bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PL04-02: Synthetic lethality: Targeting DNA repair mechanisms in clinical trials
Authors: Tutt Andrew
Published: July 2012

Epithelial carcinomas are in general diseases occurring as a result of the acquisition of and selection for multiple mutations in a parental somatic cell clone in the tissues of the primary site. In the last two decades the role of genome caretakers, which function in key areas of the DNA damage response, have been recognized as important tumor suppressor genes. Inactivating mutations in these genes occur as germline and /or as somatic mutations. In either event, loss of function in a tumor cell precursor clone leads to accelerated mutation acquisition and underpins the etiology of the tumor. As an understanding of the complex network that is the DNA damage response matures additional roles for signaling pathways, already recognized to be central to the establishment of the cancer phenotype, as controllers of DNA repair are being discovered. This has relevance to identification of wider populations of patients with tumors susceptible to approaches that target DNA repair deficiency. These have claissically been with DNA damaging chemotherapy but recently the development of small molecule inhibitors of DNA repair enzymes such as Poly-ADP polymerases PARP-1 and PARP-2 have been shown to target deficiencies in DNA repair as well as sensitize to DNA damaging therapeutics such as radiation and chemotherapy. Early-phase trials with efficacy endpoints have been presented for the PARP inhibitors AG014699, Olaparib, Veliparib, Iniparib and MK4827 have all been presented. The results of the first phase II trials that explore monotherapy PARP inhibitor strategies, based on revisiting the concept of synthetic lethality, have emerged and will be reviewed. PARP inhibitors are also being explored as sensitizers to DNA damaging therapies. The phase II and III trials that have or are exploring combinations with DNA damaging therapy in these contexts will be discussed. I will then discuss biomarkers that have been proposed and are being investigated to develop optimum drug schedule and optimize patient selection for PARP inhibitor therapy approaches.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr PL04-02. doi:10.1158/1538-7445.AM2011-PL04-02
Abstract SY01-02: Mapping the landscape of conditional vulnerabilities in non-small cell lung cancer
Authors: Kim Hyunseok , Gao Hua , Minna John , Posner Bruce , White Michael A.
Published: July 2012

Recognition that cancer is a diverse disease, driven by discordant patient-specific aberrations of cell function, has launched intense efforts to identify drugs matched to the needs of individual patients. However, selection of appropriate treatment is dramatically limited by the paucity of available drugs and by the difficulty of linking treatment options to the appropriate patients. We are employing an extensive panel of non-small cell lung cancer-derived cell lines and clinically pathologically annotated tumor samples to model the diversity of molecular etiologies driving lung cancer initiation and progression. By using quantitative measures of molecular correlates together with concordant responses to whole-genome genetic perturbations and 200,000 small molecule perturbations, we have parsed this heterogeneous panel into a limited number of clades defined by shared liabilities coupled to robust molecular biomarkers. Many of these liabilities represent new intervention targets together with chemical matter that intersects those targets.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY01-02. doi:10.1158/1538-7445.AM2011-SY01-02
Abstract SY13-01: Noncoding RNAs: From bench to bedside
Authors: Calin George A.
Published: July 2012

The newly discovered differential expression in numerous tissues, key cellular processes and multiple diseases for several families of long and short noncoding RNAs (ncRNAs, genes that do not codify for proteins but for RNAs with regulatory functions), including the already famous class of microRNAs (miRNAs) strongly suggest that the scientific and medical communities have significantly underestimated the spectrum of ncRNAs whose altered expression has significant consequences in diseases. MicroRNA and other short or long noncoding RNAs alterations are involved in the initiation, progression and metastases of human cancer. The main molecular alterations are represented by variations in gene expression, usually mild and with consequences for a vast number of target protein coding genes. The causes of the widespread differential expression of noncoding RNAs in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the processing machinery. MicroRNA and other short or long noncoding RNAs expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify noncoding RNAs that may represent downstream targets of activated oncogenic pathways or that are targeting protein coding genes involved in cancer. Recent studies proved that miRNAs and non-coding ultraconserved genes are main candidates for the elusive class of cancer predisposing genes and that other types of noncoding RNAs participate in the genetic puzzle giving rise to the malignant phenotype. Last, but not least, the shown expression correlations of these new ncRNAs with cancer metastatic potential and overall survival rates suggest that at least some member of these novel classes of molecules could potentially find use as biomarkers or novel therapeutics in cancers and other diseases.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY13-01. doi:10.1158/1538-7445.AM2011-SY13-01
Mindfulness-Based Cognitive Therapy Improves Polysomnographic and Subjective Sleep Profiles in Antidepressant Users with Sleep Complaints
Authors: Britton Willoughby B. , Haynes Patricia L. , Fridel Keith W. , Bootzin Richard R.
Published: July 2012

