bluuebunny/crossref_metadata_2025 huggingface dataset:
A Polysaccharide Utilization Locus from an Uncultured Bacteroidetes Phylotype Suggests Ecological Adaptation and Substrate Versatility
Authors: Mackenzie A. K. , Naas A. E. , Kracun S. K. , Schückel J. , Fangel J. U. , Agger J. W. , Willats W. G. T. , Eijsink V. G. H. , Pope P. B.
Published: October 2014

Recent metagenomic analyses have identified uncultured bacteria that are abundant in the rumen of herbivores and that possess putative biomass-converting enzyme systems. Here we investigate the saccharolytic capabilities of a polysaccharide utilization locus (PUL) that has been reconstructed from an uncultured
Bacteroidetes
phylotype (SRM-1) that dominates the rumen microbiome of Arctic reindeer. Characterization of the three PUL-encoded outer membrane glycoside hydrolases was performed using chromogenic substrates for initial screening, followed by detailed analyses of products generated from selected substrates, using high-pressure anion-exchange chromatography with electrochemical detection. Two glycoside hydrolase family 5 (GH5) endoglucanases (GH5_g and GH5_h) demonstrated activity against β-glucans, xylans, and xyloglucan, whereas GH5_h and the third enzyme, GH26_i, were active on several mannan substrates. Synergy experiments examining different combinations of the three enzymes demonstrated limited activity enhancement on individual substrates. Binding analysis of a SusE-positioned lipoprotein revealed an affinity toward β-glucans and, to a lesser extent, mannan, but unlike the two SusD-like lipoproteins previously characterized from the same PUL, binding to cellulose was not observed. Overall, these activities and binding specificities correlated well with the glycan content of the reindeer rumen, which was determined using comprehensive microarray polymer profiling and showed an abundance of various hemicellulose glycans. The substrate versatility of this single PUL putatively expands our perceptions regarding PUL machineries, which so far have demonstrated gene organization that suggests one cognate PUL for each substrate type. The presence of a PUL that possesses saccharolytic activity against a mixture of abundantly available polysaccharides supports the dominance of SRM-1 in the Svalbard reindeer rumen microbiome.
Novel Mechanism Coupling Cyclic AMP-Protein Kinase A Signaling and Golgi Trafficking via Gyp1 Phosphorylation in Polarized Growth
Authors: Huang Zhen-Xing , Wang Haitao , Wang Yan-Ming , Wang Yue
Published: October 2014

The cyclic AMP (cAMP)-protein kinase A (PKA) signaling activates virulence expression during hyphal development in the fungal human pathogen
Candida albicans
. The hyphal growth is characterized by Golgi polarization toward the hyphal tips, which is thought to enhance directional vesicle transport. However, how the hypha-induction signal regulates Golgi polarization is unknown. Gyp1, a Golgi-associated protein and the first GTPase-activating protein (GAP) in the Rab GAP cascade, critically regulates membrane trafficking from the endoplasmic reticulum to the plasma membrane. Here, we report a novel pathway by which the cAMP-PKA signaling triggers Golgi polarization during hyphal growth. We demonstrate that Gyp1 plays a crucial role in actin-dependent Golgi polarization. Hyphal induction activates PKA, which in turn phosphorylates Gyp1. Phosphomimetic mutation of four PKA sites identified by mass spectrometry (Gyp1
4E
) caused strong Gyp1 polarization to hyphal tips, whereas nonphosphorylatable mutations (Gyp1
4A
) abolished it. Gyp1
4E
exhibited enhanced association with the actin motor Myo2, while Gyp1
4A
showed the opposite effect, providing a possible mechanism for Golgi polarization. A GAP-dead Gyp1 (Gyp1
R292K
) showed strong polarization similar to that seen with Gyp1
4E
, indicating a role for the GAP activity. Mutating the PKA sites on Gyp1 also impaired the recruitment of a late Golgi marker, Sec7. Furthermore, proper PKA phosphorylation and GAP activity of Gyp1 are required for virulence in mice. We propose that the cAMP-PKA signaling directly targets Gyp1 to promote Golgi polarization in the yeast-to-hypha transition, an event crucial for
C. albicans
infection.
Seeing the forest through the trees: uncovering phenomic complexity through interactive network visualization
Authors: Warner Jeremy L , Denny Joshua C , Kreda David A , Alterovitz Gil
Published: October 2014

Our aim was to uncover unrecognized phenomic relationships using force-based network visualization methods, based on observed electronic medical record data.

A primary phenotype was defined from actual patient profiles in the Multiparameter Intelligent Monitoring in Intensive Care II database. Network visualizations depicting primary relationships were compared to those incorporating secondary adjacencies. Interactivity was enabled through a phenotype visualization software concept: the Phenomics Advisor.

Subendocardial infarction with cardiac arrest was demonstrated as a sample phenotype; there were 332 primarily adjacent diagnoses, with 5423 relationships. Primary network visualization suggested a treatment-related complication phenotype and several rare diagnoses; re-clustering by secondary relationships revealed an emergent cluster of smokers with the metabolic syndrome.

