bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptome landscape of the human placenta
Authors: Kim Jinsil , Zhao Keyan , Jiang Peng , Lu Zhi-xiang , Wang Jinkai , Murray Jeffrey C , Xing Yi
Published: March 2012

Background

The placenta is a key component in understanding the physiological processes involved in pregnancy. Characterizing genes critical for placental function can serve as a basis for identifying mechanisms underlying both normal and pathologic pregnancies. Detailing the placental tissue transcriptome could provide a valuable resource for genomic studies related to placental disease.

Results

We have conducted a deep RNA sequencing (RNA-Seq) study on three tissue components (amnion, chorion, and decidua) of 5 human placentas from normal term pregnancies. We compared the placental RNA-Seq data to that of 16 other human tissues and observed a wide spectrum of transcriptome differences both between placenta and other human tissues and between distinct compartments of the placenta. Exon-level analysis of the RNA-Seq data revealed a large number of exons with differential splicing activities between placenta and other tissues, and 79% (27 out of 34) of the events selected for RT-PCR test were validated. The master splicing regulator ESRP1 is expressed at a proportionately higher level in amnion compared to all other analyzed human tissues, and there is a significant enrichment of ESRP1-regulated exons with tissue-specific splicing activities in amnion. This suggests an important role of alternative splicing in regulating gene function and activity in specific placental compartments. Importantly, genes with differential expression or splicing in the placenta are significantly enriched for genes implicated in placental abnormalities and preterm birth. In addition, we identified 604-1007 novel transcripts and 494-585 novel exons expressed in each of the three placental compartments.

Conclusions

Our data demonstrate unique aspects of gene expression and splicing in placental tissues that provide a basis for disease investigation related to disruption of these mechanisms. These data are publicly available providing the community with a rich resource for placental physiology and disease-related studies.
Effects of probiotics and antibiotics on the intestinal homeostasis in a computer controlled model of the large intestine
Authors: Rehman Ateequr , Heinsen Femke-Anouska , Koenen Marjorie E , Venema Koen , Knecht Henrik , Hellmig Stephan , Schreiber Stefan , Ott Stephan J
Published: March 2012

Background

Antibiotic associated diarrhea and Clostridium difficile infection are frequent complications of broad spectrum antibiotic therapy. Probiotic bacteria are used as therapeutic and preventive agents in these disorders, but the exact functional mechanisms and the mode of action are poorly understood. The effects of clindamycin and the probiotic mixture VSL#3 (containing the 8 bacterial strains Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei and Lactobacillus delbrueckii subsp. Bulgaricus) consecutively or in combination were investigated and compared to controls without therapy using a standardized human fecal microbiota in a computer-controlled in vitro model of large intestine. Microbial metabolites (short chain fatty acids, lactate, branched chain fatty acids, and ammonia) and the intestinal microbiota were analyzed.

Results

Compared to controls and combination therapy, short chain fatty acids and lactate, but also ammonia and branched chain fatty acids, were increased under probiotic therapy. The metabolic pattern under combined therapy with antibiotics and probiotics had the most beneficial and consistent effect on intestinal metabolic profiles. The intestinal microbiota showed a decrease in several indigenous bacterial groups under antibiotic therapy, there was no significant recovery of these groups when the antibiotic therapy was followed by administration of probiotics. Simultaneous application of anti- and probiotics had a stabilizing effect on the intestinal microbiota with increased bifidobacteria and lactobacilli.

Conclusions

Administration of VSL#3 parallel with the clindamycin therapy had a beneficial and stabilizing effect on the intestinal metabolic homeostasis by decreasing toxic metabolites and protecting the endogenic microbiota from destruction. Probiotics could be a reasonable strategy in prevention of antibiotic associated disturbances of the intestinal homeostasis and disorders.
Clostridium difficile genotypes other than ribotype 078 that are prevalent among human, animal and environmental isolates
Authors: Janezic Sandra , Ocepek Matjaz , Zidaric Valerija , Rupnik Maja
Published: March 2012

Background

Characterising the overlap of C. difficile genotypes in different reservoirs can improve our understanding of possible transmission routes of this pathogen. Most of the studies have focused on a comparison of the PCR ribotype 078 isolated from humans and animals. Here we describe for the first time a comparison of C. difficile genotypes isolated during longer time intervals from different sources including humans, animals and the non-hospital environment.

Results

Altogether 786 isolates from time interval 2008-2010 were grouped into 90 PCR ribotypes and eleven of them were shared among all host types and the environment. Ribotypes that were most common in humans were also present in water and different animals (014/020, 002, 029). Interestingly, non-toxigenic isolates were very common in the environment (30.8%) in comparison to humans (6.5%) and animals (7.7%). A high degree of similarity was observed for human and animal isolates with PFGE. In human isolates resistance to erithromycin, clindamycin and moxifloxacin was detected, while all animal isolates were susceptible to all antibiotics tested.