Background: Many antidepressant medications (ADM) are associated with disruptions in sleep continuity that can compromise medication adherence and impede successful treatment. The present study investigated whether mindfulness meditation (MM) training could improve self-reported and objectively measured polysomnographic (PSG) sleep profiles in depressed individuals who had achieved at least partial remission with ADM, but still had residual sleep complaints. Methods: Twenty-three ADM users with sleep complaints were randomized into an 8-week Mindfulness-Based Cognitive Therapy (MBCT) course or a waitlist control condition. Pre-post measurements included PSG sleep studies and subjectively reported sleep, residual depression symptoms. Results: Compared to controls, the MBCT participants improved on both PSG and subjective measures of sleep. They showed a pattern of decreased wake time and increased sleep efficiency. Sleep depth, as measured by stage 1 and slow-wave sleep, did not change as a result of mindfulness training. Conclusions: MM is associated with increases in both objectively and subjectively measured sleep continuity in ADM users. MM training may serve as more desirable and cost-effective alternative to discontinuation or supplementation with hypnotics, and may contribute to a more sustainable recovery from depression.
Cognitive Impairment in Systemic Lupus Erythematosus Women with Elevated Autoantibodies and Normal Single Photon Emission Computerized Tomography
Authors: Peretti Charles-Siegfried , Peretti Charles Roger , Kozora Elizabeth , Papathanassiou Dimitri , Chouinard Virginie-Anne , Chouinard Guy
Published: July 2012

Background: Systemic lupus erythematosus (SLE) is known to induce psychiatric disorders, from psychoses to maladaptive coping. Brain autoantibodies were proposed to explain SLE neuropsychiatric disorders and found to be elevated before the onset of clinical symptoms. We assessed cognition in Caucasian SLE women with elevated autoantibodies without overt neuropsychiatric syndromes, in conjunction with single photon emission computerized tomography (SPECT). Methods: 31 women meeting SLE criteria of the American College of Rheumatology (ACR) were included. Patients who met the ACR neuropsychiatric definition were excluded. Matched controls were 23 healthy women from the Champagne-Ardenne region, France. Participants completed neuropsychological and autoantibodies measurements, and 19 completed SPECT. Results: 61% (19/31) of women with SLE and 53% (9/17) of those with normal SPECT had significant global cognitive impairment defined as 4 T-scores <40 in cognitive tests, compared to 0% (0/23) of controls. SLE women also had significantly greater cognitive dysfunction (mean T-score) on the Wechsler Adult Intelligence Scale (WAIS) visual backspan, Trail Making Test A and B, WAIS Digit Symbol Substitution Test and Stroop Interference, compared to controls. Elevated antinuclear antibody correlated with impairment in the WAIS visual span, WAIS visual backspan, and cancellation task; elevated anti-double-stranded DNA antibody and anticardiolipin correlated respectively with impairment in the Trail Making Test A and WAIS auditive backspan. Two SLE women had abnormal SPECT. Conclusions: A high prevalence of cognitive deficits was found in Caucasian SLE women compared to normal women, which included impairment in cognitive domains important for daily activities. Elevated autoantibodies tended to correlate with cognitive dysfunction.
Economics of Medically Unexplained Symptoms: A Systematic Review of the Literature
Authors: Konnopka Alexander , Schaefert Rainer , Heinrich Sven , Kaufmann Claudia , Luppa Melanie , Herzog Wolfgang , König Hans-Helmut
Published: July 2012

Objective: To review cost-of-illness studies (COI) and economic evaluations (EE) conducted for medically unexplained symptoms and to analyze their methods and results. Methods: We searched the databases PubMed, PsycINFO and National Health Service Economic Evaluations Database of the University of York. Cost data were inflated to 2006 using country-specific gross domestic product inflators and converted to 2006 USD purchasing power parities. Results: We identified 5 COI and 8 EE, of which 6 were cost-minimization analyses and 2 were cost-effectiveness analyses. All studies used patient level data collected between 1980 and 2004 and were predominantly conducted in the USA (n = 10). COI found annual excess health care costs of somatizing patients between 432 and 5,353 USD in 2006 values. Indirect costs were estimated by only one EE and added up to about 18,000 USD per year. In EE, educational interventions for physicians as well as cognitive-behavioral therapy approaches for patients were evaluated. For both types of interventions, effectiveness was either shown within EE or by previous studies. Most EE found (often insignificant) cost reductions resulting from the interventions, but only two studies explicitly combined changes in costs with data on effectiveness to cost-effectiveness ratios (ratio of additional costs to additional effects). Conclusions: Medically unexplained symptoms cause relevant annual excess costs in health care that are comparable to mental health problems like depression or anxiety disorders and which may be reduced by interventions targeting physicians as well as patients. More extensive research on indirect costs and cost-effectiveness is needed.
Effects of Medical Nutrition Therapy on Body Fat and Metabolic Syndrome Components in Premenopausal Overweight Women
Authors: Lim Hyunjung , Son Ji-Young , Choue Ryowon
Published: July 2012

Background/Aims: To evaluate the effects of medical nutrition therapy (MNT) on body composition and metabolic syndrome (MetS) components in premenopausal Korean women with a body mass index ≥23. Methods: Participants (n = 160) were classified into MetS (n = 44) or non-MetS (n = 116) groups based on the criteria proposed by the revised National Cholesterol Education Program-Adult Treatment Panel III and the International Diabetes Federation classification. Anthropometric and dietary assessments and blood analyses were performed for all participants prior to and following 12 weeks of MNT. Results: Following MNT, body fat decreased in both groups by roughly 11% (p < 0.001), and the number of participants meeting the criteria for MetS thus decreased from 44 to 19 (56.8%). Mean waist circumference (WC), blood pressure (BP), plasma triglyceride (TG) and blood glucose levels decreased in the MetS group (p < 0.001). Body fat reduction in the MetS group was correlated with changes in WC (r = 0.584), systolic BP (r = 0.451), diastolic BP (r = 0.429) and plasma TG (r = 0.488) levels after adjusting for covariates (p < 0.05). Conclusions: Body fat reduction and MetS component improvement was achieved by MNT in overweight women. Changes in MetS components appear to be related to body fat reduction. MNT should focus on body fat reduction when used as a primary prevention for MetS.
Diagnosis and Treatment of Bladder Endometriosis: State of the Art
Authors: Maccagnano Carmen , Pellucchi Federico , Rocchini Lorenzo , Ghezzi Massimo , Scattoni Vincenzo , Montorsi Francesco , Rigatti Patrizio , Colombo Renzo
Published: July 2012

