bluuebunny/crossref_metadata_2025 huggingface dataset:
Food Supply Strategies in the Romanian Eneolithic: Sheep/Goat Husbandry and Fishing Activities from Hârşova Tell and Borduşani-Popină (5th Millennium BC)
Authors: Bréhard Stéphanie , Radu Valentin , Martin Alexis , Hanot Pauline , Popovici Dragomir , Bălăşescu Adrian
Published: February 2014

Previously observed specialization in sheep/goat kill-off patterns from Romanian Eneolithic sites raises the question of a limited duration of the slaughtering period. In order to provide reliable month of death distribution for sheep/goats, the approach developed here takes into account uncertainties regarding the age-at-death and the month of birth, based on classic archaeozoological techniques. We show that sheep slaughtering rarely occurred from late spring to early autumn or from summer to mid-fall, both at Hârşova tell and Borduşani-Popină. Conversely, it is very likely that fishing activities took place primarily from spring to early autumn. This points to the existence of seasonal and complementary food supply strategies at both sites. Several possible explanations for these seasonal strategies are discussed. We also highlight the homogeneity in the management of domestic herds between the two sites, raising the question of a certain standardization in pastoral practices on a larger scale.
Effect of SMAT preprocessing on MAO fabricated nanocomposite coating
Authors: Gheytani M. , Bagheri H. R. , Masiha H. R. , Aliofkhazraei M. , Sabour Rouhaghdam A. , Shahrabi T.
Published: February 2014

The role of fine microstructure of AZ31B magnesium alloy metallic samples on the morphology, corrosion and wear resistance of the coatings formed by microarc oxidation technique was investigated. Surface nanocrystallisation was carried out through surface mechanical attrition treatment, and a nanocrystalline surface with the grain size of 5–10 nm was obtained. The coatings were studied by optical microscope and SEM images, and corrosion and wear tests were conducted on the samples. Comparison between the maximum and minimum results obtained for the corrosion polarisation resistance indicated 700% increase for different coating conditions. Similar comparison for the wear test results indicated 105% increase in wear resistance for different coating conditions.
Serological investigation of patients with a previous history of heparin-induced thrombocytopenia who are reexposed to heparin
Authors: Warkentin Theodore E. , Sheppard Jo-Ann I.
Published: February 2014

Key Points

Heparin rechallenge despite prior HIT often induces platelet-activating anti-PF4/heparin antibodies but no faster than seen with typical HIT. Risk of HIT recurring after heparin rechallenge is low but possible if IgG with heparin-independent platelet-activating properties are made.
Characterization of the RNase R association with ribosomes
Authors: Malecki Michal , Bárria Cátia , Arraiano Cecilia M
Published: February 2014

Background

In this study we employed the TAP tag purification method coupled with mass spectrometry analysis to identify proteins that co-purify with Escherichia coli RNase R during exponential growth and after temperature downshift.

Results

Our initial results suggested that RNase R can interact with bacterial ribosomes. We subsequently confirmed this result using sucrose gradient ribosome profiling joined with western blot analysis. We found that RNase R co-migrates with the single 30S ribosomal subunits. Independent data involving RNase R in the rRNA quality control process allowed us to hypothesize that the RNase R connection with ribosomes has an important physiological role.

Conclusions

This study leads us to conclude that RNase R can interact with ribosomal proteins and that this interaction may be a result of this enzyme involvement in the ribosome quality control.
A coalescence of two syndromes in a girl with terminal deletion and inverted duplication of chromosome 5
Authors: Krgovic Danijela , Blatnik Ana , Burmas Ante , Zagorac Andreja , Kokalj Vokac Nadja
Published: February 2014

Background

Rearrangements involving chromosome 5p often result in two syndromes, Cri-du-chat (CdC) and Trisomy 5p, caused by a deletion and duplication, respectively. The 5p15.2 has been defined as a critical region for CdC syndrome; however, genotype-phenotype studies allowed isolation of particular characteristics such as speech delay, cat-like cry and mental retardation, caused by distinct deletions of 5p. A varied clinical outcome was also observed in patients with Trisomy 5p. Duplications of 5p10-5p13.1 manifest themselves in a more severe phenotype, while trisomy of regions distal to 5p13 mainly causes mild and indistinct features. Combinations of a terminal deletion and inverted duplication of 5p are infrequent in literature. Consequences of these chromosomal rearrangements differ, depending on size of deletion and duplication in particular cases, although authors mainly describe the deletion as the cause of the observed clinical picture.

Case presentation

Here we present a 5-month-old Slovenian girl, with de novo terminal deletion and inverted duplication of chromosome 5p. Our patient presents features of both CdC and Trisomy 5. The most prominent features observed in our patient are a cat-like cry and severe malformations of the right ear.

Conclusion

The cat-like cry, characteristic of CdC syndrome, is noted in our patient despite the fact that the deletion is not fully consistent with previously defined cat-like cry critical region in this syndrome. Features like dolichocephaly, macrocephaly and ear malformations, associated with duplication of the critical region of Trisomy 5p, are also present, although this region has not been rearranged in our case. Therefore, the true meaning of the described chromosomal rearrangements is discussed.
Labour management and Obstetric outcomes among pregnant women admitted in latent phase compared to active phase of labour at Bugando Medical Centre in Tanzania
Authors: Chuma Clotrida , Kihunrwa Albert , Matovelo Dismas , Mahendeka Marietha
Published: February 2014

Background

Interventions given to women admitted in latent or active phase of labor may influence the outcomes of labor and ameliorate complications which can affect the mother and fetus. Labour management, maternal and fetal outcomes among low risk women presenting both in latent phase and active phase of labour in Tanzania have not recently been explored.

