bluuebunny/crossref_metadata_2025_split huggingface dataset:
The inhibition of assembly of HIV-1 virus-like particles by 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB) is counteracted by Vif and requires its Zinc-binding domain
Authors: DaFonseca Sandrina , Coric Pascale , Gay Bernard , Hong Saw See , Bouaziz Serge , Boulanger Pierre 
Published: December 2008

AbstractBackgroundDSB, the 3-O-(3',3'dimethylsuccinyl) derivative of betulinic acid, blocks the last step of protease-mediated processing of HIV-1 Gag precursor (Pr55Gag), which leads to immature, noninfectious virions. When administered to Pr55Gag-expressing insect cells (Sf9), DSB inhibits the assembly and budding of membrane-enveloped virus-like particles (VLP). In order to explore the possibility that viral factors could modulate the susceptibility to DSB of the VLP assembly process, several viral proteins were coexpressed individually with Pr55Gag in DSB-treated cells, and VLP yields assayed in the extracellular medium.ResultsWild-type Vif (Vifwt) restored the VLP production in DSB-treated cells to levels observed in control, untreated cells. DSB-counteracting effect was also observed with Vif mutants defective in encapsidation into VLP, suggesting that packaging and anti-DSB effect were separate functions in Vif. The anti-DSB effect was abolished for VifC133S and VifS116V, two mutants which lacked the zinc binding domain (ZBD) formed by the four H108C114C133H139coordinates with a Zn atom. Electron microscopic analysis of cells coexpressing Pr55Gag and Vifwtshowed that a large proportion of VLP budded into cytoplasmic vesicles and were released from Sf9 cells by exocytosis. However, in the presence of mutant VifC133S or VifS116V, most of the VLP assembled and budded at the plasma membrane, as in control cells expressing Pr55Gag alone.ConclusionThe function of HIV-1 Vif protein which negated the DSB inhibition of VLP assembly was independent of its packaging capability, but depended on the integrity of ZBD. In the presence of Vifwt, but not with ZBD mutants VifC133S and VifS116V, VLP were redirected to a vesicular compartment and egressed via the exocytic pathway.
Voxel-based structural magnetic resonance imaging (MRI) study of patients with early onset schizophrenia
Authors: Yoshihara Yujiro , Sugihara Genichi , Matsumoto Hideo , Suckling John , Nishimura Katsuhiko , Toyoda Takao , Isoda Haruo , Tsuchiya Kenji J , Takebayashi Kiyokazu , Suzuki Katsuaki , Sakahara Harumi , Nakamura Kazuhiko , Mori Norio , Takei Nori 
Published: December 2008

AbstractBackgroundInvestigation into the whole brain morphology of early onset schizophrenia (EOS) to date has been sparse. We studied the regional brain volumes in EOS patients, and the correlations between regional volume measures and symptom severity.MethodsA total of 18 EOS patients (onset under 16 years) and 18 controls matched for age, gender, parental socioeconomic status, and height were examined. Voxel-based morphometric analysis using the Brain Analysis Morphological Mapping (BAMM) software package was employed to explore alterations of the regional grey (GM) and white matter (WM) volumes in EOS patients. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS).ResultsEOS patients had significantly reduced GM volume in the left parahippocampal, inferior frontal, and superior temporal gyri, compared with the controls. They also had less WM volume in the left posterior limb of the internal capsule and the left inferior longitudinal fasciculus. The positive symptom score of PANSS (higher values corresponding to more severe symptoms) was negatively related to GM volume in the bilateral posterior cingulate gyrus. The negative symptom score was positively correlated with GM volume in the right thalamus. As for the association with WM volume, the positive symptom score of PANSS was positively related to cerebellar WM (vermis region), and negatively correlated with WM in the brain stem (pons) and in the bilateral cerebellum (hemisphere region).ConclusionOur findings of regional volume alterations of GM and WM in EOS patients coincide with those of previous studies of adult onset schizophrenia patients. However, in brain regions that had no overall structural differences between EOS patients and controls (that is, the bilateral posterior cingulate gyrus, the right thalamus, the cerebellum, and the pons), within-subject analysis of EOS patients alone revealed that there were significant associations of the volume in these areas and the symptom severity. These findings suggest that at an early stage of the illness, especially for those with onset before brain maturation, a wide range of disturbed neural circuits, including these brain regions that show no apparent morphological changes, may contribute to the formation of the symptomatology.
Essential operating principles for tumor spheroid growth
Authors: Engelberg Jesse A , Ropella Glen EP , Hunt C Anthony 
Published: December 2008