Background: The bladder is the most common affected site in urinary tract endometriosis, being diagnosed during gynecologic follow-up. The surgical urological treatment might lead to good results. Study Objective: To define the state of the art in the diagnosis and treatment of bladder endometriosis. Methods: We performed a literature review by searching the MEDLINE database for articles published between 1996 and 2011, limiting the searches to the words: urinary tract endometriosis, bladderendometriosis, symptoms, diagnosis and treatment.Results: Deep pelvic endometriosis usually involves the urinary system, with the bladder being affected in 85% of cases. The diagnosis has to be considered as a step-by-step procedure. Currently, the treatment is usually surgical, consisting of either transurethral resection or partial cystectomy, and eventually associated with hormonal therapy. The hormonal therapy alone counteracts only the stimulus of endometriotic tissue proliferation, with no effects on the scarring caused by this tissue. The overall recurrence rate is about 30% for combined therapies and about 35% for the hormonal treatment alone. Conclusions: The bladder is the most common affected site in urinary tract endometriosis. Most of the time, this condition is diagnosed because of the complaint of urinary symptoms during gynecologic follow-up procedures for a deep pelvic endometriosis: a close collaboration between the gynecologist and the urologist is advisable, especially in highly specialized centers. The surgical urological treatment might lead to good results in terms of patients’ compliance and prognosis.
Omega-3 Fatty Acids Ameliorate Atherosclerosis by Favorably Altering Monocyte Subsets and Limiting Monocyte Recruitment to Aortic Lesions
Authors: Brown Amanda L. , Zhu Xuewei , Rong Shunxing , Shewale Swapnil , Seo Jeongmin , Boudyguina Elena , Gebre Abraham K. , Alexander-Miller Martha A. , Parks John S.
Published: July 2012

Objective—

Fish oil, containing omega-3 fatty acids, attenuates atherosclerosis. We hypothesized that omega-3 fatty acid–enriched oils are atheroprotective through alteration of monocyte subsets and their trafficking into atherosclerotic lesions.

Methods and Results—

Low–density lipoprotein receptor knockout and apolipoprotein E
−/−
mice were fed diets containing 10% (calories) palm oil and 0.2% cholesterol, supplemented with an additional 10% palm oil, echium oil (containing 18:4 n-3), or fish oil. Compared with palm oil–fed low–density lipoprotein receptor knockout mice, echium oil and fish oil significantly reduced plasma cholesterol, splenic Ly6C
hi
monocytosis by ≈50%, atherosclerosis by 40% to 70%, monocyte trafficking into the aortic root by ≈50%, and atherosclerotic lesion macrophage content by 30% to 44%. In contrast, atherosclerosis and monocyte trafficking into the artery wall was not altered by omega-3 fatty acids in apolipoprotein E
−/−
mice; however, Ly6C
hi
splenic monocytes positively correlated with aortic root intimal area across all diet groups. In apolipoprotein E
−/−
mice, fish oil reduced the percentage of blood Ly6C
hi
monocytes, despite an average 2-fold higher plasma cholesterol relative to palm oil.

Conclusion—

The presence of splenic Ly6C
hi
monocytes parallels the appearance of atherosclerotic disease in both low–density lipoprotein receptor knockout and apolipoprotein E
−/−
mice. Furthermore, omega-3 fatty acids favorably alter monocyte subsets independently from effects on plasma cholesterol and reduce monocyte recruitment into atherosclerotic lesions.
Cholesterol-Induced Membrane Microvesicles As Novel Carriers of Damage–Associated Molecular Patterns
Authors: Liu Ming-Lin , Scalia Rosario , Mehta Jawahar L. , Williams Kevin Jon
Published: July 2012

Objective—

Cholesterol enrichment occurs in vivo when phagocytes ingest retained and aggregated lipoproteins, damaged or senescent cells, and related debris. We previously reported that enrichment of human monocyte/macrophages with unesterified cholesterol (UC) triggers the release of highly procoagulant microvesicles ([MVs], also called microparticles) through induction of apoptosis. We determined whether UC-induced MVs (UCMVs) might transmit endogenous danger signals and, if so, what molecular processes might be responsible for their production, recognition, and detoxification.

