Miracle-dz/UniFAR-FTUs huggingface dataset:
Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils

Significance We show that tumor reprogramming of hematopoiesis in bone marrow occurs at the onset of malignant conversion and results in systemic expansion of circulating activated neutrophils that preferentially accumulate in lungs. Our data are, to our knowledge, the first to show that activation and not inhibition of myeloid differentiation is responsible for expansion and activity of T cell-suppressive myeloid cells; a tumor-derived factor targets the immature hematopoietic compartment to drive myeloid expansion; granulocyte-colony stimulating factor (G-CSF) is the only hematopoietic growth factor to increase in serum during early tumor development; prolonged G-CSF induces production of Rb1low neutrophils and not short-term mobilization; and G-CSF acts in a cell intrinsic manner to expand multipotent progenitors to increase production of tumor-derived Ly6G+ neutrophils. Expansion of myeloid cells associated with solid tumor development is a key contributor to neoplastic progression. Despite their clinical relevance, the mechanisms controlling myeloid cell production and activity in cancer remains poorly understood. Using a multistage mouse model of breast cancer, we show that production of atypical T cell-suppressive neutrophils occurs during early tumor progression, at the onset of malignant conversion, and that these cells preferentially accumulate in peripheral tissues but not in the primary tumor. Production of these cells results from activation of a myeloid differentiation program in bone marrow (BM) by a novel mechanism in which tumor-derived granulocyte-colony stimulating factor (G-CSF) directs expansion and differentiation of hematopoietic stem cells to skew hematopoiesis toward the myeloid lineage. Chronic skewing of myeloid production occurred in parallel to a decrease in erythropoiesis in BM in mice with progressive disease. Significantly, we reveal that prolonged G-CSF stimulation is both necessary and sufficient for the distinguishing characteristics of tumor-induced immunosuppressive neutrophils. These results demonstrate that prolonged G-CSF may be responsible for both the development and activity of immunosuppressive neutrophils in cancer.
Selective Depletion of Alloreactive T Lymphocytes Using Patient-Derived Nonhematopoietic Stimulator Cells in Allograft Engineering

Background. Selective depletion of alloreactive T cells in vitro results in efficient graft-versus-host disease prophylaxis in allogeneic hematopoietic stem-cell transplantation, but it is accompanied by increased recurrence of leukemia. To spare donor T-cell-mediated graft-versus-leukemia immunity against hematopoiesis-restricted minor histocompatibility (minor-H) antigens, we explored the use of patient-derived nonhematopoietic antigen-presenting cells (APC) as allogeneic stimulators for selective allodepletion in leukemia-reactive donor T-cell lines. Methods. Primary keratinocytes, dermal fibroblasts, and bone marrow fibroblasts were generated from skin biopsies and diagnostic bone marrow aspirates of acute myeloid leukemia patients in vitro. Cell cultures were analyzed for expansion, phenotype, and immunostimulatory capacity in comparison with CD40-activated B cells as professional APC. In addition, nonhematopoietic APCs were used for selective allodepletion in vitro. Results. Patient-derived fibroblasts could be reliably expanded to large cell numbers, whereas keratinocytes had limited growth potential. Interferon-&ggr;-pretreated fibroblasts showed increased expression of human leukocyte antigen (HLA)-class I and II molecules, CD40, and CD54. Fibroblasts and CD40-activated B cells comparably stimulated HLA-A*0301-specific CD8+ T cells after transient expression of HLA-A*0301 as a model alloantigen. Finally, fibroblasts could be effectively applied to selectively deplete alloreactivity within leukemia-reactive donor CD8+ T-cell lines by targeting the activation-induced antigen CD137. Conclusions. Primary fibroblasts can be efficiently used as allogeneic nonhematopoietic APC for selective depletion of donor T cells reactive to HLA and ubiquitously expressed minor-H antigen disparities in leukemia-stimulated CD8+ T-cell lines. Therefore, harnessing alloreactivity to hematopoietic minor-H antigens in addition to leukemia-associated antigens might increase graft-versus-leukemia immunity of donor lymphocyte grafts in allogeneic hematopoietic stem-cell transplantation.
Cultural proximity and interactivity in the processes of narrative reception

This study aims to further our understanding of the reception processes associated with the consumption of new interactive audiovisual products by individuals from different cultures. Through a quasi-experimental research, it analysed reception of a film produced in Germany, in two different European socio-cultural contexts (Spain and The Netherlands). A 2 × 2 factorial design was used, the independent variables being cultural proximity (high, low) and the modality in which the movie was viewed (interactive, non-interactive). Cultural proximity influenced the processes of evaluating the movie, but viewing modality showed no significant differences. Identification with the protagonists of the movie was associated in both cultural contexts with enjoyment, self-perceived physical sensations and emotional induction. These results are relevant for explaining how receivers from different cultures react to audiovisual productions of different origin and to new forms of consumption.
Leptin alone and in combination with interleukin-1-beta induced cartilage degradation potentially inhibited by EPA and DHA

