bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of IREB2 and transforming growth factor beta-1 genetic variants in COPD: a replication case-control study
Authors: Chappell Sally L , Daly Leslie , Lotya Juzer , Alsaegh Aiman , Guetta-Baranes Tamar , Roca Josep , Rabinovich Roberto , Morgan Kevin , Millar Ann B , Donnelly Seamas C , Keatings Vera , MacNee William , Stolk Jan , Hiemstra Pieter S , Miniati Massimo , Monti Simonetta , O'Connor Clare M , Kalsheker Noor
Published: February 2011

Background

Genetic factors are known to contribute to COPD susceptibility and these factors are not fully understood. Conflicting results have been reported for many genetic studies of candidate genes based on their role in the disease. Genome-wide association studies in combination with expression profiling have identified a number of new candidates includingIREB2. A meta-analysis has implicated transforming growth factor beta-1 (TGFbeta1) as a contributor to disease susceptibility.

Methods

We have examined previously reported associations in both genes in a collection of 1017 white COPD patients and 912 non-diseased smoking controls. Genotype information was obtained for seven SNPs in theIREB2gene, and for four SNPs in theTGFbeta1gene. Allele and genotype frequencies were compared between COPD cases and controls, and odds ratios were calculated. The analysis was adjusted for age, sex, smoking and centre, including interactions of age, sex and smoking with centre.

Results

Our data replicate the association ofIREB2SNPs in association with COPD for SNP rs2568494, rs2656069 and rs12593229 with respective adjusted p-values of 0.0018, 0.0039 and 0.0053. No significant associations were identified forTGFbeta1.

Conclusions

These studies have therefore confirmed that theIREB2locus is a contributor to COPD susceptibility and suggests a new pathway in COPD pathogenesis invoking iron homeostasis.
Viral-mediated oncolysis is the most critical factor in the late-phase of the tumor regression process upon vaccinia virus infection
Authors: Weibel Stephanie , Raab Viktoria , Yu Yong A , Worschech Andrea , Wang Ena , Marincola Francesco M , Szalay Aladar A
Published: February 2011

Background

In principle, the elimination of malignancies by oncolytic virotherapy could proceed by different mechanisms - e.g. tumor cell specific oncolysis, destruction of the tumor vasculature or an anti-tumoral immunological response. In this study, we analyzed the contribution of these factors to elucidate the responsible mechanism for regression of human breast tumor xenografts upon colonization with an attenuated vaccinia virus (VACV).

Methods

Breast tumor xenografts were analyzed 6 weeks post VACV infection (p.i.; regression phase) by immunohistochemistry and mouse-specific expression arrays. Viral-mediated oncolysis was determined by tumor growth analysis combined with microscopic studies of intratumoral virus distribution. The tumor vasculature was morphologically characterized by diameter and density measurements and vessel functionality was analyzed by lectin perfusion and extravasation studies. Immunological aspects of viral-mediated tumor regression were studied in either immune-deficient mouse strains (T-, B-, NK-cell-deficient) or upon cyclophosphamide-induced immunosuppression (MHCII+-cell depletion) in nude mice.

Results

Late stage VACV-infected breast tumors showed extensive necrosis, which was highly specific to cancer cells. The tumor vasculature in infected tumor areas remained functional and the endothelial cells were not infected. However, viral colonization triggers hyperpermeability and dilatation of the tumor vessels, which resembled the activated endothelium in wounded tissue. Moreover, we demonstrated an increased expression of genes involved in leukocyte-endothelial cell interaction in VACV-infected tumors, which orchestrate perivascular inflammatory cell infiltration. The immunohistochemical analysis of infected tumors displayed intense infiltration of MHCII-positive cells and colocalization of tumor vessels with MHCII+/CD31+ vascular leukocytes. However, GI-101A tumor growth analysis upon VACV-infection in either immunosuppressed nude mice (MHCII+-cell depleted) or in immune-deficient mouse strains (T-, B-, NK-cell-deficient) revealed that neither MHCII-positive immune cells nor T-, B-, or NK cells contributed significantly to VACV-mediated tumor regression. In contrast, tumors of immunosuppressed mice showed enhanced viral spreading and tumor necrosis.

Conclusions

Taken together, these results indicate that VACV-mediated oncolysis is the primary mechanism of tumor shrinkage in the late regression phase. Neither the destruction of the tumor vasculature nor the massive VACV-mediated intratumoral inflammation was a prerequisite for tumor regression. We propose that approaches to enhance viral replication and spread within the tumor microenvironment should improve therapeutical outcome.
Reduced antioxidant defense in early onset first-episode psychosis: a case-control study
Authors: Micó Juan Antonio , Rojas-Corrales Maria Olga , Gibert-Rahola Juan , Parellada Mara , Moreno Dolores , Fraguas David , Graell Montserrat , Gil Javier , Irazusta Jon , Castro-Fornieles Josefina , Soutullo Cesar , Arango Celso , Otero Soraya , Navarro Ana , Baeza Inmaculada , Martínez-Cengotitabengoa Mónica , González-Pinto Ana
Published: February 2011

Background

Our objective is to determine the activity of the antioxidant defense system at admission in patients with early onset first psychotic episodes compared with a control group.

Methods

Total antioxidant status (TAS) and lipid peroxidation (LOOH) were determined in plasma. Enzyme activities and total glutathione levels were determined in erythrocytes in 102 children and adolescents with a first psychotic episode and 98 healthy controls.