Abstract

Background
Our objective was to discover in silico axioms that are plausible representations of the operating principles realized during characteristic growth of EMT6/Ro mouse mammary tumor spheroids in culture. To reach that objective we engineered and iteratively falsified an agent-based analogue of EMT6 spheroid growth. EMT6 spheroids display consistent and predictable growth characteristics, implying that individual cell behaviors are tightly controlled and regulated. An approach to understanding how individual cell behaviors contribute to system behaviors is to discover a set of principles that enable abstract agents to exhibit closely analogous behaviors using only information available in an agent's immediate environment. We listed key attributes of EMT6 spheroid growth, which became our behavioral targets. Included were the development of a necrotic core surrounded by quiescent and proliferating cells, and growth data at two distinct levels of nutrient.

Results
We then created an analogue made up of quasi-autonomous software agents and an abstract environment in which they could operate. The system was designed so that upon execution it could mimic EMT6 cells forming spheroids in culture. Each agent used an identical set of axiomatic operating principles. In sequence, we used the list of targeted attributes to falsify and revise these axioms, until the analogue exhibited behaviors and attributes that were within prespecified ranges of those targeted, thereby achieving a level of validation.

Conclusion
The finalized analogue required nine axioms. We posit that the validated analogue's operating principles are reasonable representations of those utilized by EMT6/Ro cells during tumor spheroid development.
Is there an association between fibromyalgia and below-normal levels of urinary cortisol?
Authors: Izquierdo–Álvarez Silvia , Bocos–Terraz Julia Pilar , Bancalero–Flores Jose Luis , Pavón–Romero Lenin , Serrano–Ostariz Enrique , de Miquel Cayetano Alegre 
Published: December 2008

Abstract

Background
Adynamia in fibromyalgia (FM) may be an expression of a functional deficit of the hypothalamic-pituitary-adrenal axis and be associated with below-normal levels of urinary cortisol. Our aim was to demonstrate that urinary cortisol was lower in patients with FM than in healthy subjects.

Findings
We measured urinary cortisol levels for a sample of 47 women aged 29 to 64 years (mean age 53 years), diagnosed with FM 2–3 years previously, and compared the results with those for a control sample of 58 healthy women of a similar age. Samples of 24-hour urine were appropriately collected and levels of urinary cortisol were measured using the fluorescence polarization immunoassay method. The mean cortisol value for the women with FM was 65.40 ± 27.10 μg/L, significantly lower than the mean cortisol level for the control group, at 90.83 ± 38.17 μg/L (p < 0.001).

Conclusion
Our study confirms that women with FM have significantly lower urinary cortisol levels than healthy women.
Long-Term Benefit of High-Dose Epirubicin in Adjuvant Chemotherapy for Node-Positive Breast Cancer: 15-Year Efficacy Results of the Belgian Multicentre Study
Authors: de Azambuja Evandro , Paesmans Marianne , Beauduin Marc , Vindevoghel Anita , Cornez Nathalie , Finet Claude , Ries Fernand , Closon-Dejardin Marie Thérèse , Kerger Joseph , Gobert Philippe , Focan Christian , Tagnon Alain , Dolci Stella , Nogaret Jean M. , di Leo Angelo , Piccart-Gebhart Martine J. 
Published: December 2008

Purpose The 4-year results of this trial demonstrated that a higher dose of epirubicin with cyclophosphamide (HEC) is superior to a lower dose of epirubicin, 60 mg/m2 (EC), for event-free survival (EFS; 27% reduction), but is not superior to classical oral cyclophosphamide, methotrexate, and fluorouracil (CMF) in the adjuvant treatment of node-positive breast cancer. Herein we report the 15-year data on efficacy and long-term toxicity of this three-arm Belgian multicenter trial. Patients and Methods Between March 1988 and December 1996, 777 eligible patients were randomly assigned to six cycles of CMF, eight cycles of EC, or eight cycles HEC. Results The 15-year EFS was 45% for patients who received CMF, 39% for patients who received EC, and 50% for patients who received HEC. The hazard ratios (HR) were 0.77 for HEC versus EC (95% CI, 0.60 to 0.98; P = .03), 0.90 for HEC versus CMF (P = .39), and 0.86 for EC versus CMF (P = .21). No difference in overall survival (OS) was seen. Cardiac toxicity was more frequent with HEC than with CMF (11 patients v 1 patient; P = .006), but no more than with EC (P = .21). Conclusion Treatment with HEC demonstrated superior EFS when compared with lower-dose epirubicin. However, we do not recommend the use of HEC regimen in daily clinical practice, mainly because of the higher risk of cardiotoxicity related to the cumulative doses of epirubicin and the lack of superiority of anthracyclines over CMF in our study.
Trends in Racial and Age Disparities in Definitive Local Therapy of Early-Stage Breast Cancer
Authors: Freedman Rachel A. , He Yulei , Winer Eric P. , Keating Nancy L. 
Published: December 2008