Network visualization reveals phenotypic patterns that may have remained occult in pairwise correlation analysis. Visualization of complex data, potentially offered as point-of-care tools on mobile devices, may allow clinicians and researchers to quickly generate hypotheses and gain deeper understanding of patient subpopulations.
Re-examining health IT policy: what will it take to derive value from our investment?
Authors: Riskin Loren , Koppel Ross , Riskin Daniel
Published: October 2014

Despite substantial investments in health information technology (HIT), the nation's goals of reducing cost and improving outcomes through HIT remain elusive. This period of transition, with new Office of National Coordinator for HIT leadership, upcoming Meaningful Use Stage III definitions, and increasing congressional oversight, is opportune to consider needed course corrections in HIT strategy. This article describes current problems and recommended changes in HIT policy, including approaches to usability, interoperability, and quality measurement. Recommendations refrain from interim measures, such as electronic health record adoption rates, and instead focus on measurable national value to benefit the economy, to reduce healthcare costs, and to improve clinical efficiency and care quality.
Competing with injuries: injuries prior to and during the 15th FINA World Championships 2013 (aquatics)
Authors: Mountjoy Margo , Junge Astrid , Benjamen Sarah , Boyd Kevin , Diop Mohamed , Gerrard David , van den Hoogenband Cees-Rein , Marks Saul , Martinez-Ruiz Enrique , Miller Jim , Nanousis Kyriakos , Shahpar Farhad Moradi , Veloso Jose , van Mechelen William , Verhagen Evert
Published: October 2014

Background

Injury and illness surveillance is the foundation for the development of prevention strategies.

Objective

To examine injuries among the aquatic disciplines in the 4 weeks prior to and during the 2013 FINA World Championships.

Methods

The study was comprised of two components: (1) a retrospective athlete survey recording injuries in the 4 weeks prior to the Championships and (2) a prospective recording of injuries and illnesses by the medical teams of the participating countries and the local host medical team.

Results

One-third of the 1116 responding athletes reported an injury/physical complaint in the 4 weeks prior to the Championships. Significantly more women (36.7%) than men (28.6%) reported injuries. Divers reported the highest rate of injury/physical complaints (55.7%). At the start of the Championships, 70% of injured respondents (n=258) were still symptomatic; however, full participation was expected by 76%. During the Championships, 186 new injuries were reported (8.3/100 registered athletes) with the highest injury incidence rate in water polo (15.3/100 registered athletes). The most common injured body part was the shoulder (21%). A total of 199 illnesses were reported during the Championships (9.0/100 registered athletes) with the most common diagnosis of illness being gastrointestinal infection. Environmental exposure (allergy, otitis and jellyfish stings) was responsible for 27% of all illnesses in open water swimming.

Conclusions

Injuries pose a significant health risk for elite aquatic athletes. A prospective study would improve understanding of out-of-competition injuries. Future injury and illness surveillance at FINA World Championships is required to direct and measure the impact of prevention strategies.
Lifetime smoking habits among Norwegian men and women born between 1890 and 1994: a cohort analysis using cross-sectional data
Authors: Lund Ingeborg , Lund Karl Erik
Published: October 2014

Objectives

Providing lifetime smoking prevalence data and gender-specific cigarette consumption data for use in epidemiological studies of tobacco-induced cancer in Norway. Characterising smoking patterns in birth cohorts is essential for evaluating the impact of tobacco control interventions and predicting smoking-related mortality.

Setting

Norway.

Participants

Previously analysed annual surveys of smoking habits from 1954 to 1992, and individual lifetime smoking histories collected in 1965 from a sample of people born in 1893–1927, were supplemented with new annual surveys of smoking habits from 1993 to 2013. Age range 15–74 years.

Primary outcome measure

Current smoking proportions in 5-year gender-and-birth cohorts of people born between 1890 and 1994.

Results

The proportion of smokers increased in male cohorts until the 1950s, when the highest proportion of male smokers (76–78%) was observed among those born in 1915–1934. Among women, the peak (52%) occurred 20 years later, in women born in 1940–1949. After 1970 smoking has declined in all cohorts of men and women. In the 1890–1894 cohorts, male smoking prevalence was several times higher than female, but the gap declined until no gender difference was present among those born after 1950. Gender-specific per capita consumption was even more skewed, and men have consumed over 70% of all cigarettes since 1930. The incidence of lung cancer for men peaked at around 2000, with the highest incidence rate estimated at ca. 38%. The incidence of lung cancer for women is still increasing, and estimated incidence rate for 2011 was 25.2%.

Conclusions

In an epidemiological perspective, men have had a longer and more intense exposure to cigarettes than women. The gender-specific incidence of lung cancer reflects the gender difference in consumption over time.
What do parents of children with dysphagia think about their MDT? A qualitative study
Authors: Cowpe (Jebson) Emma , Hanson Ben , Smith Christina H
Published: October 2014

Objectives

To seek the experiences and perspectives of parents caring for children with dysphagia, with emphasis on their experiences of working within their child's multidisciplinary team (MDT).

Setting

This research was completed in community settings, within families’ homes across the UK.

Participants

14 families self-selected to participate in the study. Criteria specified that participants must care for a child under the age of 18 and to decrease ambiguity the term ‘diagnosis of dysphagia’ was defined as the need for modified (thickened) fluids. Exclusion criteria: caring for an adult over the age of 18; diet and fluid modifications for reasons other than dysphagia (eg, for symptomatic treatment of gastro-oesophageal reflux disease. Participants were interviewed within their homes using a semistructured questionnaire and data was analysed using a descriptive phenomenological approach through use of thematic coding and constant comparison. Themes and relationships were inductively generated from the data.