Results

A decrease in antioxidant defense was found in patients, measured as decreased TAS and glutathione levels. Lipid damage (LOOH) and glutathione peroxidase activity was higher in patients than controls. Our study shows a decrease in the antioxidant defense system in early onset first episode psychotic patients.

Conclusions

Glutathione deficit seems to be implicated in psychosis, and may be an important indirect biomarker of oxidative stress in early-onset schizophrenia. Oxidative damage is present in these patients, and may contribute to its pathophysiology.
The dimensional structure of the functional abilities in cases of long-term sickness absence
Authors: Broersen Jake PJ , Mulders Henny PG , Schellart Antonius JM , van der Beek Allard J
Published: February 2011

Background

The health problems that working people suffer can affect their functional abilities and, consequently, can cause a mismatch between those abilities and the demands of the work, leading to sickness absence. A lasting decrease in functional abilities can lead to long-term sickness absence and work disability, with negative consequences for both the worker and the larger society. The objective of this study was to identify common disability characteristics among large groups of long-term sick-listed and disabled employees.

Methods

As part of the disability benefit entitlement procedure in the Netherlands, an insurance physician assesses the functional abilities of the claimant in a standardised form, known as the List of Functional Abilities (LFA), which consists of six sections containing a total of 106 items. For the purposes of this study, we compiled data from 50,931 assessments. These data were used in an exploratory factor analyses, and the results were then used to construct scales. The stability of dimensional structure of the LFA and of the internal consistency of the scales was studied using data from 80,968 assessments carried out earlier, under a slightly different legislation.

Results

Three separate factor analyses carried out on the functional abilities of five sections of the LFA resulted in 14 scale variables, and one extra scale variable was based on the items from the sixth section. The resulting scale variables showed Cronbach's Alphas ranging from 0.59 to 0.97, with the exception of one of 0.54. The dimensional structure of the LFA in the verification population differed in some aspects. The Cronbach's Alphas of the verification population ranged from 0.58 to 0.97, again with the exception of the same scale: Alpha = 0.49.

Conclusion

The differences between the dimensional structures of the primary data and the earlier data we found in this study restrict the possibilities to generalise the results. The scales we constructed can be utilised to produce a compact description of the functional abilities of groups of claimants in the Netherlands. Moreover, the matching work demands can be used to identify jobs low on those demands as being the most accessible for the specific type of disabled employees, particularly severely disabled individuals.
Elastic Stable Intramedullary Nailing (ESIN), Orthoss® and Gravitational Platelet Separation - System (GPS®): An effective method of treatment for pathologic fractures of bone cysts in children
Authors: Rapp Marion , Svoboda Daniel , Wessel Lucas M , Kaiser Martin M
Published: February 2011

Background

The different treatment strategies for bone cysts in children are often associated with persistence and high recurrence rates of the lesions. The safety and clinical outcomes of a combined mechanical and biological treatment with elastic intramedullary nailing, artificial bone substitute and autologous platelet rich plasma are evaluated.

Methods

From 02/07 to 01/09 we offered all children with bone cysts the treatment combination of elastic intramedullary nailing (ESIN), artificial bone substitute (Orthoss®) and autologous platelet rich plasma, concentrated by the Gravitational Platelet Separation (GPS®) - System. All patients were reviewed radiologically for one year following the removal of the intramedullary nailing, which was possible because of cyst obliteration.

Results

A cohort of 12 children (4 girls, 8 boys) was recruited. The mean patient age was 11.4 years (range 7-15 years). The bone defects (ten humeral, two femoral) included eight juvenile and four aneurysmal bone cysts. Five patients suffered from persistent cysts following earlier unsuccessful treatment of humeral bone cyst after pathologic fracture; the other seven presented with acute pathologic fractures. No peri- or postoperative complications occurred. The radiographic findings showed a total resolution of the cysts in ten cases (Capanna Grade 1); in two cases a small residual cyst remained (Capanna Grade 2). The intramedullary nails were removed six to twelve months (mean 7.7) after the operation; in one case, a fourteen year old boy (Capanna Grade 2), required a further application of GPS®and Orthoss®to reach a total resolution of the cyst. At follow-up (20-41 months, mean 31.8 months) all patients showed very good functional results and had returned to sporting activity. No refracture occurred, no further procedure was necessary.

Conclusions

The combination of elastic intramedullary nailing, artificial bone substitute and autologous platelet rich plasma (GPS®) enhances the treatment of bone cysts in children, with no resulting complications.
Amyloidosis cutis dyschromica in two female siblings: cases report
Authors: Yang Wenlin , Lin Yangyang , Yang Jian , Lin Wensheng
Published: February 2011

Background

Cutaneous amyloidosis has been classified into primary cutaneous amyloidosis (PCA, OMIM #105250), secondary cutaneous amyloidosis and systemic cutaneous amyloidosis. PCA is the deposition of amyloid in previously apparent normal skin without systemic involvement. Amyloidosis cutis dyschromica (ACD) is a rare distinct type of PCA. Here, the unique clinical and histological findings of two Chinese female siblings with ACD were described.