Conclusion

Our results show that many other types in addition to PCR Ribotype 078 are shared between humans and animals and that the most prevalent genotypes in humans have the ability to survive also in the environment and several animal hosts. The genetic relatedness observed with PFGE suggests that transmission of given genotype from one reservoir to the other is likely to occur.
The arbuscular mycorrhizal status has an impact on the transcriptome profile and amino acid composition of tomato fruit
Authors: Salvioli Alessandra , Zouari Inès , Chalot Michel , Bonfante Paola
Published: March 2012

Background

Arbuscular mycorrhizal (AM) symbiosis is the most widespread association between plant roots and fungi in natural and agricultural ecosystems. This work investigated the influence of mycorrhization on the economically relevant part of the tomato plant, by analyzing its impact on the physiology of the fruit. To this aim, a combination of phenological observations, transcriptomics (Microarrays and qRT-PCR) and biochemical analyses was used to unravel the changes that occur on fruits from Micro-Tom tomato plants colonized by the AM fungus Glomus mosseae.

Results

Mycorrhization accelerated the flowering and fruit development and increased the fruit yield. Eleven transcripts were differentially regulated in the fruit upon mycorrhization, and the mycorrhiza-responsive genes resulted to be involved in nitrogen and carbohydrate metabolism as well as in regulation and signal transduction. Mycorrhization has increased the amino acid abundance in the fruit from mycorrhizal plants, with glutamine and asparagine being the most responsive amino acids.

Conclusions

The obtained results offer novel data on the systemic changes that are induced by the establishment of AM symbiosis in the plant, and confirm the work hypothesis that AM fungi may extend their influence from the root to the fruit.
Omega-3 index and smoking in patients with acute ST-elevation myocardial infarction taking statins: a case-control study in Korea
Authors: Kim Young Joo , Jeong Dong Wook , Lee Jeong Gyu , Lee Han Cheol , Lee Sang Yeoup , Kim Yun Jin , Yi Yu Hyeon , Park Yong Soon , Cho Young Hye , Bae Mi Jin , Choi Eun Jung
Published: March 2012

Background

n-3 fatty acids and lifestyle also are closely related to risk of CVD. Most Koreans have higher fish consumption than people of Western populations. However, little is known about the recommended value of omega-3 index in Korean patients with acute ST-elevation myocardial infarction (STEMI) taking statins. Here, we tested the hypothesis that lower omega-3 fatty acids and/or smoking are associated with acute STEMI, even though patients with dyslipidemia who were taking statins and who attained their LDL-C goals.

Methods

We conducted a case-control study in which omega-3 fatty acids and lifestyle factors were determined in 24 consecutive Korean patients taking statins with angiographically confirmed acute STEMI and 68 healthy controls without acute STEMI. The omega-3 index was calculated by the sum of eicosapentaenoic acid and docosahexaenoic acid in erythrocyte membranes. Multivariable adjusted regression analysis was used to assess independent associations between acute STEMI, omega-3 index, and lifestyle factors after adjusting for age, sex, and body mass index (BMI).

Results

The mean age of total subjects was 59.9 years, and 57.6% of the subjects were male. The omega-3 index was significantly lower in cases (8.83%) than controls (11.13%; P < 0.001); however, total trans-fatty acids were not different between the two groups. The omega-3 index was inversely associated with odds for being a case (OR 0.16 (95% CI 0.03-1.14); P = 0.047), while smoking was positively associated with odds for being a case (OR 6.67 (95% CI 1.77-25.23); P = 0.005) after adjusting for all confounding variables.

Conclusion

This study shows that relative to controls, acute STEMI cases are more likely to be smokers and to have a lower omega-3 index, even though the cases were taking statins. An omega-3 index of at least 11% and abstinence from smoking are associated with cardioprotection for Koreans.
Anti-inflammatory recombinant TSG-6 stabilizes the progression of focal retinal degeneration in a murine model
Authors: Tuo Jingsheng , Cao Xiaoguang , Shen Defen , Wang Yujuan , Zhang Jun , Oh Joo Youn , Prockop Darwin J , Chan Chi-Chao
Published: March 2012

Background

Inflammatory responses are detected in the retina of patients with age-related macular degeneration andCcl2-/-/Cx3cr1-/-mice on rd8 background,(Ccl2-/-/Cx3cr1-/-mice) a model that develops progressive age-related macular degeneration-like retinal lesions including focal photoreceptor degeneration, abnormal retinal pigment epithelium and A2E accumulation. Tumor necrosis factor-inducible gene 6 protein is an anti-inflammatory protein and has been shown to improve myocardial infarction outcome and chemically injured cornea in mice by suppressing inflammation. In this study, we evaluated the effect of an intravitreous injection of recombinant TSG-6 on the retinal lesions ofCcl2-/-/Cx3cr1-/-mice.

Methods

Recombinant TSG-6 (400 ng) was administered by intravitreous injection into the right eye of six-week-old Ccl2-/-/Cx3cr1-/-mice. Their left eye was injected with phosphate-buffered saline as a control. Funduscopic pictures were taken before injection and sequentially once a month after injection. The mice were killed two months after injection and the ocular histology examined. Retinal A2E, a major component of lipofuscin, was measured by high performance liquid chromatography. The microarray of ocular mRNA of 92 immunological genes was performed. The genes showing differentiated expression in microarray were further compared between the injected right eye and the contralateral (control) eye by [real-time quantitative reverse transcription polymerase chain reaction] qRT-PCR.