ABSTRACT Osteoarthritis (OA) is the most common form of arthritis. Obesity has been believed to be an important risk factor for OA development and the progression of not only load-bearing joints, but low-load-bearing joints as well. Increased leptin has been the focus of a link between obesity and OA. In this study, the effects of pathological (100ng/ml) or supra-pathological (10μg/ml) concentrations of leptin alone or in combination with IL1β on cartilage metabolisms were studied in porcine cartilage explant. The involved mechanisms were examined in human articular chondrocytes (HACs). Moreover, the protective effect of omega-3 polyunsaturated acids, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) was also investigated. Leptin (10μg/ml) alone or in combination with IL1β could induce cartilage destruction, although lower concentrations had no effect. Leptin activated NFκB, ERK, JNK and p38 in HACs, which led to the induction of MMP3, MMP13 and ADAMTS4 secretions. The combined effect could further induce those enzymes through the additive effect on activation of NFκB and JNK. Interestingly, both EPA and DHA could inhibit cartilage damage induced by leptin plus IL1β by reducing the activation of NFκB and JNK, which led to the decrease of ADAMTS4 secretion. Altogether, only a supra-pathological concentration of leptin alone or in combination with IL1β could induce cartilage destruction, whereas a pathological one could not. This effect could be inhibited by EPA and DHA. To gain greater understanding of the link between leptin and OA, the effect of different levels of leptin on several states of OA cartilage requires further investigation.
The biometric measurement of alcohol consumption.

BACKGROUND Proper ascertainment of the history of alcohol consumption by an individual is an important component of medical diagnosis of disease and influences the implementation of appropriate treatment strategies that include prescription of medication, as well as intervention for the negative physical and social consequences of hazardous/harmful levels of alcohol consumption. Biological (biometric) diagnostic tests that provide information on current and past quantity and frequency of alcohol consumption by an individual, prior to onset of organ damage, continue to be sought. METHODS Platelet monoamine oxidase B (MAO-B) protein was quantitated in 2 populations of subjects who had histories of different levels of alcohol consumption. Levels were assayed by immunoblotting or by ELISA. The development and evaluation of the new ELISA-based measure of platelet MAO-B protein levels is described. RESULTS One subject population constituted a nontreatment-seeking, cross-sectional subject sample, and the other population was a longitudinally followed, hospitalized group of subjects. An algorithm combining measures of platelet MAO-B protein with the plasma levels of carbohydrate-deficient transferrin (CDT) and with liver enzymes (aspartate aminotransferase or γ-glutamyltransferase [GGT]) can detect hazardous/harmful alcohol use (HHAU) with the highest sensitivity and specificity in the cross-sectional nontreatment-seeking population. In the treatment-seeking population, low MAO-B protein levels at admission are associated with heavy drinking prior to admission, and these protein levels increase over a period of abstinence from alcohol. CONCLUSIONS The platelet MAO-B protein measurement is particularly effective for male alcohol consumers. The combined use of MAO-B protein measures together with measures of CDT and GGT does, however, improve the diagnostic utility of both markers for ascertaining HHAU in women. Furthermore, measurement of changes in platelet MAO-B protein levels during treatment for alcohol dependence may help monitor the success of the treatment program.
Development of a novel affinity chromatography resin for platform purification of lambda fabs

Antigen‐binding fragments (Fabs) are novel formats in the growing pipeline of biotherapeutics. Sharing similar features to monoclonal antibodies (mAbs) with regard to expression, Fabs are considered as unchallenging for upstream development. Yet for downstream processing, the mature mAb downstream purification platform is not directly applicable. New approaches need to be found to achieve a lean purification process that maintains quality, productivity, and timelines while being generically applicable independent of the expression system. In a successful collaboration, BAC BV, GE Healthcare, and Novartis Pharma AG have developed a new affinity chromatography medium (resin) suitable to support cGMP manufacturing of lambda Fabs. We show that using this novel chromatography medium for the capture step, a purification platform for lambda Fabs can be established. © 2014 American Institute of Chemical Engineers Biotechnol. Prog. , 30:1311–1318, 2014
Pharmacokinetics of antibiotics in neonates