Cases presentations

Patient 1 was a 34-year-old female, presented with mildly pruritic, diffuse mottled hyperpigmentation and hypopigmentation. The lesions involved all over the body since she was 10 years old. There were a few itchy blisters appearing on her arms, lower legs and truck, especially on the sun-exposed areas in summer. Some hypopigmented macules presented with slight atrophy. Patient 2 was 39-year-old, the elder sister of patient 1. She had similar skin lesions since the same age as the former. The atrophy and blisters on the skin of the patient with amyloidosis cutis dyschromica have not been described in previous literature. Histological examinations of the skin biopsies taken from both patients revealed amyloid deposits in the whole papillary dermis. Depending on the histological assessment, the two cases were diagnosed as amyloidosis cutis dyschromica.

Conclusion

The two cases suggest that the atrophy and blisters may be the uncommon manifestations of amyloidosis cutis dyschromica. It alerts clinicians to consider the possibility of ACD when meeting patients with cutaneous dyschromia. Skin biopsy is essential and family consultation of genetic investigation is very important in such cases.
Human Nek6 is a monomeric mostly globular kinase with an unfolded short N-terminal domain
Authors: Meirelles Gabriela V , Silva Júlio C , Mendonça Yuri de A , Ramos Carlos HI , Torriani Iris L , Kobarg Jörg
Published: February 2011

Background

The NIMA-related kinases (Neks) are widespread among eukaryotes. In mammalians they represent an evolutionarily conserved family of 11 serine/threonine kinases, with 40-45% amino acid sequence identity to the Aspergillus nidulans mitotic regulator NIMA within their catalytic domains. Neks have cell cycle-related functions and were recently described as related to pathologies, particularly cancer, consisting in potential chemotherapeutic targets. Human Nek6, -7 and -9 are involved in the control of mitotic spindle formation, acting together in a mitotic kinase cascade, but their mechanism of regulation remain elusive.

Results

In this study we performed a biophysical and structural characterization of human Nek6 with the aim of obtaining its low resolution and homology models. SAXS experiments showed that hNek6 is a monomer of a mostly globular, though slightly elongated shape. Comparative molecular modeling together with disorder prediction analysis also revealed a flexible disordered N-terminal domain for hNek6, which we found to be important to mediate interactions with diverse partners. SEC-MALS experiments showed that hNek6 conformation is dependent on its activation/phosphorylation status, a higher phosphorylation degree corresponding to a bigger Stokes radius. Circular dichroism spectroscopy confirmed our in silico predictions of secondary structure content and thermal stability shift assays revealed a slightly higher stability of wild-type hNek6 compared to the activation loop mutant hNek6(S206A).

Conclusions

Our data present the first low resolution 3D structure of hNek6 protein in solution. SAXS, comparative modeling and SEC-MALS analysis revealed that hNek6 is a monomeric kinase of slightly elongated shape and a short unfolded N-terminal domain.
Role of hypoxia and glycolysis in the development of multi-drug resistance in human tumor cells and the establishment of an orthotopic multi-drug resistant tumor model in nude mice using hypoxic pre-conditioning
Authors: Milane Lara , Duan Zhenfeng , Amiji Mansoor
Published: February 2011

Background

The development of multi-drug resistant (MDR) cancer is a significant challenge in the clinical treatment of recurrent disease. Hypoxia is an environmental selection pressure that contributes to the development of MDR. Many cancer cells, including MDR cells, resort to glycolysis for energy acquisition. This study aimed to explore the relationship between hypoxia, glycolysis, and MDR in a panel of human breast and ovarian cancer cells. A second aim of this study was to develop an orthotopic animal model of MDR breast cancer.

Methods

Nucleic and basal protein was extracted from a panel of human breast and ovarian cancer cells; MDR cells and cells pre-exposed to either normoxic or hypoxic conditions. Western blotting was used to assess the expression of MDR markers, hypoxia inducible factors, and glycolytic proteins. Tumor xenografts were established in the mammary fat pad ofnu/numice using human breast cancer cells that were pre-exposed to either hypoxic or normoxic conditions. Immunohistochemistry was used to assess the MDR character of excised tumors.

Results

Hypoxia induces MDR and glycolysisin vitro, but the cellular response is cell-line specific and duration dependent. Using hypoxic, triple-negative breast cancer cells to establish 100 mm3tumor xenografts in nude mice is a relevant model for MDR breast cancer.

Conclusion

Hypoxic pre-conditiong and xenografting may be used to develop a multitude of orthotopic models for MDR cancer aiding in the study and treatment of the disease.
Sequence and gene expression of chloroquine resistance transporter (pfcrt) in the association of in vitro drugs resistance of Plasmodium falciparum
Authors: Chaijaroenkul Wanna , Ward Stephen A , Mungthin Mathirut , Johnson David , Owen Andrew , Bray Patrick G , Na-Bangchang Kesara
Published: February 2011

Background

Plasmodium falciparum chloroquine resistance (CQR) transporter protein (PfCRT) is known to be the important key of CQR. Recent studies have definitively demonstrated a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Although these mutations are predictive of chloroquine resistance, they are not quantitatively predictive of the degree of resistance.

Methods

In this study, a total of 95 recently adapted P. falciparum isolates from Thailand were included in the analysis. Parasites were characterized for their drug susceptibility phenotypes and genotypes with respect to pfcrt. From the original 95 isolates, 20 were selected for complete pfcrt sequence analysis.

Results

Almost all of the parasites characterized carried the previously reported mutations K76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at K76A and E198K. There was a suggestion that parasites carrying E198K were less resistant than those that did not. In addition, pfcrt and pfmdr1 gene expression were investigated by real-time PCR. No relationship between the expression level of either of these genes and response to drug was observed.

