bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245408 (XL147), an Oral Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors
Authors: Shapiro Geoffrey I. , Rodon Jordi , Bedell Cynthia , Kwak Eunice L. , Baselga Jose , Braña Irene , Pandya Shuchi S. , Scheffold Christian , Laird A. Douglas , Nguyen Linh T. , Xu Yi , Egile Coumaran , Edelman Gerald 
Published: October 2013

Abstract
Purpose: SAR245408 is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I study determined the maximum tolerated dose (MTD) of two dosing schedules [first 21 days of a 28-day period (21/7) and continuous once-daily dosing (CDD)], pharmacokinetic and pharmacodynamic profiles, and preliminary efficacy.
Experimental Design: Patients with refractory advanced solid malignancies were treated with SAR245408 using a 3 + 3 design. Pharmacokinetic parameters were determined after single and repeated doses. Pharmacodynamic effects were evaluated in plasma, hair sheath cells, and skin and tumor biopsies.
Results: Sixty-nine patients were enrolled. The MTD of both schedules was 600 mg; dose-limiting toxicities were maculopapular rash and hypersensitivity reaction. The most frequent drug-related adverse events included dermatologic toxicities, diarrhea, nausea, and decreased appetite. Plasma pharmacokinetics showed a median time to maximum concentration of 8 to 22 hours, mean terminal elimination half-life of 70 to 88 hours, and 5- to 13-fold accumulation after daily dosing (first cycle). Steady-state concentration was reached between days 15 and 21, and exposure was dose-proportional with doses up to 400 mg. SAR245408 inhibited the PI3K pathway (∼40%–80% reduction in phosphorylation of AKT, PRAS40, 4EBP1, and S6 in tumor and surrogate tissues) and, unexpectedly, also inhibited the MEK/ERK pathway. A partial response was seen in one patient with advanced non–small cell lung cancer. Eight patients were progression-free at 6 months. Pharmacodynamic and clinical activity were observed irrespective of tumor PI3K pathway molecular alterations.
Conclusions: SAR245408 was tolerable at doses associated with PI3K pathway inhibition. The recommended phase II dose of the capsule formulation is 600 mg administered orally with CDD. Clin Cancer Res; 20(1); 233–45. ©2013 AACR.
Learning to Read an Alphabet of Human Faces Produces Left-lateralized Training Effects in the Fusiform Gyrus
Authors: Moore Michelle W. , Durisko Corrine , Perfetti Charles A. , Fiez Julie A. 
Published: October 2013

Abstract
Numerous functional neuroimaging studies have shown that most orthographic stimuli, such as printed English words, produce a left-lateralized response within the fusiform gyrus (FG) at a characteristic location termed the visual word form area (VWFA). We developed an experimental alphabet (FaceFont) comprising 35 face–phoneme pairs to disentangle phonological and perceptual influences on the lateralization of orthographic processing within the FG. Using functional imaging, we found that a region in the vicinity of the VWFA responded to FaceFont words more strongly in trained versus untrained participants, whereas no differences were observed in the right FG. The trained response magnitudes in the left FG region correlated with behavioral reading performance, providing strong evidence that the neural tissue recruited by training supported the newly acquired reading skill. These results indicate that the left lateralization of the orthographic processing is not restricted to stimuli with particular visual-perceptual features. Instead, lateralization may occur because the anatomical projections in the vicinity of the VWFA provide a unique interconnection between the visual system and left-lateralized language areas involved in the representation of speech.
Evaluation of a Two-Source Snow–Vegetation Energy Balance Model for Estimating Surface Energy Fluxes in a Rangeland Ecosystem
Authors: Kongoli Cezar , Kustas William P. , Anderson Martha C. , Norman John M. , Alfieri Joseph G. , Flerchinger Gerald N. , Marks Danny 
Published: October 2013