Methods and Results—

Injection of UCMVs into rats provoked extensive leukocyte rolling and adherence to postcapillary venules in vivo. Likewise, exposure of mouse aortic explants or cultured human endothelial cells to UCMVs augmented the adhesion of human monocytes by several fold and increased endothelial cell intercellular adhesion molecule-1 via nuclear factor-κB activation. To explore molecular mechanisms, we found that UC enrichment of human monocytes, in the absence of other stimuli, induced mitochondrial complex II–dependent accumulation of superoxide and peroxides. A subset of these moieties was exported on UCMVs and mediated endothelial activation. Strikingly, aortic explants from mice lacking lectin–like oxidized low–density lipoprotein receptor-1, a pattern-recognition receptor, were essentially unable to respond to UCMVs, whereas simultaneously treated explants from wild-type mice responded robustly by increasing monocyte recruitment.
Moreover, high-density lipoprotein
and its associated enzyme paraoxonase-1 exerted unexpected roles in the
detoxification of UCMVs.

Conclusion—

Overall, our study implicates MVs from cholesterol–loaded human cells as novel carriers of danger signals. By promoting maladaptive immunologic and thrombotic responses, these particles may contribute to atherothrombosis and other conditions in vivo.
Understanding Cardiomyopathy Phenotypes Based on the Functional Impact of Mutations in the Myosin Motor
Authors: Moore Jeffrey R. , Leinwand Leslie , Warshaw David M.
Published: July 2012

Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are inherited diseases with a high incidence of death due to electric abnormalities or outflow tract obstruction. In many of the families afflicted with either disease, causative mutations have been identified in various sarcomeric proteins. In this review, we focus on mutations in the cardiac muscle molecular motor, myosin, and its associated light chains. Despite the >300 identified mutations, there is still no clear understanding of how these mutations within the same myosin molecule can lead to the dramatically different clinical phenotypes associated with HCM and DCM. Localizing mutations within myosin's molecular structure provides insight into the potential consequence of these perturbations to key functional domains of the motor. Review of biochemical and biophysical data that characterize the functional capacities of these mutant myosins suggests that mutant myosins with enhanced contractility lead to HCM, whereas those displaying reduced contractility lead to DCM. With gain and loss of function potentially being the primary consequence of a specific mutation, how these functional changes trigger the hypertrophic response and lead to the distinct HCM and DCM phenotypes will be the future investigative challenge.
Cooperative Binding of KLF4, pELK-1, and HDAC2 to a G/C Repressor Element in the SM22α Promoter Mediates Transcriptional Silencing During SMC Phenotypic Switching In Vivo
Authors: Salmon Morgan , Gomez Delphine , Greene Elizabeth , Shankman Laura , Owens Gary K.
Published: July 2012

Rationale:

We previously identified conserved G/C Repressor elements in the promoters of most smooth muscle cell (SMC) marker genes and demonstrated that mutation of this element within the SM22α promoter nearly abrogated repression of this transgene after vascular wire injury or within lesions of ApoE−/− mice. However, the mechanisms regulating the activity of the G/C Repressor are unknown, although we have previously shown that phenotypic switching of cultured SMC is dependent on Krupple-like factor (KLF)4.

Objective:

The goals of the present studies were to ascertain if (1) injury-induced repression of SM22α gene after vascular injury is mediated through KLF4 binding to the G/C Repressor element and (2) the transcriptional repressor activity of KLF4 on SMC marker genes is dependent on cooperative binding with pELK-1 (downstream activator of the mitogen-activated protein kinase pathway) and subsequent recruitment of histone de-acetylase 2 (HDAC2), which mediates epigenetic gene silencing.

Methods and Results:

Chromatin immunoprecipitation (ChIP) assays were performed on chromatin derived from carotid arteries of mice having either a wild-type or G/C Repressor mutant SM22α promoter-LacZ transgene. KLF4 and pELK-1 binding to the SM22α promoter was markedly increased after vascular injury and was G/C Repressor dependent. Sequential ChIP assays and proximity ligation analyses in cultured SMC treated with platelet-derived growth factor BB or oxidized phospholipids showed formation of a KLF4, pELK-1, and HDAC2 multiprotein complex dependent on the SM22α G/C Repressor element.

Conclusions:

Silencing of SMC marker genes during phenotypic switching is partially mediated by sequential binding of pELK-1 and KLF4 to G/C Repressor elements. The pELK-1-KLF4 complex in turn recruits HDAC2, leading to reduced histone acetylation and epigenetic silencing.
Development and Validation of New Anxiety and Bipolar Symptom Scales for an Expanded Version of the IDAS (the IDAS-II)
Authors: Watson David , O’Hara Michael W. , Naragon-Gainey Kristin , Koffel Erin , Chmielewski Michael , Kotov Roman , Stasik Sara M. , Ruggero Camilo J.
Published: July 2012

The original Inventory of Depression and Anxiety Symptoms (IDAS) contains 11 nonoverlapping scales assessing specific depression and anxiety symptoms. In creating the expanded version of the IDAS (the IDAS-II), our goal was to create new scales assessing other important aspects of the anxiety disorders as well as key symptoms of bipolar disorder. Factor analyses of the IDAS-II item pool led to the creation of seven new scales (Traumatic Avoidance, Checking, Ordering, Cleaning, Claustrophobia, Mania, Euphoria) plus an expanded version of Social Anxiety. These scales are internally consistent and show strong convergent and significant discriminant validity in relation to other self-report and interview-based measures of anxiety, depression, and mania. Furthermore, the scales demonstrate substantial criterion and incremental validity in relation to interview-based measures of DSM-IV ( Diagnostic and Statistical Manual of Mental Disorders, fourth edition) symptoms and disorders. Thus, the expanded IDAS-II now assesses a broad range of depression, anxiety, and bipolar symptoms.
A retrospective analysis of the effects of meloxicam on the longevity of aged cats with and without overt chronic kidney disease
Authors: Gowan Richard A , Baral Randolph M , Lingard Amy E , Catt Melissa J , Stansen Wibke , Johnston Laura , Malik Richard
Published: July 2012