The pharmacodynamics in neonates are different from those in adults and children because the absorption, distribution, metabolism and excretion of drugs in neonates are always changing for the following reasons. In neonates, the proportion of extracellular fluid is large; the amount of plasma protein is small; renal function is immature; and the hepatic enzyme system is immature. In addition, individual birthweights, gestational ages in weeks, cardiopulmonary functions and renal excretory functions vary. All of these factors should be considered when selecting the dose and administration method of a drug. In concrete terms the distribution volume is large, which causes a low maximum concentration. In addition neonate renal excretory function is low and the hepatic enzyme system is immature, thus the half‐life of drugs is prolonged. Therefore, the same dose per unit time as that for children (including infants) needs to be administered to neonates at dosing intervals that may be prolonged according to renal function.
Accurate Semantic Similarity Measurement of Biomedical Nomenclature by Means of Fuzzy Logic

Semantic similarity measurement of biomedical nomenclature aims to determine the likeness between two biomedical expressions that use different lexicographies for representing the same real biomedical concept. There are many semantic similarity measures for trying to address this issue, many of them have represented an incremental improvement over the previous ones. In this work, we present yet another incremental solution that is able to outperform existing approaches by using a sophisticated aggregation method based on fuzzy logic. Results show us that our strategy is able to consistently beat existing approaches when solving well-known biomedical benchmark data sets.
Population receptive field analysis of the primary visual cortex complements perimetry in patients with homonymous visual field defects

Significance Partial damage of the primary visual cortex (V1), or damage to the white matter inputs to V1 (optic radiation), cause blindness in specific regions of the visual field. We use functional MRI to measure responses in individual patients with a localized, chronic V1 injury that resulted in blindness in a quarter of the visual field. The fMRI responses of patients and controls are generally similar, but in some patients differences from controls can be measured. Importantly, responses in spared early visual cortex are not always congruent with visual perception. Understanding how the properties of early visual areas respond to injury will lead to better strategies for visual rehabilitation. Injury to the primary visual cortex (V1) typically leads to loss of conscious vision in the corresponding, homonymous region of the contralateral visual hemifield (scotoma). Several studies suggest that V1 is highly plastic after injury to the visual pathways, whereas others have called this conclusion into question. We used functional magnetic resonance imaging (fMRI) to measure area V1 population receptive field (pRF) properties in five patients with partial or complete quadrantic visual field loss as a result of partial V1+ or optic radiation lesions. Comparisons were made with healthy controls deprived of visual stimulation in one quadrant [“artificial scotoma” (AS)]. We observed no large-scale changes in spared-V1 topography as the V1/V2 border remained stable, and pRF eccentricity versus cortical-distance plots were similar to those of controls. Interestingly, three observations suggest limited reorganization: (i) the distribution of pRF centers in spared-V1 was shifted slightly toward the scotoma border in 2 of 5 patients compared with AS controls; (ii) pRF size in spared-V1 was slightly increased in patients near the scotoma border; and (iii) pRF size in the contralesional hemisphere was slightly increased compared with AS controls. Importantly, pRF measurements yield information about the functional properties of spared-V1 cortex not provided by standard perimetry mapping. In three patients, spared-V1 pRF maps overlapped significantly with dense regions of the perimetric scotoma, suggesting that pRF analysis may help identify visual field locations amenable to rehabilitation. Conversely, in the remaining two patients, spared-V1 pRF maps failed to cover sighted locations in the perimetric map, indicating the existence of V1-bypassing pathways able to mediate useful vision.
Engineering the Recruitment of Phosphotyrosine Binding Domain-containing Adaptor Proteins Reveals Distinct Roles for RET Receptor-mediated Cell Survival*

The RET receptor tyrosine kinase is important for several different biological functions during development. The recruitment at the phosphorylated Tyr1062 site in RET of a number of different phosphotyrosine binding (PTB) domain-containing adaptor proteins, including Shc and Frs2, plays a dominant role for the multiple different biological functions of the RET receptor during development, including stimulation of cell survival. Here, we demonstrate that a competitive recruitment of Shc as opposed to Frs2 mediates the survival signaling arising from RET activation. Based on results from a peptide array, we have genetically engineered the PTB domain binding site of RET to rewire its recruitment of the PTB proteins Shc and Frs2. An engineered RET that has a competitive interaction with Shc at the expense of Frs2, but not a RET receptor that only recruits Frs2, activates cell survival signaling pathways and is protective from cell death in neuronal SK-N-MC cells. Thus, cell type-specific functions involve a competitive recruitment of different PTB adaptor molecules by RET that activate selective signaling pathways.
Civil Society Vocabularies and Signaling Value: Cases From Colombia and Ecuador

