bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progress toward inducing immunologic tolerance to factor VIII
Authors: Scott David W. , Pratt Kathleen P. , Miao Carol H. 
Published: March 2013

Abstract
A major problem in treating hemophilia A patients with therapeutic factor VIII (FVIII) is that 20% to 30% of these patients produce neutralizing anti-FVIII antibodies. These antibodies block (inhibit) the procoagulant function of FVIII and thus are termed “inhibitors.” The currently accepted clinical method to attempt to eliminate inhibitors is immune tolerance induction (ITI) via a protocol requiring intensive FVIII treatment until inhibitor titers drop. Although often successful, ITI is extremely costly and is less likely to succeed in patients with high-titer inhibitors. During the past decade, significant progress has been made in clarifying mechanisms of allo- and autoimmune responses to FVIII and in suppression of these responses. Animal model studies are suggesting novel, less costly methods to induce tolerance to FVIII. Complementary studies of anti-FVIII T-cell responses using blood samples from human donors are identifying immunodominant T-cell epitopes in FVIII and possible targets for tolerogenic efforts. Mechanistic experiments using human T-cell clones and lines are providing a clinically relevant counterpoint to the animal model studies. This review highlights recent progress toward the related goals of lowering the incidence of anti-FVIII immune responses and promoting durable, functional immune tolerance to FVIII in patients with an existing inhibitor.
Coupled coincidence point theorems in (intuitionistic) fuzzy normed spaces
Authors: Cho YJ , Martínez-Moreno J , Roldán A , Roldán C 
Published: March 2013

Abstract
In this paper, we prove some coupled coincidence point theorems in fuzzy normed spaces. Our results improve and restate the proof lines of the main results given in the papers (Eshaghi Gordji et al. in Math. Comput. Model. 54:1897-1906, 2011) and (Sintunavarat et al. in Fixed Point Theory Appl. 2011:81, 2011).

MSC:47H10, 54H25, 34B15.
A detailed molecular analysis of complete Bovine Leukemia Virus genomes isolated from B-cell lymphosarcomas
Authors: Moratorio Gonzalo , Fischer Sabrina , Bianchi Sergio , Tomé Lorena , Rama Gonzalo , Obal Gonzalo , Carrión Federico , Pritsch Otto , Cristina Juan 
Published: March 2013

Abstract
It is widely accepted that the majority of cancers result from multiple cellular events leading to malignancy after a prolonged period of clinical latency, and that the immune system plays a critical role in the control of cancer progression. Bovine leukemia virus (BLV) is an oncogenic member of the Retroviridae family. Complete genomic sequences of BLV strains isolated from peripheral blood mononuclear cells (PBMC) from cattle have been previously reported. However, a detailed characterization of the complete genome of BLV strains directly isolated from bovine tumors is much needed in order to contribute to the understanding of the mechanisms of leukemogenesis induced by BLV in cattle. In this study, we performed a molecular characterization of BLV complete genomes from bovine B-cell lymphosarcoma isolates. A nucleotide substitution was found in the glucocorticoid response element (GRE) site of the 5' long terminal repeat (5'LTR) of the BLV isolates. All amino acid substitutions in Tax previously found to be related to stimulate high transcriptional activity of 5'LTR were not found in these studies. Amino acid substitutions were found in the nucleocapsid, gp51 and G4 proteins. Premature stop-codons in R3 were observed. Few mutations or amino acid substitutions may be needed to allow BLV provirus to achieve silencing. Substitutions that favor suppression of viral expression in malignant B cells might be a strategy to circumvent effective immune attack.
Identification and characterization of two distinct PPP1R2 isoforms in human spermatozoa
Authors: Korrodi-Gregório Luis , Ferreira Mónica , Vintém Ana Paula , Wu Wenjuan , Muller Thorsten , Marcus Katrin , Vijayaraghavan Srinivasan , Brautigan David L , da Cruz e Silva Odete A B , Fardilha Margarida , da Cruz e Silva Edgar F 
Published: March 2013