The study sought to examine the effect of long-term meloxicam treatment on the survival of cats with and without naturally-occurring chronic kidney disease at the initiation of therapy. The databases of two feline-only clinics were searched for cats older than 7 years that had been treated continuously with meloxicam for a period of longer than 6 months. Only cats with complete medical records available for review were recruited into the study.The median longevity in the renal group was 18.6 years [95% confidence interval (CI) 17.5–19.2] and the non-renal group was 22 years [95% CI 18.5–23.8]. The median longevity after diagnosis of CKD was 1608 days [95% confidence interval 1344–1919] which compares favourably to previously published survival times of cats with CKD. In both groups the most common cause of death was neoplasia. Long-term treatment with oral meloxicam did not appear to reduce the lifespan of cats with pre-existent stable CKD, even for cats in IRIS stages II and III. Therefore, to address the need for both quality of life and longevity in cats with chronic painful conditions, meloxicam should be considered as a part of the therapeutic regimen.
Brain transcriptome variation among behaviorally distinct strains of zebrafish (Danio rerio)
Authors: Drew Robert E , Settles Matthew L , Churchill Erin J , Williams Shayna M , Balli Soniya , Robison Barrie D
Published: July 2012

Background

Domesticated animal populations often show profound reductions in predator avoidance and fear-related behavior compared to wild populations. These reductions are remarkably consistent and have been observed in a diverse array of taxa including fish, birds, and mammals. Experiments conducted in common environments indicate that these behavioral differences have a genetic basis. In this study, we quantified differences in fear-related behavior between wild and domesticated zebrafish strains and used microarray analysis to identify genes that may be associated with this variation.

Results

Compared to wild zebrafish, domesticated zebrafish spent more time near the water surface and were more likely to occupy the front of the aquarium nearest a human observer. Microarray analysis of the brain transcriptome identified high levels of population variation in gene expression, with 1,749 genes significantly differentially expressed among populations. Genes that varied among populations belonged to functional categories that included DNA repair, DNA photolyase activity, response to light stimulus, neuron development and axon guidance, cell death, iron-binding, chromatin reorganization, and homeobox genes. Comparatively fewer genes (112) differed between domesticated and wild strains with notable genes includinggpr177(wntless), selenoprotein P1a, synaptophysin and synaptoporin, and acyl-CoA binding domain containing proteins (acbd3andacbd4).

Conclusions

Microarray analysis identified a large number of genes that differed among zebrafish populations and may underlie behavioral domestication. Comparisons with similar microarray studies of domestication in rainbow trout and canids identified sixteen evolutionarily or functionally related genes that may represent components of shared molecular mechanisms underlying convergent behavioral evolution during vertebrate domestication. However, this conclusion must be tempered by limitations associated with comparisons among microarray studies and the low level of population-level replication inherent to these studies.
Genetic polymorphisms located in genes related to immune and inflammatory processes are associated with end-stage renal disease: a preliminary study
Authors: Jimenez-Sousa Ma Angeles , López Elisabeth , Fernandez-Rodríguez Amanda , Tamayo Eduardo , Fernández-Navarro Pablo , Segura-Roda Laura , Heredia María , Gómez-Herreras José I , Bustamante Jesús , García-Gómez Juan Miguel , Bermejo-Martin Jesús F , Resino Salvador
Published: July 2012

Background

Chronic kidney disease progression has been linked to pro-inflammatory cytokines and markers of inflammation. These markers are also elevated in end-stage renal disease (ESRD), which constitutes a serious public health problem.

Objective

To investigate whether single nucleotide polymorphisms (SNPs) located in genes related to immune and inflammatory processes, could be associated with ESRD development.

Design and methods

A retrospective case-control study was carried out on 276 patients with ESRD and 288 control subjects. Forty-eight SNPs were genotyped via SNPlex platform. Logistic regression was used to assess the relationship between each sigle polymorphism and the development of ESRD.

Results

Four polymorphisms showed association with ESRD: rs1801275 in the interleukin 4 receptor (IL4R) gene (OR: 0.66 (95%CI = 0.46-0.95); p = 0.025; overdominant model), rs4586 in chemokine (C-C motif) ligand 2 (CCL2) gene (OR: 0.70 (95%CI = 0.54-0.90); p = 0.005; additive model), rs301640 located in an intergenic binding site for signal transducer and activator of transcription 4 (STAT4) (OR: 1.82 (95%CI = 1.17-2.83); p = 0.006; additive model) and rs7830 in the nitric oxide synthase 3 (NOS3) gene (OR: 1.31 (95%CI = 1.01-1.71); p = 0.043; additive model). After adjusting for multiple testing, results lost significance.