Methods

This was a descriptive cross-sectional study. It was done from February to April 2013. Case notes were collected serially until the sample size was reached. A structured checklist was used to extract data. Data was analyzed using SPSS version 17. A p < 0.05 was considered significant at 95% confidence interval.

Results

Five hundred case notes of low risk pregnant women were collected, half of each presented in latent phase and active phase of labour. Key interventions including augmentation with oxytocin, artificial rupture of membranes and caesarean section were significantly higher in the latent phase group than the active phase group 84(33.6%) versus 52(20.8%) p < 0.05; 96(38.6%) versus 56(22.4%) p < 0.05 and 87(34.8%) versus 60(24.0%) p < 0.05 respectively. Spontaneous vertex delivery was higher among pregnant women admitted initially in active phase than in latent phase groups 180(72.0%), versus 153(61.2%) p > 0.01). There were more women in the active phase group who sustained genital tract tear and postpartum haemorrhage than in the latent phase group 101(18.6%), versus 38(15.6%) p < 0.01 and 46(18.4%), versus 17(6.6%) p < 0.05 respectively.

Conclusions

Pregnant women admitted at BMC in latent phase of labour are subjected to more obstetric interventions than those admitted in the active phase. There is need to produce guidelines on management of women admitted in latent phase of labour at BMC to reduce the risk of unnecessary interventions.
Association of TLR7 and TSHR copy number variation with Graves’ disease and Graves’ ophthalmopathy in Chinese population in Taiwan
Authors: Liao Wen-Ling , Wan Lei , Wang Tzu-Yuan , Chen Ching-Chu , Tse Siu-San , Lu Chieh-Hsiang , Tsai Fuu-Jen
Published: February 2014

Background

Graves’ disease (GD) and Graves’ ophthalmopathy (GO) are autoimmune disorders, which might be influenced by genetic factors. Copy number variation (CNV) is an important source of genomic diversity in humans, and influences disease susceptibility. This study investigated the association between CNV in the TSHR and TLR7 genes and the development of GD and GO in a Chinese population in Taiwan.

Methods

For this case-control study, sample from 196 healthy controls and 484 GD patients, including 203 patients with GO were studied. CNV was detected by real-time polymerase chain reaction (PCR) using TaqMan™ probes and the relative copy number (CN) was estimated by using the comparative Ct method.

Results

The differences in the distribution of TSHR CNV in healthy controls and GD patients were statistically significant (p value = 0.01). However, the difference in the distribution of TSHR CNV in the control group and the GO group was not statistically significant (p value = 0.06). For TLR7 CNV, the results were not significantly different when we compared the distribution in healthy controls and GD patients and in healthy controls and GO patients (p values for Fisher’s exact test were 0.13 and 0.09, respectively). However, a lower than normal CNV for TLR7 (CNV < 2 for female and CNV < 1 for male) was found to have a protective effect against the development of GD (odds ratio (OR) = 0.24; 95% confidence interval (CI), 0.07-0.75) after adjusting for age and gender.

Conclusions

These results suggested that TSHR and TLR7 CNV might be associated with susceptibility to GD.
Blind spectrum sensing using symmetry property of cyclic autocorrelation function: from theory to practice
Authors: Safatly Lise , Aziz Babar , Nafkha Amor , Louet Yves , Nasser Youssef , El-Hajj Ali , Kabalan Karim Y
Published: February 2014

Spectrum sensing has been identified as the key step of the cognition cycle and the most important function for the establishment of cognitive radio. In this paper, a blind cyclostationary feature detector, which is based on the symmetry property of cyclic autocorrelation function (SP-CAF), is implemented and tested using universal software radio peripheral platform and GNU Radio open-source software development toolkit. Performance of the SP-CAF is compared to the classical energy detector via various tests conducted in real scenarios where both detection algorithms are employed to blindly sense the spectrum for opportunistic access. This study shows that the blind cyclostationary feature detector outperforms the classical energy detector while guaranteeing acceptable complexity and low sensing time. Moreover, different experimental results indicate that the blind sensing detector can achieve high detection probability at a low false alarm probability under real channel conditions and low signal-to-noise ratio.
Sustained efficacy and safety of a 300IR daily dose of a sublingual solution of birch pollen allergen extract in adults with allergic rhinoconjunctivitis: results of a double‐blind, placebo‐controlled study
Authors: Worm Margitta , Rak Sabina , de Blay Frédéric , Malling Hans‐Jorgen , Melac Michel , Cadic Véronique , Zeldin Robert K
Published: February 2014

Background

Allergic rhinoconjunctivitis (ARC) due to birch pollen is a growing health concern in Europe. Here, we report the efficacy and safety of 300IR birch pollen sublingual solution administered discontinuously for 2 consecutive years to patients with birch‐associated allergic rhinoconjunctivitis.