AbstractBackgroundProtein Ser/Thr Phosphatase PPP1CC2 is an alternatively spliced isoform of PPP1C that is highly enriched in testis and selectively expressed in sperm. Addition of the phosphatase inhibitor toxins okadaic acid or calyculin A to caput and caudal sperm triggers and stimulates motility, respectively. Thus, the endogenous mechanisms of phosphatase inhibition are fundamental for controlling sperm function and should be characterized. Preliminary results have shown a protein phosphatase inhibitor activity resembling PPP1R2 in bovine and primate spermatozoa.ResultsHere we show conclusively, for the first time, that PPP1R2 is present in sperm. In addition, we have also identified a novel protein, PPP1R2P3. The latter was previously thought to be an intron-less pseudogene. We show that the protein corresponding to the pseudogene is expressed. It has PPP1 inhibitory potency similar to PPP1R2. The potential phosphosites in PPP1R2 are substituted by non-phosphorylable residues, T73P and S87R, in PPP1R2P3. We also confirm that PPP1R2/PPP1R2P3 are phosphorylated at Ser121 and Ser122, and report a novel phosphorylation site, Ser127. Subfractionation of sperm structures show that PPP1CC2, PPP1R2/PPP1R2P3 are located in the head and tail structures.ConclusionsThe conclusive identification and localization of sperm PPP1R2 and PPP1R2P3 lays the basis for future studies on their roles in acrosome reaction, sperm motility and hyperactivation. An intriguing possibility is that a switch in PPP1CC2 inhibitory subunits could be the trigger for sperm motility in the epididymis and/or sperm hyperactivation in the female reproductive tract.
Differential miRNA expression profiles in proliferating or differentiated keratinocytes in response to gamma irradiation
Authors: Joly-Tonetti Nicolas , Viñuelas José , Gandrillon Olivier , Lamartine Jérôme 
Published: March 2013

Abstract

Background
MicroRNAs (miRNAs), a group of short non-coding RNAs that negatively regulate gene expression, have recently emerged as potential modulators of cellular response to ionizing radiations both in vitro and in vivo in various cell types and tissues. However, in epidermal cells, the involvement of the miRNA machinery in the cellular response to ionizing radiations remains to be clarified. Indeed, understanding the mechanisms of cutaneous radiosensitivity is an important issue since skin is the most exposed organ to ionizing radiations and among the most sensitive.

Results
We settled up an expression study of miRNAs in primary human skin keratinocytes using a microfluidic system of qPCR assay, which permits to assess the expression of almost 700 annotated miRNAs. The keratinocytes were cultured to a proliferative or a differentiated state mimicking basal or suprabasal layers of human epidermis. These cells were irradiated at 10 mGy or 6 Gy and RNA was extracted 3 hours after irradiation. We found that proliferative cells irradiated at 6 Gy display a global fall of miRNA expression whereas differentiated cells exposed to the same dose display a global increase of miRNAs expression. We identified twenty miRNAs weakly but significantly modulated after 6 Gy irradiation, whereas only 2 miRNAs were modulated after low-dose irradiation in proliferating cells. To go further into the biological meaning of this miRNA response, we over-expressed some of the responding miRNA in proliferating cells: we observed a significant decrease of cell viability 72 hours after irradiation. Functional annotation of their predicted targets revealed that G-protein related pathways might be regulated by these responding miRNAs.

Conclusions
Our results reveal that human primary keratinocytes exposed to ionizing irradiation expressed a miRNA pattern strongly related to the differentiation status of irradiated cells. We also demonstrate that some miRNAs play a role in the radiation response to ensure the short-term survival of irradiated keratinocytes.
The protein translocation systems in plants – composition and variability on the example of Solanum lycopersicum
Authors: Paul Puneet , Simm Stefan , Blaumeiser Andreas , Scharf Klaus-Dieter , Fragkostefanakis Sotirios , Mirus Oliver , Schleiff Enrico 
Published: March 2013

Abstract

Background
Protein translocation across membranes is a central process in all cells. In the past decades the molecular composition of the translocation systems in the membranes of the endoplasmic reticulum, peroxisomes, mitochondria and chloroplasts have been established based on the analysis of model organisms. Today, these results have to be transferred to other plant species. We bioinformatically determined the inventory of putative translocation factors in tomato (Solanum lycopersicum) by orthologue search and domain architecture analyses. In addition, we investigated the diversity of such systems by comparing our findings to the model organisms Saccharomyces cerevisiae, Arabidopsis thaliana and 12 other plant species.