Results

Participants universally expressed a desire to be involved with their child's MDT; this study identified the following facilitators and barriers to collaboration: accessing services, professional knowledge and professional skillset. Participants described three means of responding to these barriers: reacting emotionally, seeking solutions and making decisions.

Conclusions

This study recorded in-depth reports of participants’ experiences of working with healthcare providers. Despite government-driven efforts towards person-centred healthcare and social care, participants shared accounts of times when this has not occurred, describing a negative impact on the well-being and quality of life of their child and family.
Management of a unilateral non‐healing corneal ulcer and uveitis in a laughing kookaburra (Dacelo novaeguineae)
Authors: Sabater Mikel , Pérez Marisa
Published: October 2014

A six‐year‐old male laughing kookaburra (Dacelo novaeguineae) was presented for evaluation of unilateral ocular lesions. The bird had a non‐healing corneal ulcer and uveitis in the left eye. The combination of medical (oral meloxicam and ciprofloxacin eye drops) and surgical debridement with dry cotton‐tip applicators after prepping the cornea with povidone‐iodine solution proved to be effective in order to achieve a complete healing of the cornea and to control the uveitis observed in the present case. This case report is written in order to provide more information about the management of non‐healing corneal ulcers in avian species.
Declining fecundity and factors affecting embryo quality in the American lobster (Homarus americanus) from the Bay of Fundy
Authors: Koopman Heather N. , Westgate Andrew J. , Siders Zachary A.
Published: October 2014

Recent perturbations in ecosystem and environmental dynamics in the habitat of the American lobster have led to increases in abundance, with unprecedented high landings in some regions. Despite the commercial value of this species, surprisingly little is known about maternal and environmental influences on its reproductive output. We measured fecundity and embryo quality in 1370 ovigerous lobsters from the Bay of Fundy, Canada, during 2008–2013. Female size was generally positively correlated with fecundity (P < 0.001), although some of the very large (and presumably old) females brooded significantly fewer eggs than expected. Egg energy content and lipid content and composition exhibited significant annual differences, indicating environmentally based variation. The most striking difference was a 31% decline in fecundity from 2008 to 2013 (8%–10% per year). We hypothesize that recent warming trends could be responsible for reduced fecundity. Decreased fecundity may be a cause for concern for future recruitment in this population, which has been shown to be an important source of larvae for the Gulf of Maine metapopulation.
Cholesterol-enriched diet disrupts the blood-testis barrier in rabbits
Authors: Morgan Daniel H. , Ghribi Othman , Hui Liang , Geiger Jonathan D. , Chen Xuesong
Published: October 2014

About 15% of heterosexual couples in the USA suffer from infertility issues; male infertility accounts for ∼50% of all infertility cases and roughly 50% of male infertility is idiopathic. Increased levels of plasma cholesterol affect spermatogenesis and male fertility negatively, but by unclear mechanisms. Clearly, spermatogenesis occurs in immune-privileged seminiferous tubules that are protected by the blood-testis barrier (BTB), and BTB disruption results in sperm damage and male infertility. Accordingly, using rabbits fed a 2% cholesterol-enriched diet for 2, 4, and 6 wk to raise levels of plasma cholesterol, we tested the hypothesis that elevated levels of plasma cholesterol disrupt the BTB functionally and biochemically. The cholesterol-enriched diet increased lipid deposition dramatically and time-dependently in the seminiferous tubules and disrupted the BTB as evidenced by increased IgG staining within the seminiferous tubules. Total protein levels of the tight-junction proteins ZO-1 and occludin were increased in the seminiferous tubules of rabbits fed the cholesterol-enriched diet, and the distribution patterns of tight-junction proteins were markedly affected, including an increased accumulation of tight-junction proteins in endosomes. Disruption of the integrity of the BTB due to increased plasma levels of cholesterol might play a role in male infertility.
Nox2-dependent glutathionylation of endothelial NOS leads to uncoupled superoxide production and endothelial barrier dysfunction in acute lung injury
Authors: Wu Feng , Szczepaniak William S. , Shiva Sruti , Liu Huanbo , Wang Yinna , Wang Ling , Wang Ying , Kelley Eric E. , Chen Alex F. , Gladwin Mark T. , McVerry Bryan J.
Published: October 2014

Microvascular barrier integrity is dependent on bioavailable nitric oxide (NO) produced locally by endothelial NO synthase (eNOS). Under conditions of limited substrate or cofactor availability or by enzymatic modification, eNOS may become uncoupled, producing superoxide in lieu of NO. This study was designed to investigate how eNOS-dependent superoxide production contributes to endothelial barrier dysfunction in inflammatory lung injury and its regulation. C57BL/6J mice were challenged with intratracheal LPS. Bronchoalveolar lavage fluid was analyzed for protein accumulation, and lung tissue homogenate was assayed for endothelial NOS content and function. Human lung microvascular endothelial cell (HLMVEC) monolayers were exposed to LPS in vitro, and barrier integrity and superoxide production were measured. Biopterin species were quantified, and coimmunoprecipitation (Co-IP) assays were performed to identify protein interactions with eNOS that putatively drive uncoupling. Mice exposed to LPS demonstrated eNOS-dependent increased alveolar permeability without evidence for altered canonical NO signaling. LPS-induced superoxide production and permeability in HLMVEC were inhibited by the NOS inhibitor nitro-l-arginine methyl ester, eNOS-targeted siRNA, the eNOS cofactor tetrahydrobiopterin, and superoxide dismutase. Co-IP indicated that LPS stimulated the association of eNOS with NADPH oxidase 2 (Nox2), which correlated with augmented eNOS S-glutathionylation both in vitro and in vivo. In vitro, Nox2-specific inhibition prevented LPS-induced eNOS modification and increases in both superoxide production and permeability. These data indicate that eNOS uncoupling contributes to superoxide production and barrier dysfunction in the lung microvasculature after exposure to LPS. Furthermore, the results implicate Nox2-mediated eNOS- S-glutathionylation as a mechanism underlying LPS-induced eNOS uncoupling in the lung microvasculature.
Nitrite therapy improves survival postexposure to chlorine gas
Authors: Honavar Jaideep , Doran Stephen , Oh Joo-Yeun , Steele Chad , Matalon Sadis , Patel Rakesh P.
Published: October 2014

