Miracle-dz/UniFAR-FTUs huggingface dataset:
Phase I Clinical Study With Multiple Peptide Vaccines in Combination With Tetanus Toxoid and GM-CSF in Advanced-stage HLA-A*0201-positive Melanoma Patients

Successful induction of functional tumor-specific T cells by peptide vaccination in animal models has resulted in many clinical trials to test this approach in advanced-stage melanoma patients. In this phase I clinical trial, 11 end-stage melanoma patients were vaccinated intradermally with 3 peptides: MART-1(26-35) E27L (ELAGIGILTV), tyrosinase(368-376) N375Q (YMDGTMSQV), and gp100(209-217) T210M (IMQVPFSV), admixed with tetanus toxoid and granulocyte-monocyte colony stimulating factor. The peptide vaccine was well tolerated at all tested doses, and led to grade 1-2 toxicity only. Although all patients did show a rise in antitetanus IgG titers, in only 3 patients peptide-specific CD8+ T-cells were induced. In 2 cases, the response was directed against MART-1(26-35) and consisted of 0.2% and 3.3% of the CD8+ population; however, in both instances these cells did not produce interferon-γ on stimulation with the unmodified peptide. The third patient mounted a small (0.1%) response against gp100. In a fourth patient, a nonfunctional tyrosinase-specific response (0.6%) was found that was present before vaccination, but was not affected in size nor in function by the vaccine. None of the 11 patients responded clinically according to response evaluation criteria in solid tumors criteria. Although this study is a small scale phase I clinical trial, the efficacy that was observed was disappointingly low. In accordance with previously published peptide vaccination studies, these results add to the increasing evidence that peptide vaccination in itself is not potent enough as an effective melanoma immunotherapy in advanced-stage patients.
Efficiency analysis on DCM interleaved boost power converters

One of the main challenges in power converters for photovoltaic (PV) energy conversion is their efficiency. In this sense, discontinuous conduction mode (DCM) is able to improve efficiency, mainly due to zero current commutation and the reduction of the reverse recovery losses. Furthermore, interleaved DCM power converters are able to extend this operating mode to higher power applications, due to the reduction on the differential mode (DM) filter requirements, by dividing total current among N phases and interleaving its ripples. One additional requirement is that high efficiency must be maintained over the entire operating range. For this purpose, the number of active phases can be dynamically adjusted as a function of load power. Even though this technique, known as phase shedding, has been used in continuous conductiond mode (CCM) and boundary conduction mode (BCM), it has not yet been implemented for DCM. In this paper, the criterion for establishing the efficiency boundaries as a function of the number of phases in DCM is presented. In this criterion, the losses in semiconductor devices and passive components as a function of N are considered. Furthermore losses in the input and output DM filters are taken into account, considering the total ripple reduction achieved with the interleaved operation.
LSU Digital Commons LSU Digital Commons Cellular efflux of auxin catalyzed by the Arabidopsis MDR/PGP Cellular efflux of auxin catalyzed by the Arabidopsis MDR/PGP transporter AtPGP1 transporter AtPGP1

Directional transport of the phytohormone auxin is required for the establishment and maintenance of plant polarity, but the underlying molecular mechanisms have not been fully elucidated. Plant homologs of human multiple drug resistance/P-glycoproteins (MDR/PGPs) have been implicated in auxin transport, as defects in MDR1 ( AtPGP19 ) and AtPGP1 result in reductions of growth and auxin transport in Arabidopsis ( atpgp1 , atpgp19 ), maize ( brachytic2 ) and sorghum ( dwarf3 ). Here we examine the localization, activity, substrate speciﬁcity and inhibitor sensitivity of AtPGP1. AtPGP1 exhibits non-polar plasma membrane localization at the shoot and root apices, as well as polar localization above the root apex. Protoplasts from Arabidopsis pgp1 leaf mesophyll cells exhibit reduced efﬂux of natural and synthetic auxins with reduced sensitivity to auxin efﬂux inhibitors. Expression of AtPGP1 in yeast and in the standard mammalian expression system used to analyze human MDR-type proteins results in enhanced efﬂux of indole-3-acetic acid (IAA) and the synthetic auxin 1-naphthalene acetic acid (1-NAA), but not the inactive auxin 2-NAA. AtPGP1-mediated efﬂux is sensitive to auxin efﬂux and ABC transporter inhibitors. As is seen in planta , AtPGP1 also appears to mediate some efﬂux of IAA oxidative breakdown products associated with apical sites of high auxin accumulation. However, unlike what is seen in planta , some additional transport of the benzoic acid is observed in yeast and mammalian cells expressing AtPGP1 , suggesting that other factors present in plant tissues confer enhanced auxin speciﬁcity to PGP-mediated transport.
Inactivation of the 25-Hydroxyvitamin D 1α-Hydroxylase and Vitamin D Receptor Demonstrates Independent and Interdependent Effects of Calcium and Vitamin D on Skeletal and Mineral Homeostasis*