Conclusion

Our preliminary data suggest that four genetic polymorphisms located in genes related to inflammation and immune processes could help to predict the risk of developing ESRD.
Incidence and risk factors for infection in oral cancer patients undergoing different treatments protocols
Authors: Panghal Manju , Kaushal Vivek , Kadayan Sangeeta , Yadav Jaya Parkash
Published: July 2012

Background

Over the past decade, advances in cancer treatments have been counterbalanced by a rising number of immunosuppressed patients with a multitude of new risk factors for infection. Hence, the aim of this study was to determine risk factors, infectious pathogens in blood and oral cavity of oral cancer patients undergoing different treatment procedures.

Methods

The present prospective cohort analysis was conducted on the patients undergoing treatment in the radiotherapy unit of Regional Cancer Institute, Pt. B.D. Sharma University of Health Sciences, Rohtak, Haryana, during the period of January 2007 to October 2009. Total 186 patients with squamous cell carcinoma of oral cavity were analyzed in the study. Based on treatment procedures patients were divided into three groups, group I were under radiotherapy, group II under chemotherapy and group III were of radio chemotherapy together. Clinical isolates from blood and oral cavity were identified by following general microbiological, staining and biochemical methods. The absolute neutrophile counts were done by following the standard methods.

Results

Prevalent bacterial pathogens isolated wereStaphylococcus aureus,Escherichia coli,Staphylococcus epidermidis,Pseudomonas aeruginosa,Klebsiella pneumonia,Proteus mirabilis,Proteus vulgarisand the fungal pathogens wereCandida albicans,Aspergillus fumigatus. The predominant gram negative bacteria,Pseudomonas aeruginosaandKlebsiella pneumoniawere isolated from blood of radiotherapy and oral cavity of chemotherapy treated cases respectively. The predominance of gram positive bacteria (Staphylococcus aureusandStaphylococcus epidermidis) were observed in blood of chemotherapy, radio chemotherapy cases and oral cavity of radiotherapy, radio chemotherapy treated cases. Our study also revealed the presence ofC. albicansfungi as most significant oral cavity pathogens in radiotherapy and radio chemotherapy cases.

Conclusion

Gram positive bacteria and Gram negative were reported from the blood of all the three groups of patients. Oral mucositis played a significant role in oral cavity infection and make patients more prone toC. albicansinfection.
Novel HER2 Aptamer Selectively Delivers Cytotoxic Drug to HER2-positive Breast Cancer Cells in Vitro
Authors: Liu Zhe , Duan Jin-Hong , Song Yong-Mei , Ma Jie , Wang Feng-Dan , Lu Xin , Yang Xian-Da
Published: July 2012

Background

Aptamer-based tumor targeted drug delivery system is a promising approach that may increase the efficacy of chemotherapy and reduce the related toxicity. HER2 protein is an attractive target for tumor-specific drug delivery because of its overexpression in multiple malignancies, including breast, gastric, ovarian, and lung cancers.

Methods

In this paper, we developed a new HER2 aptamer (HB5) by using systematic evolution of ligands by exponential enrichment technology (SELEX) and exploited its role as a targeting ligand for delivering doxorubicin (Dox) to breast cancer cells in vitro.

Results

The selected
aptamer
was an 86-nucleotide DNA molecule that bound to an epitope peptide of HER2 with a K
d of 18.9 nM. The aptamer also bound to the extracellular domain (ECD) of HER2 protein
with a K

d

of 316 nM
, and had minimal cross reactivity to albumin or trypsin. In addition, the aptamer was found to preferentially bind to HER2-positive but not HER2-negative breast cancer cells. An aptamer-doxorubicin complex (Apt-Dox) was formulated by intercalating Dox into the DNA structure of HB5. The Apt-Dox complex could selectively deliver Dox to HER2-positive breast cancer cells while reducing the drug intake by HER2-negative cells in vitro. Moreover, Apt-Dox retained the cytotoxicity of Dox against HER2-positive
breast cancer
cells, but reduced the cytotoxicity to HER2-negative cells.

Conclusions

The results suggest that the selected HER2 aptamer may have application potentials in targeted therapy against HER2-positive
breast cancer cells
.
Acute injury in the peripheral nervous system triggers an alternative macrophage response
Authors: Ydens Elke , Cauwels Anje , Asselbergh Bob , Goethals Sofie , Peeraer Lieve , Lornet Guillaume , Almeida-Souza Leonardo , Van Ginderachter Jo A , Timmerman Vincent , Janssens Sophie
Published: July 2012

Background

The activation of the immune system in neurodegeneration has detrimental as well as beneficial effects. Which aspects of this immune response aggravate the neurodegenerative breakdown and which stimulate regeneration remains an open question. To unravel the neuroprotective aspects of the immune system we focused on a model of acute peripheral nerve injury, in which the immune system was shown to be protective.

Methods

To determine the type of immune response triggered after axotomy of the sciatic nerve, a model for Wallerian degeneration in the peripheral nervous system, we evaluated markers representing the two extremes of a type I and type II immune response (classicalvs.alternative) using real-time quantitative polymerase chain reaction (RT-qPCR), western blot, and immunohistochemistry.

Results

Our results showed that acute peripheral nerve injury triggers an anti-inflammatory and immunosuppressive response, rather than a pro-inflammatory response. This was reflected by the complete absence of classical macrophage markers (iNOS, IFNγ, and IL12p40), and the strong up-regulation of tissue repair markers (arginase-1, Ym1, and Trem2). The signal favoring the alternative macrophage environment was induced immediately after nerve damage and appeared to be established within the nerve, well before the infiltration of macrophages. In addition, negative regulators of the innate immune response, as well as the anti-inflammatory cytokine IL-10 were induced. The strict regulation of the immune system dampens the potential tissue damaging effects of an over-activated response.

