfusion responses, toxicities, expansion, and persistence of CART19s in enrolled patients were observed and monitored.

Results: We enrolled 15 patients with R/R ALL. The median transduction efficiency of CART19s was 33%. In vitro cytotoxicity assays were conducted and showed prominent antileukemia activities with CART19s. The patients received CART19s infusion at doses of 1.1 × 106/kg to 9.8 × 106/kg. Twelve patients achieved complete remission 1 month after CART19s infusion. CART19s expanded and persisted in peripheral blood and bone marrow. At 150 days, the overall survival rate and leukemia-free survival rate were 65.5% and 37.8%, respectively. The cumulative incidence of relapse and the nonrelapse mortality rate were 54.5% and 7.7%, respectively. Four patients underwent subsequent haploidentical hematopoietic stem cell transplantation. In this trial, 10 patients experienced cytokine release syndrome (CRS). Grade 3 CRS developed in 40% of patients and was associated with a higher disease burden on day −1 and a higher number of previous relapses.

Conclusions: This trial demonstrated potent antileukemia activities of CART19s in Chinese patients with R/R ALL. Disease relapse remained the main obstacle. However, patients with a high risk of relapse after CART19s might benefit from subsequent haploidentical hematopoietic stem cell transplantation. Clin Cancer Res; 23(13); 3297–306. ©2016 AACR.
Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways
Authors: Derakhshan Adeeb , Chen Zhong , Van Waes Carter
Published: December 2016

The Cancer Genome Atlas (TCGA) has unveiled genomic deregulation of various components of the extrinsic and intrinsic apoptotic pathways in different types of cancers. Such alterations are particularly common in head and neck squamous cell carcinomas (HNSCC), which frequently display amplification and overexpression of the Fas-associated via death domain (FADD) and inhibitor of apoptosis proteins (IAP) that complex with members of the TNF receptor family. Second mitochondria-derived activator of caspases (SMAC) mimetics, modeled after the endogenous IAP antagonist SMAC, and IAP inhibitors represent important classes of novel small molecules currently in phase I/II clinical trials. Here we review the physiologic roles of IAPs, FADD, and other components involved in cell death, cell survival, and NF-κB signaling pathways in cancers, including HNSCC. We summarize the results of targeting IAPs in preclinical models of HNSCC using SMAC mimetics. Synergistic activity of SMAC mimetics together with death agonists TNFα or TRAIL occurred in vitro, whereas their antitumor effects were augmented when combined with radiation and chemotherapeutic agents that induce TNFα in vivo. In addition, clinical trials testing SMAC mimetics as single agents or together with chemo- or radiation therapies in patients with HNSCC and solid tumors are summarized. As we achieve a deeper understanding of the genomic alterations and molecular mechanisms underlying deregulated death and survival pathways in different cancers, the role of SMAC mimetics and IAP inhibitors in cancer treatment will be elucidated. Such developments could enhance precision therapeutics and improve outcomes for cancer patients. Clin Cancer Res; 23(6); 1379–87. ©2016 AACR.
Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma
Authors: Dong Zhong-Yi , Zhong Wen-Zhao , Zhang Xu-Chao , Su Jian , Xie Zhi , Liu Si-Yang , Tu Hai-Yan , Chen Hua-Jun , Sun Yue-Li , Zhou Qing , Yang Jin-Ji , Yang Xue-Ning , Lin Jia-Xin , Yan Hong-Hong , Zhai Hao-Ran , Yan Li-Xu , Liao Ri-Qiang , Wu Si-Pei , Wu Yi-Long
Published: December 2016

Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non–small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood.

Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.

Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors.

Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti–PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012–24. ©2016 AACR.
Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade
Authors: Williams Michelle M. , Lee Linus , Hicks Donna J. , Joly Meghan M. , Elion David , Rahman Bushra , McKernan Courtney , Sanchez Violeta , Balko Justin M. , Stricker Thomas , Estrada Monica Valeria , Cook Rebecca S.
Published: December 2016

An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of MCL1 as compared with BCL2 or BCL2L1 (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα+ tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα+ breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measured in situ using Mcl-1/Bim proximity ligation assays. Importantly, MCL1 gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression of BCL2 or BCL2L1 and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1–selective inhibitors for targeted tumor cell killing.

Implications: Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class. Mol Cancer Res; 15(3); 259–68. ©2016 AACR.
Immunophenotyping and Transcriptomic Outcomes in PDX-Derived TNBC Tissue
Authors: Snowden Eileen , Porter Warren , Hahn Friedrich , Ferguson Mitchell , Tong Frances , Parker Joel S. , Middlebrook Aaron , Ghanekar Smita , Dillmore W. Shannon , Blaesius Rainer
Published: December 2016

Cancer tissue functions as an ecosystem of a diverse set of cells that interact in a complex tumor microenvironment. Genomic tools applied to biopsies in bulk fail to account for this tumor heterogeneity, whereas single-cell imaging methods limit the number of cells which can be assessed or are very resource intensive. The current study presents methods based on flow cytometric analysis and cell sorting using known cell surface markers (CXCR4/CD184, CD24, THY1/CD90) to identify and interrogate distinct groups of cells in triple-negative breast cancer clinical biopsy specimens from patient-derived xenograft (PDX) models. The results demonstrate that flow cytometric analysis allows a relevant subgrouping of cancer tissue and that sorting of these subgroups provides insights into cancer cell populations with unique, reproducible, and functionally divergent gene expression profiles. The discovery of a drug resistance signature implies that uncovering the functional interaction between these populations will lead to deeper understanding of cancer progression and drug response.