Results
The literature search end up in a total of 130 translocation components in yeast and A. thaliana, which are either experimentally confirmed or homologous to experimentally confirmed factors. From our bioinformatic analysis (PGAP and OrthoMCL), we identified (co-)orthologues in plants, which in combination yielded 148 and 143 orthologues in A. thaliana and S. lycopersicum, respectively. Interestingly, we traced 82% overlap in findings from both approaches though we did not find any orthologues for 27% of the factors by either procedure. In turn, 29% of the factors displayed the presence of more than one (co-)orthologue in tomato. Moreover, our analysis revealed that the genomic composition of the translocation machineries in the bryophyte Physcomitrella patens resemble more to higher plants than to single celled green algae. The monocots (Z. mays and O. sativa) follow more or less a similar conservation pattern for encoding the translocon components. In contrast, a diverse pattern was observed in different eudicots.

Conclusions
The orthologue search shows in most cases a clear conservation of components of the translocation pathways/machineries. Only the Get-dependent integration of tail-anchored proteins seems to be distinct. Further, the complexity of the translocation pathway in terms of existing orthologues seems to vary among plant species. This might be the consequence of palaeoploidisation during evolution in plants; lineage specific whole genome duplications in Arabidopsis thaliana and triplications in Solanum lycopersicum.
Early surgery versus optimal current step-up practice for chronic pancreatitis (ESCAPE): design and rationale of a randomized trial
Authors: Ahmed Ali Usama , Issa Yama , Bruno Marco J , van Goor Harry , van Santvoort Hjalmar , Busch Olivier RC , Dejong Cornelis HC , Nieuwenhuijs Vincent B , van Eijck Casper H , van Dullemen Hendrik M , Fockens Paul , Siersema Peter D , Gouma Dirk J , van Hooft Jeanin E , Keulemans Yolande , Poley Jan W , Timmer Robin , Besselink Marc G , Vleggaar Frank P , Wilder-Smith Oliver H , Gooszen Hein G , Dijkgraaf Marcel GW , Boermeester Marja A ,   for the Dutch Pancreatitis Study Group
Published: March 2013

Abstract

Background
In current practice, patients with chronic pancreatitis undergo surgical intervention in a late stage of the disease, when conservative treatment and endoscopic interventions have failed. Recent evidence suggests that surgical intervention early on in the disease benefits patients in terms of better pain control and preservation of pancreatic function. Therefore, we designed a randomized controlled trial to evaluate the benefits, risks and costs of early surgical intervention compared to the current stepwise practice for chronic pancreatitis.

Methods/design
The ESCAPE trial is a randomized controlled, parallel, superiority multicenter trial. Patients with chronic pancreatitis, a dilated pancreatic duct (≥ 5 mm) and moderate pain and/or frequent flare-ups will be registered and followed monthly as potential candidates for the trial. When a registered patient meets the randomization criteria (i.e. need for opioid analgesics) the patient will be randomized to either early surgical intervention (group A) or optimal current step-up practice (group B). An expert panel of chronic pancreatitis specialists will oversee the assessment of eligibility and ensure that allocation to either treatment arm is possible. Patients in group A will undergo pancreaticojejunostomy or a Frey-procedure in case of an enlarged pancreatic head (≥ 4 cm). Patients in group B will undergo a step-up practice of optimal medical treatment, if needed followed by endoscopic interventions, and if needed followed by surgery, according to predefined criteria. Primary outcome is pain assessed with the Izbicki pain score during a follow-up of 18 months. Secondary outcomes include complications, mortality, total direct and indirect costs, quality of life, pancreatic insufficiency, alternative pain scales, length of hospital admission, number of interventions and pancreatitis flare-ups. For the sample size calculation we defined a minimal clinically relevant difference in the primary endpoint as a difference of at least 15 points on the Izbicki pain score during follow-up. To detect this difference a total of 88 patients will be randomized (alpha 0.05, power 90%, drop-out 10%).