Methods

Birch pollen‐allergic adults were randomized in this double blind study to 300IR birch pollen sublingual solution or placebo, daily, starting 4 months before and continuing through the pollen season for two pollen seasons. Randomization was stratified according to the presence or absence of oral allergy syndrome (OAS). The primary efficacy endpoint was the Average Adjusted Symptom Score (AAdSS) over the second pollen season and was analyzed by ANCOVA. Secondary efficacy endpoints included the AAdSS over the first pollen period. Safety was evaluated by means of adverse event monitoring.

Results

574 patients (284 in the active group and 290 in the placebo group) were randomized and 496 completed the study. Over the second pollen period, the least square (LS) mean AAdSS was significantly lower in the 300IR group than in the placebo group (LS mean difference −2.04, 95% CI [−2.69, −1.40], (p <0.0001) with a relative reduction of 30.6%. Results were consistent in patients with and without OAS (−33.6% and −28.4%, respectively). A significant reduction in LS mean AAdSS was also observed over the first pollen season. The most frequently reported adverse events were application site reactions: oral pruritus, throat irritation, and mouth edema. There were no reports of anaphylaxis.

Conclusions

Pre‐ and co‐seasonal treatment with 300IR birch pollen sublingual solution demonstrated sustained clinical efficacy over 2 pollen seasons and was well tolerated in adults with birch pollen‐associated allergic rhinoconjunctivitis. Efficacy results were consistent in patients with and without oral allergy syndrome.

Trial registration

ClinicalTrials.gov: NCT01731249.
Lesion of the subiculum reduces the spread of amyloid beta pathology to interconnected brain regions in a mouse model of Alzheimer’s disease
Authors: George Sonia , Rönnbäck Annica , Gouras Gunnar K , Petit Géraldine H , Grueninger Fiona , Winblad Bengt , Graff Caroline , Brundin Patrik
Published: February 2014

Background

The progressive development of Alzheimer’s disease (AD) pathology follows a spatiotemporal pattern in the human brain. In a transgenic (Tg) mouse model of AD expressing amyloid precursor protein (APP) with the arctic (E693G) mutation, pathology spreads along anatomically connected structures. Amyloid-β (Aβ) pathology first appears in the subiculum and is later detected in interconnected brain regions, including the retrosplenial cortex. We investigated whether the spatiotemporal pattern of Aβ pathology in the Tg APP arctic mice to interconnected brain structures can be interrupted by destroying neurons using a neurotoxin and thereby disconnecting the neural circuitry.

Results

We performed partial unilateral ibotenic acid lesions of the subiculum (first structure affected by Aβ pathology) in young Tg APParc mice, prior to the onset of pathology. We assessed Aβ/C99 pathology in mice aged up to 6 months after injecting ibotenate into the subiculum. Compared to the brains of intact Tg APP arctic mice, we observed significantly decreased Aβ/C99 pathology in the ipsilateral dorsal subiculum, CA1 region of the hippocampus and the retrosplenial cortex; regions connecting to and from the dorsal subiculum. By contrast, Aβ/C99 pathology was unchanged in the contralateral hippocampus in the mice with lesions.

Conclusion

These results, obtained in an animal model of AD, support the notion that Aβ/C99 pathology is transmitted between interconnected neurons in AD.
Rheumatoid arthritis patients exhibit impaired Candida albicans-specific Th17 responses
Authors: Bishu Shrinivas , Su Ee Wern , Wilkerson Erich R , Reckley Kelly A , Jones Donald M , McGeachy Mandy J , Gaffen Sarah L , Levesque Marc C
Published: February 2014

Introduction

Accumulating data implicate the CD4+ T cell subset (Th17 cells) in rheumatoid arthritis (RA). IL-17 is an inflammatory cytokine that induces tumor necrosis factor (TNF)α, IL-1β and IL-6, all of which are targets of biologic therapies used to treat RA. RA patients are well documented to experience more infections than age-matched controls, and biologic therapies further increase the risk of infection. The Th17/IL-17 axis is vital for immunity to fungi, especially the commensal fungus Candida albicans. Therefore, we were prompted to examine the relationship between RA and susceptibility to C. albicans because of the increasing interest in Th17 cells and IL-17 in driving autoimmunity, and the advent of new biologics that target this pathway.

Methods

We analyzed peripheral blood and saliva from 48 RA and 33 healthy control subjects. To assess C. albicans-specific Th17 responses, PBMCs were co-cultured with heat-killed C. albicans extract, and IL-17A levels in conditioned supernatants were measured by ELISA. The frequency of Th17 and Th1 cells was determined by flow cytometry. As a measure of IL-17A-mediated effector responses, we evaluated C. albicans colonization rates in the oral cavity, salivary fungicidal activity and levels of the antimicrobial peptide β-defensin 2 (BD2) in saliva.

Results

Compared to controls, PBMCs from RA subjects exhibited elevated baseline production of IL-17A (P = 0.004), although they had similar capacity to produce IL-17A in response to Th17 cell differentiating cytokines (P = 0.91). However RA PBMCs secreted less IL-17A in response to C. albicans antigens (P = 0.006). Significantly more RA patients were colonized with C. albicans in the oral cavity than healthy subjects (P = 0.02). Concomitantly, RA saliva had reduced concentrations of salivary BD2 (P = 0.02). Nonetheless, salivary fungicidal activity was preserved in RA subjects (P = 0.70).