Exposure to relatively high levels of chlorine (Cl2) gas can occur in mass-casualty scenarios associated with accidental or intentional release. Recent studies have shown a significant postexposure injury phase to the airways, pulmonary, and systemic vasculatures mediated in part by oxidative stress, inflammation, and dysfunction in endogenous nitric oxide homeostasis pathways. However, there is a need for therapeutics that are amenable to rapid and easy administration in the field and that display efficacy toward toxicity after chlorine exposure. In this study, we tested whether nitric oxide repletion using nitrite, by intramuscular injection after Cl2 exposure, could prevent Cl2 gas toxicity. C57bl/6 male mice were exposed to 600 parts per million Cl2 gas for 45 min, and 24-h survival was determined with or without postexposure intramuscular nitrite injection. A single injection of nitrite (10 mg/kg) administered either 30 or 60 min postexposure significantly improved 24-h survival (from ∼20% to 50%). Survival was associated with decreased neutrophil accumulation in the airways. Rendering mice neutropenic before Cl2 exposure improved survival and resulted in loss of nitrite-dependent survival protection. Interestingly, female mice were more sensitive to Cl2-induced toxicity compared with males and were also less responsive to postexposure nitrite therapy. These data provide evidence for efficacy and define therapeutic parameters for a single intramuscular injection of nitrite as a therapeutic after Cl2 gas exposure that is amenable to administration in mass-casualty scenarios.
Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension
Authors: Nozik-Grayck Eva , Woods Crystal , Taylor Joann M. , Benninger Richard K. P. , Johnson Richard D. , Villegas Leah R. , Stenmark Kurt R. , Harrison David G. , Majka Susan M. , Irwin David , Farrow Kathryn N.
Published: October 2014

Excess superoxide has been implicated in pulmonary hypertension (PH). We previously found lung overexpression of the antioxidant extracellular superoxide dismutase (EC-SOD) attenuates PH and pulmonary artery (PA) remodeling. Although comprising a small fraction of total SOD activity in most tissues, EC-SOD is abundant in arteries. We hypothesize that the selective loss of vascular EC-SOD promotes hypoxia-induced PH through redox-sensitive signaling pathways. EC-SODloxp/loxp× Tgcre/SMMHCmice (SMC EC-SOD KO) received tamoxifen to conditionally deplete smooth muscle cell (SMC)-derived EC-SOD. Mice were exposed to hypobaric hypoxia for 35 days, and PH was assessed by right ventricular systolic pressure measurements and right ventricle hypertrophy. Vascular remodeling was evaluated by morphometric analysis and two-photon microscopy for collagen. We examined cGMP content and soluble guanylate cyclase expression and activity in lung, lung phosphodiesterase 5 (PDE5) expression and activity, and expression of endothelial nitric oxide synthase and GTP cyclohydrolase-1 (GTPCH-1), the rate-limiting enzyme in tetrahydrobiopterin synthesis. Knockout of SMC EC-SOD selectively decreased PA EC-SOD without altering total lung EC-SOD. PH and vascular remodeling induced by chronic hypoxia was augmented in SMC EC-SOD KO. Depletion of SMC EC-SOD did not impact content or activity of lung soluble guanylate cyclase or PDE5, yet it blunted the hypoxia-induced increase in cGMP. Although total eNOS was not altered, active eNOS and GTPCH-1 decreased with hypoxia only in SMC EC-SOD KO. We conclude that the localized loss of PA EC-SOD augments chronic hypoxic PH. In addition to oxidative inactivation of NO, deletion of EC-SOD seems to reduce eNOS activity, further compromising pulmonary vascular function.
Animal models of bronchopulmonary dysplasia. The preterm and term rabbit models
Authors: D'Angio Carl T. , Ryan Rita M.
Published: October 2014

Bronchopulmonary dysplasia (BPD) is an important lung developmental pathophysiology that affects many premature infants each year. Newborn animal models employing both premature and term animals have been used over the years to study various components of BPD. This review describes some of the neonatal rabbit studies that have contributed to the understanding of BPD, including those using term newborn hyperoxia exposure models, premature hyperoxia models, and a term newborn hyperoxia model with recovery in moderate hyperoxia, all designed to emulate aspects of BPD in human infants. Some investigators perturbed these models to include exposure to neonatal infection/inflammation or postnatal malnutrition. The similarities to lung injury in human premature infants include an acute inflammatory response with the production of cytokines, chemokines, and growth factors that have been implicated in human disease, abnormal pulmonary function, disordered lung architecture, and alveolar simplification, development of fibrosis, and abnormal vascular growth factor expression. Neonatal rabbit models have the drawback of limited access to reagents as well as the lack of readily available transgenic models but, unlike smaller rodent models, are able to be manipulated easily and are significantly less expensive than larger animal models.
Value and probability coding in a feedback-based learning task utilizing food rewards
Authors: Tricomi Elizabeth , Lempert Karolina M.
Published: October 2014