Results

The continuous monitoring of the fundus for two months showed a slower progression or alleviation of retinal lesions in the treated right eyes as compared with the untreated left eyes. Among 23 pairs of eyes, the lesion levels improved in 78.3%, stayed the same in 8.7% and progressed in 13.0%. Histology confirmed the clinical observation. Even though there was no difference in the level of A2E between the treated and the untreated eyes, microarray analysis of 92 immune genes showed thatIL-17awas substantially decreased after the treatment. Expression ofTNF-αshowed a similar pattern toIL-17a. The results were consistent in duplicated arrays and confirmed by qRT-PCR.

Conclusions

We concluded that intravitreous administration of recombinant TSG-6 might stabilize retinal lesions inCcl2-/-/Cx3cr1-/-mice on rd8 background. Modulation of ocular immunological gene expressions, especially IL-17a, could be one of the mechanisms.
Immune response to a potyvirus with exposed amino groups available for chemical conjugation
Authors: Manuel-Cabrera Carlos Alberto , Márquez-Aguirre Ana , Rodolfo Hernández-Gutiérrez , Ortiz-Lazareno Pablo César , Chavez-Calvillo Gabriela , Carrillo-Tripp Mauricio , Silva-Rosales Laura , Gutiérrez-Ortega Abel
Published: March 2012

Background

The amino terminus of the tobacco etch virus (TEV) capsid protein is located on the external surface of infectious TEV particles, as proposed by previous studies and an in silico model. The epsilon amino groups on the exposed lysine residues are available for chemical conjugation to any given protein, and can thus act as antigen carriers. The availability of amino groups on the surfaces of TEV particles was determined and the immune response to TEV evaluated.

Results

Using a biotin-tagged molecule that reacts specifically with amino groups, we found that the TEV capsid protein has amino groups on its surface available for coupling to other molecules via crosslinkers. Intraperitoneal TEV was administered to female BALB/c mice, and both their humoral and cellular responses measured. Different IgG isotypes, particularly IgG2a, directed against TEV were induced. In a cell proliferation assay, only spleen cells from vaccinated mice that were stimulated in vitro with TEV showed significant proliferation of CD3+/CD4+ and CD3+/CD8+ subpopulations and secreted significant amounts of interferon γ.

Conclusions

TEV has surface amino groups that are available for chemical coupling. TEV induces both humoral and cellular responses when administered alone intraperitoneally to mice. Therefore, TEV should be evaluated as a vaccine adjuvant when chemically coupled to antigens of choice.
Calcium affects on vascular endpoints
Authors: Patel Vaishali B , Vacek James L , Graves Leland , Bhattacharya Rajib K
Published: March 2012

Calcium is one of the most abundant minerals in the body and its metabolism is one of the basic biologic processes in humans. Although historically linked primarily to bone structural development and maintenance, calcium is now recognized as a key component of many physiologic pathways necessary for optimum health including cardiovascular, neurological, endocrine, renal, and gastrointestinal systems. A recent meta-analysis published in August 2011 showed a potential increase in cardiovascular events related to calcium supplementation. The possible mechanism of action of this correlation has not been well elucidated. This topic has generated intense interest due to the widespread use of calcium supplements, particularly among the middle aged and elderly who are at the most risk from cardiac events. Prior studies did not control for potential confounding factors such as the use of statins, aspirin or other medications. These controversial results warrant additional well-designed studies to investigate the relationship between calcium supplementation and cardiovascular outcomes. The purpose of this review is to highlight the current literature in regards to calcium supplementation and cardiovascular health; and to identify areas of future research.
Controlled human wood smoke exposure: oxidative stress, inflammation and microvascular function
Authors: Forchhammer Lykke , Møller Peter , Riddervold Ingunn Skogstad , Bønløkke Jakob , Massling Andreas , Sigsgaard Torben , Loft Steffen
Published: March 2012

Background

Exposure to wood smoke is associated with respiratory symptoms, whereas knowledge on systemic effects is limited. We investigated effects on systemic inflammation, oxidative stress and microvascular function (MVF) after controlled wood smoke exposure.

Methods

In a randomised, double-blinded, cross-over study 20 non-smoking atopic subjects were exposed at rest to 14, 220, or 354 μg/m3 of particles from a well-burning modern wood stove for 3 h in a climate controlled chamber with 2 week intervals. We investigated the level of oxidatively damaged DNA, inflammatory markers and adhesion molecules before and 0, 6 and 20 h after exposure. Six h after exposure we measured MVF non-invasively by digital peripheral artery tonometry following arm ischemia.

Results

The MVF score was unaltered after inhalation of clean air (1.58 ± 0.07; mean ± SEM), low (1.51 ± 0.07) or high (1.61 ± 0.09) concentrations of wood smoke particles in atopic subjects, whereas unexposed non-atopic subjects had higher score (1.91 ± 0.09). The level of oxidatively damaged DNA, mRNA of ITGAL, CCL2, TNF, IL6, IL8, HMOX1, and OGG1 and surface marker molecules ICAM1, ITGAL and L-selectin in peripheral blood mononuclear cells were not affected by inhalation of wood smoke particles.

Conclusions

Exposure to wood smoke had no effect on markers of oxidative stress, DNA damage, cell adhesion, cytokines or MVF in atopic subjects.
Pure curcumin decreases the expression of WT1 by upregulation of miR-15a and miR-16-1 in leukemic cells
Authors: Gao Shen-meng , Yang Jun-jun , Chen Chi-qi , Chen Jun-jie , Ye Li-ping , Wang Lu-yao , Wu Jian-bo , Xing Chong-yun , Yu Kang
Published: March 2012

Background

Pure curcumin has been reported to down-regulate the expression of WT1 in leukemic cells. However, the molecular mechanism underlying the down-regulation of WT1 by curcumin is not completely delineated. The purpose of this present study is to identify a new miRNA-mediated mechanism which plays an important role in the anti-proliferation effects of curcumin in leukemic cells.