We employed a genetic approach to determine whether deficiency of 1,25-dihydroxyvitamin D (1,25(OH)2D) and deficiency of the vitamin D receptor (VDR) produce the same alterations in skeletal and calcium homeostasis and whether calcium can subserve the skeletal functions of 1,25(OH)2D and the VDR. Mice with targeted deletion of the 25-hydroxyvitamin D 1α-hydroxylase (1α(OH)ase-/-) gene, the VDR gene, and both genes were exposed to 1) a high calcium intake, which maintained fertility but left mice hypocalcemic; 2) this intake plus three times weekly injections of 1,25(OH)2D3, which normalized calcium in the 1α(OH)ase-/- mice only; or 3) a “rescue” diet, which normalized calcium in all mutants. These regimens induced different phenotypic changes, thereby disclosing selective modulation by calcium and the vitamin D system. Parathyroid gland size and the development of the cartilaginous growth plate were each regulated by calcium and by 1,25(OH)2D3 but independent of the VDR. Parathyroid hormone secretion and mineralization of bone reflected ambient calcium levels rather than the 1,25(OH)2D/VDR system. In contrast, increased calcium absorption and optimal osteoblastogenesis and osteoclastogenesis were modulated by the 1,25(OH)2D/VDR system. These studies indicate that the calcium ion and the 1,25(OH)2D/VDR system exert discrete effects on skeletal and calcium homeostasis, which may occur coordinately or independently.
RNA interference-based functional knockdown of the voltage-gated potassium channel Kv7.2 in dorsal root ganglion neurons after in vitro and in vivo gene transfer by adeno-associated virus vectors

Activation of the neuronal potassium channel Kv7.2 encoded by the KCNQ2 gene has recently been shown to be an attractive mechanism to inhibit nociceptive transmission. However, potent, selective, and clinically proven activators of Kv7.2/Kv7.3 currents with analgesic properties are still lacking. An important prerequisite for the development of new drugs is a model to test the selectivity of novel agonists by abrogating Kv7.2/Kv7.3 function. Since constitutive knockout mice are not viable, we developed a model based on RNA interference-mediated silencing of KCNQ2. By delivery of a KCNQ2-specific short hairpin RNA with adeno-associated virus vectors, we completely abolished the activity of the specific Kv7.2/Kv7.3-opener ICA-27243 in rat sensory neurons. Results obtained in the silencing experiments were consistent between freshly prepared and cryopreserved dorsal root ganglion neurons, as well as in dorsal root ganglion neurons dissociated and cultured after in vivo administration of the silencing vector by intrathecal injections into rats. Interestingly, the tested associated virus serotypes substantially differed with respect to their transduction capability in cultured neuronal cell lines and primary dorsal root ganglion neurons and the in vivo transfer of transgenes by intrathecal injection of associated virus vectors. However, our study provides the proof-of-concept that RNA interference-mediated silencing of KCNQ2 is a suitable approach to create an ex vivo model for testing the specificity of novel Kv7.2/Kv7.3 agonists.
Variantenwörterbuch des Deutschen: Die Standardsprache in Österreich, der Schweiz und Deutschland sowie in Liechtenstein, Luxemburg, Ostbelgien und Südtirol

The lexicon contains approximately 12,000 words and usages of standard language with nationally- or regionally-limited distribution, or differences in usage including their standard German equivalents. The lexicon is based on the analysis of an extensive corpus from all countries and states in which German is the national or regional official language, with an analysis of the language of the Internet as an additional data source.
Social relations, physical activity, and well-being in older adults.