For the consequences of our actions to guide behavior, the brain must represent different types of outcome-related information. For example, an outcome can be construed as negative because an expected reward was not delivered or because an outcome of low value was delivered. Thus behavioral consequences can differ in terms of the information they provide about outcome probability and value. We investigated the role of the striatum in processing probability-based and value-based negative feedback by training participants to associate cues with food rewards and then employing a selective satiety procedure to devalue one food outcome. Using functional magnetic resonance imaging, we examined brain activity related to receipt of expected rewards, receipt of devalued outcomes, omission of expected rewards, omission of devalued outcomes, and expected omissions of an outcome. Nucleus accumbens activation was greater for rewarding outcomes than devalued outcomes, but activity in this region did not correlate with the probability of reward receipt. Activation of the right caudate and putamen, however, was largest in response to rewarding outcomes relative to expected omissions of reward. The dorsal striatum (caudate and putamen) at the time of feedback also showed a parametric increase correlating with the trialwise probability of reward receipt. Our results suggest that the ventral striatum is sensitive to the motivational relevance, or subjective value, of the outcome, while the dorsal striatum codes for a more complex signal that incorporates reward probability. Value and probability information may be integrated in the dorsal striatum, to facilitate action planning and allocation of effort.
A Constrained Algorithm Based NMFαfor Image Representation
Authors: Yang Chenxue , Li Tao , Ye Mao , Liu Zijian , Bao Jiao
Published: October 2014

Nonnegative matrix factorization (NMF) is a useful tool in learning a basic representation of image data. However, its performance and applicability in real scenarios are limited because of the lack of image information. In this paper, we propose a constrained matrix decomposition algorithm for image representation which contains parameters associated with the characteristics of image data sets. Particularly, we impose label information as additional hard constraints to theα-divergence-NMF unsupervised learning algorithm. The resulted algorithm is derived by using Karush-Kuhn-Tucker (KKT) conditions as well as the projected gradient and its monotonic local convergence is proved by using auxiliary functions. In addition, we provide a method to select the parameters to our semisupervised matrix decomposition algorithm in the experiment. Compared with the state-of-the-art approaches, our method with the parameters has the best classification accuracy on three image data sets.
Non-albicans CandidaInfection: An Emerging Threat
Authors: Deorukhkar Sachin C. , Saini Santosh , Mathew Stephen
Published: October 2014

The very nature of infectious diseases has undergone profound changes in the past few decades. Fungi once considered as nonpathogenic or less virulent are now recognized as a primary cause of morbidity and mortality in immunocompromised and severely ill patients.Candidaspp. are among the most common fungal pathogens.Candida albicanswas the predominant cause of candidiasis. However, a shift toward non-albicans Candidaspecies has been recently observed. These non-albicans Candidaspecies demonstrate reduced susceptibility to commonly used antifungal drugs. In the present study, we investigated the prevalence of non-albicans Candidaspp. amongCandidaisolates from various clinical specimens and analysed their virulence factors and antifungal susceptibility profile. A total of 523Candidaspp. were isolated from various clinical specimens. Non-albicans Candidaspecies were the predominant pathogens isolated. Non-albicans Candidaspecies also demonstrated the production of virulence factors once attributed toCandida albicans. Non-albicans Candidademonstrated high resistance to azole group of antifungal agents. Therefore, it can be concluded that non-albicans Candidaspecies have emerged as an important cause of infections. Their isolation from clinical specimen can no longer be ignored as a nonpathogenic isolate nor can it be dismissed as a contaminant.
Lipid Peroxidation and Antioxidant Status in Nonobese Type 2 Diabetes Mellitus
Authors: Khemka Vineet Kumar , Choudhuri Subhadip , Ganguly Anirban , Ghosh Arindam , Bir Aritri , Banerjee Anindita
Published: October 2014

The aim of the study was to investigate the association between lipid peroxidation and antioxidant status in nonobese type 2 diabetes mellitus (T2DM) and further to correlate whether their significant association is putatively associated with the pathogenesis of T2DM. A number of 102 nonobese T2DM subjects and 95 nondiabetic subjects as healthy controls were enrolled in this cross-sectional study. Serum samples were collected in cryovials for malondialdehyde (MDA) and thiol assays. Total thiol or sulfhydryl (–SH) groups in peripheral blood mononuclear cells (PBMCs) and sera, as well as level of MDA, a marker for lipid peroxidation in serum, were measured spectrophotometrically. Serum MDA level was found significantly higher whereas serum and PBMC total thiol levels were diminished significantly among nonobese T2DM subjects compared to HC subjects. Moreover, serum MDA level is found to have a significant inverse correlation with serum total thiol and PBMC thiol levels among DM subjects, but no significant correlation was observed in HC individuals. A significant inverse correlation between serum MDA and serum total thiol levels among nonobese T2DM subjects suggests a close association of increased oxidative stress with decreased antioxidant status in nonobese T2DM.
Arthrodesis of the Trapeziometacarpal Joint Using a Chevron Osteotomy and Plate Fixation
Authors: Shyamalan G. , Jordan R. W. , Jarvis A.
Published: October 2014