Conclusion

Data from the present study suggest that other genes must contribute to the degree of resistance once the resistance phenotype is established through mutations in pfcrt.
Bmi-1 promotes invasion and metastasis, and its elevated expression is correlated with an advanced stage of breast cancer
Authors: Guo Bao-Hong , Feng Yan , Zhang Rong , Xu Li-Hua , Li Man-Zhi , Kung Hsiang-Fu , Song Li-Bing , Zeng Mu-Sheng
Published: February 2011

Background

B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi-1) acts as an oncogene in various tumors, and its overexpression correlates with a poor outcome in several human cancers. Ectopic expression of Bmi-1 can induce epithelial-mesenchymal transition (EMT) and enhance the motility and invasiveness of human nasopharyngeal epithelial cells (NPECs), whereas silencing endogenous Bmi-1 expression can reverse EMT and reduce the metastatic potential of nasopharyngeal cancer cells (NPCs). Mouse xenograft studies indicate that coexpression of Bmi-1 and H-Ras in breast cancer cells can induce an aggressive and metastatic phenotype with an unusual occurrence of brain metastasis; although, Bmi-1 overexpression did not result in oncogenic transformation of MCF-10A cells. However, the underlying molecular mechanism of Bmi-1-mediated progression and the metastasis of breast cancer are not fully elucidated at this time.

Results

Bmi-1 expression is more pronouncedly increased in primary cancer tissues compared to matched adjacent non-cancerous tissues. High Bmi-1 expression is correlated with advanced clinicopathologic classifications (T, N, and M) and clinical stages. Furthermore, a high level of Bmi-1 indicates an unfavorable overall survival and serves as a high risk marker for breast cancer. In addition, inverse transcriptional expression levels of Bmi-1 and E-cadherin are detected between the primary cancer tissues and the matched adjacent non-cancerous tissues. Higher Bmi-1 levels are found in the cancer tissue, whereas the paired adjacent non-cancer tissue shows higher E-cadherin levels. Overexpression of Bmi-1 increases the motility and invasive properties of immortalized human mammary epithelial cells, which is concurrent with the increased expression of mesenchymal markers, the decreased expression of epithelial markers, the stabilization of Snail and the dysregulation of the Akt/GSK3β pathway. Consistent with these observations, the repression of Bmi-1 in highly metastatic breast cancer cells remarkably reduces cellular motility, invasion and transformation, as well as tumorigenesis and lung metastases in nude mice. In addition, the repression of Bmi-1 reverses the expression of EMT markers and inhibits the Akt/GSK3β/Snail pathway.

Conclusions

This study demonstrates that Bmi-1 promotes the invasion and metastasis of human breast cancer and predicts poor survival.
Sodium ion channel mutations in glioblastoma patients correlate with shorter survival
Authors: Joshi Avadhut D , Parsons D Williams , Velculescu Victor E , Riggins Gregory J
Published: February 2011

Background

Glioblastoma Multiforme (GBM) is the most common and invasive astrocytic tumor associated with dismal prognosis. Treatment for GBM patients has advanced, but the median survival remains a meager 15 months. In a recent study, 20,000 genes from 21 GBM patients were sequenced that identified frequent mutations in ion channel genes. The goal of this study was to determine whether ion channel mutations have a role in disease progression and whether molecular targeting of ion channels is a promising therapeutic strategy for GBM patients. Therefore, we compared GBM patient survival on the basis of presence or absence of mutations in calcium, potassium and sodium ion transport genes. Cardiac glycosides, known sodium channel inhibitors, were then tested for their ability to inhibit GBM cell proliferation.

Results

Nearly 90% of patients showed at least one mutation in ion transport genes. GBM patients with mutations in sodium channels showed a significantly shorter survival compared to patients with no sodium channel mutations, whereas a similar comparison based on mutational status of calcium or potassium ion channel mutations showed no survival differences. Experimentally, targeting GBM cells with cardiac glycosides such as digoxin and ouabain demonstrated preferential cytotoxicity against U-87 and D54 GBM cells compared to non-tumor astrocytes (NTAs).

Conclusions

These pilot studies of GBM patients with sodium channel mutations indicate an association with a more aggressive disease and significantly shorter survival. Moreover, inhibition of GBM cells by ion channel inhibitors such as cardiac glycosides suggest a therapeutic strategy with relatively safe drugs for targeting GBM ion channel mutations. Key Words: glioblastoma multiforme, ion channels, mutations, small molecule inhibitors, cardiac glycosides.
Autotaxin is induced by TSA through HDAC3 and HDAC7 inhibition and antagonizes the TSA-induced cell apoptosis
Authors: Li Song , Wang Baolu , Xu Yan , Zhang Junjie
Published: February 2011

Background

Autotaxin (ATX) is a secreted glycoprotein with the lysophospholipase D (lysoPLD) activity to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a bioactive lysophospholipid involved in diverse biological actions. ATX is highly expressed in some cancer cells and contributes to their tumorigenesis, invasion, and metastases, while in other cancer cells ATX is silenced or expressed at low level. The mechanism of ATX expression regulation in cancer cells remains largely unknown.