PurposeGuidelines recommend breast-conserving surgery (BCS) with radiation or mastectomy for definitive local therapy of stage I/II breast cancers. We assessed receipt of definitive local therapy for early-stage breast cancer by race/ethnicity and age and examined trends over time.Patients and MethodsWe calculated rates of definitive local therapy (mastectomy or BCS with radiation) for 375,547 adult women with stage I or II breast cancer diagnosed during 1988 to 2004 using Surveillance, Epidemiology, and End Results registry data. We assessed the probability of definitive local therapy and trends over time using multivariate logistic regression.ResultsOverall, 85.8% of women had definitive local therapy. As mastectomy rates decreased (76.5% in 1988 to 38.0% in 2004; P < .001), definitive local therapy rates also decreased (95.2% in 1988 to 79.2% in 2004; P < .001). In adjusted analyses, rates of definitive local therapy were modestly lower for black and Hispanic (v white) women and higher for Asian women. Differences for black and Asian women were stable over time (P = .61 and P = .35 for interaction), but increased for Hispanic women (P = .0003). Although age differences narrowed over time, women older than 70 years and women ≤ 60 years had lower rates of definitive local therapy than women 61 to 70 years throughout the study period.ConclusionAs breast conservation has increasingly substituted mastectomy, our findings suggest fewer women are receiving definitive local breast cancer therapy, with persistent disparities for black and Hispanic women as well as women age ≤ 60 and older than 70 years. Interventions to assure receipt of radiation after BCS are needed to eliminate these disparities.
Effect of Recombinant Adenovirus-p53 Combined With Radiotherapy on Long-Term Prognosis of Advanced Nasopharyngeal Carcinoma
Authors: Pan Jian-ji , Zhang Shan-wen , Chen Chuan-beng , Xiao Shao-wen , Sun Yan , Liu Chang-qin , Su Xing , Li Dong-ming , Xu Gang , Xu Bo , Lu You-yong 
Published: December 2008

Purpose To centrally assess the safety, efficacy, and 6-year follow-up of recombinant adenovirus-p53 (rAd-p53) combined with radiotherapy (RT) for patients with nasopharyngeal carcinoma (NPC). Patients and Methods A randomized controlled clinical study on rAd-p53 combined with RT in 42 patients with NPC was compared with a control group of 40 patients with NPC treated with RT alone. In the group receiving rAd-p53 combined with RT, rAd-p53 was intratumorally injected once a week for 8 weeks. Concurrent RT (70 Gy in 35 fractions) was given to the nasopharyngeal tumor and neck lymph node. Patients and tumors were monitored for adverse events and responses. Results rAd-p53–specific p53 mRNA was detected in postinjection of rAd-p53 biopsies from 16 (94.1%) of 17 patients. Upregulation of p21/WAF1 and Bax and downregulation of vascular endothelial growth factor were observed in postinjection tumor biopsy. Complete response rate in the group receiving rAd-p53 combined with RT was observed at 2.73 times that of the group receiving RT alone (66.7% v 24.4%). Six-year follow-up data showed that rAd-p53 significantly increased the 5-year locoregional tumor control rate by 25.3% for patients with NPC treated with irradiation (P = .002). The 5-year overall survival rate and 5-year disease-free survival rate of the group receiving rAd-p53 combined with RT were 7.5% (P = .34) and 11.7% (P = .21) higher than those of the group receiving RT alone. No dose-limiting toxicity or adverse events appeared, except for transient fever after rAd-p53 administration. Conclusion In patients with NPC, rAd-p53 was safe and biologically active. Our results indicated that rAd-p53 improves radiotherapeutic tumor control and survival rate in patients with NPC.
Complete Cytoreductive Surgery Plus Intraperitoneal Chemohyperthermia With Oxaliplatin for Peritoneal Carcinomatosis of Colorectal Origin
Authors: Elias Dominique , Lefevre Jérémie H. , Chevalier Julie , Brouquet Antoine , Marchal Frédéric , Classe Jean-Marc , Ferron Gwenaël , Guilloit Jean-Marc , Meeus Pierre , Goéré Diane , Bonastre Julia 
Published: December 2008

