bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ras-Driven Transcriptome Analysis Identifies Aurora Kinase A as a Potential Malignant Peripheral Nerve Sheath Tumor Therapeutic Target
Authors: Patel Ami V. , Eaves David , Jessen Walter J. , Rizvi Tilat A. , Ecsedy Jeffrey A. , Qian Mark G. , Aronow Bruce J. , Perentesis John P. , Serra Eduard , Cripe Timothy P. , Miller Shyra J. , Ratner Nancy 
Published: July 2012

AbstractPurpose: Patients with neurofibromatosis type 1 (NF1) develop malignant peripheral nerve sheath tumors (MPNST), which are often inoperable and do not respond well to current chemotherapies or radiation. The goal of this study was to use comprehensive gene expression analysis to identify novel therapeutic targets.Experimental Design: Nerve Schwann cells and/or their precursors are the tumorigenic cell types in MPNST because of the loss of the NF1 gene, which encodes the RasGAP protein neurofibromin. Therefore, we created a transgenic mouse model, CNP-HRas12V, expressing constitutively active HRas in Schwann cells and defined a Ras-induced gene expression signature to drive a Bayesian factor regression model analysis of differentially expressed genes in mouse and human neurofibromas and MPNSTs. We tested functional significance of Aurora kinase overexpression in MPNST in vitro and in vivo using Aurora kinase short hairpin RNAs (shRNA) and compounds that inhibit Aurora kinase.Results: We identified 2,000 genes with probability of linkage to nerve Ras signaling of which 339 were significantly differentially expressed in mouse and human NF1-related tumor samples relative to normal nerves, including Aurora kinase A (AURKA). AURKA was dramatically overexpressed and genomically amplified in MPNSTs but not neurofibromas. Aurora kinase shRNAs and Aurora kinase inhibitors blocked MPNST cell growth in vitro. Furthermore, an AURKA selective inhibitor, MLN8237, stabilized tumor volume and significantly increased survival of mice with MPNST xenografts.Conclusion: Integrative cross-species transcriptome analyses combined with preclinical testing has provided an effective method for identifying candidates for molecular-targeted therapeutics. Blocking Aurora kinases may be a viable treatment platform for MPNST. Clin Cancer Res; 18(18); 5020–30. ©2012 AACR.
Predictability of Precipitation from Continental Radar Images. Part V: Growth and Decay
Authors: Radhakrishna Basivi , Zawadzki Isztar , Fabry Frédéric 
Published: July 2012

Abstract
In a Lagrangian frame of reference, the accuracy of rainfall systems predicted by nowcasting algorithms can be improved by incorporating the growth and decay of the rainfall. The scale dependence of predictability of growth and decay of continental-scale precipitating systems is studied with the help of the U.S. national radar composites. The growth and decay of precipitating systems is estimated in a time interval τ by correcting the precipitation image for advection and rotation at time t + τ with respect to the precipitation image at time t and then subtracting the former from the latter. Results show that the two-dimensional correlation of growth and decay has an elliptical structure, indicating that growth and decay is nonisotropic. The probability density function of precipitation intensities and of growth and decay follows a Gaussian distribution. The scale-dependence analysis of growth and decay patterns indicates that the growth and decay of rainfall may be predictable up to about 2 h for scales larger than 250 km.
Idealized Annually Averaged Macroturbulent Hadley Circulation in a Shallow-Water Model
Authors: Adam Ori , Harnik Nili 
Published: July 2012