Results

In the present study, we demonstrated that trichostatin A (TSA), a well-known HDAC inhibitor (HDACi), significantly induced ATX expression in SW480 and several other cancer cells with low or undetectable endogenous ATX expression. ATX induction could be observed when HDAC3 and HDAC7 were down-regulated by their siRNAs. It was found that HDAC7 expression levels were low in the cancer cells with high endogenous ATX expression. Exogenous over-expression of HDAC7 inhibited ATX expression in these cells in a HDAC3-dependent manner. These data indicate that HDAC3 and HDAC7 collaboratively suppress ATX expression in cancer cells, and suggest that TSA induce ATX expression by inhibiting HDAC3 and HDAC7. The biological significance of this regulation mechanism was revealed by demonstrating that TSA-induced ATX protected cancer cells against TSA-induced apoptosis by producing LPA through its lysoPLD activity, which could be reversed by BrP-LPA and S32826, the inhibitors of the ATX-LPA axis.

Conclusions

We have demonstrated that ATX expression is repressed by HDAC3 and HDAC7 in cancer cells. During TSA treatment, ATX is induced due to the HDAC3 and HDAC7 inhibition and functionally antagonizes the TSA-induced apoptosis. These results reveal an internal HDACi-resistant mechanism in cancer cells, and suggest that the inhibition of ATX-LPA axis would be helpful to improve the efficacy of HDACi-based therapeutics against cancer.
Induction of heme oxygenase-1 protects against nutritional fibrosing steatohepatitis in mice
Authors: Wang Rong Qi , Nan Yue Min , Wu Wen Juan , Kong Ling Bo , Han Fang , Zhao Su Xian , Kong Li , Yu Jun
Published: February 2011

Background

Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced liver injury. However, its role on liver fibrosis remains unclear. This study aims to elucidate the effect and the mechanism of HO-1 in nutritional fibrosing steatohepatitis in mice.

Methods

Male C57BL/6J mice were fed with a methionine-choline deficient (MCD) diet for eight weeks to induce hepatic fibrosis. HO-1 chemical inducer (hemin), HO-1 chemical inhibitor zinc protoporphyrin IX (ZnPP-IX) and/or adenovirus carrying HO-1 gene (Ad-HO-1) were administered to mice, respectively. Liver injury was assessed by serum ALT, AST levels and histological examination; hepatic lipid peroxides levels were determined; the expression levels of several fibrogenic related genes were assayed by real-time quantitative PCR and Western blot.

Results

MCD feeding mice showed progressive hepatic injury including hepatic steatosis, inflammatory infiltration and fibrosis. Induction of HO-1 by hemin or Ad-HO-1 significantly attenuated the severity of liver injury. This effect was associated with the up-regulation of HO-1, reduction of hepatic lipid peroxides levels, down-regulation of inflammatory factors tumor necrosis factor-alpha, interleukin-6 and suppressor of cytokine signaling-1 as well as the pro-fibrotic genes alpha-smooth muscle actin, transforming growth factor-β1, matrix metallopeptidase-2 and matrix metallopeptidase-9. A contrary effect was observed in mice treated with ZnPP-IX.

Conclusions

The present study provided the evidence for the protective role of HO-1 in ameliorating MCD diet-induced fibrosing steatohepatitis. Modulation of HO-1 expression might serve as a therapeutic approach for fibrotic steatohepatitis.
Multimodality imaging of anomalous pulmonary veins
Authors: Nepomuceno Roman , Zeglinski Matthew , Lerner Jordyn , Czarnecki Wlodzimierz , Kirkpatrick Iain DC , Strzelczyk Jacek , Jassal Davinder S
Published: February 2011

Partial anomalous pulmonary venous connection (PAPVC) is an extremely rare congenital condition where one or more of the pulmonary veins are connected to the venous circulation. Although initially suspected with unexplained right ventricular enlargement on transthoracic echocardiography (TTE), cardiac MRI is able to delineate the anatomical variant. We present a case of a 65-year-old male diagnosed with left sided PAPVC using multimodality cardiac imaging.
Deciphering the complexities of the wheat flour proteome using quantitative two-dimensional electrophoresis, three proteases and tandem mass spectrometry
Authors: Dupont Frances M , Vensel William H , Tanaka Charlene K , Hurkman William J , Altenbach Susan B
Published: February 2011

Background

Wheat flour is one of the world's major food ingredients, in part because of the unique end-use qualities conferred by the abundant glutamine- and proline-rich gluten proteins. Many wheat flour proteins also present dietary problems for consumers with celiac disease or wheat allergies. Despite the importance of these proteins it has been particularly challenging to use MS/MS to distinguish the many proteins in a flour sample and relate them to gene sequences.

Results

Grain from the extensively characterized spring wheat cultivarTriticum aestivum'Butte 86' was milled to white flour from which proteins were extracted, then separated and quantified by 2-DE. Protein spots were identified by separate digestions with three proteases, followed by tandem mass spectrometry analysis of the peptides. The spectra were used to interrogate an improved protein sequence database and results were integrated using the Scaffold program. Inclusion of cultivar specific sequences in the database greatly improved the results, and 233 spots were identified, accounting for 93.1% of normalized spot volume. Identified proteins were assigned to 157 wheat sequences, many for proteins unique to wheat and nearly 40% from Butte 86. Alpha-gliadins accounted for 20.4% of flour protein, low molecular weight glutenin subunits 18.0%, high molecular weight glutenin subunits 17.1%, gamma-gliadins 12.2%, omega-gliadins 10.5%, amylase/protease inhibitors 4.1%, triticins 1.6%, serpins 1.6%, purinins 0.9%, farinins 0.8%, beta-amylase 0.5%, globulins 0.4%, other enzymes and factors 1.9%, and all other 3%.