Purpose To compare the long-term survival of patients with isolated and resectable peritoneal carcinomatosis (PC) in comparable groups of patients treated with systemic chemotherapy containing oxaliplatin or irinotecan or by cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC). Patients and Methods All patients with gross PC from colorectal adenocarcinoma who had undergone cytoreductive surgery plus HIPEC from 1998 to 2003 were evaluated. The standard group was constituted by selecting patients with colorectal PC treated with palliative chemotherapy during the same period, but who had not benefited from HIPEC because the technique was unavailable in the center at that time. Results Forty-eight patients were retrospectively included in the standard group and were compared with 48 patients who had undergone HIPEC and were evaluated prospectively. All characteristics were comparable except age and tumor differentiation. There was no difference in systemic chemotherapy, with a mean of 2.3 lines per patient. Median follow-up was 95.7 months in the standard group versus 63 months in the HIPEC group. Two-year and 5-year overall survival rates were 81% and 51% for the HIPEC group, respectively, and 65% and 13% for the standard group, respectively. Median survival was 23.9 months in the standard group versus 62.7 months in the HIPEC group (P < .05, log-rank test). Conclusion Patients with isolated, resectable PC achieve a median survival of 24 months with modern chemotherapies, but only surgical cytoreduction plus HIPEC is able to prolong median survival to roughly 63 months, with a 5-year survival rate of 51%.
Foci of Listeria monocytogenes persist in the bone marrow
Authors: Hardy Jonathan , Chu Pauline , Contag Christopher H. 
Published: December 2008

SUMMARY
Murine listeriosis is one of the most comprehensive and well-studied models of infection, and Listeria monocytogenes has provided seminal information regarding bacterial pathogenesis. However, many aspects of the mouse model remain poorly understood, including carrier states and chronic colonization which represent important features of the spectrum of host-pathogen interaction. Bone marrow has recently been shown to harbor L. monocytogenes, which spreads from this location to the central nervous system. Bone could, therefore, be an important chronic reservoir, but this infection is difficult to study because it involves only a few bacteria and the extent of infection cannot be assessed until after the animal is sacrificed. We employed in vivo bioluminescence imaging to localize L. monocytogenes bone infections over time in live mice, revealing that the bacteria grow in discrete foci. These lesions can persist in many locations in the legs of mice and are not accompanied by a histological indication such as granuloma or a neutrophil infiltratate. We demonstrate that highly attenuated hly mutants, which have defective intracellular replication, are capable of prolonged focal infection of the bone marrow for periods of up to several weeks. These results support the recently proposed hypothesis that the bone marrow is a unique niche for L. monocytogenes.
The fission yeast model for the lysosomal storage disorder Batten disease predicts disease severity caused by mutations in CLN3
Authors: Haines Rebecca L. , Codlin Sandra , Mole Sara E. 
Published: December 2008

SUMMARY
The function of the CLN3 protein, which is mutated in patients with the neurodegenerative lysosomal storage disorder Batten disease, has remained elusive since it was identified 13 years ago. Here, we exploited the Schizosaccharomyces pombe model to gain new insights into CLN3 function. We modelled all missense mutations of CLN3 in the orthologous protein Btn1p, as well as a series of targeted mutations, and assessed trafficking and the ability of the mutant proteins to rescue four distinct phenotypes of btn1Δ cells. Mutating the C-terminal cysteine residues of Btn1p caused it to be internalised into the vacuole, providing further evidence that this protein functions from pre-vacuole compartments. Mutations in the lumenal regions of the multi-spanning membrane protein, especially in the third lumenal domain which contains a predicted amphipathic helix, had the most significant impact on Btn1p function, indicating that these domains of CLN3 are functionally important. Only one mutant protein was able to rescue the cell curving phenotype (p.Glu295Lys), and since this mutation is associated with a very protracted disease progression, this phenotype could be used to predict the disease severity of novel mutations in CLN3. The ability to predict disease phenotypes in S. pombe confirms this yeast as an invaluable tool to understanding Batten disease.
MDM2-A, a common Mdm2 splice variant, causes perinatal lethality, reduced longevity and enhanced senescence
Authors: Volk Erin L. , Schuster Katja , Nemeth Katie M. , Fan Liying , Harris Linda C. 
Published: December 2008