Implications: PDX-derived human breast cancer tissue was investigated at the single-cell level, and cell subpopulations defined by surface markers were identified which suggest specific roles for distinct cellular compartments within a solid tumor. Mol Cancer Res; 15(4); 429–38. ©2016 AACR.
Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth
Authors: Guan Xiangnan , LaPak Kyle M. , Hennessey Rebecca C. , Yu Christina Y. , Shakya Reena , Zhang Jianying , Burd Christin E.
Published: December 2016

Senescent cells within the tumor microenvironment (TME) adopt a proinflammatory, senescence-associated secretory phenotype (SASP) that promotes cancer initiation, progression, and therapeutic resistance. Here, exposure to palbociclib (PD-0332991), a CDK4/6 inhibitor, induces senescence and a robust SASP in normal fibroblasts. Senescence caused by prolonged CDK4/6 inhibition is DNA damage–independent and associated with Mdm2 downregulation, whereas the SASP elicited by these cells is largely reliant upon NF-κB activation. Based upon these observations, it was hypothesized that the exposure of nontransformed stromal cells to PD-0332991 would promote tumor growth. Ongoing clinical trials of CDK4/6 inhibitors in melanoma prompted a validation of this hypothesis using a suite of genetically defined melanoma cells (i.e., Ras mutant, Braf mutant, and Ras/Braf wild-type). When cultured in the presence of CDK4/6i-induced senescent fibroblasts, melanoma cell lines exhibited genotype-dependent proliferative responses. However, in vivo, PD-0332991–treated fibroblasts enhanced the growth of all melanoma lines tested and promoted the recruitment of Gr-1–positive immune cells. These data indicate that prolonged CDK4/6 inhibitor treatment causes normal fibroblasts to enter senescence and adopt a robust SASP. Such senescent cells suppress the antitumor immune response and promote melanoma growth in immunocompetent, in vivo models.

Implications: The ability of prolonged CDK4/6 inhibitor treatment to induce cellular senescence and a robust SASP in primary cells may hinder therapeutic efficacy and promote long-term, gerontogenic consequences that should be considered in clinical trials aiming to treat melanoma and other cancer types. Mol Cancer Res; 15(3); 237–49. ©2016 AACR.
Design and Implementation of Single Phase AC-DC Buck-Boost Converter for Power Factor Correction and Harmonic Elimination
Authors: Jayahar Damodaran , Ranihemamalini R. , Rathnakannan K.
Published: December 2016

This paper discusses the Power Factor Correction (PFC) for single phase ACDC Buck-Boost Converter (BBC) operated in Continuous Conduction Mode (CCM) using inductor average current mode control. The proposed control technique employs Proportional-Integral (PI) controller in the outer voltage loop and the Inductor Average Current Mode Control (IACMC) in the inner current loop for PFC BBC. The IACMC has advantages such as robustness when there are large variations in line voltage and output load. The PI controller is developed by using state space average model of BBC. The simulation of the proposed system with its control circuit is implemented in MatLab/Simulink. The simulation results show a nearly unity power factor can be attained and there is almost no change in power factor when the line frequency is at various ranges. Experimental results are provided to show its validity and feasibility.
Keyword
Automatic Generation Control of Two Equal Areas with Traditional Controllers
Authors: Rani Ankita , Singh Harinder , Arora Krishan
Published: December 2016

Automatic generation control (AGC) is major issue in power system whose main purpose is to maintain the frequency and tie line power flow during normal period in an interconnected system. . Thus, It is the responsibility of the Power system engineers to ensure that adequate power is delivered to the load reliably and economically so that nominal condition will be re-established The main focus is to maintain the value of frequency in its prescribed limit. We use renewable source which are important as well as non renewable sources at the level of extinct. As renewable alone cannot reliable then we use interconnection of both for making the system reliable and more efficient.This research paper is devoted to explore the interconnection of the automatic generation control of hydro power system and wind system. The wind system is comprised with governor dead band, generation rate constraint and turbine dynamics where as the hydro system is comprised with generation rate constraint. The traditional PI controller does not have adequate control performance with the consideration of nonlinearities and turbine dynamics. To overcome this drawback, PID controllers helps in solving optimization problems by exploitation of random search. It will provide the system security also for maintain the frequency in prescribed limit with the help of simulation.
Design and Simulation of PFC Converter for Brushless SRM Drive
Authors: Subbamma M. Rama , Madhusudhan V. , Anjaneyulu K.S.R
Published: December 2016

In most of the industrial applications, Switched Reluctance Motor (SRM) is mainly employed due to the reasons like having low maintenance and high efficiency. SRM consists of windings only on its stator, but would not have any windings on rotor thus having very simple construction. The available supply is AC. But AC cannot be directly supplied to SRM when used for air-conditioner application which is employed in this paper. Also power factor in the system needs to be corrected when using a SRM drive. Thus AC supply is fed to power factor correction (PFC) converter which is Buck-Boost converter here in this paper. The output of the PFC converter is fed to SRM through a simple asymmetrical converter. This PFC circuit consists of a simple diode bridge rectifier with Buck-Boost DC-DC converter. A suitable control circuit was proposed to control the input power factor under various loading conditions. This paper gives analysis of SRM drive for air-conditioner application with Buck-Boost converter based PFC circuit. A Matlab/simulink based model is developed and simulation results are presented. Simulation is carried out for different speed response.