Abstract
The utility of a snow–vegetation energy balance model for estimating surface energy fluxes is evaluated with field measurements at two sites in a rangeland ecosystem in southwestern Idaho during the winter of 2007: one site dominated by aspen vegetation and the other by sagebrush. Model parameterizations are adopted from the two-source energy balance (TSEB) modeling scheme, which estimates fluxes from the vegetation and surface substrate separately using remotely sensed measurements of land surface temperature. Modifications include development of routines to account for surface snowmelt energy flux and snow masking of vegetation. Comparisons between modeled and measured surface energy fluxes of net radiation and turbulent heat showed reasonable agreement when considering measurement uncertainties in snow environments and the simplified algorithm used for the snow surface heat flux, particularly on a daily basis. There was generally better performance over the aspen field site, likely due to more reliable input data of snow depth/snow cover. The model was robust in capturing the evolution of surface energy fluxes during melt periods. The model behavior was also consistent with previous studies that indicate the occurrence of upward sensible heat fluxes during daytime owing to solar heating of vegetation limbs and branches, which often exceeds the downward sensible heat flux driving the snowmelt. However, model simulations over aspen trees showed that the upward sensible heat flux could be reversed for a lower canopy fraction owing to the dominance of downward sensible heat flux over snow. This indicates that reliable vegetation or snow cover fraction inputs to the model are needed for estimating fluxes over snow-covered landscapes.
Innate immune response after acute myocardial infarction and pharmacomodulatory action of tacrolimus in reducing infarct size and preserving myocardial integrity
Authors: Sheu Jiunn-Jye , Sung Pei-Hsun , Leu Steve , Chai Han-Tan , Zhen Yen-Yi , Chen Yi-Ching , Chua Sarah , Chen Yung-Lung , Tsai Tzu-Hsien , Lee Fan-Yen , Chang Hsueh-Wen , Ko Sheung-Fat , Yip Hon-Kan 
Published: October 2013

Abstract

Background
This study investigated the association between innate immune reaction and myocardial damage after acute myocardial infarction (AMI) and anti-inflammatory role of tacrolimus in reducing infarct size. Male mini-pigs (n=18) were equally categorized into sham control (SC), untreated AMI (by ligation of left anterior descending coronary artery), and AMI-Tacrolimus (AMI-Tac) (0.5 mg intra-coronary injection 30 minutes post-AMI). Cardiac magnetic resonance imaging (MRI) was performed at post-AMI days 2, 5 and 21 before sacrificing the animals.

Results
By post-AMI day 21, left ventricular ejection fraction (LVEF) was lowest in untreated AMI animals, significantly higher in SC than in AMI-Tac group (all p<0.003). Infarct areas at basal, middle, and apical levels, numbers of CD14+ and iNOS+ cells in infarct area (IA) and peri-IA, and protein expression of CD14, CD68, and Ly6g from circulating inflammatory cells showed an opposite pattern compared with that of LVEF in all groups (all p<0.005). Protein expressions of MCP-1, MIP-1, TNF-α, NF-κB, iNOS, and IL-12 in IA and peri-IA exhibited an identical pattern compared to that of CD14, CD68, and Ly6g from circulating inflammatory cells (all p<0.01). Expressions of myocardial damage biomarkers in IA and peri-IA [γ-H2AX, β-myosin heavy chain (MHC), Smad3, TGF-β] were highest in AMI and higher in AMI-Tac than in SC, whereas expressions of myocardial integrity biomarkers (connexin43, mitochondrial cytochrome-C, α-MHC, BMP-2, Smad1/5) were opposite to those of damage biomarkers (all p<0.001).

Conclusion
Innate immune responses were markedly augmented and LVEF was significantly reduced after AMI but were remarkably improved after tacrolimus treatment.
High-level expression of sugar inducible gene2 (HSI2) is a negative regulator of drought stress tolerance in Arabidopsis
Authors: Sharma Nirmala , Bender Yarnel , Boyle Kerry , Fobert Pierre R 
Published: October 2013

Abstract

Background

HIGH-LEVEL EXPRESSION OF SUGAR INDUCIBLE GENE2 (HSI2), also known as VAL1, is a B3 domain transcriptional repressor that acts redundantly with its closest relative, HSI2-LIKE1 (HSL1), to suppress the seed maturation program following germination. Mutant hsi2 hsl1 seedlings are arrested early in development and differentially express a number of abiotic stress-related genes. To test the potential requirement for HSI2 during abiotic stress, hsi2 single mutants and plants overexpressing HSI2 were subjected to simulated drought stress by withholding watering, and characterized through physiological, metabolic and gene expression studies.

