bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells
Authors: Grabinski Nicole , Ewald Florian , Hofmann Bianca T , Staufer Katharina , Schumacher Udo , Nashan Björn , Jücker Manfred 
Published: November 2012

Abstract

Background
Due to the frequent dysregulation of the PI3K/AKT/mTOR signaling pathway, mTOR represents a suitable therapeutic target in hepatocellular carcinoma (HCC). However, emerging data from clinical trials of HCC patients indicate that mTOR inhibition by RAD001 (Everolimus) alone has only moderate antitumor efficacy which may be due to the feedback activation of AKT after mTOR inhibition. In this study, we analyzed the effects of dual inhibition of mTOR and AKT on the proliferation of HCC cell lines. In addition, we measured the feedback activation of each of the AKT isoforms after mTOR inhibition in HCC cell lines and their enzymatic activity in primary samples from HCC patients.

Methods
The activation status of specific AKT isoforms in human HCC samples and corresponding healthy liver tissue was analyzed using an AKT isoform specific in vitro kinase assay. AKT isoform activation after mTOR inhibition was analyzed in three HCC cell lines (Hep3B, HepG2 and Huh7), and the impact of AKT signaling on proliferation after mTOR inhibition was investigated using the novel AKT inhibitor MK-2206 and AKT isoform specific knockdown cells.

Results
AKT isoforms become differentially activated during feedback activation following RAD001 treatment. The combination of mTOR inhibition and AKT isoform knockdown showed only a weak synergistic effect on proliferation of HCC cell lines. However, the combinatorial treatment with RAD001 and the pan AKT inhibitor MK-2206 resulted in a strong synergism, both in vitro and in vivo. Moreover, by analyzing primary HCC tissue samples we were able to demonstrate that a hotspot mutation (H1047R) of PI3KCA, the gene encoding the catalytic subunit of PI3K, was associated with increased in vitro kinase activity of all AKT isoforms in comparison to healthy liver tissue of the patient.

Conclusion
Our results demonstrate that dual targeting of mTOR and AKT by use of RAD001 and the pan AKT inhibitor MK-2206 does effectively inhibit proliferation of HCC cell lines. These data suggest that combined treatment with RAD001 and MK-2206 may be a promising therapy approach in the treatment of hepatocellular carcinoma.
Involvement of formyl peptide receptors in receptor for advanced glycation end products (RAGE) - and amyloid beta 1-42-induced signal transduction in glial cells
Authors: Slowik Alexander , Merres Julika , Elfgen Anne , Jansen Sandra , Mohr Fabian , Wruck Christoph J , Pufe Thomas , Brandenburg Lars-Ove 
Published: November 2012

Abstract

Background
Recent studies suggest that the chemotactic G-protein-coupled-receptor (GPCR) formyl-peptide-receptor-like-1 (FPRL1) and the receptor-for-advanced-glycation-end-products (RAGE) play an important role in the inflammatory response involved in neurodegenerative disorders such as Alzheimer’s disease (AD).
Therefore, the expression and co-localisation of mouse formyl peptide receptor (mFPR) 1 and 2 as well as RAGE in an APP/PS1 transgenic mouse model using immunofluorescence and real-time RT-PCR were analysed. The involvement of rat or human FPR1/FPRL1 (corresponds to mFPR1/2) and RAGE in amyloid-β 1–42 (Aβ1-42)-induced signalling were investigated by extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation. Furthermore, the cAMP level in primary rat glial cells (microglia and astrocytes) and transfected HEK 293 cells was measured. Formyl peptide receptors and RAGE were inhibited by a small synthetic antagonist WRW4 and an inactive receptor variant delta-RAGE, lacking the intracytoplasmatic domains.

Results
We demonstrated a strong increase of mFPR1/2 and RAGE expression in the cortex and hippocampus of APP/PS1 transgenic mice co-localised to the glial cells. In addition, the Aβ1-42-induced signal transduction is dependant on FPRL1, but also on FPR1. For the first time, we have shown a functional interaction between FPRL1/FPR1 and RAGE in RAGE ligands S100B- or AGE-mediated signalling by ERK1/2 phosphorylation and cAMP level measurement. In addition a possible physical interaction between FPRL1 as well as FPR1 and RAGE was shown with co-immunoprecipitation and fluorescence microscopy.