Conclusions

This is the first successful effort to identify the majority of abundant flour proteins for a single wheat cultivar, relate them to individual gene sequences and estimate their relative levels. Many genes for wheat flour proteins are not expressed, so this study represents further progress in describing the expressed wheat genome. Use of cultivar-specific contigs helped to overcome the difficulties of matching peptides to gene sequences for members of highly similar, rapidly evolving storage protein families. Prospects for simplifying this process for routine analyses are discussed. The ability to measure expression levels for individual flour protein genes complements information gained from efforts to sequence the wheat genome and is essential for studies of effects of environment on gene expression.
The effect of progesterone replacement on gene expression in the corpus luteum during induced regression and late luteal phase in the bonnet monkey (Macaca radiata)
Authors: Suresh Padmanaban S , Jayachandra Kadthur C , Medhamurthy Rudraiah
Published: February 2011

Background

In higher primates, although LH/CG play a critical role in the control of corpus luteum (CL) function, the direct effects of progesterone (P4) in the maintenance of CL structure and function are unclear. Several experiments were conducted in the bonnet monkey to examine direct effects of P4 on gene expression changes in the CL, during induced luteolysis and the late luteal phase of natural cycles.

Methods

To identify differentially expressed genes encoding PR, PR binding factors, cofactors and PR downstream signaling target genes, the genome-wide analysis data generated in CL of monkeys after LH/P4 depletion and LH replacement were mined and validated by real-time RT-PCR analysis. Initially, expression of these P4 related genes were determined in CL during different stages of luteal phase. The recently reported model system of induced luteolysis, yet capable of responsive to tropic support, afforded an ideal situation to examine direct effects of P4 on structure and function of CL. For this purpose, P4 was infused via ALZET pumps into monkeys 24 h after LH/P4 depletion to maintain mid luteal phase circulating P4 concentration (P4 replacement). In another experiment, exogenous P4 was supplemented during late luteal phase to mimic early pregnancy.

Results

Based on the published microarray data, 45 genes were identified to be commonly regulated by LH and P4. From these 19 genes belonging to PR signaling were selected to determine their expression in LH/P4 depletion and P4 replacement experiments. These 19 genes when analyzed revealed 8 genes to be directly responsive to P4, whereas the other genes to be regulated by both LH and P4. Progesterone supplementation for 24 h during the late luteal phase also showed changes in expression of 17 out of 19 genes examined.

Conclusion

These results taken together suggest that P4 regulates, directly or indirectly, expression of a number of genes involved in the CL structure and function.
A delta-doped quantum well system with additional modulation doping
Authors: Luo Dong-Sheng , Lin Li-Hung , Su Yi-Chun , Wang Yi-Ting , Peng Zai Fong , Lo Shun-Tsung , Chen Kuang Yao , Chang Yuan-Huei , Wu Jau-Yang , Lin Yiping , Lin Sheng-Di , Chen Jeng-Chung , Huang Chun-Feng , Liang Chi-Te
Published: February 2011

A delta-doped quantum well with additional modulation doping may have potential applications. Utilizing such a hybrid system, it is possible to experimentally realize an extremely high two-dimensional electron gas (2DEG) density without suffering inter-electronic-subband scattering. In this article, the authors report on transport measurements on a delta-doped quantum well system with extra modulation doping. We have observed a 0-10 direct insulator-quantum Hall (I-QH) transition where the numbers 0 and 10 correspond to the insulator and Landau level filling factor ν = 10 QH state, respectively. In situ titled-magnetic field measurements reveal that the observed direct I-QH transition depends on the magnetic component perpendicular to the quantum well, and the electron system within this structure is 2D in nature. Furthermore, transport measurements on the 2DEG of this study show that carrier density, resistance and mobility are approximately temperature (T)-independent over a wide range of T. Such results could be an advantage for applications in T-insensitive devices.
Facile purification of colloidal NIR-responsive gold nanorods using ions assisted self-assembly
Authors: Liu Lianke , Guo Zhirui , Xu Lina , Xu Ruizhi , Lu Xiang
Published: February 2011

Anisotropic metal nanoparticles have been paid much attention because the broken symmetry of these nanoparticles often leads to novel properties. Anisotropic gold nanoparticles obtained by wet chemical methods inevitably accompany spherical ones due to the intrinsically high symmetry of face-centred cubic metal. Therefore, it is essential for the purification of anisotropic gold nanoparticles. This work presents a facile, low cost while effective solution to the challenging issue of high-purity separation of seed-mediated grown NIR-responsive gold nanorods from co-produced spherical and cubic nanoparticles in solution. The key point of our strategy lies in different shape-dependent solution stability between anisotropic nanoparticles and symmetric ones and selective self-assembly and subsequent precipitation can be induced by introducing ions to the as-made nanorod solution. As a result, gold nanorods of excellent purity (97% in number density) have been obtained within a short time, which has been confirmed by SEM observation and UV-vis-NIR spectroscopy respectively. Based on the experimental facts, a possible shape separation mechanism was also proposed.
Higher titers of some H5N1 and recent human H1N1 and H3N2 influenza viruses in Mv1 Lu vs. MDCK cells
Authors: Hamilton Sara B , Wyatt Diane E , Wahlgren Brett T , O'Dowd Maureen K , Morrissey Jane M , Daniels Deirdre E , Lednicky John A
Published: February 2011

Background

The infectivity of influenza A viruses can differ among the various primary cells and continuous cell lines used for such measurements. Over many years, we observed that all things equal, the cytopathic effects caused by influenza A subtype H1N1, H3N2, and H5N1 viruses were often detected earlier in a mink lung epithelial cell line (Mv1 Lu) than in MDCK cells. We asked whether virus yields as measured by the 50% tissue culture infectious dose and plaque forming titer also differed in MDCK and Mv1 Lu cells infected by the same influenza virus subtypes.