Abstract
The interaction of midlatitude eddies and the thermally driven Hadley circulation is studied using an idealized shallow-water model on the rotating sphere. The contributions of the annually averaged differential heating, vertical advection of momentum from a stationary boundary layer, and the gross effect of eddies, parameterized by Rayleigh damping, including a hemispherically asymmetric damping, are examined at steady state.
The study finds that the relative dominance of eddies, as quantified by the local Rossby number, is predicted by an effective macroturbulent Hadley circulation Prandtl number Pr. In addition, viscous solutions of the Hadley circulation width and strength, subtropical jet amplitude, and equator-to-pole temperature difference scale as deviations from the respective inviscid solutions.
Semianalytic solutions for the steady circulation are derived in the limit of weak eddy dominance (small Pr) as deviations from the respective inviscid solutions. These solutions follow a three-region paradigm: weak temperature gradient at the ascending branch of the Hadley circulation, monotonically decreasing angular momentum at the descending branch, and modified radiative–convective equilibrium at the extratropics. Using the three-region solutions, scaling relations found in the full solutions are reproduced analytically. The weak eddy-dominance solutions diverge from the full solutions as Pr increases and may become invalid for Pr &gt; 1 due to the breakdown of the three-region global circulation structure.
The qualitative predictions of the response of the Hadley circulation to heating based on the weak eddy-dominance solutions and Pr are in agreement with the findings of more complex models and the observed atmosphere.
North Australian Sea Surface Temperatures and the El Niño–Southern Oscillation in the CMIP5 Models
Authors: Catto Jennifer L. , Nicholls Neville , Jakob Christian 
Published: July 2012

Abstract
Aspects of the climate of Australia are linked to interannual variability of the sea surface temperatures (SSTs) to the north of the country. SST anomalies in this region have been shown to exhibit strong, seasonally varying links to ENSO and tropical Pacific SSTs.
Previously, the models participating in phase 3 of the Coupled Model Intercomparison Project (CMIP3) have been evaluated and found to vary in their abilities to represent both the seasonal cycle of correlations between the Niño-3.4 and north Australian SSTs and the evolution of SSTs during composite El Niño and La Niña events. In this study, the new suite of models participating in the CMIP5 is evaluated using the same method. In the multimodel mean, the representation of the links is slightly improved, but generally the models do not capture the strength of the negative correlations during the second half of the year. The models also still struggle to capture the SST evolution in the north Australian region during El Niño and La Niña events.
Referral Patterns of Nonmalignant Patients to an Irish Specialist Palliative Medicine Service
Authors: Wallace Elaine M. , Tiernan Eoin 
Published: July 2012

Background: Our perception is that the proportion of referrals made to the specialist palliative medicine service (SPMS) in our institution for patients with a primary diagnosis of nonmalignant disease is high and that these patients are often referred late in their illness. We aimed to review the symptom burden and referral patterns of patients with a noncancer diagnosis to the SPMS in our centre. Methods: All new non-malignant referrals to the SPMS in 2009 were included. Data were collected from patients' medical records and analyzed using Excel. Results: Ninety-two referrals were identified: 60 (65%) female, 32 (35%) male. Mean age 76.5 years (21-92). Reasons for referral included: end-of-life care (n=55, 60%), symptom control (n=23, 25%), home care support (n=13, 14%) and psychological support (n=1, 1%). Mean time from admission to referral was 24.9 days (<1-165). Fifty-six (61%) patients were commenced on a syringe driver (CSCI), with a mean time spent on a CSCI of 2.8 days (< 1-17). Primary outcomes included: death (n=72, 78.5%), home discharge (n=9, 10%), discharge to another care institution (n=6, 6.5%), discharge from service (n=3, 3%) and hospice transfer (n=2, 2%). Mean time from referral to outcome was 4.6 days (<1-35). Conclusion: The proportion of noncancer patients referred to the SPMS is our institution is high. This study confirms that nonmalignant referrals are commonly sent to the SPMS when patients are actively dying or very imminently dying. Further education of colleagues is warranted in the role of the SPMS, particularly with regard to earlier referral.
A method for utilizing co-primary efficacy outcome measures to screen regimens for activity in two-stage Phase II clinical trials
Authors: Sill Michael W , Rubinstein Larry , Litwin Samuel , Yothers Greg 
Published: July 2012