SUMMARY
MDM2 is the predominant negative regulator of p53 that functions to maintain the appropriate level of expression and activity of this central tumor suppressor. Mdm2-a is a commonly identified splice variant of Mdm2; however, its physiological function is unclear. To gain insight into the activity of MDM2-A and its potential impact on p53, an Mdm2-a transgenic mouse model was generated. Mdm2-a transgenic mice displayed a homozygous-lethal phenotype that could be rescued by a reduction in p53 expression, demonstrating a dependence upon p53. Mdm2-a hemizygous mice exhibited reduced longevity, and enhanced senescence was observed in their salivary glands. In addition, the transgenic mice lacked typical, accelerated aging phenotypes. Growth of transgenic mouse embryonic fibroblasts (MEFs) was inhibited relative to wild-type MEFs, and MDM2-A was shown to bind to full-length MDM2 in an interaction that could increase p53 activity via reduced MDM2 inhibition. Evidence of p53 activation was shown in the Mdm2-a transgenic MEFs, including p53-dependent growth inhibition and elevated expression of the p53 target protein p21. In addition, MDM2-A increased senescence in a p21-independent manner. In conclusion, unexpected roles for MDM2-A in longevity and senescence were identified in a transgenic mouse model, suggesting that Mdm2 splice variants might be determinants of these phenotypes in vivo.
Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells
Authors: Santoriello Cristina , Deflorian Gianluca , Pezzimenti Federica , Kawakami Koichi , Lanfrancone Luisa , d’Adda di Fagagna Fabrizio , Mione Marina 
Published: December 2008

SummaryConstitutively active, ‘oncogenic’ H-RAS can drive proliferation and transformation in human cancer, or be a potent inducer of cellular senescence. Moreover, aberrant activation of the Ras pathway owing to germline mutations can cause severe developmental disorders. In this study we have generated transgenic zebrafish that constitutively express low levels, or can be induced to express high levels, of oncogenic H-RAS. We observed that fish carrying the integrated transgene in their germline display several hallmarks of Costello syndrome, a rare genetic disease caused by activating mutations in the gene H-RAS, and can be used as a model for the disease. In Costello-like fish, low levels of oncogenic H-RAS expression are associated with both reduced proliferation and an increase in senescence markers in adult progenitor cell compartments in the brain and heart, together with activated DNA damage responses. Overexpression of H-RAS through a heat-shock-inducible promoter in larvae led to hyperproliferation, activation of the DNA damage response and tp53-dependent cell cycle arrest. Thus, oncogene-induced senescence of adult proliferating cells contributes to the development of Costello syndrome and provides an alternative pathway to transformation in the presence of widespread constitutively active H-RAS expression.
A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle
Authors: Dutton Kirsten , Abbas Leila , Spencer Joanne , Brannon Claire , Mowbray Catriona , Nikaido Masataka , Kelsh Robert N. , Whitfield Tanya T. 
Published: December 2008

SUMMARYIn humans, mutations in the SOX10 gene are a cause of the auditory-pigmentary disorder Waardenburg syndrome type IV (WS4) and related variants. SOX10 encodes an Sry-related HMG box protein essential for the development of the neural crest; deafness in WS4 and other Waardenburg syndromes is usually attributed to loss of neural-crest-derived melanocytes in the stria vascularis of the cochlea. However, SOX10 is strongly expressed in the developing otic vesicle and so direct roles for SOX10 in the otic epithelium might also be important. Here, we examine the otic phenotype of zebrafish sox10 mutants, a model for WS4. As a cochlea is not present in the fish ear, the severe otic phenotype in these mutants cannot be attributed to effects on this tissue. In zebrafish sox10 mutants, we see abnormalities in all otic placodal derivatives. Gene expression studies indicate deregulated expression of several otic genes, including fgf8, in sox10 mutants. Using a combination of mutant and morphant data, we show that the three sox genes belonging to group E (sox9a, sox9b and sox10) provide a link between otic induction pathways and subsequent otic patterning: they act redundantly to maintain sox10 expression throughout otic tissue and to restrict fgf8 expression to anterior macula regions. Single-cell labelling experiments indicate a small and transient neural crest contribution to the zebrafish ear during normal development, but this is unlikely to account for the strong defects seen in the sox10 mutant. We discuss the implication that the deafness in WS4 patients with SOX10 mutations might reflect a haploinsufficiency for SOX10 in the otic epithelium, resulting in patterning and functional abnormalities in the inner ear.