Results

The 50% tissue culture infectious dose and plaque forming titer of many influenza A subtype H1N1, H3N2, and H5N1 viruses was higher in Mv1 Lu than in MDCK cells.

Conclusions

The yields of influenza subtype H1N1, H3N2, and H5N1 viruses can be higher in Mv1 Lu cells than in MDCK cells.
Genetic variability of attachment (G) and Fusion (F) protein genes of human metapneumovirus strains circulating during 2006-2009 in Kolkata, Eastern India
Authors: Agrawal Anurodh S , Roy Tapasi , Ghosh Swati , Chawla-Sarkar Mamta
Published: February 2011

Background

Human metapneumovirus (hMPV) is associated with the acute respiratory tract infection (ARTI) in all the age groups. However, there is limited information on prevalence and genetic diversity of human metapneumovirus (hMPV) strains circulating in India.

Objective

To study prevalence and genomic diversity of hMPV strains among ARTI patients reporting in outpatient departments of hospitals in Kolkata, Eastern India.

Methods

Nasal and/or throat swabs from 2309 patients during January 2006 to December 2009, were screened for the presence of hMPV by RT-PCR of nucleocapsid (N) gene. The G and F genes of representative hMPV positive samples were sequenced.

Results

118 of 2309 (5.11%) clinical samples were positive for hMPV. The majority (≈80%) of the positive cases were detected during July−November all through the study period. Genetic analysis revealed that 77% strains belong to A2 subgroup whereas rest clustered in B1 subgroup. G sequences showed higher diversity at the nucleotide and amino acid level. In contrast, less than 10% variation was observed in F gene of representative strains of all four years. Sequence analysis also revealed changes in the position of stop codon in G protein, which resulted in variable length (217-231 aa) polypeptides.

Conclusion

The study suggests that approximately 5% of ARTI in the region were caused by hMPV. This is the first report on the genetic variability of G and F gene of hMPV strains from India which clearly shows that the G protein of hMPV is continuously evolving. Though the study partially fulfills lacunae of information, further studies from other regions are necessary for better understanding of prevalence, epidemiology and virus evolution in Indian subcontinent.
Management of aplastic anemia in a woman during pregnancy: a case report
Authors: Stibbe Krista JM , Wildschut Hajo IJ , Lugtenburg Pieternella J
Published: February 2011

Introduction

Aplastic anemia is a rare disease caused by destruction of pluripotent stem cells in bone marrow. During pregnancy it could be life-threatening for both mother and child. The only causal therapy for aplastic anemia is bone marrow transplantation, which is contraindicated during pregnancy because of potential embryo toxicity. Treatment options are erythrocytes and platelet transfusions and immunosuppressive therapy. There is, however, no agreement about the optimal supportive care and treatment regime for this disorder during pregnancy.

Case Presentation

A 26-year-old nulliparous Asian woman with an uneventful medical history was admitted to the hospital at 14 weeks' gestation because of excessive vomiting. Routine laboratory tests showed pancytopenia (Hb 3.5 mmol/L, leukocytes 3.5 *109/L, platelets 45 *109L). A bone marrow biopsy confirmed aplastic anemia. Methylprednisolon, cyclosporine A, packed cells and platelet transfusions were initiated. At 33 weeks she developed neutropenia (0.1 *109/L) for which oral colistin and tobramycin were given prophylactically. At 35 weeks labor was induced, during which she developed a fever of 38.2°C. She gave birth spontaneously to a healthy son weighing 2415 grams, who had no signs of pancytopenia. After delivery the blood count of the patient did not recover and did not respond to medication. Eighteen weeks after delivery she died of sepsis complicated by cerebral bleeding and infarction due to severe thrombocytopenia and neutropenia, despite optimal supportive treatment.

Conclusion

This potential life-threatening disease has a relatively good prognosis for both mother and child after optimal treatment. Transfusion during pregnancy is the first choice treatment with recommended hemoglobin levels of >5.5 mmol/L and platelet counts of >20 *109/L. Cyclosporine A seems a reasonable alternative therapy with a reported success rate in non-pregnant patients of 70% when combined with antithymocyte globuline. Our patient died 18 weeks postpartum from cerebral bleeding and infarction due to severe thrombocytopenia despite intensive supportive treatment, methylprednisolon and cyclosporine A.
Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line
Authors: Harris Matthew , Wang Xing Guo , Jiang Zewei , Goldberg Gary L , Casadevall Arturo , Dadachova Ekaterina
Published: February 2011

Background

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide with a poor prognosis. Human papilloma virus (HPV) infection is associated with 20% HNSCC, and 50% of oropharyngeal carcinoma. HPV16 type is detected in 90% of all HPV+ HNSCC. Recently we suggested a fundamentally different approach to treatment of cancers of viral origin by targeting viral antigens on cancer cells with radiolabeled antibodies (mAbs) which promises exquisite specificity of treatment. We aimed at extending this approach to HPV-related head and neck cancer by performing radioimmunotherapy (RIT) targeting E6 and E7 oncogenes with radiolabeled mAbs.