Background Most Phase II clinical trials utilize a single primary end point to determine the promise of a regimen for future study. However, many disorders manifest themselves in complex ways. For example, migraine headaches can cause pain, auras, photophobia, and emesis. Investigators may believe that a drug is effective at reducing migraine pain and the severity of emesis during an attack. Nevertheless, they could still be interested in proceeding with the development of the drug if it is effective against only one of these symptoms. Such a study would be a candidate for a clinical trial with co-primary end points. Purpose The purpose of the article is to provide a method for designing a single arm, two-stage clinical trial with dichotomous co-primary end points of efficacy that has the ability to detect activity on either response measure with high probability when the drug is active on one or both measures, while at the same time rejecting the drug with high probability when there is little activity on both dimensions. The design enables early closure for futility and is flexible with regard to attained accrual. Methods The design is proposed in the context of cancer clinical trials with tumor response and progression-free survival (PFS) status after a certain period. Both end points are assumed to be distributed as binomial random variables, and uninteresting probabilities of success are determined from historical controls. Given the necessity of accrual flexibility, exhaustive searching algorithms to find optimum designs do not seem feasible at this time. Instead, critical values are determined for realized sample sizes using specific procedures. Then accrual windows are found to achieve a design’s desired level of significance, probability of early termination (PET), and power. Results The design is illustrated with a clinical trial that examined bevacizumab in patients with recurrent endometrial cancer. This study was negative by tumor response but positive by 6-month PFS. The procedure was compared to modified procedures in the literature, indicating that the method is competitive. Limitations Although the procedure allows investigators to construct designs with desired levels of significance and power, the PET under the null hypothesis is smaller than for single end point studies. Conclusions The impact of adding an additional end point on the sample size is often minimal, but the study gains sensitivity to activity on another dimension of treatment response. The operating characteristics are fairly robust to the level of association between the two end points. Software is available online.
Optimization of de novo transcriptome assembly from high-throughput short read sequencing data improves functional annotation for non-model organisms
Authors: Haznedaroglu Berat Z , Reeves Darryl , Rismani-Yazdi Hamid , Peccia Jordan 
Published: July 2012

Abstract

Background
The k-mer hash length is a key factor affecting the output of de novo transcriptome assembly packages using de Bruijn graph algorithms. Assemblies constructed with varying single k-mer choices might result in the loss of unique contiguous sequences (contigs) and relevant biological information. A common solution to this problem is the clustering of single k-mer assemblies. Even though annotation is one of the primary goals of a transcriptome assembly, the success of assembly strategies does not consider the impact of k-mer selection on the annotation output. This study provides an in-depth k-mer selection analysis that is focused on the degree of functional annotation achieved for a non-model organism where no reference genome information is available. Individual k-mers and clustered assemblies (CA) were considered using three representative software packages. Pair-wise comparison analyses (between individual k-mers and CAs) were produced to reveal missing Kyoto Encyclopedia of Genes and Genomes (KEGG) ortholog identifiers (KOIs), and to determine a strategy that maximizes the recovery of biological information in a de novo transcriptome assembly.

Results
Analyses of single k-mer assemblies resulted in the generation of various quantities of contigs and functional annotations within the selection window of k-mers (k-19 to k-63). For each k-mer in this window, generated assemblies contained certain unique contigs and KOIs that were not present in the other k-mer assemblies. Producing a non-redundant CA of k-mers 19 to 63 resulted in a more complete functional annotation than any single k-mer assembly. However, a fraction of unique annotations remained (~0.19 to 0.27% of total KOIs) in the assemblies of individual k-mers (k-19 to k-63) that were not present in the non-redundant CA. A workflow to recover these unique annotations is presented.

Conclusions
This study demonstrated that different k-mer choices result in various quantities of unique contigs per single k-mer assembly which affects biological information that is retrievable from the transcriptome. This undesirable effect can be minimized, but not eliminated, with clustering of multi-k assemblies with redundancy removal. The complete extraction of biological information in de novo transcriptomics studies requires both the production of a CA and efforts to identify unique contigs that are present in individual k-mer assemblies but not in the CA.
Differential microRNA response to a high-cholesterol, high-fat diet in livers of low and high LDL-C baboons
Authors: Karere Genesio M , Glenn Jeremy P , VandeBerg John L , Cox Laura A 
Published: July 2012

