Miracle-dz/UniFAR-FTUs huggingface dataset:
70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.

BACKGROUND The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. METHODS In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher. RESULTS A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. CONCLUSIONS Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).
Diurnal and Long-term Variation in Plasma Concentrations and Renal Clearances of Circulating Markers of Kidney Proximal Tubular Secretion.

BACKGROUND The renal proximal tubule is essential for removing organic solutes and exogenous medications from the circulation. We evaluated diurnal, prandial, and long-term biological variation of 4 candidate endogenous markers of proximal tubular secretion. METHODS We used LC-MS to measure plasma and urine concentrations of hippurate (HA), cinnamoylglycine (CMG), indoxyl sulfate (IS), and p-cresol sulfate (PCS) in 25 healthy adults. We measured plasma concentrations of secreted solutes at 13 time points over a 24-h period, and again after 2 weeks and 14 weeks of follow-up. We further measured 24-h renal clearances of secreted solutes at baseline, 2 weeks, and 14 weeks. RESULTS Plasma concentrations of secreted solutes varied over the 24-h baseline period. Diurnal variation was greatest for HA, followed by CMG, IS, and PCS. Plasma concentrations of HA (P = 0.002) and IS (P = 0.02), but not CMG and PCS, increased significantly following meals. Long-term intraindividual biological variation (CVI) in plasma concentrations of secreted solutes over 14 weeks varied from 21.8% for IS to 67.3% for PCS, and exceeded that for plasma creatinine (CVI, 7.1%). Variation in 24-h renal clearances was similar among the secreted solutes [intraindividual variation (CVA+I), 33.6%-47.3%] and was lower using pooled plasma samples from each study visit. CONCLUSIONS Plasma concentrations of HA, CMG, IS, and PCS fluctuate within individuals throughout the day and over weeks. Renal clearances of these secreted solutes, which serve as estimates of renal proximal tubule secretion, are also subject to intraindividual biological variation that can be improved by additional plasma measurements.
Investigating Developmental Trajectories of Morphemes as Reading Units in German

The developmental trajectory of the use of morphemes is still unclear. We investigated the emergence of morphological effects on visual word recognition in German in a large sample across the complete course of reading acquisition in elementary school. To this end, we analyzed lexical decision data on a total of 1,152 words and pseudowords from a large cross-sectional sample of German children from the beginning of Grade 2 through 6, and a group of adults. We expand earlier evidence by (a) explicitly investigating processing differences between compounds, prefixes and suffixes, (b) taking into account vocabulary knowledge as an indicator for interindividual differences. Results imply that readers of German are sensitive to morphology in very early stages of reading acquisition with trajectories depending on morphological type and vocabulary knowledge. Facilitation from compound structure comes early in development, followed by facilitation from suffixes and prefixes later on in development. This indicates that stems and different types of affixes involve distinct processing mechanisms in beginning readers. Furthermore, children with higher vocabulary knowledge benefit earlier in development and to a greater extent from morphology. Our results specify the development and functional role of morphemes as reading units.
Minocycline blocks glial cell activation and ventilatory acclimatization to hypoxia.

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation, which persists upon return to normoxia and involves plasticity in both central nervous system respiratory centers and peripheral chemoreceptors. We investigated the role of glial cells in VAH in male Sprague-Dawley rats using minocycline, an antibiotic that inhibits microglia activation and has anti-inflammatory properties, and barometric pressure plethysmography to measure ventilation. Rats received either minocycline (45mg/kg ip daily) or saline beginning 1 day before and during 7 days of chronic hypoxia (CH, PiO2 = 70 Torr). Minocycline had no effect on normoxic control rats or the hypercapnic ventilatory response in CH rats, but minocycline significantly (P < 0.001) decreased ventilation during acute hypoxia in CH rats. However, minocycline administration during only the last 3 days of CH did not reverse VAH. Microglia and astrocyte activation in the nucleus tractus solitarius was quantified from 30 min to 7 days of CH. Microglia showed an active morphology (shorter and fewer branches) after 1 h of hypoxia and returned to the control state (longer filaments and extensive branching) after 4 h of CH. Astrocytes increased glial fibrillary acidic protein antibody immunofluorescent intensity, indicating activation, at both 4 and 24 h of CH. Minocycline had no effect on glia in normoxia but significantly decreased microglia activation at 1 h of CH and astrocyte activation at 24 h of CH. These results support a role for glial cells, providing an early signal for the induction but not maintenance of neural plasticity underlying ventilatory acclimatization to hypoxia.NEW & NOTEWORTHY The signals for neural plasticity in medullary respiratory centers underlying ventilatory acclimatization to chronic hypoxia are unknown. We show that chronic hypoxia activates microglia and subsequently astrocytes. Minocycline, an antibiotic that blocks microglial activation and has anti-inflammatory properties, also blocks astrocyte activation in respiratory centers during chronic hypoxia and ventilatory acclimatization. However, minocycline cannot reverse ventilatory acclimatization after it is established. Hence, glial cells may provide signals that initiate but do not sustain ventilatory acclimatization.
Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow

Significance Transport of nutrients and clearance of waste products are prerequisites for healthy brain function. It is still debated whether solutes are transported through the interstitial space by pressure-mediated bulk flow or by diffusion. Here we have simulated interstitial bulk flow within 3D electron microscope reconstructions of hippocampal tissue. We show that the permeability is one to two orders of magnitude lower than values typically seen in the literature, arguing against bulk flow as the dominant transport mechanism. Further, we show that solutes of all sizes are more easily transported through the interstitium by diffusion than by bulk flow. We conclude that clearance of waste products from the brain is largely based on diffusion of solutes through the interstitial space. The brain lacks lymph vessels and must rely on other mechanisms for clearance of waste products, including amyloid β that may form pathological aggregates if not effectively cleared. It has been proposed that flow of interstitial fluid through the brain’s interstitial space provides a mechanism for waste clearance. Here we compute the permeability and simulate pressure-mediated bulk flow through 3D electron microscope (EM) reconstructions of interstitial space. The space was divided into sheets (i.e., space between two parallel membranes) and tunnels (where three or more membranes meet). Simulation results indicate that even for larger extracellular volume fractions than what is reported for sleep and for geometries with a high tunnel volume fraction, the permeability was too low to allow for any substantial bulk flow at physiological hydrostatic pressure gradients. For two different geometries with the same extracellular volume fraction the geometry with the most tunnel volume had 36% higher permeability, but the bulk flow was still insignificant. These simulation results suggest that even large molecule solutes would be more easily cleared from the brain interstitium by diffusion than by bulk flow. Thus, diffusion within the interstitial space combined with advection along vessels is likely to substitute for the lymphatic drainage system in other organs.
Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome

Differentiation of hematopoietic stem cells is regulated by a concert of different transcription factors. Disturbed transcription factor function can be the basis of (pre)malignancies such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Growth factor independence 1b (Gfi1b) is a repressing transcription factor regulating quiescence of hematopoietic stem cells and differentiation of erythrocytes and platelets. Here, we show that low expression of Gfi1b in blast cells is associated with an inferior prognosis of MDS and AML patients. Using different models of human MDS or AML, we demonstrate that AML development was accelerated with heterozygous loss of Gfi1b, and latency was further decreased when Gfi1b was conditionally deleted. Loss of Gfi1b significantly increased the number of leukemic stem cells with upregulation of genes involved in leukemia development. On a molecular level, we found that loss of Gfi1b led to epigenetic changes, increased levels of reactive oxygen species, as well as alteration in the p38/Akt/FoXO pathways. These results demonstrate that Gfi1b functions as an oncosuppressor in MDS and AML development.
Semantic Segmentation of Pathological Lung Tissue With Dilated Fully Convolutional Networks

Early and accurate diagnosis of interstitial lung diseases (ILDs) is crucial for making treatment decisions, but can be challenging even for experienced radiologists. The diagnostic procedure is based on the detection and recognition of the different ILD pathologies in thoracic CT scans, yet their manifestation often appears similar. In this study, we propose the use of a deep purely convolutional neural network for the semantic segmentation of ILD patterns, as the basic component of a computer aided diagnosis system for ILDs. The proposed CNN, which consists of convolutional layers with dilated filters, takes as input a lung CT image of arbitrary size and outputs the corresponding label map. We trained and tested the network on a data set of 172 sparsely annotated CT scans, within a cross-validation scheme. The training was performed in an end-to-end and semisupervised fashion, utilizing both labeled and nonlabeled image regions. The experimental results show significant performance improvement with respect to the state of the art.
Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25—CD127+Foxp3—effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1—CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1—CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.
Higher Dairy Food Intake Is Associated With Higher Spine Quantitative Computed Tomography (QCT) Bone Measures in the Framingham Study for Men But Not Women

Previous studies found that dairy foods were associated with higher areal bone mineral density (BMD). However, data on bone geometry or compartment‐specific bone density is lacking. In this cross‐sectional study, the association of milk, yogurt, cheese, cream, milk+yogurt, and milk+yogurt+cheese intakes with quantitative computed tomography (QCT) measures of bone were examined, and we determined if associations were modified by serum vitamin D (25‐OH D, tertiles) or age (<50 versus ≥50 years). Participants were 1522 men and 1104 women (aged 32 to 81 years, mean 50 years [men]; 55 years [women]) from the Framingham Heart Study with measures of dairy food intake (servings/wk) from a food‐frequency questionnaire, volumetric BMD (vBMD, integral and trabecular, g/cm3), cross‐sectional area (CSA, cm2), and estimated vertebral compressive strength (VCS, N) and 25‐OH D (radioimmunoassay). Sex‐specific multivariable linear regression was used to calculate the association of dairy food intake (energy adjusted) with each QCT measure, adjusting for covariates. Mean milk intake ±SD was 6 ± 7 servings/week in both men and women. In men, higher intake of milk, milk+yogurt, and milk+yogurt+cheese was associated with higher integral (p = 0.001 to 0.006) and trabecular vBMD (p = 0.006 to 0.057) and VCS (p = 0.001 to 0.010). Further, a higher cheese intake was related with higher CSA (p = 0.049). In women, no significant results were observed for the dairy foods, except for a positive association of cream intake with CSA (p = 0.016). The associations appeared to be stronger in older men. Across 25‐OH D tertiles, dairy was positively associated with bone health. In summary, men with higher intakes of milk, milk+yogurt, and milk+yogurt+cheese had higher trabecular and integral vBMD and VCS but not CSA. Dairy intake seems to be most beneficial for older men, and dairy continued to have positive associations among all 25‐OH D levels. © 2018 American Society for Bone and Mineral Research.
Human action recognition using key poses and atomic motions