Methods

K562 and HL-60 cells were treated with different concentrations of curcumin for 24 and 48 hours, the level of miR-15a/16-1 and WT1 were detected by qRT-PCR and Western blotting. WT1 expression and cell proliferation were detected by Western blotting and CCK-8, after curcumin treated-K562 and HL-60 cells were transfected with anti-miR-15a/16-1 oligonucleotides.

Results

We found that pure curcumin upregulated the expression of miR-15a/16-1 and downregulated the expression of WT1 in leukemic cells and primary acute myeloid leukemia (AML) cells. Overexpression of miR-15a/16-1 deduced the protein level of WT1 in leukemic cells, but downregulation of WT1 by siRNA-WT1 could not increase the expression of miR-15a/16-1 in leukemic cells. These results reveal that curcumin induced-upregulation of miR-15a/16-1 is an early event upstream to downregulation of WT1. Furthermore, anti-miR-15a/16-1 oligonucleotides (AMO) partly reversed the downregulation of WT1 induced by pure curcumin in leukemic cells and AMO promoted the growth of curcumin treated-K562 and HL-60 cells.

Conclusion

Thus, these data suggest for the first time that pure curcumin downregulated the expression of WT1 partly by upregulating the expression of miR-15a/16-1 in leukemic cells. miR-15a/16-1 mediated WT1 downregulation plays an important role in the anti-proliferation effect of curcumin in leukemic cells.
Literature survey on epidemiology and pathology of cardiac fibroma
Authors: Torimitsu Suguru , Nemoto Tetsuo , Wakayama Megumi , Okubo Yoichiro , Yokose Tomoyuki , Kitahara Kanako , Ozawa Tsukasa , Nakayama Haruo , Shinozaki Minoru , Sasai Daisuke , Ishiwatari Takao , Takuma Kensuke , Shibuya Kazutoshi
Published: March 2012

Background

Although cardiac fibroma has been regarded as benign tumor, it presents various symptoms and may lead to death. Unfortunately, only a few studies have reported the epidemiology, embryology, and histopathology of the tumor, and the factors predicting poorer outcome are still obscured.

Methods

In July 2011 we searched for English and Japanese cases of cardiac fibroma using the PubMed and IgakuChuoZasshi databases. We then extracted and sampled raw data from the selected publications in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) style as much as was possible.

Results

Details of a total of 178 patients with cardiac fibroma were retrieved. The mean age was 11.4 years (median: 2.8 years). Tumor sizes ranged from 8.0 to 150.0 mm (mean 53.1 mm). The left ventricle was found to be the most common site associated with the tumor at a rate of 57.3%, followed by the right ventricle, and interventricular septum. The highest mortality was found in patients with septal involvement (58.6%). In all, 111 patients survived among the 160 patients with a recorded outcome. A younger age of the patient at the time of diagnosis was associated with a decreased survival rate. In addition, a significant positive association was found between ages for patients younger than 17 years of age and the diameter of the tumor at the time of diagnosis (r = 0.341, P = 0.006).

Conclusions

Both the younger age of patients at the time of diagnosis and septal involvement can be regarded as factors significantly indicating a poor prognosis. Furthermore, our statistical analyses support the following hypotheses. First, the high ratio of tumor-to-heart size may generate low cardiac output and therefore lead to poor outcome. Second, the ratio of the sites where cardiac fibroma occurred corresponds with the ratio of the muscular weight of the cardiac chamber. Third, cardiac fibroma involving the interventricular septum more frequently induces conduction system disease.
A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study
Authors: Kim Hyung-cheol , Lee Ji-Young , Sung Hyuna , Choi Ji-Yeob , Park Sue K , Lee Kyoung-Mu , Kim Young Jin , Go Min Jin , Li Lian , Cho Yoon Shin , Park Miey , Kim Dong-Joon , Oh Ji Hee , Kim Jun-Woo , Jeon Jae-Pil , Jeon Soon-Young , Min Haesook , Kim Hyo Mi , Park Jaekyung , Yoo Keun-Young , Noh Dong-Young , Ahn Sei-Hyun , Lee Min Hyuk , Kim Sung-Won , Lee Jong Won , Park Byeong-Woo , Park Woong-Yang , Kim Eun-Hye , Kim Mi Kyung , Han Wonshik , Lee Sang-Ah , Matsuo Keitaro , Shen Chen-Yang , Wu Pei-Ei , Hsiung Chia-Ni , Lee Jong-Young , Kim Hyung-Lae , Han Bok-Ghee , Kang Daehee
Published: March 2012

Introduction

Although approximately 25 common genetic susceptibility loci have been identified to be independently associated with breast cancer risk through genome-wide association studies (GWAS), the genetic risk variants reported to date only explain a small fraction of the heritability of breast cancer. Furthermore, GWAS-identified loci were primarily identified in women of European descent.

Methods

To evaluate previously identified loci in Korean women and to identify additional novel breast cancer susceptibility variants, we conducted a three-stage GWAS that included 6,322 cases and 5,897 controls.