AbstractBackgroundDysregulation of microRNA (miRNA) expression has been implicated in molecular genetic events leading to the progression and development of atherosclerosis. We hypothesized that miRNA expression profiles differ between baboons with low and high serum low-density lipoprotein cholesterol (LDL-C) concentrations in response to diet, and that a subset of these miRNAs regulate genes relevant to dyslipidemia and risk of atherosclerosis.ResultsUsing Next Generation Illumina sequencing methods, we sequenced hepatic small RNA libraries from baboons differing in their LDL-C response to a high-cholesterol, high-fat (HCHF) challenge diet (low LDL-C, n = 3; high LDL-C, n = 3), resulting in 517 baboon miRNAs: 490 were identical to human miRNAs and 27 were novel. We compared miRNA expression profiles from liver biopsies collected before and after the challenge diet and observed that HCHF diet elicited expression of more miRNAs compared to baseline (chow) diet for both low and high LDL-C baboons. Eighteen miRNAs exhibited differential expression in response to HCHF diet in high LDL-C baboons compared to 10 miRNAs in low LDL-C baboons. We used TargetScan/Base tools to predict putative miRNA targets; miRNAs expressed in high LDL-C baboons had significantly more gene targets than miRNAs expressed in low LDL-C responders. Further, we identified miRNA isomers and other non-coding RNAs that were differentially expressed in response to the challenge diet in both high LDL-C and low LDL-C baboons.ConclusionsWe sequenced and annotated baboon liver miRNAs from low LDL-C and high LDL-C responders using high coverage Next Gen sequencing methods, determined expression changes in response to a HCHF diet challenge, and predicted target genes regulated by the differentially expressed miRNAs. The identified miRNAs will enrich the database for non-coding small RNAs including the extent of variation in these sequences. Further, we identified other small non-coding RNAs differentially expressed in response to diet. Our discovery of differentially expressed baboon miRNAs in response to a HCHF diet challenge that differ by LDL-C phenotype is a fundamental step in understating the role of non-coding RNAs in dyslipidemia.
Rumen microbial and fermentation characteristics are affected differently by bacterial probiotic supplementation during induced lactic and subacute acidosis in sheep
Authors: Lettat Abderzak , Nozière Pierre , Silberberg Mathieu , Morgavi Diego P , Berger Claudette , Martin Cécile 
Published: July 2012

Abstract

Background
Ruminal disbiosis induced by feeding is the cause of ruminal acidosis, a digestive disorder prevalent in high-producing ruminants. Because probiotic microorganisms can modulate the gastrointestinal microbiota, propionibacteria- and lactobacilli-based probiotics were tested for their effectiveness in preventing different forms of acidosis.

Results
Lactic acidosis, butyric and propionic subacute ruminal acidosis (SARA) were induced by feed chalenges in three groups of four wethers intraruminally dosed with wheat, corn or beet pulp. In each group, wethers were either not supplemented (C) or supplemented with Propionibacterium P63 alone (P) or combined with L. plantarum (Lp + P) or L. rhamnosus (Lr + P). Compared with C, all the probiotics stimulated lactobacilli proliferation, which reached up to 25% of total bacteria during wheat-induced lactic acidosis. This induced a large increase in lactate concentration, which decreased ruminal pH. During the corn-induced butyric SARA, Lp + P decreased Prevotella spp. proportion with a concomitant decrease in microbial amylase activity and total volatile fatty acids concentration, and an increase in xylanase activity and pH. Relative to the beet pulp-induced propionic SARA, P and Lr + P improved ruminal pH without affecting the microbial or fermentation characteristics. Regardless of acidosis type, denaturing gradient gel electrophoresis revealed that probiotic supplementations modified the bacterial community structure.

Conclusion
This work showed that the effectiveness of the bacterial probiotics tested depended on the acidosis type. Although these probiotics were ineffective in lactic acidosis because of a deeply disturbed rumen microbiota, some of the probiotics tested may be useful to minimize the occurrence of butyric and propionic SARA in sheep. However, their modes of action need to be further investigated.
Body mass index contributes to sympathovagal imbalance in prehypertensives
Authors: Pal Gopal Krushna , Chandrasekaran Adithan , Hariharan Ananthanarayanan Palghat , Dutta Tarun Kumar , Pal Pravati , Nanda Nivedita , Venugopal Lalitha 
Published: July 2012

Abstract

Background
The present study was conducted to assess the nature of sympathovagal imbalance (SVI) in prehypertensives by short-term analysis of heart rate variability (HRV) to understand the alteration in autonomic modulation and the contribution of BMI to SVI in the genesis of prehypertension.