The context for civil society organizations (CSOs) in developing regions—restrictive policies, heightened accusatory and delegitimizing discourse, and decreasing international funds—leads in practice to major concerns for organized civil society. To confront this, CSOs are responding with the objective of explaining the work of organized civil society and its value. This article examines the discourses and tools used by organized civil society to frame its value in society in Latin America through the country cases of Colombia and Ecuador. Specifically, we look at the discourses and tools produced by national and subnational civil society networks that serve the sector as a whole. The article identifies key vocabularies found in the academic literature and discussed within policy spheres about civil society—mapping and spatial strategies, sustainability, and resilience. The article concludes with both opportunities and challenges to the application of these discourses and tools and with suggestions for next steps for research.
Immunohistochemical studies of the localization of neurons containing the enzyme that synthesizes dopamine, GABA, or γ‐hydroxybutyrate in the rat substantia nigra and striatum

γ‐Hydroxybutyrate (GHB) is an endogenous metabolite of γ‐aminobutyric acid (GABA), which is synthesized in the neuronal compartment of the central nervous system. This substance possesses several properties that support its role as a neurotransmitter/neuromodulator in brain. In particular, it is synthesized by a specific pathway that transforms GABA into succinic semialdehyde via GABA‐T activity; then succinic semialdehyde is converted into GHB by a specific succinic semialdehyde reductase (SSR). The last enzyme is considered as a marker for neurons that synthesize GHB. This compound binds in brain to receptors whose distribution, ontogenesis, kinetics, and pharmacology are specific. Endogenous GHB, but also GHB exogenously administered to rats, participate in the regulation of dopaminergic activity of the nigrostriatal pathway. To investigate the distribution of GHB neurons in this pathway and the anatomic relationships between dopaminergic and GHB neurons, immunocytochemical identification of dopamine, GABA, and GHB neurons was carried out in the substantia nigra and striatum of the rat. The following markers for these neurons were used: anti‐tyrosine hydroxylase (TH) antibodies for dopamine neurons, anti‐glutamate decarboxylase (GAD) antibodies for GABA neurons, and anti‐succinic semialdehyde reductase (SSR) antibodies for GHB neurons. GABA neurons were studied because GAD and SSR co‐exist frequently in the same neuron, and GABA alone also exerts its own regulatory effects on dopaminergic neurons. This study reveals the co‐existence of GAD/SSR and GAD/SSR/TH in numerous neurons of the substantia nigra. However, some neurons appear to be only GAD or SSR positive. In the striatum, TH‐positive terminals surround many GHB neurons. GAD innervation is abundant in close contact with unlabeled neurons in the caudate‐putamen, whereas distinct SSR‐positive punctuates are also present. The existence of SSR‐reactive synapses and neurons was confirmed in the striatum at the electron microscopic level. On the basis of these results, a clear anatomo‐functional relationship between GHB and dopamine networks cannot be defined; however, we propose the modulation by GHB of striatal intrinsic neurons that could then interfere with the presynaptic control of dopaminergic activity. J. Comp. Neurol. 426:549–560, 2000. © 2000 Wiley‐Liss, Inc.
Gendered work engagement: qualitative insights from Jordan

Abstract Work engagement is assumed, implicitly, to be gender-neutral where women and men have equal opportunities to demonstrate their engagement in the workplace. This paper questions this assumption and integrates gender into the notion of work engagement by investigating and contextualising the factors that affect the genderedness of work engagement. It uses gendered organisation theory and engagement theory to expose the gendered nature of work engagement. Interviewing thirty-six employees from three telecommunication companies in Jordan, it is found that the notion of work engagement is neither gender neutral nor universal, and that the presence of inequality regimes means that women may have less opportunity to experience engagement, and certainly the opportunity will vary across contexts.
Improving health care quality: the implementation of whistleblowing

In line with the current literature, the purpose of this paper is to contribute to a better understanding of whistleblowing procedures and their influence on overall organisational quality. To this end, institutional, organisational, and cultural barriers to whistleblowing implementation have been investigated. ,A qualitative analysis based on three explorative case studies investigates and compares different whistleblowing practices implemented in health care organisations, operating within the Italian National Health Service (INHS). ,INHS organisations have implemented whistleblowing procedures in different ways, despite the fact that the procedures are laid down by law. These differences are mainly due to cultural, administrative, organisational, and process barriers, which have a deep impact on whistleblowing integration in managerial practices and their influence on the overall quality of health processes and services. ,This research paper was limited by the analysis of three Italian public health care organisations, which did not allow the generalisability of findings. Therefore, the study offers interesting insights on the way effective whistleblowing systems should be implemented in order to support managers to improve organisation’s management and service quality. ,The paper represents one of the first attempts to structurally analyse the practice of whistleblowing in an Italian healthcare system. Therefore the study has mainly focussed not only on the analysis of whistleblowing practices, but also on their impacts on the improvement of organisational processes’ quality and, subsequently, on social well-being.