Results

In the validation study using Stage I of the 2,273 cases and 2,052 controls, seven GWAS-identified loci [5q11.2/MAP3K1 (rs889312 and rs16886165), 5p15.2/ROPN1L (rs1092913), 5q12/MRPS30 (rs7716600), 6q25.1/ESR1 (rs2046210 and rs3734802), 8q24.21 (rs1562430), 10q26.13/FGFR2 (rs10736303), and 16q12.1/TOX3 (rs4784227 and rs3803662)] were significantly associated with breast cancer risk in Korean women (Ptrend < 0.05). To identify additional genetic risk variants, we selected the most promising 17 SNPs in Stage I and replicated these SNPs in 2,052 cases and 2,169 controls (Stage II). Four SNPs were further evaluated in 1,997 cases and 1,676 controls (Stage III). SNP rs13393577 at chromosome 2q34, located in the Epidermal Growth Factor Receptor 4 (ERBB4) gene, showed a consistent association with breast cancer risk with combined odds ratios (95% CI) of 1.53 (1.37-1.70) (combined P for trend = 8.8 × 10-14).

Conclusions

This study shows that seven breast cancer susceptibility loci, which were previously identified in European and/or Chinese populations, could be directly replicated in Korean women. Furthermore, this study provides strong evidence implicating rs13393577 at 2q34 as a new risk variant for breast cancer.
An integrative probabilistic model for identification of structural variation in sequencing data
Authors: Sindi Suzanne S , Önal Selim , Peng Luke C , Wu Hsin-Ta , Raphael Benjamin J
Published: March 2012

Paired-end sequencing is a common approach for identifying structural variation (SV) in genomes. Discrepancies between the observed and expected alignments indicate potential SVs. Most SV detection algorithms use only one of the possible signals and ignore reads with multiple alignments. This results in reduced sensitivity to detect SVs, especially in repetitive regions. We introduce GASVPro, an algorithm combining both paired read and read depth signals into a probabilistic model that can analyze multiple alignments of reads. GASVPro outperforms existing methods with a 50 to 90% improvement in specificity on deletions and a 50% improvement on inversions. GASVPro is available at http://compbio.cs.brown.edu/software.
Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation
Authors: Teschendorff Andrew E , Jones Allison , Fiegl Heidi , Sargent Alexandra , Zhuang Joanna J , Kitchener Henry C , Widschwendter Martin
Published: March 2012

Background

Recently, it has been proposed that epigenetic variation may contribute to the risk of complex genetic diseases like cancer. We aimed to demonstrate that epigenetic changes in normal cells, collected years in advance of the first signs of morphological transformation, can predict the risk of such transformation.

Methods

We analyzed DNA methylation (DNAm) profiles of over 27,000 CpGs in cytologically normal cells of the uterine cervix from 152 women in a prospective nested case-control study. We used statistics based on differential variability to identify CpGs associated with the risk of transformation and a novel statistical algorithm called EVORA (Epigenetic Variable Outliers for Risk prediction Analysis) to make predictions.

Results

We observed many CpGs that were differentially variable between women who developed a non-invasive cervical neoplasia within 3 years of sample collection and those that remained disease-free. These CpGs exhibited heterogeneous outlier methylation profiles and overlapped strongly with CpGs undergoing age-associated DNA methylation changes in normal tissue. Using EVORA, we demonstrate that the risk of cervical neoplasia can be predicted in blind test sets (AUC = 0.66 (0.58 to 0.75)), and that assessment of DNAm variability allows more reliable identification of risk-associated CpGs than statistics based on differences in mean methylation levels. In independent data, EVORA showed high sensitivity and specificity to detect pre-invasive neoplasia and cervical cancer (AUC = 0.93 (0.86 to 1) and AUC = 1, respectively).

Conclusions

We demonstrate that the risk of neoplastic transformation can be predicted from DNA methylation profiles in the morphologically normal cell of origin of an epithelial cancer. Having profiled only 0.1% of CpGs in the human genome, studies of wider coverage are likely to yield improved predictive and diagnostic models with the accuracy needed for clinical application.

Trial registration

The ARTISTIC trial is registered with the International Standard Randomised Controlled Trial Number ISRCTN25417821.
Relationship Between Deficits in Overall Quality of Life and Non–Small-Cell Lung Cancer Survival
Authors: Sloan Jeff A. , Zhao Xinghua , Novotny Paul J. , Wampfler Jason , Garces Yolanda , Clark Matthew M. , Yang Ping
Published: March 2012

Purpose

Evidence has suggested a clinically meaningful relationship between self-reported quality of life (QOL) of a patient with cancer at the time of receiving a cancer diagnosis and overall survival (OS). This study evaluated the prognostic value of QOL assessments with regard to OS in a large cohort of patients with lung cancer.

Patients and Methods

A total of 2,442 patients with non–small-cell lung cancer were observed between 1997 and 2007 and completed a single-item measure of overall QOL within the first 6 months of receiving a lung cancer diagnosis; these were dichotomized using an a priori definition of a clinically deficient score (CDS; ≤ 50 v > 50). Kaplan-Meier estimates and Cox models were used to evaluate the prognostic importance of QOL on OS alone and in the presence of covariates. Logistic regression modeling was used to identify which clinical and patient characteristics were related to a clinically meaningful deficit in QOL.