BACKGROUND A randomized controlled trial was conducted to examine: (a) the effect of two physical activity modes on changes in subjective well-being (SWB) over the course of a 12-month period in older, formerly sedentary adults (N = 174, M age = 65.5 years) and (b) the role played by physical activity participation and social support in changes in SWB over time. METHOD Participants were randomized into either an aerobic activity group or a stretching and toning group. Structural equation modeling was employed to conduct multiple sample latent growth curve analyses of individual growth in measures of SWB (happiness, satisfaction with life, and loneliness) over time. RESULTS A curvilinear growth pattern was revealed with well-being significantly improving over the course of the intervention followed by significant declines at the 6-month follow-up. Subsequent structural analyses were conducted showing that frequency of exercise participation was a significant predictor of improvement in satisfaction with life, whereas social relations were related to increases in satisfaction with life and reductions in loneliness. Improvements in social relations and exercise frequency also helped to buffer the declines in satisfaction with life at follow-up. CONCLUSIONS It appears that social relations integral to the exercise environment are significant determinants of subjective well-being in older adults. Findings are discussed in terms of how physical activity environments might be structured to maximize improvements in more global well-being constructs such as satisfaction with life.
Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myélome.

PURPOSE Survival of patients with multiple myeloma is highly heterogeneous, from periods of a few weeks to more than 10 years. We used gene expression profiles of myeloma cells obtained at diagnosis to identify broadly applicable prognostic markers. PATIENTS AND METHODS In a training set of 182 patients, we used supervised methods to identify individual genes associated with length of survival. A survival model was built from these genes. The validity of our model was assessed in our test set of 68 patients and in three independent cohorts comprising 853 patients with multiple myeloma. RESULTS The 15 strongest genes associated with the length of survival were used to calculate a risk score and to stratify patients into low-risk and high-risk groups. The survival-predictor score was significantly associated with survival in both the training and test sets and in the external validation cohorts. The Kaplan-Meier estimates of rates of survival at 3 years were 90.5% (95% CI, 85.6% to 95.3%) and 47.4% (95% CI, 33.5% to 60.1%), respectively, in our patients having a low risk or high risk independently of traditional prognostic factors. High-risk patients constituted a homogeneous biologic entity characterized by the overexpression of genes involved in cell cycle progression and its surveillance, whereas low-risk patients were heterogeneous and displayed hyperdiploid signatures. CONCLUSION Gene expression-based survival prediction and molecular features associated with high-risk patients may be useful for developing prognostic markers and may provide basis to treat these patients with new targeted antimitotics.
Etude du comportement mécanique de micropieux modèles en chambre d'étalonnage. Application aux effets de groupe

Ce travail de recherche s'inscrit dans le cadre de l'etude du comportement mecanique des micropieux, avec application aux effets de groupe. Il s'appuie sur la realisation d'essais de chargement de micropieux modeles en chambre d'etalonnage, en vue de quantifier les interactions entre modeles lorsque ceux-ci sont disposes en groupes elementaires, avec un entr'axe suffisamment faible. On met en particulier en evidence l'effet de parametres tels que l'entr'axe, l'ordre d'installation des modeles, l'etat de contrainte applique au massif sur le developpement d'interactions entre les modeles et l'on en tire des conclusions preliminaires concernant des ameliorations possibles aux methodes de mise en place actuellement utilisees. Une approche des courbes de mobilisation du frottement lateral et de la resistance en pointe est aussi proposee et l'on s'interesse finalement au cas des sollicitations cycliques, avec application a un programme de stabilite cyclique.
Distribution of GABA receptor ρ subunit transcripts in the rat brain