Results
The hsi2 mutants demonstrated reduced wilting and maintained higher relative water content than wild-type after withholding watering, while the overexpressing lines displayed the opposite phenotype. The hsi2 mutant displayed lower constitutive and ABA-induced stomatal conductance than wild-type and accumulated lower levels of ABA metabolites and several osmolytes and osmoprotectants following water withdrawal. Microarray comparisons between wild-type and the hsi2 mutant revealed that steady-state levels of numerous stress-induced genes were up-regulated in the mutant in the absence of stress but down-regulated at visible wilting. Plants with altered levels of HSI2 responded to exogenous application of ABA and a long-lived ABA analog, but the hsi2 mutant did not show altered expression of several ABA-responsive or ABA signalling genes 4 hr after application.

Conclusions
These results implicate HSI2 as a negative regulator of drought stress response in Arabidopsis, acting, at least in part, by regulating transpirational water loss. Metabolic and global transcript profiling comparisons of the hsi2 mutant and wild-type plants do not support a model whereby the greater drought tolerance observed in the hsi2 mutant is conferred by the accumulation of known osmolytes and osmoprotectants. Instead, data are consistent with mutants experiencing a relatively milder dehydration stress following water withdrawal.
SORBS2 and TLR3 induce premature senescence in primary human fibroblasts and keratinocytes
Authors: Liesenfeld Melanie , Mosig Sandy , Funke Harald , Jansen Lars , Runnebaum Ingo B , Dürst Matthias , Backsch Claudia 
Published: October 2013

AbstractBackgroundGenetic aberrations are required for the progression of HPV-induced cervical precancers. A prerequisite for clonal expansion of cancer cells is unlimited proliferative capacity. In a cell culture model for cervical carcinogenesis loss of genes located on chromosome 4q35→qter and chromosome 10p14-p15 were found to be associated with escape from senescence. Moreover, by LOH and I-FISH analyses a higher frequency of allele loss of these regions was also observed in cervical carcinomas as compared to CIN3. The aim of this study was to identify candidate senescence-related genes located on chromosome 4q35→qter and chromosome 10p14-p15 which may contribute to clonal expansion at the transition of CIN3 to cancer.MethodsMicroarray expression analyses were used to identify candidate genes down-regulated in cervical carcinomas as compared to CIN3. In order to relate these genes with the process of senescence their respective cDNAs were overexpressed in HPV16-immortalized keratinocytes as well as in primary human fibroblasts and keratinocytes using lentivirus mediated gene transduction.ResultsOverall fifteen genes located on chromosome 4q35→qter and chromosome 10p14-p15 were identified. Ten of these genes could be validated in biopsies by RT-PCR. Of interest is the novel finding that SORBS2 and TLR3 can induce senescence in primary human fibroblasts and keratinocytes but not in HPV-immortalized cell lines. Intriguingly, the endogenous expression of both genes increases during finite passaging of primary keratinocytes in vitro.ConclusionsThe relevance of the genes SORBS2 and TLR3 in the process of cellular senescence warrants further investigation. In ongoing experiments we are investigating whether this increase in gene expression is also characteristic of replicative senescence.
Preliminary estimation of the prevalence of chemotherapy-induced dysgeusia in Japanese patients with cancer
Authors: Imai Hiroo , Soeda Hiroshi , Komine Keigo , Otsuka Kazunori , Shibata Hiroyuki 
Published: October 2013

Abstract

Background
Although dysgeusia is a common adverse event in chemotherapy patients; it has not been evaluated using objective methods, and its prevalence and frequency have not been quantified.

Methods
Salt-impregnated taste strips were used to objectively assess dysgeusia in patients receiving chemotherapy at Akita University (n = 38) and those off chemotherapy (n = 9). Participant characteristics, and ongoing and previous chemotherapies were evaluated, and their associations with dysgeusia analyzed.

Results
Dysgeusia developed in 38.8% (14/38) of chemotherapy patients, and was most prevalent in patients receiving 5-fluorouracil (5-FU) or its oral analogs (48.1%, 13/27). Particularly, dysgeusia developed in 55.6% (10/18) of patients receiving oral 5-FU analogs; however, prevalence in patients receiving and off chemotherapy was not significantly different. Patients aged ≥70 years also tended to experience dysgeusia (75.0%, 6/8).