Introduction. Trapeziometacarpal (TM) osteoarthritis is common. Despite the availability of numerous surgical options, none has been definitively proven to be superior. This study aims to determine the union rate and key strength following arthrodesis using a chevron osteotomy and plate fixation.Methods. 32 consecutive cases of TM joint arthrodesis performed between 2001 and 2006 were retrospectively identified. A chevron osteotomy was used to resect joint surfaces and fixation obtained using an AO mini T-plate. The patients were followed up for a mean of 65 months. Outcomes included visual analogue pain score, patient satisfaction, pinch strength, radiographic union, radiographic signs of scaphotrapezial arthritis, and complications.Results. The 32 cases included 16 females and 8 males with an average age of 56 years. Overall there was a 90% patient satisfaction rate. Average key pinch strength was 8.4 kg and pain score was 2.5. The union rate was 94%, and the two patients with nonunion underwent successful revision surgery. Only one case of radiographic progression of scaphotrapezoid arthritis was identified during followup.Conclusion. TM joint arthrodesis using a chevron osteotomy and plate fixation has high patient satisfaction and low nonunion rates. The authors endorse this technique in the management of TM joint osteoarthritis.
RAGE Expression in Tumor-Associated Macrophages Promotes Angiogenesis in Glioma
Authors: Chen Xuebo , Zhang Leying , Zhang Ian Y. , Liang Junling , Wang Huaqing , Ouyang Mao , Wu Shihua , da Fonseca Anna Carolina Carvalho , Weng Lihong , Yamamoto Yasuhiko , Yamamoto Hiroshi , Natarajan Rama , Badie Behnam
Published: October 2014

Interaction of RAGE (the receptor for advanced glycation endproducts) with its ligands can promote tumor progression, invasion, and angiogenesis. Although blocking RAGE signaling has been proposed as a potential anticancer strategy, functional contributions of RAGE expression in the tumor microenvironment (TME) have not been investigated in detail. Here, we evaluated the effect of genetic depletion of RAGE in TME on the growth of gliomas. In both invasive and noninvasive glioma models, animal survival was prolonged in RAGE knockout (Ager−/−) mice. However, the improvement in survival in Ager−/− mice was not due to changes in tumor growth rate but rather to a reduction in tumor-associated inflammation. Furthermore, RAGE ablation in the TME abrogated angiogenesis by downregulating the expression of proangiogenic factors, which prevented normal vessel formation, thereby generating a leaky vasculature. These alterations were most prominent in noninvasive gliomas, in which the expression of VEGF and proinflammatory cytokines were also lower in tumor-associated macrophages (TAM) in Ager−/− mice. Interestingly, reconstitution of Ager−/− TAM with wild-type microglia or macrophages normalized tumor vascularity. Our results establish that RAGE signaling in glioma-associated microglia and TAM drives angiogenesis, underscoring the complex role of RAGE and its ligands in gliomagenesis. Cancer Res; 74(24); 7285–97. ©2014 AACR.
Plasma Choline Metabolites and Colorectal Cancer Risk in the Women's Health Initiative Observational Study
Authors: Bae Sajin , Ulrich Cornelia M. , Neuhouser Marian L. , Malysheva Olga , Bailey Lynn B. , Xiao Liren , Brown Elissa C. , Cushing-Haugen Kara L. , Zheng Yingye , Cheng Ting-Yuan David , Miller Joshua W. , Green Ralph , Lane Dorothy S. , Beresford Shirley A.A. , Caudill Marie A.
Published: October 2014

Few studies have examined associations between plasma choline metabolites and risk of colorectal cancer. Therefore, we investigated associations between plasma biomarkers of choline metabolism [choline, betaine, dimethylglycine, and trimethylamine N-oxide (TMAO)] and colorectal cancer risk among postmenopausal women in a case–control study nested within the Women's Health Initiative Observational Study. We selected 835 matched case–control pairs, and cases were further stratified by tumor site (proximal, distal, or rectal) and stage (local/regional or metastatic). Colorectal cancer was assessed by self-report and confirmed by medical records over the mean of 5.2 years of follow-up. Baseline plasma choline metabolites were measured by LC/MS-MS. In multivariable-adjusted conditional logistic regression models, plasma choline tended to be positively associated with rectal cancer risk [OR (95% confidence interval, CI)highest vs. lowest quartile = 2.44 (0.93–6.40); P trend = 0.08], whereas plasma betaine was inversely associated with colorectal cancer overall [0.68 (0.47–0.99); P trend = 0.01] and with local/regional tumors [0.64 (0.42–0.99); P trend = 0.009]. Notably, the plasma betaine:choline ratio was inversely associated with colorectal cancer overall [0.56 (0.39–0.82); P trend = 0.004] as well as with proximal [0.66 (0.41–1.06); P trend = 0.049], rectal [0.27 (0.10–0.78); P trend = 0.02], and local/regional [0.50 (0.33–0.76); P trend = 0.001] tumors. Finally, plasma TMAO, an oxidative derivative of choline produced by intestinal bacteria, was positively associated with rectal cancer [3.38 (1.25–9.16); P trend = 0.02] and with overall colorectal cancer risk among women with lower (vs. higher) plasma vitamin B12 levels (P interaction = 0.003). Collectively, these data suggest that alterations in choline metabolism, which may arise early in disease development, may be associated with higher risk of colorectal cancer. The positive association between plasma TMAO and colorectal cancer risk is consistent with an involvement of the gut microbiome in colorectal cancer pathogenesis. Cancer Res; 74(24); 7442–52. ©2014 AACR.
Unique Molecular Landscapes in Cancer: Implications for Individualized, Curated Drug Combinations
Authors: Wheler Jennifer , Lee J. Jack , Kurzrock Razelle
Published: October 2014