Conclusions

RA subjects exhibit detectable impairments in oral immune responses to C. albicans, a strongly Th17-dependent opportunistic pathogen, despite an overall elevated baseline production of IL-17A.
Persistence and selection of an expanded B-cell clone in the setting of rituximab therapy for Sjögren’s syndrome
Authors: Hershberg Uri , Meng Wenzhao , Zhang Bochao , Haff Nancy , St Clair E William , Cohen Philip L , McNair Patrice D , Li Ling , Levesque Marc C , Luning Prak Eline T
Published: February 2014

Introduction

Subjects with primary Sjögren’s syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab.

Methods

To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period.

Results

Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection.

Conclusions

For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an expanded clone may provide a novel means of measuring the chronicity and selection of expanded B-cell populations in humans.
Attribute illumination of basement faults, examples from Cuu Long Basin basement, Vietnam and the Midcontinent, USA
Authors: Mai Ha T. , Elebiju Olubunmi O. , Marfurt Kurt J.
Published: February 2014

Geometric attributes such as coherence and curvature have been very successful in delineating faults in sedimentary basins. Albeit not a common exploration objective, fractured and faulted basement forms important reservoirs in Southern California, Mexico, India, Yemen, and Vietnam. Basement faulting controls hydrothermally altered dolomite in the Appalachian Basin of the USA, and is suspected to play a role in diagenetic alteration of carbonates in the Fort Worth Basin of north Texas where copper has been found in some wells, as well as in Osage County, Oklahoma, not far from the classic Mississippi type lead-zinc deposits. Because of the absence of stratified, coherent reflectors, illumination of basement faults is more problematic than illumination of faults within the sedimentary column. To address these limitations, we make simple modifications to well-established vector attributes including structural dip, azimuth, and amplitude gradients, in combination with variance, and most positive and most negative principal curvature to provide greater interpreter interaction. Using these methods, we can better illuminate fracture “sweet spots” and estimate their intensity and orientation. We apply these methods to better characterize faults in the granite basement of the Cuu Long Basin, Vietnam, and the granite and rhyolite-metarhyolite basement of Osage County, Oklahoma, USA. Cuu Long forms an important unconventional reservoir. In Osage County, we suspect basement control of shallower fractures in the Mississippi chat deposits.
Benefit From Procarbazine, Lomustine, and Vincristine in Oligodendroglial Tumors Is Associated With Mutation ofIDH
Authors: Cairncross J. Gregory , Wang Meihua , Jenkins Robert B. , Shaw Edward G. , Giannini Caterina , Brachman David G. , Buckner Jan C. , Fink Karen L. , Souhami Luis , Laperriere Normand J. , Huse Jason T. , Mehta Minesh P. , Curran Walter J.
Published: February 2014

Purpose

Patients with 1p/19q codeleted anaplastic oligodendroglial tumors who participated in RTOG (Radiation Therapy Oncology Group) 9402 lived much longer after chemoradiotherapy (CRT) than radiation therapy (RT) alone. However, some patients with noncodeleted tumors also benefited from CRT; survival curves separated after the median had been reached, and significantly more patients lived ≥ 10 years after CRT than RT. Thus, 1p/19q status may not identify all responders to CRT.

Patients and Methods

Using trial data, we inquired whether an IDH mutation or germ-line polymorphism associated with IDH-mutant gliomas identified the patients in RTOG 9402 who benefited from CRT.

Results

IDH status was evaluable in 210 of 291 patients; 156 (74%) had mutations. rs55705857 was evaluable in 245 patients; 76 (31%) carried the G risk allele. Both were associated with longer progression-free survival after CRT, and mutant IDH was associated with longer overall survival (9.4 v 5.7 years; hazard ratio [HR], 0.59; 95% CI, 0.40 to 0.86; P = .006). For those with wild-type tumors, CRT did not prolong median survival (1.3 v 1.8 years; HR, 1.14; 95% CI, 0.63 to 2.04; P = .67) or 10-year survival rate (CRT, 6% v RT, 4%). Patients with codeleted mutated tumors (14.7 v 6.8 years; HR, 0.49; 95% CI, 0.28 to 0.85; P = .01) and noncodeleted mutated tumors (5.5 v 3.3 years; HR, 0.56; 95% CI, 0.32 to 0.99; P < .05) lived longer after CRT than RT.

Conclusion

IDH mutational status identified patients with oligodendroglial tumors who did (and did not) benefit from alkylating-agent chemotherapy with RT. Although patients with codeleted tumors lived longest, patients with noncodeleted IDH-mutated tumors also lived longer after CRT.
Pharmacokinetics-Based Integration of Multiple Doses of Intravenous Pegaspargase in a Pediatric Regimen for Adults With Newly Diagnosed Acute Lymphoblastic Leukemia
Authors: Douer Dan , Aldoss Ibrahim , Lunning Matthew A. , Burke Patrick W. , Ramezani Laleh , Mark Lisa , Vrona Janice , Park Jae H. , Tallman Martin S. , Avramis Vassilios I. , Pullarkat Vinod , Mohrbacher Ann M.
Published: February 2014

Purpose

Asparaginase treatment is standard in all pediatric acute lymphoblastic leukemia (ALL) regimens, whereas in adults, it is either excluded or administered for a shorter duration. Several adult ALL protocols are adapting pediatric regimens, but the optimal implementation of asparaginase is not well studied, considering its potential higher toxicity. We studied a pegaspargase dosing strategy based on its pharmacokinetic characteristics in adults.