Human action recognition is a fundamental skill for personal assistive robotics to observe and automatically react to human's daily activities. Generally, one human activity can be intuitively considered as a sequence of key poses and atomic motions. Thus, a human action recognition algorithm based on key poses and atomic motions is proposed in this paper. Firstly, the normalized relative orientations of human joints are computed as the skeletal features. Secondly, the skeletal feature sequences are segmented into static segments and dynamic segments based on the kinetic energy. Then, the codebook of key poses is constructed from the static segments using clustering algorithms, and the codebook of atomic motions is constructed from the associated dynamic segments with any two key poses. Lastly, the activity patterns are constructed and the Naïve Bayes Nearest Neighbor algorithm is utilized to classify human activities based on the training and testing activity pattern matching. The Cornell CAD-60 dataset is used to test the proposed algorithm. The experimental results show that the proposed algorithm can obtain a better performance than the state-of-the-art algorithms.
Preparing healthcare students who participate in interprofessional education for interprofessional collaboration: A constructivist grounded theory study protocol

ABSTRACT This article presents a qualitative research protocol to explore and understand the interprofessional collaboration (IPC) preparation process implemented by clinical tutors and students of different professions involved in interprofessional education (IPE). Many studies have shown that IPE initiatives improve students’ understanding of the roles and responsibilities of other professionals. This improves students’ attitudes towards other professions, facilitating mutual respect, and IPC. However, there is limited information about how students are prepared to work collaboratively within interprofessional teams. This is a constructivist grounded theory (GT) study, which will involve data collection through in-depth semi-structured interviews (to 9–15 students and 6–9 clinical tutors), participant observations, and the analysis of documentation. After analysing, coding, integrating, and comparing the data if necessary, a second round of interviews could be conducted to explore any particularly interesting aspects or clarify any issues. This will then be followed by focused and theoretical coding. Qualitative data analysis will be conducted with the support of NVivo 10 software (Victoria, Australia). A better conceptual understanding will help to understand if IPE experiences have contributed to the acquisition of competencies considered important for IPC, and if they have facilitated the development of teamwork attitudes.
Effect of ultrafine powders on the structural formation processes and mechanical properties of Al–7%Si alloy

The multi-component system interaction mechanisms associated with ultrafine powders (TiO2 and ZrO2) and fluorine-containing salts (K2ZrF6, Na3AlF6 and Na5Al3F14) with the Al–7%Si melt are studied. The formation of a multi-phase system with a high concentration of crystallization centres (N ≈ 7 · 1012 U/cm3) was identified. We experimentally show that the injection of an ultrafine powders modifying mixture containing refractory metal oxides and fluorine-containing salts into a Al–7%Si melt leads to a significant reduction in the a silicon plate size (by 1.5 times) and the Fe-containing phases (by 4 times). An equal distribution of the eutectic phase (α-Al + β-Si) is established in the Al– 7%Si alloy. As a result of microstructural changes when the modifying mixture was injected, a factor of 2 increase in the Al–7%Si alloy ductility was observed.
Small Fractions of Muscular Dystrophy Embryonic Stem Cells Yield Severe Cardiac and Skeletal Muscle Defects in Adult Mouse Chimeras

Duchenne muscular dystrophy (DMD) is characterized by the loss of the protein dystrophin, leading to muscle fragility, progressive weakening, and susceptibility to mechanical stress. Although dystrophin‐negative mdx mouse models have classically been used to study DMD, phenotypes appear mild compared to patients. As a result, characterization of muscle pathology, especially in the heart, has proven difficult. We report that injection of mdx embryonic stem cells (ESCs) into Wild Type blastocysts produces adult mouse chimeras with severe DMD phenotypes in the heart and skeletal muscle. Inflammation, regeneration and fibrosis are observed at the whole organ level, both in dystrophin‐negative and dystrophin‐positive portions of the chimeric tissues. Skeletal and cardiac muscle function are also decreased to mdx levels. In contrast to mdx heterozygous carriers, which show no significant phenotypes, these effects are even observed in chimeras with low levels of mdx ESC incorporation (10%‐30%). Chimeric mice lack typical compensatory utrophin upregulation, and show pathological remodeling of Connexin‐43. In addition, dystrophin‐negative and dystrophin–positive isolated cardiomyocytes show augmented calcium response to mechanical stress, similar to mdx cells. These global effects highlight a novel role of mdx ESCs in triggering muscular dystrophy even when only low amounts are present. Stem Cells 2017;35:597–610