Conclusions
The results suggest that both formyl peptide receptors play an essential role in Aβ1-42-induced signal transduction in glial cells. The interaction with RAGE could explain the broad ligand spectrum of formyl peptide receptors and their important role for inflammation and the host defence against infections.
Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial
Authors: Smith David C. , Smith Matthew R. , Sweeney Christopher , Elfiky Aymen A. , Logothetis Christopher , Corn Paul G. , Vogelzang Nicholas J. , Small Eric J. , Harzstark Andrea L. , Gordon Michael S. , Vaishampayan Ulka N. , Haas Naomi B. , Spira Alexander I. , Lara Primo N. , Lin Chia-Chi , Srinivas Sandy , Sella Avishay , Schöffski Patrick , Scheffold Christian , Weitzman Aaron L. , Hussain Maha 
Published: November 2012

Purpose Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort. Patients and Methods Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment. Results One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%). Conclusion Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.
Use of Radiation Therapy in the Last 30 Days of Life Among a Large Population-Based Cohort of Elderly Patients in the United States
Authors: Guadagnolo B. Ashleigh , Liao Kai-Ping , Elting Linda , Giordano Sharon , Buchholz Thomas A. , Shih Ya-Chen Tina 
Published: November 2012

Purpose: Our goal was to evaluate use and associated costs of radiation therapy (RT) in the last month of life among those dying of cancer. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) -Medicare linked databases to analyze claims data for 202,299 patients dying as a result of lung, breast, prostate, colorectal, and pancreas cancers from 2000 to 2007. Logistic regression modeling was used to conduct adjusted analyses of potential impacts of demographic, health services, and treatment-related variables on receipt of RT and treatment with greater than 10 days of RT. Costs were calculated in 2009 dollars. Results: Among the 15,287 patients (7.6%) who received RT in the last month of life, its use was associated with nonclinical factors such as race, gender, income, and hospice care. Of these patients, 2,721 (17.8%) received more than 10 days of treatment. Nonclinical factors that were associated with greater likelihood of receiving more than 10 days of RT in the last 30 days of life included: non-Hispanic white race, no receipt of hospice care, and treatment in a freestanding, versus a hospital-associated facility. Hospice care was associated with 32% decrease in total costs of care in the last month of life among those receiving RT. Conclusion: Although utilization of RT overall was low, almost one in five of patients who received RT in their final 30 days of life spent more than 10 of those days receiving treatment. More research is needed into physician decision making regarding use of RT for patients with end-stage cancer.
High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia
Authors: O'Brien Susan , Schiller Gary , Lister John , Damon Lloyd , Goldberg Stuart , Aulitzky Walter , Ben-Yehuda Dina , Stock Wendy , Coutre Steven , Douer Dan , Heffner Leonard T. , Larson Melissa , Seiter Karen , Smith Scott , Assouline Sarit , Kuriakose Philip , Maness Lori , Nagler Arnon , Rowe Jacob , Schaich Markus , Shpilberg Ofer , Yee Karen , Schmieder Guenter , Silverman Jeffrey A. , Thomas Deborah , Deitcher Steven R. , Kantarjian Hagop 
Published: November 2012

Purpose Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) –negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and Methods Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m2, without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). Results The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). Conclusion High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.
The Genetic Architecture of Biofilm Formation in a Clinical Isolate of Saccharomyces cerevisiae
Authors: Granek Joshua A , Murray Debra , Kayrkçi Ömür , Magwene Paul M 
Published: November 2012

Abstract
Biofilms are microbial communities that form on surfaces. They are the primary form of microbial growth in nature and can have detrimental impacts on human health. Some strains of the budding yeast Saccharomyces cerevisiae form colony biofilms, and there is substantial variation in colony architecture between biofilm-forming strains. To identify the genetic basis of biofilm variation, we developed a novel version of quantitative trait locus mapping, which leverages cryptic variation in a clinical isolate of S. cerevisiae. We mapped 13 loci linked to heterogeneity in biofilm architecture and identified the gene most closely associated with each locus. Of these candidate genes, six are members of the cyclic AMP–protein kinase A pathway, an evolutionarily conserved cell signaling network. Principal among these is CYR1, which encodes the enzyme that catalyzes production of cAMP. Through a combination of gene expression measurements, cell signaling assays, and gene overexpression, we determined the functional effects of allelic variation at CYR1. We found that increased pathway activity resulting from protein coding and expression variation of CYR1 enhances the formation of colony biofilms. Four other candidate genes encode kinases and transcription factors that are targets of this pathway. The protein products of several of these genes together regulate expression of the sixth candidate, FLO11, which encodes a cell adhesion protein. Our results indicate that epistatic interactions between alleles with both positive and negative effects on cyclic AMP–protein kinase A signaling underlie much of the architectural variation we observe in colony biofilms. They are also among the first to demonstrate genetic variation acting at multiple levels of an integrated signaling and regulatory network. Based on these results, we propose a mechanistic model that relates genetic variation to gene network function and phenotypic outcomes.
Patterns of Transcriptome Divergence in the Male Accessory Gland of Two Closely Related Species of Field Crickets
Authors: Andrés Jose A , Larson Erica L , Bogdanowicz Steven M , Harrison Richard G 
Published: November 2012