Patients and Methods

Between 2004 and 2009, 51 adults age 18 to 57 years with newly diagnosed ALL were treated with a regimen adapted from a pediatric trial that included six doses of intravenous pegaspargase at 2,000 IU/m2 per dose. Intervals between doses were longer than 4 weeks and rationally synchronized with other chemotherapy drugs to prevent overlapping toxicities. Pegaspargase was administered with steroids to reduce hypersensitivity. Asparaginase-related toxicities were monitored after 173 pegaspargase doses.

Results

The most common grade 3/4 asparaginase-related toxicities were lengthy hyperbilirubinemia and transaminitis, occasionally resulting in subsequent treatment delays. All toxicities resolved spontaneously. Forty-five percent of patients were able to receive all six doses of pegaspargase, and 61% received ≥ three doses. In only 20% of patients, the drug was discontinued after pegaspargase-related serious toxicity. Ninety-six percent achieved complete remission, almost all within 4 weeks, and a low induction death rate was seen. Seven-year disease-free and overall survival were 58% and 51%, respectively.

Conclusion

Our dose and schedule of pegaspargase, based on its pharmacokinetics, and our detailed toxicity profile could be applied for safer adaptation of pediatric ALL protocols in adults.
Nonsentinel Lymph Node Status in Patients With Cutaneous Melanoma: Results From a Multi-Institution Prognostic Study
Authors: Pasquali Sandro , Mocellin Simone , Mozzillo Nicola , Maurichi Andrea , Quaglino Pietro , Borgognoni Lorenzo , Solari Nicola , Piazzalunga Dario , Mascheroni Luigi , Giudice Giuseppe , Patuzzo Roberto , Caracò Corrado , Ribero Simone , Marone Ugo , Santinami Mario , Rossi Carlo Riccardo
Published: February 2014

Purpose

We investigated whether the nonsentinel lymph node (NSLN) status in patients with melanoma improves the prognostic accuracy of common staging features; then we formulated a proposal for including the NSLN status in the current melanoma staging system.

Patients and Methods

We retrospectively collected the clinicopathologic data of 1,538 patients with positive SLN status who underwent completion lymph node dissection (CLND) at nine Italian centers. Multivariable Cox regression survival analysis was used to identify independent prognostic factors. Literature meta-analysis was used to summarize the available evidence on the prognostic value of the NSLN status in patients with positive SLN.

Results

NSLN metastasis was observed in 353 patients (23%). After a median follow-up of 45 months, NSLN status was an independent prognostic factor for melanoma-specific survival (hazard ratio [HR] = 1.34; 95% CI, 1.18 to 1.52; P < .001). NSLN status efficiently stratified the prognosis of patients with two to three positive lymph nodes (n = 387; HR = 1.39; 95% CI, 1.07 to 1.81; P = .013), independently of other staging features. Searching the literature, this patient subgroup was investigated in other two studies. Pooling the results (n = 620 patients; 284 NSLN negative and 336 NSLN positive), we found that NSLN status is a highly significant prognostic factor (summary HR = 1.59; 95% CI, 1.27 to 1.98; P < .001) in patients with two to three positive lymph nodes.

Conclusion

These findings support the independent prognostic value of the NSLN status in patients with two to three positive lymph nodes, suggesting that this information should be considered for the routine staging in patients with melanoma.
Evaluation of Alternate Categorical Tumor Metrics and Cut Points for Response Categorization Using the RECIST 1.1 Data Warehouse
Authors: Mandrekar Sumithra J. , An Ming-Wen , Meyers Jeffrey , Grothey Axel , Bogaerts Jan , Sargent Daniel J.
Published: February 2014

Purpose

We sought to test and validate the predictive utility of trichotomous tumor response (TriTR; complete response [CR] or partial response [PR] v stable disease [SD] v progressive disease [PD]), disease control rate (DCR; CR/PR/SD v PD), and dichotomous tumor response (DiTR; CR/PR v others) metrics using alternate cut points for PR and PD. The data warehouse assembled to guide the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was used.

Methods

Data from 13 trials (5,480 patients with metastatic breast cancer, non–small-cell lung cancer, or colorectal cancer) were randomly split (60:40) into training and validation data sets. In all, 27 pairs of cut points for PR and PD were considered: PR (10% to 50% decrease by 5% increments) and PD (10% to 20% increase by 5% increments), for which 30% and 20% correspond to the RECIST categorization. Cox proportional hazards models with landmark analyses at 12 and 24 weeks stratified by study and number of lesions (fewer than three v three or more) and adjusted for average baseline tumor size were used to assess the impact of each metric on overall survival (OS). Model discrimination was assessed by using the concordance index (c-index).

Results

Standard RECIST cut points demonstrated predictive ability similar to the alternate PR and PD cut points. Regardless of tumor type, the TriTR, DiTR, and DCR metrics had similar predictive performance. The 24-week metrics (albeit with higher c-index point estimate) were not meaningfully better than the 12-week metrics. None of the metrics did particularly well for breast cancer.