With increasingly sophisticated technologies in molecular biology and “omic” platforms to analyze patients' tumors, more molecular diversity and complexity in cancer are being observed. Recently, we noted unique genomic profiles in a group of patients with metastatic breast cancer based on an analysis with next-generation sequencing. Among 57 consecutive patients, no two had the same molecular portfolio. Applied genomics therefore appears to represent a disruptive innovation in that it unveils a heterogeneity to metastatic cancer that may be ill-suited to canonical clinical trials and practice paradigms. Upon recognizing that patients have unique tumor landscapes, it is possible that there may be a “mismatch” between our traditional clinical trials system that selects patients based on common characteristics to evaluate a drug (drug-centric approach) and optimal treatment based on curated, individualized drug combinations for each patient (patient-centric approach). Cancer Res; 74(24); 7181–4. ©2014 AACR.
Extracellular Lumican Inhibits Pancreatic Cancer Cell Growth and Is Associated with Prolonged Survival after Surgery
Authors: Li Xinqun , Truty Mark A. , Kang Ya'an , Chopin-Laly Xavier , Zhang Ran , Roife David , Chatterjee Deyali , Lin E. , Thomas Ryan M. , Wang Huamin , Katz Matthew H. , Fleming Jason B.
Published: October 2014

Purpose: To evaluate the relevance between lumican expression patterns and the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC), and to investigate the role of lumican in PDAC progression.

Experimental Design: One hundred thirty-one patient tumors were chosen for tissue microarray staining, and Cox regression analysis was used to test the associations between lumican expression and clinical, pathologic, and oncologic outcomes in all patients. Primary PDAC cells and recombinant human lumican protein were used to establish a working model to mimic the in vivo interactions between stromal lumican and PDAC cells. Using this model, we tested the effects of lumican on EGFR signaling via Akt and hypoxia-inducible factor-1α (HIF1α) and its subsequent influence on glucose consumption, lactate production, intracellular ATP, and apoptotic cell death.

Results: Lumican was present in the stroma surrounding PDAC cells in roughly one-half of primary tumors and the direct xenografts. Patients with stromal lumican were associated with a profound reduction in metastatic recurrence after surgery and 3-fold longer survival than patients without stromal lumican. In PDAC cells, extracellular lumican reduced EGFR expression and phosphorylation through enhanced dimerization and internalization of EGFR and the resultant inhibition of Akt kinase activity. Lumican also reduced HIF1α expression and activity via Akt. PDAC cells with enhanced HIF1α activity were resistant to lumican-induced inhibition of glucose consumption, lactate production, intracellular ATP, and apoptosis.

Conclusions: There is a positive association between stromal lumican in primary PDAC tumors and prolonged survival after tumor resection. Lumican plays a restrictive role in EGFR-expressing pancreatic cancer progression. Clin Cancer Res; 20(24); 6529–40. ©2014 AACR.
Systemic Delivery of Microencapsulated 3-Bromopyruvate for the Therapy of Pancreatic Cancer
Authors: Chapiro Julius , Sur Surojit , Savic Lynn Jeanette , Ganapathy-Kanniappan Shanmugasundaram , Reyes Juvenal , Duran Rafael , Thiruganasambandam Sivarajan Chettiar , Moats Cassandra Rae , Lin MingDe , Luo Weibo , Tran Phuoc T. , Herman Joseph M. , Semenza Gregg L. , Ewald Andrew J. , Vogelstein Bert , Geschwind Jean-François
Published: October 2014

Purpose: This study characterized the therapeutic efficacy of a systemically administered formulation of 3-bromopyruvate (3-BrPA), microencapsulated in a complex with β-cyclodextrin (β-CD), using an orthotopic xenograft mouse model of pancreatic ductal adenocarcinoma (PDAC).

Experimental Design: The presence of the β-CD–3-BrPA complex was confirmed using nuclear magnetic resonance spectroscopy. Monolayer as well as three-dimensional organotypic cell culture was used to determine the half-maximal inhibitory concentrations (IC50) of β-CD–3-BrPA, free 3-BrPA, β-CD (control), and gemcitabine in MiaPaCa-2 and Suit-2 cell lines, both in normoxia and hypoxia. Phase-contrast microscopy, bioluminescence imaging (BLI), as well as zymography and Matrigel assays were used to characterize the effects of the drug in vitro. An orthotopic lucMiaPaCa-2 xenograft tumor model was used to investigate the in vivo efficacy.

Results: β-CD–3-BrPA and free 3-BrPA demonstrated an almost identical IC50 profile in both PDAC cell lines with higher sensitivity in hypoxia. Using the Matrigel invasion assay as well as zymography, 3-BrPA showed anti-invasive effects in sublethal drug concentrations. In vivo, animals treated with β-CD–3-BrPA demonstrated minimal or no tumor progression as evident by the BLI signal as opposed to animals treated with gemcitabine or the β-CD (60-fold and 140-fold signal increase, respectively). In contrast to animals treated with free 3-BrPA, no lethal toxicity was observed for β-CD–3-BrPA.