Methods
Body mass index (BMI), basal heart rate (BHR), blood pressure (BP), rate pressure product (RPP) and HRV indices such as total power (TP), low-frequency power (LF), normalized LF (LFnu), high-frequency power (HF), normalized HF (HFnu), LF-HF ratio, mean heart rate (mean RR), square root of the mean squared differences of successive normal to normal intervals (RMSSD), standard deviation of normal to normal RR interval (SDNN), the number of interval differences of successive NN intervals greater than 50 ms (NN50) and the proportion derived by dividing NN50 by the total number of NN intervals (pNN50) were assessed in three groups of subjects: normotensives having normal BMI (Group 1), prehypertensives having normal BMI (Group 2) and prehypertensives having higher BMI (Group 3). SVI was assessed from LF-HF ratio and correlated with BMI, BHR, BP and RPP in all the groups by Pearson correlation. The contribution of BMI to SVI was assessed by multiple regression analysis.

Results
LF and LFnu were significantly increased and HF and HFnu were significantly decreased in prehypertensive subjects in comparison to normotensive subjects and the magnitude of these changes was more prominent in subjects with higher BMI compared to that of normal BMI. LF-HF ratio, the sensitive indicator of sympathovagal balance had significant correlation with BMI (P = 0.000) and diastolic blood pressure (DBP) (P = 0.002) in prehypertensives. BMI was found to be an independent contributing factor to SVI (P = 0.001) in prehypertensives.

Conclusions
It was concluded that autonomic imbalance in prehypertensives manifested in the form of increased sympathetic activity and vagal inhibition. In prehypertensives with higher BMI, vagal withdrawal was predominant than sympathetic overactivity. Magnitude of SVI (alteration in LF-HF ratio) was linked to changes in BMI and DBP. BMI had an independent influence on LF-HF ratio. It was advised that life-style modifications such as yoga and exercise would enable achieve the sympathovagal balance and blood pressure homeostasis in prehypertensives.
The diagnosis of urinary tract infections in young children (DUTY): protocol for a diagnostic and prospective observational study to derive and validate a clinical algorithm for the diagnosis of UTI in children presenting to primary care with an acute illness
Authors: Downing Harriet , Thomas-Jones Emma , Gal Micaela , Waldron Cherry-Ann , Sterne Jonathan , Hollingworth William , Hood Kerenza , Delaney Brendan , Little Paul , Howe Robin , Wootton Mandy , Macgowan Alastair , Butler Christopher C , Hay Alastair D ,   DUTY study team
Published: July 2012

Abstract

Background
Urinary tract infection (UTI) is common in children, and may cause serious illness and recurrent symptoms. However, obtaining a urine sample from young children in primary care is challenging and not feasible for large numbers. Evidence regarding the predictive value of symptoms, signs and urinalysis for UTI in young children is urgently needed to help primary care clinicians better identify children who should be investigated for UTI. This paper describes the protocol for the Diagnosis of Urinary Tract infection in Young children (DUTY) study. The overall study aim is to derive and validate a cost-effective clinical algorithm for the diagnosis of UTI in children presenting to primary care acutely unwell.

Methods/design
DUTY is a multicentre, diagnostic and prospective observational study aiming to recruit at least 7,000 children aged before their fifth birthday, being assessed in primary care for any acute, non-traumatic, illness of ≤ 28 days duration. Urine samples will be obtained from eligible consented children, and data collected on medical history and presenting symptoms and signs. Urine samples will be dipstick tested in general practice and sent for microbiological analysis. All children with culture positive urines and a random sample of children with urine culture results in other, non-positive categories will be followed up to record symptom duration and healthcare resource use. A diagnostic algorithm will be constructed and validated and an economic evaluation conducted.
The primary outcome will be a validated diagnostic algorithm using a reference standard of a pure/predominant growth of at least >103, but usually >105 CFU/mL of one, but no more than two uropathogens.
We will use logistic regression to identify the clinical predictors (i.e. demographic, medical history, presenting signs and symptoms and urine dipstick analysis results) most strongly associated with a positive urine culture result. We will then use economic evaluation to compare the cost effectiveness of the candidate prediction rules.

Discussion
This study will provide novel, clinically important information on the diagnostic features of childhood UTI and the cost effectiveness of a validated prediction rule, to help primary care clinicians improve the efficiency of their diagnostic strategy for UTI in young children.