Conclusions

We here demonstrate that acute peripheral nerve injury triggers an inherent protective environment by inducing the M2 phenotype of macrophages and the expression of arginase-1. We believe that the M2 phenotype, associated with a sterile inflammatory response and tissue repair, might explain their neuroprotective capacity. As such, shifting the neurodegeneration-induced immune responses towards an M2/Th2 response could be an important therapeutic strategy.
Glossopharyngeal neuralgia secondary to vascular compression in a patient with multiple sclerosis: a case report
Authors: Gaitour Emil , Nick Saeed Talebzadeh , Roberts Charles , Gonzalez-Toledo Eduardo , Munjampalli Sai , Minagar Alireza , Vrooman Bruce , Souzdalnitski Dmitri , Zamnifekri Behrouz
Published: July 2012

Introduction

Glossopharyngeal neuralgia is an uncommon, painful syndrome, characterized by paroxysms of pain in the sensory distribution of the 9th cranial nerve. Idiopathic glossopharyngeal neuralgia may be due to compression of the glossopharyngeal nerve by adjacent vessels, while secondary glossopharyngeal neuralgia is associated with identifiable lesions affecting the glossopharyngeal nerve at different levels of its neuroanatomic pathway. Glossopharyngeal neuralgia is rare in the general population, but is more common in patients with multiple sclerosis.

Case presentation

A 56-year-old Caucasian woman with multiple sclerosis and migraine presented to our facility with intermittent lancinating pain to the right of her throat, tongue, and the floor of her mouth that had been occurring for the past year. The pain was intense, sharp, and stabbing, which lasted two to six seconds with radiation to the right ear. Initially, the attacks were infrequent, however, they had become more intense and frequent over time. Our patient reported weight loss, headache, painful swallowing, and the inability to maintain sleep due to painful attacks. A neurological examination revealed a right-handed woman with trigger points in the back of the tongue and throat on the right side. She also had dysphagia, hoarseness, and pain in the distribution of the right glossopharyngeal nerve. Mild right hemiparesis, hyperreflexia, dysmetria, and an ataxic gait were present. A magnetic resonance imaging scan of the brain was consistent with multiple sclerosis and magnetic resonance angiography demonstrated a loop of the posterior inferior cerebellar artery compressing the right glossopharyngeal nerve. She responded satisfactorily to carbamazepine. Microvascular decompression and Gamma Knife® radiosurgery were discussed in case of failure of the medical treatment; however, she declined these options.

Conclusions

Glossopharyngeal neuralgia in multiple sclerosis may occur due to vascular compressive lesions and it should not be solely attributed to the underlying demyelinating process. Vascular compression of the glossopharyngeal nerve could independently cause glossopharyngeal neuralgia in patients with multiple sclerosis, and vascular imaging to exclude such a diagnosis is recommended.
The role for scientists in tackling food insecurity and climate change
Authors: Beddington John R , Asaduzzaman Mohammed , Clark Megan E , Bremauntz Adrian Fernández , Guillou Marion D , Jahn Molly M , Lin Erda , Mamo Tekalign , Negra Christine , Nobre Carlos A , Scholes Robert J , Sharma Rita , Van Bo Nguyen , Wakhungu Judi
Published: July 2012

To adapt to climate change and ensure food security, major interventions are required to transform current patterns and practices of food production, distribution and consumption. The scientific community has an essential role to play in informing concurrent, strategic investments to establish climate-resilient agricultural production systems, minimize greenhouse gas emissions, make efficient use of resources, develop low-waste supply chains, ensure adequate nutrition, encourage healthy eating choices and develop a global knowledge system for sustainability. This paper outlines scientific contributions that will be essential to the seven policy recommendations for achieving food security in the context of climate change put forward by the Commission on Sustainable Agriculture and Climate Change. These include improved understanding of agriculture’s vulnerability to climate change, food price dynamics, food waste and consumption patterns and monitoring technologies as well as multidisciplinary investigation of regionally appropriate responses to climate change and food security challenges.
Gene expression profiling and functional analysis of angiogenic markers in murine collagen-induced arthritis
Authors: Raatz Yvonne , Ibrahim Saleh , Feldmann Marc , Paleolog Ewa M
Published: July 2012

Introduction

Dysregulated angiogenesis is implicated in the pathogenesis of rheumatoid arthritis (RA). To provide a more profound understanding of arthritis-associated angiogenesis, we evaluated the expression of angiogenesis-modulating genes at onset, peak and declining phases of collagen-induced arthritis (CIA), a well-established mouse model for RA.

Methods

CIA was induced in DBA/1 mice with type II collagen. Functional capillary density in synovial tissue of knee joints was determined by intravital fluorescence microscopy. To assess the ability of arthritic joint homogenates to induce angiogenesis, an endothelial chemotaxis assay and an in vivo matrigel plug assay were employed. The temporal expression profile of angiogenesis-related genes in arthritic paws was analysed by quantitative real-time RT-PCR using an angiogenesis focused array as well as gene specific PCR. Finally, we investigated the therapeutic effect of a monoclonal antibody specifically blocking the binding of VEGF to neuropilin (NRP)-1.