Conclusion: The microencapsulation of 3-BrPA represents a promising step towards achieving the goal of systemically deliverable antiglycolytic tumor therapy. The strong anticancer effects of β-CD–3-BrPA combined with its favorable toxicity profile suggest that clinical trials, particularly in patients with PDAC, should be considered. Clin Cancer Res; 20(24); 6406–17. ©2014 AACR.
Does Integrative Medicine Enhance Balance in Aging Adults? Proof of Concept for the Benefit of Electroacupuncture Therapy in Parkinson's Disease
Authors: Toosizadeh Nima , Lei Hong , Schwenk Michael , Sherman Scott J. , Sternberg Esther , Mohler Jane , Najafi Bijan
Published: October 2014

Background: Postural balance and potentially fall risk increases among older adults living with neurological diseases, especially Parkinson's disease (PD). Since conventional therapies such as levodopa or deep brain stimulation may fail to alleviate or may even worsen balance, interest is growing in evaluating alternative PD therapies. Objective: The purpose of the current study was to assess improvement in postural balance in PD patients following electroacupuncture (EA) as an alternative therapy. Methods: 15 aging adults (71.2 ± 6.3 years) with idiopathic PD and 44 healthy age-matched participants (74.6 ± 6.5 years) were recruited. The PD participants were randomly assigned (at a ratio of 2:1) to an intervention (n = 10) or to a control group (n = 5). The intervention group received a 30-min EA treatment on a weekly basis for 3 weeks, while the control group received a sham treatment. Outcomes were assessed at baseline and after the final therapy. Measurements included balance assessment, specifically the ratio of medial-lateral (ML) center-of-gravity (COG) sway to anterior-posterior (AP) sway (COGML/AP) and ankle/hip sway during eyes-open, eyes-closed, and eyes-open dual-task trials, the Unified Parkinson's Disease Rating Scale (UPDRS), as well as quality of life, concerns for fall, and pain questionnaires. Results: No difference was observed for the assessed parameters between the intervention and the control group at baseline. After treatment, an improvement in balance performance was observed in the intervention group. Compared with the healthy population, PD patients prior to treatment had larger COGML/AP sway with more dependency on upper-body movements for maintaining balance. Following EA therapy, COGML/AP sway was reduced by 31% and ankle/hip sway increased by 46% in the different conditions (p = 0.02 for the dual-task condition). The clinical rating revealed an overall improvement (p < 0.01) in mentation, behavior, and mood (UPDRS part I, 49%), activities of daily living (UPDRS part II, 46%), and motor examination (UPDRS part III, 40%). There was a significant reduction (p < 0.02) in the specific items regarding UPDRS fall status (67%) and rigidity (48%). Changes were small and nonsignificant in the controls (p > 0.29). Conclusions: This pilot study demonstrates improvement in rigidity and balance following EA. These preliminary results suggest EA could be a promising alternative treatment for balance disturbance in PD.
Influence of Hospitalization for Cardiovascular Versus Noncardiovascular Reasons on Subsequent Mortality in Patients With Chronic Heart Failure Across the Spectrum of Ejection Fraction
Authors: Desai Akshay S. , Claggett Brian , Pfeffer Marc A. , Bello Natalie , Finn Peter V. , Granger Christopher B. , McMurray John J.V. , Pocock Stuart , Swedberg Karl , Yusuf Salim , Solomon Scott D.
Published: October 2014

Background—

Noncardiovascular (non-CV) comorbidities may contribute to hospitalizations in patients with heart failure (HF). We examined the incidence of mortality following hospitalization for cardiovascular (CV) versus non-CV reasons in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program.

Methods and Results—

First hospitalizations for CV or non-CV reasons during the CHARM trial (N=7599) were related to subsequent risk of all-cause death using time-updated proportional hazards models. Over median 37.7 month follow-up, 2816 subjects (37.1%) were not hospitalized, 2893 (38.1%) were first hospitalized for CV reasons, and 1890 (24.9%) for non-CV reasons. The death rate (per 100 patient-years) among those not hospitalized was 2.8 compared with 17.8 after CV and 16.5 after non-CV hospitalization (both
P
<0.001 versus not hospitalized). Mortality at 30 days was higher after CV than non-CV hospitalization; however, among 30-day survivors of CV and non-CV hospitalization, rates of subsequent mortality were similar (14.5 versus 14.6 per 100 patient-years;
P
=0.62). Rates of CV hospitalization were higher for those with ejection fraction (EF) ≤40% than those with EF >40% (
P
<0.001), but rates of non-CV hospitalization did not vary by EF. Low EF patients had higher risk for mortality than preserved EF patients after any hospitalization, but within each EF subgroup, mortality in 30-day survivors of CV versus non-CV hospitalization was similar.

Conclusions—

Non-CV hospitalization is frequent in patients with symptomatic heart failure and associated with risk of subsequent mortality similar to CV hospitalization across the spectrum of EF. These findings may have implications for developing strategies to prevent readmissions.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00634309 (CHARM-Added), NCT00634712 (CHARM-Preserved), NCT00634400 (CHARM-Alternative).