Conclusion

Alternative cut points to RECIST standards provided no meaningful improvement in OS prediction. Metrics assessed at 12 weeks have good predictive performance.
Perturbation of Hypothalamic MicroRNA Expression Patterns in Male Rats After Metabolic Distress: Impact of Obesity and Conditions of Negative Energy Balance
Authors: Sangiao-Alvarellos Susana , Pena-Bello Lara , Manfredi-Lozano María , Tena-Sempere Manuel , Cordido Fernando
Published: February 2014

The hypothalamus plays a crucial role in body weight homeostasis through an intricate network of neuronal circuits that are under the precise regulation of peripheral hormones and central transmitters. Although deregulated function of such circuits might be a major contributing factor in obesity, the molecular mechanisms responsible for the hypothalamic control of energy balance remain partially unknown. MicroRNAs (miRNAs) have been recognized as key regulators of different biological processes, including insulin sensitivity and glucose metabolism. However, the roles of miRNA pathways in the control of metabolism have been mostly addressed in peripheral tissues, whereas the potential deregulation of miRNA expression in the hypothalamus in conditions of metabolic distress remains as yet unexplored. In this work, we used high-throughput screening to define to what extent the hypothalamic profiles of miRNA expression are perturbed in two extreme conditions of nutritional stress in male rats, namely chronic caloric restriction and high-fat diet–induced obesity. Our analyses allowed the identification of sets of miRNAs, including let-7a, mir-9*, mir-30e, mir-132, mir-145, mir-200a, and mir-218, whose expression patterns in the hypothalamus were jointly altered by caloric restriction and/or a high-fat diet. The predicted targets of these miRNAs include several elements of key inflammatory and metabolic pathways, including insulin and leptin. Our study is the first to disclose the impact of nutritional challenges on the hypothalamic miRNA expression profiles. These data will help to characterize the molecular miRNA signature of the hypothalamus in extreme metabolic conditions and pave the way for targeted mechanistic analyses of the involvement of deregulated central miRNAs pathways in the pathogenesis of obesity and related disorders.
Nicotine Improves Obesity and Hepatic Steatosis and ER Stress in Diet-Induced Obese Male Rats
Authors: Seoane-Collazo Patricia , de Morentin Pablo B. Martínez , Fernø Johan , Diéguez Carlos , Nogueiras Rubén , López Miguel
Published: February 2014

Nicotine, the main addictive component of tobacco, promotes body weight reduction in humans and rodents. Recent evidence has suggested that nicotine acts in the central nervous system to modulate energy balance. Specifically, nicotine modulates hypothalamic AMP-activated protein kinase to decrease feeding and to increase brown adipose tissue thermogenesis through the sympathetic nervous system, leading to weight loss. Of note, most of this evidence has been obtained in animal models fed with normal diet or low-fat diet (LFD). However, its effectiveness in obese models remains elusive. Because obesity causes resistance towards many factors involved in energy homeostasis, the aim of this study has been to compare the effect of nicotine in a diet-induced obese (DIO) model, namely rats fed a high-fat diet, with rats fed a LFD. Our data show that chronic peripheral nicotine treatment reduced body weight by decreasing food intake and increasing brown adipose tissue thermogenesis in both LFD and DIO rats. This overall negative energy balance was associated to decreased activation of hypothalamic AMP-activated protein kinase in both models. Furthermore, nicotine improved serum lipid profile, decreased insulin serum levels, as well as reduced steatosis, inflammation, and endoplasmic reticulum stress in the liver of DIO rats but not in LFD rats. Overall, this evidence suggests that nicotine diminishes body weight and improves metabolic disorders linked to DIO and might offer a clear-cut strategy to develop new therapeutic approaches against obesity and its metabolic complications.
Myostatin Regulates Tissue Potency and Cardiac Calcium-Handling Proteins
Authors: Jackson Melissa F. , Li Naisi , Rodgers Buel D.
Published: February 2014

Attenuating myostatin enhances striated muscle growth, reduces adiposity, and improves cardiac contractility. To determine whether myostatin influences tissue potency in a manner that could control such pleiotropic actions, we generated label-retaining mice with wild-type and mstn−/− (Jekyll) backgrounds in which slow-cycling stem, transit-amplifying, and progenitor cells are preferentially labeled by histone 2B/green fluorescent protein. Jekyll mice were born with fewer label-retaining cells (LRCs) in muscle and heart, consistent with increased stem/progenitor cell contributions to embryonic growth of both tissues. Cardiac LRC recruitment from noncardiac sources occurred in both groups, but lasted longer in Jekyll hearts, whereas heightened β-adrenergic sensitivity of mstn−/− hearts was explained by elevated SERCA2a, phospholamban, and β2-adrenergic receptor levels. Jekyll mice were also born with more adipose LRCs despite significantly smaller tissue weights. Reduced adiposity in mstn−/− animals is therefore due to reduced lipid deposition as adipoprogenitor pools appear to be enhanced. By contrast, increased bone densities of mstn−/− mice are likely compensatory to hypermuscularity because LRC counts were similar in Jekyll and wild-type tibia. Myostatin therefore significantly influences the potency of different tissues, not just muscle, as well as cardiac Ca2+-handling proteins. Thus, the pleiotropic phenotype of mstn−/− animals may not be due to enhanced muscle development per se, but also to altered stem/progenitor cell pools that ultimately influence tissue potency.
Coevolution of the Spexin/Galanin/Kisspeptin Family: Spexin Activates Galanin Receptor Type II and III
Authors: Kim Dong-Kyu , Yun Seongsik , Son Gi Hoon , Hwang Jong-Ik , Park Cho Rong , Kim Jae Il , Kim Kyungjin , Vaudry Hubert , Seong Jae Young
Published: February 2014