The γ‐aminobutyric acid (GABA) receptor ρ subunits recently cloned from rat and human retina are thought to form GABA receptor channels belonging to a pharmacologically distinct receptor class, termed GABAC. In this work we have examined the distribution of ρ1, ρ2 and ρ3 subunits, and found expression of all three transcripts in several regions of the rat nervous system.
Hyperbranched polymer drug delivery treatment for lung metastasis of salivary adenoid cystic carcinoma in nude mice

Salivary adenoid cystic carcinoma (SACC) is associated with a high rate of lung metastasis. When lung metastasis occurs, the effects of traditional chemotherapy on SACC are poor. Hyperbranched polymer drug delivery (degradable hyperbranched polyglycerols, dHPGs) can be used as a strategy to load several drugs, and obtain beneficial effects on SACC lung metastasis through enhanced permeability and retention. In the present study, hydroxycamptothecin (HPT)-conjugated dHPG (dHPG-HPT) was synthesized and its effects on SACC xenografts in the lungs of nude mice were evaluated. SACC cells with a high potential for pulmonary metastasis (SACC-LM cells) were injected into the tail vein of mice, establishing a nude mouse model. The mice were randomly divided into the three following groups: Control, HPT and dHPG-HPT. Saline (control), HPT or dHPG-HPT were injected into the mice. After two weeks, the mice were euthanized and their lungs were removed. The lungs were paraffin-embedded for hematoxylin and eosin, and immunohistochemical staining analyses. Primary antibodies directed against vascular endothelial growth factor (VEGF), cluster of differentiation 34 (CD34), proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase 9 (MMP9) were used. Gross observation demonstrated that the volumes of SACC lung metastasis nodules were significantly decreased in the dHPG-HPT group compared with the control and HPT groups. Immunohistochemical analysis revealed a lower expression of VEGF, CD34, PCNA and MMP9 in the dHPG-HPT group. The results of the current study suggest that dHPG-HPT can suppress the growth of SACC xenografts in nude mice, providing a theoretical basis for macromolecular drug delivery-based treatment of SACC.
An analysis of critical incidents describing the essence of oncology nursing.

PURPOSE To describe oncology nurses' perceptions of the meaning of their work using particularly relevant anecdotes. DESIGN Multi-institutional, descriptive, qualitative. SETTING Six sites in different regions of the United States; rural and urban cancer and noncancer centers. SAMPLE 38 oncology nurses (mean age = 35 years; average time in nursing = 10 years and in oncology = 7 years; 47% bachelor's degrees in nursing, 29% diploma, 13% associate degree in nursing, and 11% master's prepared). METHODS Phenomenological; content analysis of interviews. FINDINGS Nurses described three roles, each characterized by a set of activities: (a) maintaining the values of the healthcare establishment as characterized by monitoring, acting on patients' behalf, protecting patients, and bringing patients into line, (b) participating in patients' experiences as characterized by "being there" for patients, being with dying patients, and, in a sense, becoming part of patients' families, and (c) reconciling healthcare values and the experiences of patients as characterized by teaching and telling the truth. CONCLUSIONS Nurses not only demonstrated self-confidence, courage, emotional strength, and a desire to be empathetic but also displayed an unexamined belief that they understood their patients' experiences, were isolated in their work, and experienced difficulty dealing with suffering. IMPLICATIONS FOR NURSING PRACTICE Future research should establish whether nurses' understanding of their patients' experiences correlates with patients' accounts of those experiences and whether nurses' sense of isolation is indicative of a pattern of inadequate supportive resources.
Protocols Design and Uncontrollable Topologies Construction for Multi-Agent Networks

This note investigates the controllability issues of multi-agent systems, where each node contains generic linear dynamics. First, a neighbor-based control protocol is proposed, under which it is shown that the controllability of a multi-agent system is solely decided by its communication topology structure. We then further consider the effects of communication topology on the controllability from a graph theory point of view by explicitly constructing topologies. The construction exhibits a partition of the designed graph with identified leaders under which the system is shown to be uncontrollable.
Régulation du facteur de transcription SNAIL1 au cours de la transition épithélio-mésenchymateuse dans les cellules mammaires MCF10A : implication de la protéine-kinase CK2