Results

QOL deficits at time of lung cancer diagnosis were significantly associated with OS (hazard ratio [HR], 1.55; P < .001), as were performance status, older age, smoking history, male sex, treatment factors, and stage of disease. The median survival for patients with CDS QOL was 1.6 years versus 5.6 years for patients with non-CDS QOL. After controlling for all these covariates, the indication of a clinically deficient baseline QOL still contributed significantly to the prediction of patient survival (HR, 0.67; P < .001).

Conclusion

Overall QOL measured by a simple single item at the time of lung cancer diagnosis is a significant and independent prognostic factor for survival in patients with lung cancer.
Genetic Variations and Patient-Reported Quality of Life Among Patients With Lung Cancer
Authors: Sloan Jeff A. , de Andrade Mariza , Decker Paul , Wampfler Jason , Oswold Curtis , Clark Matthew , Yang Ping
Published: March 2012

Purpose

Recent evidence has suggested a relationship between the baseline quality of life (QOL) self-reported by patients with cancer and genetic disposition. We report an analysis exploring relationships among baseline QOL assessments and candidate genetic variations in a large cohort of patients with lung cancer.

Patients and Methods

QOL data were provided by 1,299 patients with non–small-cell lung cancer observed at the Mayo Clinic between 1997 and 2007. Overall QOL and subdomains were assessed by either Lung Cancer Symptom Scale or Linear Analog Self Assessment measures; scores were transformed to a scale of 0 to 10, with higher scores representing better status. Baseline QOL scores assessed within 1 year of diagnosis were dichotomized as clinically deficient (CD) or not. A total of 470 single nucleotide polymorphisms (SNPs) in 56 genes of three biologic pathways were assessed for association with QOL measures. Logistic regression with training/validation samples was used to test the association of SNPs with CD QOL.

Results

Six SNPs on four genes were replicated using our split schemes. Three SNPs in the MGMT gene (adjusted analysis, rs3858300; unadjusted analysis, rs10741191 and rs3852507) from DNA repair pathway were associated with overall QOL. Two SNPs (rs2287396 [GSTZ1] and rs9524885 [ABCC4]) from glutathione metabolic pathway were associated with fatigue in unadjusted analysis. In adjusted analysis, two SNPs (rs2756109 [ABCC2] and rs9524885 [ABCC4]) from glutathione metabolic pathway were associated with pain.

Conclusion

We identified three SNPs in three glutathione metabolic pathway genes and three SNPs in two DNA repair pathway genes associated with QOL measures in patients with non–small-cell lung cancer.
Dissecting the Heterogeneity of Triple-Negative Breast Cancer
Authors: Metzger-Filho Otto , Tutt Andrew , de Azambuja Evandro , Saini Kamal S. , Viale Giuseppe , Loi Sherene , Bradbury Ian , Bliss Judith M. , Azim Hatem A. , Ellis Paul , Di Leo Angelo , Baselga José , Sotiriou Christos , Piccart-Gebhart Martine
Published: March 2012

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.
Randomized, Double-Blind, Placebo-Controlled Phase III Trial Comparing Docetaxel and Prednisone With or Without Bevacizumab in Men With Metastatic Castration-Resistant Prostate Cancer: CALGB 90401
Authors: Kelly William Kevin , Halabi Susan , Carducci Michael , George Daniel , Mahoney John F. , Stadler Walter M. , Morris Michael , Kantoff Philip , Monk J. Paul , Kaplan Ellen , Vogelzang Nicholas J. , Small Eric J.
Published: March 2012

Purpose

A randomized, placebo-controlled study based on preclinical and clinical data that supports the potential role of vascular endothelial growth factor in prostate cancer was performed to evaluate the addition of bevacizumab to standard docetaxel and prednisone therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).

Patients and Methods

Patients with chemotherapy-naive progressive mCRPC with Eastern Cooperative Oncology Group performance status ≤ 2 and adequate bone marrow, hepatic, and renal function were randomly assigned to receive docetaxel 75 mg/m2 intravenously (IV) over 1 hour for 21 days plus prednisone 5 mg orally twice per day (DP) with either bevacizumab 15 mg/kg IV every 3 weeks (DP + B) or placebo. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), 50% decline in prostate-specific antigen, objective response (OR), and toxicity.

Results

In total, 1,050 patients were randomly assigned. The median OS for patients given DP + B was 22.6 months compared with 21.5 months for patients treated with DP (hazard ratio, 0.91; 95% CI, 0.78 to 1.05; stratified log-rank P = .181). The median PFS time was superior in the DP + B arm (9.9 v 7.5 months, stratified log-rank P < .001) as was the proportion of patients with OR (49.4% v 35.5%; P = .0013). Grade 3 or greater treatment-related toxicity was more common with DP + B (75.4% v 56.2%; P ≤ .001), as was the number of treatment-related deaths (4.0% v 1.2%; P = .005).

Conclusion

Despite an improvement in PFS and OR, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC and was associated with greater toxicity.
Primary tibial vein aneurysm: a source of pulmonary emboli
Authors: Haqqani O P , Stratigis J D , Maloney S P , O'Donnell T F , Iafrati M D
Published: March 2012

Objective

To describe a case of a rare type of venous aneurysm (posterior tibial) with associated pulmonary embolus. We will discuss options and considerations germane to the diagnostic evaluation and possible interventions for this challenging clinical scenario.