The novel neuropeptide spexin (SPX) was discovered using bioinformatics. The function of this peptide is currently under investigation. Here, we identified SPX along with a second SPX gene (SPX2) in vertebrate genomes. Syntenic analysis and relocating SPXs and their neighbor genes on reconstructed vertebrate ancestral chromosomes revealed that SPXs reside in the near vicinity of the kisspeptin (KISS) and galanin (GAL) family genes on the chromosomes. Alignment of mature peptide sequences showed some extent of sequence similarity among the 3 peptide groups. Gene structure analysis indicated that SPX is more closely related to GAL than KISS. These results suggest that the SPX, GAL, and KISS genes arose through local duplications before 2 rounds (2R) of whole-genome duplication. Receptors of KISS and GAL (GAL receptor [GALR]) are phylogenetically closest among rhodopsin-like G protein-coupled receptors, and synteny revealed the presence of 3 distinct receptor families KISS receptor, GALR1, and GALR2/3 before 2R. A ligand-receptor interaction study showed that SPXs activate human, Xenopus, and zebrafish GALR2/3 family receptors but not GALR1, suggesting that SPXs are natural ligands for GALR2/3. Particularly, SPXs exhibited much higher potency toward GALR3 than GAL. Together, these results identify the coevolution of SPX/GAL/KISS ligand genes with their receptor genes. This study demonstrates the advantage of evolutionary genomics to explore the evolutionary relationship of a peptide gene family that arose before 2R by local duplications.
Clinical Relevance of Thyroid-Stimulating Autoantibodies in Pediatric Graves' Disease—A Multicenter Study
Authors: Diana T. , Brown R. S. , Bossowski A. , Segni M. , Niedziela M. , König J. , Bossowska A. , Ziora K. , Hale A. , Smith J. , Pitz S. , Kanitz M. , Kahaly G. J.
Published: February 2014

Context and Objective:

The incidence of TSH receptor (TSHR) stimulating autoantibodies (TSAbs) in pediatric Graves' disease (GD) is controversial. This large, multicenter study evaluated the clinical relevance of TSAbs in children with GD both with Graves' orbitopathy (GO) and without orbital disease.

Design:

We conducted a cross-sectional retrospective study.

Setting:

Sera were collected in seven American and European academic referral centers and evaluated in a central laboratory.

Patients and Samples:

A total of 422 serum samples from 157 children with GD, 101 control individuals with other thyroid and nonthyroid autoimmune diseases, and 50 healthy children were studied.

Main Outcome Measures:

TSAbs were measured using a novel, chimeric TSHR bioassay and a cAMP response element-dependent luciferase. TSH binding-inhibitory Ig (TBII) and parameters of thyroid function were also determined.

Results:

In 82 untreated children with GD, sensitivity, specificity, and positive and negative predictive values for TSAb and TBII were: 100 and 92.68% (P = .031), 100 and 100%, 100 and 100%, and 100 and 96.15%, respectively. TSAb and TBII were present in 147 (94%) and 138 (87.9%) of the 157 children with GD (P < .039), respectively; and in 247 (94%) and 233 (89%) of the 263 samples from this group (P < .0075), respectively. In children with GD and GO, TSAb and TBII were noted in 100 and 96% (P < .001), respectively. Hyperthyroid children with GD and GO showed markedly higher TSAb levels compared to those with thyroidal GD only (P < .0001). No significant differences were noted for TBII between the two groups. After a 3-year (median) medical treatment, the decrease of TSAb levels was 69% in GD vs 20% in GD and GO (P < .001). All 31 samples of euthyroid children with GO were TSAb positive; in contrast, only 24 were TBII positive (P = .016). All children with Hashimoto's thyroiditis, nonautoimmune hyperthyroidism, type 1 diabetes, and juvenile arthritis and the healthy controls were TSAb and TBII negative.

Conclusions:

Serum TSAb level is a sensitive, specific, and reproducible biomarker for pediatric GD and correlates well with disease severity and extrathyroidal manifestations.
Correlated changes in life history traits in response to selection for faster pre-adult development in the fruit fly Drosophila melanogaster
Authors: Yadav Pankaj , Sharma Vijay Kumar
Published: February 2014

Insects including the fruit fly Drosophila melanogaster are under intense pressure to develop rapidly because they inhabit ephemeral habitats. We have previously shown that when selection for faster development was artificially imposed on D. melanogaster in the laboratory, reduction of pre-adult development time and shortening of the clock period occurs, suggesting a role for circadian clocks in the regulation of life history traits. Circadian clocks in D. melanogaster have also been implicated in the control of metabolic pathways, ageing processes, oxidative stress and defense responses to exogenous stressors. In order to rigorously examine correlations between pre-adult development time and other life history traits, we assayed pre-adult survivorship, starvation and desiccation resistance, body size and body weight, fecundity and adult lifespan in faster developing populations of D. melanogaster. The results revealed that selection for faster pre-adult development significantly reduced several adult fitness traits in the faster developing flies without affecting pre-adult survivorship. Although overall fecundity of faster developing flies was reduced, their egg output per unit body weight was significantly higher than that of controls, indicating that reduction in adult lifespan might be due to disproportionate investment in reproduction. Thus our results suggest that selection for faster pre-adult development in D. melanogaster yields flies with higher reproductive fitness. Because these flies also have shorter clock periods, our results can be taken to suggest that pre-adult development time and circadian clock period are correlated with various adult life history traits in D. melanogaster, implying that circadian clocks may have adaptive significance.
Сommunication Science and Ideology
Authors: Татищев  , Tatishchev Yu.
Published: February 2014