AbstractOne of the central questions in evolutionary genetics is how much of the genome is involved in the early stages of divergence between populations, causing them to be reproductively isolated. In this article, we investigate genomic differentiation in a pair of closely related field crickets (Gryllus firmus and G. pennsylvanicus). These two species are the result of allopatric divergence and now interact along an extensive hybrid zone in eastern North America. Genes encoding seminal fluid proteins (SFPs) are often divergent between species, and it has been hypothesized that these proteins may play a key role in the origin and maintenance of reproductive isolation between diverging lineages. Hence, we chose to scan the accessory gland transcriptome to enable direct comparisons of differentiation for genes known to encode SFPs with differentiation in a much larger set of genes expressed in the same tissue. We have characterized differences in allele frequency between two populations for &gt;6000 SNPs and &gt;26,000 contigs. About 10% of all SNPs showed nearly fixed differences between the two species. Genes encoding SFPs did not have significantly elevated numbers of fixed SNPs per contig, nor did they seem to show larger differences than expected in their average allele frequencies. The distribution of allele frequency differences across the transcriptome is distinctly bimodal, but the relatively high proportion of fixed SNPs does not necessarily imply “ancient” divergence between these two lineages. Further studies of linkage disequilibrium and introgression across the hybrid zone are needed to direct our attention to those genome regions that are important for reproductive isolation.
Neurodevelopmental Burden at Age 5 Years in Patients With Univentricular Heart
Authors: Sarajuuri Anne , Jokinen Eero , Mildh Leena , Tujulin Anna-Mari , Mattila Ilkka , Valanne Leena , Lönnqvist Tuula 
Published: November 2012

BACKGROUND:
Despite increasing survival, patients with hypoplastic left heart syndrome (HLHS) and other forms of functionally univentricular heart defects (UVHs) remain at increased risk of long-term neurodevelopmental deficits.

METHODS:
A nationwide sample of 23 patients with HLHS, 13 with UVH, and 40 controls were followed prospectively until the age of 5 years, when neurologic, neuropsychological, and motor examinations and brain MRI were performed.

RESULTS:
The median full-scale IQ was significantly lower in patients with HLHS (97, P &lt; .001) and patients with UVH (112, P = .024) compared with controls (121). Major neurodevelopmental impairment was found in 26% of the patients with HLHS and 23% of those with UVH, and minor neurologic dysfunction was found in 43% and 46%, respectively. MRI revealed abnormalities, mostly ischemic changes of different degrees, in 82% of the patients with HLHS and in 56% of those with UVH. Prominent changes were significantly associated with neurodevelopmental findings and parental reports of adaptive behavior. In linear regression, significant risk factors for a worse outcome were a history of clinical seizures in connection with the primary operation, a lower diameter of the neonatal ascending aorta, and several pre-, peri-, and postoperative factors related to the primary and bidirectional Glenn operations.

CONCLUSIONS:
Although median cognitive performance was within the normal range, neurodevelopmental and brain MRI abnormalities were found in the majority of the patients with UVH, and especially in those with HLHS, at preschool age. Both a narrowed ascending aorta and operation-related factors contributed to these findings.
Effectiveness of Lifestyle Interventions in Child Obesity: Systematic Review With Meta-analysis
Authors: Ho Mandy , Garnett Sarah P. , Baur Louise , Burrows Tracy , Stewart Laura , Neve Melinda , Collins Clare 
Published: November 2012