Conclusions
Association with dysgeusia may be higher for some chemotherapeutic drugs. Dysgeusia should be routinely assessed in chemotherapy patients with objective methods such as paper strips; interventions for its prevention may be required.
Antibacterial and anti-inflammatory effects of Syzygium jambos L. (Alston) and isolated compounds on acne vulgaris
Authors: Sharma Richa , Kishore Navneet , Hussein Ahmed , Lall Namrita 
Published: October 2013

Abstract

Background
Acne vulgaris is a chronic skin disorder leading to inflammation as a result of the production of reactive oxygen species due to the active involvement of Propionibacterium acnes (P. acnes) in the infection site of the skin. The current study was designed to assess the potential of the leaf extract of Syzygium jambos L. (Alston) and its compounds for antibacterial and anti-inflammatory activity against the pathogenic P. acnes.

Methods
The broth dilution method was used to assess the antibacterial activity. The cytotoxicity investigation on mouse melanocyte (B16-F10) and human leukemic monocyte lymphoma (U937) cells was done using sodium 3’-[1-(phenyl amino-carbonyl)-3,4-tetrazolium]-bis-[4-methoxy-6-nitrobenzene sulfonic acid hydrate (XTT) reagent. The non-toxic concentrations of the samples was investigated for the suppression of cytokines interleukin 8 (IL 8) and tumour necrosis factor (TNF α) by testing the supernatants in the co-culture of the human U937 cells and heat killed P. acnes using enzyme immunoassay kits (ELISA). The statistical analysis was done using the Graph Pad Prism 4 program.

Results
Bioassay guided isolation of ethanol extract of the leaves of S. jambos led to the isolation of three known compounds namely; squalene, an anacardic acid analogue and ursolic acid which are reported for the first time from this plant. The ethanol extract of S. jambos and one of the isolated compound namely, anacardic acid analogue were able to inhibit the growth of P. acnes with a noteworthy minimum inhibitory concentration (MIC) value of 31.3 and 7.9 μg/ml, respectively. The ethanol extract and three commercially acquired compounds namely; myricetin, myricitrin, gallic acid exhibited significant antioxidant activity with fifty percent inhibitory concentration (IC50) ranging between 0.8-1.9 μg/ml which was comparable to that of vitamin C, the reference antioxidant agent. The plant extract, compounds ursolic acid and myricitrin (commercially acquired) significantly inhibited the release of inflammatory cytokines IL 8 and TNF α by suppressing them by 74 - 99%. TEM micrographs showed the lethal effects of selected samples against P. acnes.

Conclusions
The interesting antibacterial, antioxidant and anti-inflammatory effects of S. jambos shown in the present study warrant its further investigation in clinical studies for a possible alternative anti-acne agent.
Ex vivo tetramer staining and cell surface phenotyping for early activation markers CD38 and HLA-DR to enumerate and characterize malaria antigen-specific CD8+ T-cells induced in human volunteers immunized with a Plasmodium falciparum adenovirus-vectored malaria vaccine expressing AMA1
Authors: Schwenk Robert , Banania Glenna , Epstein Judy , Kim Yohan , Peters Bjoern , Belmonte Maria , Ganeshan Harini , Huang Jun , Reyes Sharina , Stryhn Anette , Ockenhouse Christian F , Buus Soren , Richie Thomas L , Sedegah Martha 
Published: October 2013

Abstract

Background
Malaria is responsible for up to a 600,000 deaths per year; conveying an urgent need for the development of a malaria vaccine. Studies with whole sporozoite vaccines in mice and non-human primates have shown that sporozoite-induced CD8+ T cells targeting liver stage antigens can mediate sterile protection. There is a need for a direct method to identify and phenotype malaria vaccine-induced CD8+ T cells in humans.

Methods
Fluorochrome-labelled tetramers consisting of appropriate MHC class I molecules in complex with predicted binding peptides derived from Plasmodium falciparum AMA-1 were used to label ex vivo AMA-1 epitope specific CD8+ T cells from research subjects responding strongly to immunization with the NMRC-M3V-Ad-PfCA (adenovirus-vectored) malaria vaccine. The identification of these CD8+ T cells on the basis of their expression of early activation markers was also investigated.

Results
Analyses by flow cytometry demonstrated that two of the six tetramers tested: TLDEMRHFY: HLA-A*01:01 and NEVVVKEEY: HLA-B*18:01, labelled tetramer-specific CD8+ T cells from two HLA-A*01:01 volunteers and one HLA-B*18:01 volunteer, respectively. By contrast, post-immune CD8+ T cells from all six of the immunized volunteers exhibited enhanced expression of the CD38 and HLA-DRhi early activation markers. For the three volunteers with positive tetramer staining, the early activation phenotype positive cells included essentially all of the tetramer positive, malaria epitope- specific CD8+ T cells suggesting that the early activation phenotype could identify all malaria vaccine-induced CD8+ T cells without prior knowledge of their exact epitope specificity.