Methods

Case presentation and literature review.

Results

A 36-year-old man presented to an outside hospital with a three-day history of left calf pain, acute shortness of breath and syncope elicited by exercise. Work-up demonstrated a pulmonary embolus and a posterior tibial venous aneurysm with mural thrombus. The patient presented to us 18 months later with persistent calf pain seeking an alternative to recommendations of lifelong anticoagulation. The patient was treated with surgical resection of the venous aneurysm with subsequent discontinuation of his anticoagulation. There were no surgical or thrombotic complications of this treatment course and the patient's discomfort improved.

Conclusion

Primary aneurysms of the tibial veins as a cause of pulmonary emboli are rare. A review of the literature suggests that anticoagulation alone does not provide effective amelioration of thromboembolic risk from lower extremity venous aneurysms. We have reported a case of successful surgical treatment of a posterior tibial venous aneurysm and recommend that surgical correction be strongly considered for accessible venous aneurysms.
Foot-sparing postoperative compression bandage: a possible alternative to the traditional bandage
Authors: Ricci S , Moro L , Trillo L , Incalzi R Antonelli
Published: March 2012

Objectives:

To verify whether a foot-sparing bandage is effective for patients who have undergone varicose vein surgery, being in the C2 class, having a normal deep venous system and actively walking.

Methods:

Ninety consecutive lower legs meeting the inclusion criteria underwent treatment with an inelastic foot-sparing bandage. Patient's satisfaction, efficacy and local effects were systematically documented.

Results:

The bandage was well tolerated and highly effective. Four of the first 20 cases experienced a slight morning oedema of the foot, which disappeared while walking. Thus, in the remaining cases we covered the foot and distal limb with a custom short tubular-shaped ‘sock’ providing 10 mmHg compression, only during the first 24 hours.

Conclusion:

The foot-sparing inelastic bandage is effective, cheap and tolerated by well-selected patients who have undergone varicose vein surgery.
Thermodynamic characterization of the Saccharomyces cerevisiae telomerase RNA pseudoknot domain in vitro
Authors: Liu Fei , Kim Yoora , Cruickshank Charmion , Theimer Carla A.
Published: March 2012

Recent structural and functional characterization of the pseudoknot in the Saccharomyces cerevisiae telomerase RNA (TLC1) has demonstrated that tertiary structure is present, similar to that previously described for the human and Kluyveromyces lactis telomerase RNAs. In order to biophysically characterize the identified pseudoknot secondary and tertiary structures, UV-monitored thermal denaturation experiments, nuclear magnetic resonance spectroscopy, and native gel electrophoresis were used to investigate various potential conformations in the pseudoknot domain in vitro, in the absence of the telomerase protein. Here, we demonstrate that alternative secondary structures are not mutually exclusive in the S. cerevisiae telomerase RNA, tertiary structure contributes 1.5 kcal mol−1 to the stability of the pseudoknot (∼half the stability observed for the human telomerase pseudoknot), and identify additional base pairs in the 3′ pseudoknot stem near the helical junction. In addition, sequence conservation in an adjacent overlapping hairpin appears to prevent dimerization and alternative conformations in the context of the entire pseudoknot-containing region. Thus, this work provides a detailed in vitro characterization of the thermodynamic features of the S. cerevisiae TLC1 pseudoknot region for comparison with other telomerase RNA pseudoknots.
Digital PCR Analysis of Maternal Plasma for Noninvasive Detection of Sickle Cell Anemia
Authors: Barrett Angela N , McDonnell Thomas C R , Chan K C Allen , Chitty Lyn S
Published: March 2012

BACKGROUND

Cell-free fetal DNA (cffDNA) constitutes approximately 10% of the cell-free DNA in maternal plasma and is a suitable source of fetal genetic material for noninvasive prenatal diagnosis (NIPD). The objective of this study was to determine the feasibility of using digital PCR for NIPD in pregnancies at risk of sickle cell anemia.

METHODS

Minor-groove binder (MGB) TaqMan probes were designed to discriminate between wild-type hemoglobin A and mutant (hemoglobin S) alleles encoded by the HBB (hemoglobin, beta) gene in cffDNA isolated from maternal plasma samples obtained from pregnancies at risk of sickle cell anemia. The fractional fetal DNA concentration was assessed in male-bearing pregnancies with a digital PCR assay for the Y chromosome–specific marker DYS14. In pregnancies with a female fetus, a panel of biallelic insertion/deletion polymorphism (indel) markers was developed for the quantification of the fetal DNA fraction. We used digital real-time PCR to analyze the dosage of the variant encoding hemoglobin S relative to that encoding wild-type hemoglobin A.

RESULTS

The sickle cell genotype was correctly determined in 82% (37 of 45) of male fetuses and 75% (15 of 20) of female fetuses. Mutation status was determined correctly in 100% of the cases (25 samples) with fractional fetal DNA concentrations >7%. The panel of indels was informative in 65% of the female-bearing pregnancies.