BACKGROUND AND OBJECTIVES:The effects of lifestyle interventions on cardio-metabolic outcomes in overweight children have not been reviewed systematically. The objective of the study was to examine the impact of lifestyle interventions incorporating a dietary component on both weight change and cardio-metabolic risks in overweight/obese children.METHODS:English-language articles from 1975 to 2010, available from 7 databases, were used as data sources. Two independent reviewers assessed articles against the following eligibility criteria: randomized controlled trial, participants overweight/obese and ≤18 years, comparing lifestyle interventions to no treatment/wait-list control, usual care, or written education materials. Study quality was critically appraised by 2 reviewers using established criteria; Review Manager 5.1 was used for meta-analyses.RESULTS:Of 38 eligible studies, 33 had complete data for meta-analysis on weight change; 15 reported serum lipids, fasting insulin, or blood pressure. Lifestyle interventions produced significant weight loss compared with no-treatment control conditions: BMI (−1.25kg/m2, 95% confidence interval [CI] −2.18 to −0.32) and BMI z score (−0.10, 95% CI −0.18 to −0.02). Studies comparing lifestyle interventions to usual care also resulted in significant immediate (−1.30kg/m2, 95% CI −1.58 to −1.03) and posttreatment effects (−0.92 kg/m2, 95% CI −1.31 to −0.54) on BMI up to 1 year from baseline. Lifestyle interventions led to significant improvements in low-density lipoprotein cholesterol (−0.30 mmol/L, 95% CI −0.45 to −0.15), triglycerides (−0.15 mmol/L, 95% CI −0.24 to −0.07), fasting insulin (−55.1 pmol/L, 95% CI −71.2 to −39.1) and blood pressure up to 1 year from baseline. No differences were found for high-density lipoprotein cholesterol.CONCLUSIONS:Lifestyle interventions can lead to improvements in weight and cardio-metabolic outcomes. Further research is needed to determine the optimal length, intensity, and long-term effectiveness of lifestyle interventions.
Efficiency of molar distalization associated with second and third molar eruption stage
Authors: Flores-Mir Carlos , McGrath Lisa , Heo Giseon , Major Paul W. 
Published: November 2012

ABSTRACT

Objective:
To evaluate the efficiency of molar distalization associated with the second and third molar eruption stage.

Materials and Methods:
A systematic computerized database search was conducted using several databases. Adaptations of the terms molar distalization and distalizing appliances were used. The reference lists of all the selected articles were also searched for any potential articles that might have been missed in the electronic search. The data provided in the selected publications were grouped and analyzed in terms of molar distalization with respect to various eruption stages of maxillary second and third molars.

Results:
Out of the 13 initially identified articles only four fulfilled the final selection criteria. Three of the four studies showed no statistical significance in linear molar distalization based on the eruptive stage of the second and/or third molars, while one study found that the amount of distal movement of the first molars was significantly greater in the group with unerupted second molars. Only one study found that the amount of molar tipping that occurred as a result of distalization was related to the eruption stage of the maxillary molars. Similarly, three of the four studies found that molar distalization time was not significantly affected by eruption of the second or third molars.

Conclusion:
The effect of maxillary second and third molar eruption stage on molar distalization—both linear and angular distalization—appears to be minimal. This conclusion is only based on low–level of evidence clinical trials. The large variability in the outcomes should be considered clinically.
Real-Time Improvement of Continuous Glucose Monitoring Accuracy
Authors: Facchinetti Andrea , Sparacino Giovanni , Guerra Stefania , Luijf Yoeri M. , DeVries J. Hans , Mader Julia K. , Ellmerer Martin , Benesch Carsten , Heinemann Lutz , Bruttomesso Daniela , Avogaro Angelo , Cobelli Claudio ,   on behalf of the AP@home Consortium
Published: November 2012

OBJECTIVE
Reliability of continuous glucose monitoring (CGM) sensors is key in several applications. In this work we demonstrate that real-time algorithms can render CGM sensors smarter by reducing their uncertainty and inaccuracy and improving their ability to alert for hypo- and hyperglycemic events.

RESEARCH DESIGN AND METHODS
The smart CGM (sCGM) sensor concept consists of a commercial CGM sensor whose output enters three software modules, able to work in real time, for denoising, enhancement, and prediction. These three software modules were recently presented in the CGM literature, and here we apply them to the Dexcom SEVEN Plus continuous glucose monitor. We assessed the performance of the sCGM on data collected in two trials, each containing 12 patients with type 1 diabetes.

RESULTS
The denoising module improves the smoothness of the CGM time series by an average of ∼57%, the enhancement module reduces the mean absolute relative difference from 15.1 to 10.3%, increases by 12.6% the pairs of values falling in the A-zone of the Clarke error grid, and finally, the prediction module forecasts hypo- and hyperglycemic events an average of 14 min ahead of time.

CONCLUSIONS
We have introduced and implemented the sCGM sensor concept. Analysis of data from 24 patients demonstrates that incorporation of suitable real-time signal processing algorithms for denoising, enhancement, and prediction can significantly improve the performance of CGM applications. This can be of great clinical impact for hypo- and hyperglycemic alert generation as well in artificial pancreas devices.