Results

Although arthritic paw homogenates displayed angiogenic activity in vitro and in vivo, and synovia of arthritic paws appeared highly vascularised on histological examination, the functional capillary density in arthritic knee synovia was significantly decreased, whereas capillary diameter was increased. Of the 84 genes analysed, 41 displayed a differential expression in arthritic paws as compared to control paws. Most significant alterations were seen at the peak of clinical arthritis. Increased mRNA expression could be observed for VEGF receptors (Flt-1, Flk-1, Nrp-1, Nrp-2), as well as for midkine, hepatocyte growth factor, insulin-like growth factor-1 and angiopoietin-1. Signalling through NRP-1 accounted in part for the chemotactic activity for endothelial cells observed in arthritic paw homogenates. Importantly, therapeutic administration of anti-NRP1B antibody significantly reduced disease severity and progression in CIA mice.

Conclusions

Our findings confirm that the arthritic synovium in murine CIA is a site of active angiogenesis, but an altered balance in the expression of angiogenic factors seems to favour the formation of non-functional and dilated capillaries. Furthermore, our results validate NRP-1 as a key player in the pathogenesis of CIA, and support the VEGF/VEGF receptor pathway as a potential therapeutic target in RA.
Robust Portfolio Choice with Learning in the Framework of Regret: Single-Period Case
Authors: Lim Andrew E. B. , Shanthikumar J. George , Vahn Gah-Yi
Published: July 2012

In this paper, we formulate a single-period portfolio choice problem with parameter uncertainty in the framework of relative regret. Relative regret evaluates a portfolio by comparing its return to a family of benchmarks, where the benchmarks are the wealths of fictitious investors who invest optimally given knowledge of the model parameters, and is a natural objective when there is concern about parameter uncertainty or model ambiguity. The optimal relative regret portfolio is the one that performs well in relation to all the benchmarks over the family of possible parameter values. We analyze this problem using convex duality and show that it is equivalent to a Bayesian problem, where the Lagrange multipliers play the role of the prior distribution, and the learning model involves Bayesian updating of these Lagrange multipliers/prior. This Bayesian problem is unusual in that the prior distribution is endogenously chosen by solving the dual optimization problem for the Lagrange multipliers, and the objective function involves the family of benchmarks from the relative regret problem. These results show that regret is a natural means by which robust decision making and learning can be combined.

This paper was accepted by Dimitris Bertsimas, optimization.
When Does It Pay to Delay Supplier Qualification? Theory and Experiments
Authors: Wan Zhixi , Beil Damian R. , Katok Elena
Published: July 2012

We study a procurement setting in which the buyer seeks a low price but will not allocate the contract to a supplier who has not passed qualification screening. Qualification screening is costly for the buyer, involving product tests, site visits, and interviews. In addition to a qualified incumbent supplier, the buyer has an entrant of unknown qualification. The buyer wishes to run a price-only, open-descending reverse auction between the incumbent and the entrant, and faces a strategic choice about whether to perform qualification screening on the entrant before or after the auction. We analytically study the buyer's optimal strategy, accounting for the fact that under postauction qualification, the incumbent knows he could lose the auction but still win the contract. In our analysis, we derive the incumbent's optimal bidding strategy under postauction qualification and find that he follows a threshold structure in which high-cost incumbents hold back on bidding—or even boycott the auction—to preserve their profit margin, and only lower-cost incumbents bid to win. These results are strikingly different from the usual open-descending auction analysis where all bidders are fully qualified and bidding to win is always a dominant strategy. We test our analytical results in the laboratory, with human subjects. We find that qualitatively our theoretical predictions hold up quite well, although incumbent suppliers bid somewhat more aggressively than the theory predicts, making buyers more inclined to use postauction qualification.

This paper was accepted by Martin Lariviere, operations management.
Quadratic Core-Selecting Payment Rules for Combinatorial Auctions
Authors: Day Robert W. , Cramton Peter
Published: July 2012

We report on the use of a quadratic programming technique in recent and upcoming spectrum auctions in Europe. Specifically, we compute a unique point in the core that minimizes the sum of squared deviations from a reference point, for example, from the Vickrey-Clarke-Groves payments. Analyzing the Karush-Kuhn-Tucker conditions, we demonstrate that the resulting payments can be decomposed into a series of economically meaningful and equitable penalties. Furthermore, we discuss the benefits of this combinatorial auction, explore the use of alternative reserve pricing approaches in this context, and indicate the results of several hundred computational runs using CATS data.
A Stochastic Competitive R&D Race Where “Winner Takes All”
Authors: Canbolat Pelin G. , Golany Boaz , Mund Inbal , Rothblum Uriel G.
Published: July 2012

The paper considers a race among multiple firms that compete over the development of a product. The first firm to complete the development gains a reward, whereas the other firms gain nothing. Each firm decides how much to invest in developing the product, and the time it completes the development is a random variable that depends on the investment level. The paper provides a method for explicitly computing a unique Nash equilibrium, parametrically in the interest rate; for a given interest rate, the Nash equilibrium is determined in time that is linear in the number of firms. The structure of the solution yields insights about the behavior of the participants. Furthermore, an explicit expression for a unique globally optimal solution is obtained and compared to the unique Nash equilibrium.