Discussion
The ESCAPE trial will investigate whether early surgery in chronic pancreatitis is beneficial in terms of pain relief, pancreatic function and quality of life, compared with current step-up practice.

Trial registration
ISRCTN: ISRCTN45877994
αB-crystallin stimulates VEGF secretion and tumor cell migration and correlates with enhanced distant metastasis in head and neck squamous cell carcinoma
Authors: van de Schootbrugge Chantal , Bussink Johan , Span Paul N , Sweep Fred CGJ , Grénman Reidar , Stegeman Hanneke , Pruijn Ger JM , Kaanders Johannes HAM , Boelens Wilbert C 
Published: March 2013

AbstractBackgroundαB-crystallin is able to modulate vascular endothelial growth factor (VEGF) secretion. In many solid tumors VEGF is associated with angiogenesis, metastasis formation and poor prognosis. We set out to assess whether αB-crystallin expression is correlated with worse prognosis and whether this is related to VEGF secretion and cell motility in head and neck squamous cell carcinoma (HNSCC).MethodsαB-crystallin expression was determined immunohistochemically in tumor biopsies of 38 HNSCC patients. Locoregional control (LRC) and metastasis-free survival (MFS) of the patients were analyzed in relation to αB-crystallin expression. Additionally, the effects of αB-crystallin knockdown on VEGF secretion and cell motility were studied in vitro.ResultsPatients with higher staining fractions of αB-crystallin exhibited a significantly shorter MFS (Log-Rank test, p < 0.005). Under normoxic conditions αB-crystallin knockdown with two different siRNAs in a HNSCC cell line reduced VEGF secretion 1.9-fold and 2.1-fold, respectively. Under hypoxic conditions, a similar reduction of VEGF secretion was observed, 1.9-fold and 2.2-fold, respectively. The effect on cell motility was assessed by a gap closure assay, which showed that αB-crystallin knockdown decreased the rate by which HNSCC cells were able to close a gap by 1.5- to 2.0-fold.ConclusionsOur data suggest that αB-crystallin expression is associated with distant metastases formation in HNSCC patients. This association might relate to the chaperone function of αB-crystallin in mediating folding and secretion of VEGF and stimulating cell migration.
Design of a randomized controlled trial for multiple cancer risk behaviors among Spanish-speaking Mexican-origin smokers
Authors: Castro Yessenia , Basen-Engquist Karen , Fernandez Maria E , Strong Larkin L , Eakin Elizabeth G , Resnicow Ken , Li Yisheng , Wetter David W 
Published: March 2013

AbstractBackgroundSmoking, poor diet, and physical inactivity account for as much as 60% of cancer risk. Latinos experience profound disparities in health behaviors, as well as the cancers associated with them. Currently, there is a dearth of controlled trials addressing these health behaviors among Latinos. Further, to the best of our knowledge, no studies address all three behaviors simultaneously, are culturally sensitive, and are guided by formative work with the target population. Latinos represent 14% of the U.S. population and are the fastest growing minority group in the country. Efforts to intervene on these important lifestyle factors among Latinos may accelerate the elimination of cancer-related health disparities.Methods/designThe proposed study will evaluate the efficacy of an evidence-based and theoretically-driven Motivation And Problem Solving (MAPS) intervention, adapted and culturally-tailored for reducing cancer risk related to smoking, poor diet, and physical inactivity among high-risk Mexican-origin smokers who are overweight/obese (n = 400). Participants will be randomly assigned to one of two groups: Health Education (HE) or MAPS (HE + up to 18 MAPS counseling calls over 18 months). Primary outcomes are smoking status, servings of fruits and vegetables, and both self-reported and objectively measured physical activity. Outcome assessments will occur at baseline, 6 months, 12 months, and 18 months.DiscussionThe current study will contribute to a very limited evidence base on multiple risk factor intervention studies on Mexican-origin individuals and has the potential to inform both future research and practice related to reducing cancer risk disparities. An effective program targeting multiple cancer risk behaviors modeled after chronic care programs has the potential to make a large public health impact because of the dearth of evidence-based interventions for Latinos and the extended period of support that is provided in such a program.Trial registrationNational Institutes of Health Clinical Trials Registry #NCT01504919
Weight, height and eruption times of permanent teeth of children aged 4–15 years in Kampala, Uganda
Authors: Kutesa Annet , Nkamba Eriab Moses , Muwazi Louis , Buwembo William , Rwenyonyi Charles Mugisha 
Published: March 2013