CONCLUSIONS

Digital PCR can be used to determine the genotype of fetuses at risk for sickle cell anemia. Optimization of the fractional fetal DNA concentration is essential. More-informative indel markers are needed for this assay's comprehensive use in cases of a female fetus.
TXNIP is highly regulated in bone biopsies from patients with endogenous Cushing's syndrome and related to bone turnover
Authors: Lekva Tove , Ueland Thor , Bøyum Hege , Evang Johan Arild , Godang Kristin , Bollerslev Jens
Published: March 2012

Objective

Patients with endogenous Cushing's Syndrome (CS), as long-time treated patients with exogenous glucocorticoids (GCs), have severe systemic manifestations including secondary osteoporosis and low-energy fractures. The aim of the present study was to investigate the functional role ofTXNIPin bone with focus on osteoblast (OB) differentiation and OB-mediated osteoclast activity and functionin vitro.

Design and methods

Nine bone biopsies from CS before and after surgical treatment were screened for expressional candidate genes. Microarray analyses revealed that the gene encodingTXNIPranked among the most upregulated genes. Subsequentin vitroandin vivostudies were performed.

Results

We found thatTXNIPgene in bone is downregulated in CS following surgical treatment. Furthermore, ourin vivodata indicate novel associations between thioredoxin andTXNIP. Ourin vitrostudies showed that silencingTXNIPin OBs was followed by increased differentiation and expression and secretion of osteocalcin as well as enhanced activity of alkaline phosphatase. Moreover, treating osteoclasts with silenced TXNIP OB media showed an increased osteoclast activity.

Conclusions

TXNIPexpression in bone is highly regulated during the treatment of active CS, and by GC in bone cellsin vitro. Our data indicate that TXNIP may mediate some of the detrimental effects of GC on OB function as well as modulate OB-mediated osteoclastogenesis by regulating the OPG/RANKL ratio.
Pharmacy Communication to Adolescents and Their Physicians Regarding Access to Emergency Contraception
Authors: Wilkinson Tracey A. , Fahey Nisha , Shields Christine , Suther Emily , Cabral Howard J. , Silverstein Michael
Published: March 2012

OBJECTIVE:

Emergency contraception (EC) is an effective pregnancy prevention strategy. EC is available without a prescription to those aged 17 years or older. The objective of this study was to assess the accuracy of information provided to adolescents and their physicians when they telephone pharmacies to inquire about EC.

METHODS:

By using standardized scripts, female callers telephoned 943 pharmacies in 5 US cities posing as 17-year-old adolescents or as physicians calling on behalf of their 17-year-old patients. McNemar tests were used to compare outcomes between adolescent and physician callers.

RESULTS:

Seven hundred fifty-nine pharmacies (80%) indicated to adolescent callers, and 766 (81%) to physician callers, that EC was available on the day of the call. However, 145 pharmacies (19%) incorrectly told the adolescent callers that it would be impossible to obtain EC under any circumstances, compared with 23 pharmacies (3%) for physician callers. Pharmacies conveyed the correct age to dispense EC without a prescription in 431 adolescent calls (57%) and 466 physician calls (61%). Compared with physician callers, adolescent callers were put on hold more often (54% vs 26%) and spoke to self-identified pharmacists less often (3% vs 12%, P < .0001). When EC was not available, 36% and 33% of pharmacies called by adolescents and physicians respectively offered no additional suggestions on how to obtain it.

CONCLUSIONS:

Most pharmacies report having EC in stock. However, misinformation regarding who can take EC, and at what age it is available without a prescription, is common. Such misinformation may create barriers to timely access.
Chylothorax as a complication of coronary artery bypass grafting operation
Authors: Szabó Miklós , †Jáger Margit , Krizsó Eszter , Gilányi Ibolya , Leny Andrij , Szűcs Géza , Csánky Eszter
Published: March 2012

The authors present the case of a 72-year-old woman who underwent coronary bypass grafting. Left sided chylothorax due to accidental dissection of a thoracic duct branch developed 2 months after sternotomy. As conservative therapy has failed, surgical pleurodesis was performed successfully. Chylothorax is a rare and underestimated complication of coronary bypass grafting. The worldwide increasing number of coronary artery bypass grafting surgeries makes it important to pay attention to this condition. Thus diagnosis of the chyle is relatively easy by its high chylomicron and triglyceride content, but identification of the etiology and its treatment is sometimes challenging for the physician. The treatment of chylothorax is usually conservative. The main goal is to keep the volume of the chyle under control. The number of surgical interventions because of chylothorax is increasing due to an increase of iatrogenic etiology. Orv. Hetil., 2012, 153, 553–558.
Cleft Lip and Palate in a Patient with 5q35.2-q35.3 Microdeletion: The Importance of Chromosomal Microarray Testing in the Craniofacial Clinic
Authors: Peredo Jane , Quintero-Rivera Fabiola , Bradley James P. , Tu Marinda , Dipple Katrina M.
Published: March 2012

We report on a 3½-year-old African American female with a 1.63 Mb microdeletion in 5q35.2-q35.3. This deletion includes NSD1, the gene that causes Sotos syndrome. The patient has unilateral cleft lip and palate (CLP) status postrepair, an unrepaired alveolar cleft, speech delay, global developmental delay, macrocephaly, mild cerebral palsy, and a patent ductus arteriosus status postrepair. Dysmorphic features include a prominent forehead and midface hypoplasia. This is one of the first cases of CLP associated with Sotos syndrome and emphasizes the utility of chromosomal microarray analysis in patients with more than isolated CLP in the Craniofacial Clinic.