Conclusions
The results demonstrated that class I tetramers can identify ex vivo malaria vaccine antigen-specific CD8+ T cells and could therefore be used to determine their frequency, cell surface phenotype and transcription factor usage. The results also demonstrated that vaccine antigen-specific CD8+ T cells could be identified by activation markers without prior knowledge of their antigen-specificity, using a subunit vaccine for proof-of-concept. Whether, whole parasite or adjuvanted protein vaccines will also induce {CD38 and HLA-DRhi}+ CD8+ T cell populations reflective of the antigen-specific response will the subject of future investigations.
Diabetes in Argentina: cost and management of diabetes and its complications and challenges for health policy
Authors: Caporale Joaquín E , Elgart Jorge F , Gagliardino Juan J 
Published: October 2013

Abstract

Background
Diabetes is an expensive disease in Argentina as well as worldwide, and its prevalence is continuously rising affecting the quality of life of people with the disease and their life expectancy. It also imposes a heavy burden to the national health care budget and on the economy in the form of productivity losses.

Aims
To review and discuss a) the reported evidence on diabetes prevalence, the degree of control, the cost of care and outcomes, b) available strategies to decrease the health and economic disease burden, and c) how the disease fits in the Argentinian health care system and policy. Finally, to propose evidence-based policy options to reduce the burden of diabetes, both from an epidemiological as well as an economic perspective, on the Argentinian society. The evidence presented is expected to help the local authorities to develop and implement effective diabetes care programmes.

Methodology
A comprehensive literature review was performed using databases such as MEDLINE, EMBASE and LILACS (Latin American and Caribbean Health Sciences). Literature published from 1980 to 2011 was included. This information was complemented with grey literature, including data from national and provincial official sources, personal communications and contacts with health authorities and diabetes experts in Argentina.

Results
Overall diabetes prevalence increased from 8.4% in 2005 to 9.6% 2009 at national level. In 2009, diabetes was the seventh leading cause of death with a mortality rate of 19.2 per 100,000 inhabitants, and it accounted for 1,328,802 DALYs lost in the adult population, mainly affecting women aged over fifty. The per capita hospitalisation cost for people with diabetes was significantly higher than for people without the disease, US$ 1,628 vs. US$ 833 in 2004. Evidence shows that implementation of combined educative interventions improved quality of care and outcomes, decreased treatment costs and optimised the use of economic resources.

Conclusions
Based on the evidence reviewed, we believe that the implementation of structured health care programmes including diabetes education at every level, could improve quality of care as well as its clinical, metabolic and economic outcomes. If implemented across the country, these programmes could decrease the disease burden and optimise the use of human and economic resources.
Electroacupuncture at Jing-jiaji points for neck pain caused by cervical spondylosis: a study protocol for a randomized controlled pilot trial
Authors: Sun Zhong-ren , Yue Jin-huan , Zhang Qin-hong 
Published: October 2013

Abstract

Background
Neck pain caused by cervical spondylosis (CS) has become one of the most common health problems around the world. Electroacupuncture (EA) has been employed to relieve CS neck pain, but there is limited clinical evidence for its effectiveness.

Methods/Design
This study consists of a randomized controlled trial (RCT) with two parallel arms: an acupuncture group and an EA group. Both groups will receive acupuncture at Jing-jiaji points for 30 minutes each time, for five sessions per week for a total of 20 sessions during this four-week period. In addition, the EA group will be connected with EA apparatus. The following outcome measurements will be used in examination of subjects: the Northwick Park Neck Pain Questionnaire (NPQ), McGill Pain Questionnaire (MPQ), and Short-Form 36 (SF-36) scale. All these outcomes will be examined at the start of the study, at the end of the second week, at four weeks after randomization, and one and three months after treatment cessation respectively.

Discussion
This study aims to assess the efficacy of EA, compared with acupuncture intervention at Jing-jiaji points for the CS neck pain.

Trial registration
Chinese Clinical Trials Register:ChiCTR-TRC-13003422.