Les cellules epitheliales sont a la base de nombreuses fonctions vitales chez les mammiferes, en particulier grâce a leurs proprietes de polarisation et de cohesion dynamiques regroupees sous le terme de « Plasticite Epitheliale ». Une manifestation originale de cette plasticite est la Transition Epithelio-Mesenchymateuse (EMT, Epithelial-Mesenchymal Transition), un processus complexe qui permet a une cellule epitheliale (ou un groupe de cellules) de modifier sa composition et l'organisation de ses proteines pour se detacher de la masse cellulaire a laquelle elle appartient, et ainsi acquerir une organisation de type fibroblastique propice a la motilite cellulaire. Ce phenomene, initialement mis en evidence pour son role dans le developpement embryonnaire, met en jeu une regulation fine, sous le controle de facteurs de transcription dont certains semblent egalement jouer un role au cours de la progression tumorale. Le facteur SNAIL1 (ou SNAIL), dont le role est determinant au cours de la mise en place de nombreux organes, est egalement fortement exprime au niveau du front invasif de certains carcinomes et pourrait participer a la dissemination des cellules cancereuses au sein de l'organisme. Au cours de l'EMT, son expression, sa localisation et son activite sont soumises a une regulation complexe qui implique plusieurs modifications post-traductionnelles, en particulier la phosphorylation. Dans ce contexte, l'objectif de ma these a ete de comprendre les mecanismes de regulation de SNAIL1 par la proteine-kinase CK2 au cours de l'EMT. Ce travail a ete realise en deux etapes dont la premiere fut une caracterisation biochimique de la phosphorylation de SNAIL1 par CK2 et sa regulation par la sous-unite regulatrice CK2β. Dans un deuxieme temps, je me suis penche sur l'etude des consequences de l'inhibition du complexe CK2 par ARN interference dans les cellules epitheliales mammaires MCF10A. Ce modele a permis de mettre en evidence le role determinant de CK2β dans le maintien de l'expression d'un phenotype epithelial et d'une architecture cohesive au sein des cellules MCF10A en culture in vitro. L'ensemble de ces resultats suggere en effet que la proteine-kinase CK2, sous le controle de sa sous-unite regulatrice CK2β, exerce une regulation negative sur le niveau d'expression transcriptionnelle et la stabilite proteique de SNAIL1 visant a s'opposer a l'induction de l'EMT.
Missense Polymorphisms in BRCA1 and BRCA2 and Risk of Breast and Ovarian Cancer

Purpose: BRCA1 and BRCA2 are key tumor suppressors with a role in cellular DNA repair, genomic stability, and checkpoint control. Mutations in BRCA1 and BRCA2 often cause hereditary breast and ovarian cancer; however, missense polymorphisms in these genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is unclear. Experimental Design: We resequenced BRCA1 and BRCA2 in 194 women with a familial history of breast and/or ovarian cancer and identified nine possibly biologically relevant polymorphisms (BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Ser1613Gly, and Met1652Ile. BRCA2 Asn289His, Asn372His, Asp1420Tyr, and Tyr1915Met). We evaluated risk of breast and/or ovarian cancer by these polymorphisms in a prospective study of 5,743 women from the general population followed for 39 years and in a case-control study of 1,201 breast cancer cases and 4,120 controls. Results: We found no association between heterozygosity or homozygosity for any of the nine polymorphisms and risk of breast and/or ovarian cancer in either study. We had 80% power to exclude hazard/odds ratios for heterozygotes and/or homozygotes for all nine missense polymorphisms above 1.3 to 3.3 in the prospective study, and above 1.2 to 3.2 in the case-control study. Conclusions: Heterozygosity and homozygosity of any of the examined nine BRCA1 and BRCA2 missense polymorphisms cannot explain the increased risk of breast and/or ovarian cancer observed in families with hereditary breast and/or ovarian cancer. Therefore, genetic counseling of such families safely can disregard findings of these missense polymorphisms. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2339–42)