Abstract

Background
Tooth eruption is a continuous biological process by which developing teeth emerge through the jaws and the overlying mucosa to enter into the oral cavity. Tooth eruption time and sequence are important factors in dental treatment planning, particularly in orthodontics, but also in forensic dentistry to estimate age of a child. Tooth eruption time is influenced by many factors. In this study we set out to determine the timing of eruption of permanent teeth and assess its association with the height and weight of school children aged 4–15 years in Kampala, Uganda.

Methods
This was a cross sectional study comprising of 1041 healthy Ugandan children: boys/girls (520/521) who were consecutively selected from two primary schools in Kampala. The children were clinically assessed for tooth emergency through the oral mucosa as well as measuring their weight and height. The mean and standard deviation of tooth eruption time was estimated for boys and girls. Bivariate analysis was used to assess any significant association between tooth eruption time and demographic variables. Pearson and partial correlation analyses were used to assess any significant association between the tooth eruption time and anthropometric measurements of the children.

Results
Generally, the mean eruption times for girls were lower compared to boys except for three teeth (#25, #32 and #42) which erupted earlier in boys. The average difference in mean eruption times of all teeth between boys and girls was found to be 0.8 (range, 0–1.5) years. In partial correlation analysis, mean tooth eruption times were positively, but not significantly associated with height while controlling for weight except for the mandibular left central incisor (#31). On the other hand, in partial correlation analysis, mean tooth eruption times were positively associated with weight while controlling for height except for tooth #11, #16, #26 and #41. The weight of the child was significantly correlated with mean eruption times in 50% of the teeth.

Conclusion
In the present study, the mean tooth eruption times for girls were lower compared to boys except for three teeth (#25, #32 and #42). The height of the child did not show any significant influence on the tooth eruption times while the influence of weight on tooth eruption times was non-conclusive.
Assessing the outcomes of implantable cardioverter defibrillator treatment in a real world setting: results from hospital record data
Authors: Ghislandi Simone , Torbica Aleksandra , Boriani Giuseppe 
Published: March 2013

Abstract

Background
A plethora of clinical studies have assessed the benefits of implantable cardioverter defibrillators (ICDs) and supported their use in clinical practice. However, evidence on the safety and efficacy of ICDs appears insufficient to support expansion of their use in clinical practice, and more information on their impact in real life settings is warranted. This paper aims to investigate the impact of ICDs using a large administrative dataset reflecting actual clinical practice.

Methods
Data were obtained from the hospital discharge database of the Friuli Venezia Giulia region in Italy containing patient-level information on 169,488 cases. Data on mortality outside hospital were obtained from regional sources. Exact matching method was used to estimate the outcomes associated with ICDs: mortality, length of stay, re-hospitalization and regional expenditure. The method was applied in two steps. First, patients with ICDs were matched with those without using the following: age class (by 5 years), gender, year of admission, type of admission (day hospital vs. ordinary) and primary diagnosis. In the second step, matching included also Charlson Comorbidities Index. Exact matching average treatment effect on the treated (ATT) was used as a main measure of impact.

Results
Compared with matched controls, treatment with ICDs was associated with lower mortality (absolute risk reduction 10.6% at 1 year and 8.3% at 2 and 8.4% at 3 years, p < 0.001 and hazard ratio 0.80, p < 0.001), greater regional expenditure at index hospitalization (ATT: €9459.64, p < 0.001) and during follow up (ATT: €1707.29, p < 0.001) and higher re-hospitalization rate (ATT: 0.53, p < 0.001). No significant difference was found for length of stay (9.07 vs. 8.86 days). The results were maintained after more restrictive matching was applied.

Conclusions
Assessing the impact of innovative, expensive medical technologies on the basis of real world data is warranted, especially when there are barriers to implementation. Hospital administrative datasets can be of great value when a technology such as the ICD is implemented in a relatively small sample of patients, to allow use of exact matching techniques.