In the essay «Conceptual Principles of Ideology Creation and Dissemination» it has been made ontological understanding related to some of modern

communication science principles. It has been shown that the appearance

of communication science idea itself that took place half a century

ago was caused most of all by ideology phenomenon crisis. In this essay

the principles that can ensure the development of communication science

and expand its application in a number of public life areas. In particular, the

inclusion of society life’s ideological support function in communication science

has been justified, and the main principles related to creation of communication

science’s «ideological segment» have been marked.
Penalty-Based Algorithms for the Stochastic Obstacle Scene Problem
Authors: Aksakalli Vural , Ari Ibrahim
Published: February 2014

We consider the stochastic obstacle scene problem wherein an agent needs to traverse a spatial arrangement of possible obstacles, and the status of the obstacles may be disambiguated en route at a cost. The goal is to find an algorithm that decides what and where to disambiguate en route so that the expected length of the traversal is minimized. We present a polynomial-time method for a graph-theoretical version of the problem when the associated graph is restricted to parallel avenues with fixed policies within the avenues. We show how previously proposed algorithms for the continuous space version can be adapted to a discrete setting. We propose a generalized framework encompassing these algorithms that uses penalty functions to guide the navigation in real time. Within this framework, we introduce a new algorithm that provides near-optimal results within very short execution times. Our algorithms are illustrated via computational experiments involving synthetic data as well as an actual naval minefield data set.

Data, as supplemental material, are available at http://dx.doi.org/10.1287/ijoc.2013.0571 .
Synthesis of novel pyrazolo[3,4-d]pyrimidinone derivatives as cytotoxic inhibitors
Authors: Rahmouni Ameur , Romdhane Anis , Besbes Malek , Elie Nicolas , Touboul David , Jannet Hichem Ben
Published: February 2014

Various Î±-fonctionalized iminoethers 2 were easily prepared from ethyl 5-amino-3-substituted-1-phenyl-1H-pyrazole-4-carboxylate 1. The reaction of iminoethers 2 with ammonia afforded 3-substitued-1-phenyl-1H-pyrazolo[3,4-d] pyrimidin-4(5H)-ones 3 which were also synthesized by the addition of formamide to ethyl 5-amino-3-substituted-1-phenyl-1H-pyrazole-4-carboxylate 1. The 5-amino-3-substitued-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones 4 were obtained from hydrazonolysis of iminoethers 2. Otherwise, the condensation of these intermediates 2 with a series of some primary amines and hydroxylamine led respectively, to the corresponding 3,5-disubstitued-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones 5 and the 3-substitued-5-hydroxy-1-phenyl-1H-pyrazolo[3,4-d] pyrimidin-4-(5H)-ones 6. The synthesized compounds 1-6 were completely characterized by 1H NMR, 13C NMR, IR and HRMS. Some synthesized compounds were evaluated for their cytotoxic effect using the Human cervical adenocarcinoma Hela cell line.
Stimulus and Response Expectancies Influence the Cognitive Effects of Cigarettes
Authors: Kelemen William L.
Published: February 2014

The pharmacological, stimulus expectancy, and response expectancy effects of light cigarettes (0.60 mg yield of nicotine) compared with virtually nicotine-free cigarettes (less than 0.05 mg yield of nicotine) were examined using a between-subjects design. A total of 103 college student smokers completed tests of cognition before and after smoking one type of cigarette, which was evaluated on a number of dimensions. Cigarettes with nicotine were preferred on most dimensions, and stimulus expectancy partially mediated the relationship between nicotine and subjective effects of the cigarettes. Stimulus expectancy also mediated the effect of nicotine on tension reduction immediately after smoking, but not near the end of the experiment. Response expectancy effects of nicotine were related to predicted and actual recall performance, such that participants who performed well tended to attribute the effect to the cigarette they smoked. Implications for smoking cessation and research studies using non-nicotine cigarettes are discussed.
Improving on the Proven: Increased Efficacy and Reach With Innovations in Use of Therapeutic Nicotine
Authors: Shiffman Saul , Hughes John R.
Published: February 2014

Therapeutic nicotine (TN) has been a mainstay of evidence-based smoking cessation treatment for many years, with established patterns of application. Yet recent research and practice indicates that innovations in how TN is used and applied to new populations can substantially enhance its efficacy and reach, improving upon established approaches to TN use. In this article, we address innovations how TN is used, discussing evidence that starting treatment before the quit day, combining patch with acute TN forms, and continuing TN treatment after a lapse, all substantially improve treatment outcomes compared to current TN practices, with effects sizes in the same range as the basic effect of TN versus placebo. We also review the use of TN in populations interested in smoking reduction as a path to quitting, discussing evidence that TN improves success rates in quitting by gradual reduction, and can also be used for reduction among smokers who are not yet ready to quit, leading to increased cessation rates. The evidence suggests that innovations in how TN is used can have substantial effects on the efficacy and reach of smoking cessation treatment.