Methods

We first aimed at developing HPV16+ cell line and animal model for RIT of HNSCC as at present there are no commercially available HPV16+ HNSCC cell lines and there is only one HPV+ cell line among the collection maintained by Dusseldorf, Michigan and Turku groups. Commercially available HNSCC cell line FaDu was transfected with pLXSN16E6E7 vector containing HPV16 E6 and E7 genes. Generated novel cell lines were evaluated by PCR and western blot and the tumorigenecity was assessed in nude mice. Proof of principle RIT targeting E6 oncoprotein in 2A3 tumor-bearing nude mice was conducted using unlabeled or 188-Rhenium (188Re)-labeled C1P5 mAb to E6.

Results

Novel HPV16+ 2A3 cell line reliably expressed E6 oncoprotein. E6 expression was modifiable with proteasome inhibitor MG132 in a dose-dependent manner. The levels of E6 expression in 2A3 cell line were estimated to be around 200 HPV copies per cell. The HPV16+ 2A3 cell line preserved 100% tumorigenicity of parent FaDu cells in nude mice. During RIT of 2A3 tumors in nude mice the relatively low dose of 200 μCi 188Re-C1P5 mAb was effective in decreasing the tumor growth in comparison with untreated controls. Unlabeled C1P5 mAb also caused some decrease in tumor progression, however, much less pronounced than 188Re-C1P5 mAb.

Conclusions

We describe a proof-of-principle RIT study targeting HPV16 E6 oncoprotein with radiolabeled mAb to E6 in a stably transformed HPV16+ HNSCC cell line and tumor model in nude mice, and demonstrate potential utility of RIT as a novel molecular targeted therapy for HNSCC.
Fanconi anemia protein FANCD2 inhibits TRF1 polyADP-ribosylation through tankyrase1-dependent manner
Authors: Lyakhovich Alex , Ramirez Maria Jose , Castellanos Andres , Castella Maria , Simons Amanda M , Parvin Jeffrey D , Surralles Jordi
Published: February 2011

Background

Fanconi anemia (FA) is a rare autosomal recessive syndrome characterized by developmental abnormalities, progressive bone marrow failure, and predisposition to cancer. The key FA protein FANCD2 crosstalks with members of DNA damage and repair pathways that also play a role at telomeres. Therefore, we investigated whether FANCD2 has a similar involvement at telomeres.

Results

We reveal that FANCD2 may perform a novel function separate to the FANCD2/BRCA pathway. This function includes FANCD2 interaction with one of the telomere components, the PARP family member tankyrase-1. Moreover, FANCD2 inhibits tankyrase-1 activity in vitro. In turn, FANCD2 deficiency increases the polyADP-ribosylation of telomere binding factor TRF1.

Conclusions

FANCD2 binding and inhibiting tankyrase-1PARsylation at telomeres may provide an additional step within the FA pathway for the regulation of genomic integrity.
Allogeneic Stem-Cell Transplantation As Salvage Therapy for Patients With Diffuse Large B-Cell Non-Hodgkin's Lymphoma Relapsing After an Autologous Stem-Cell Transplantation: An Analysis of the European Group for Blood and Marrow Transplantation Registry
Authors: van Kampen Roel J.W. , Canals Carmen , Schouten Harry C. , Nagler Arnon , Thomson Kirsty J. , Vernant Jean-Paul , Buzyn Agnes , Boogaerts Marc A. , Luan Jian-Jian , Maury Sébastien , Milpied Noel J. , Jouet Jean-Pierre , Ossenkoppele Gert J. , Sureda Anna
Published: February 2011

Purpose

To analyze the outcome, including nonrelapse mortality (NRM), relapse rate (RR), progression-free survival (PFS), and overall survival (OS), of patients with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) relapsed after an autologous stem-cell transplantation (ASCT) and treated with an allogeneic stem-cell transplantation (allo-SCT).

Patients and Methods

The European Group for Blood and Marrow Transplantation database was scanned for a first allo-SCT in relapsed DLBCL after a previous ASCT between 1997 and 2006. Other inclusion criteria were age at allo-SCT ≥ 18 years and availability of an HLA-identical sibling or a matched unrelated donor. A total of 101 patients (57 males; median age, 46 years) were included. Median follow-up for survivors was 36 months.

Results

Myeloablative conditioning regimen was used in 37 patients and reduced intensity conditioning (RIC) was used in 64 patients. Three-year NRM was 28.2% (95% CI, 20% to 39%), RR was 30.1% (95% CI, 22% to 41%), PFS was 41.7% (95% CI, 32% to 52%), and OS was 53.8% (95% CI, 44% to 64%). NRM was significantly increased in patients ≥ 45 years (P = .01) and in those with an early relapse (< 12 months) after ASCT (P = .01). RR was significantly higher in refractory patients (P = .03). A time interval to relapse after ASCT of < 12 months was associated with lower PFS (P = .03). The use of RIC regimens was followed by a trend to a lower NRM (P = .1) and a trend to a higher RR (P = .1), with no differences in PFS and OS. No differences were seen between HLA-identical siblings and matched unrelated donors.

Conclusion

Allo-SCT in relapsed DLBCL after ASCT is a promising therapeutic modality. Patients with a long remission after ASCT and with sensitive disease at allo-SCT are the best candidates for this approach.