julilili42/papers huggingface dataset:
CD8+ tumour-infiltrating lymphocytes in relation to HPV status and clinical outcome in patients with head and neck cancer after postoperative chemoradiotherapy: A multicentre study of the German cancer consortium radiation oncology group (DKTK-ROG)
2015-07-14

We examined the prognostic value of tumour-infiltrating lymphocytes (TILs) in patients with squamous cell carcinoma of the head and neck (SCCHN) after surgery and postoperative cisplatin-based chemoradiotherapy. FFPE-tissue originating from the surgery of 161 patients treated in 8 DKTK partner sites was immunohistochemically stained for CD3 and CD8. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of the HPV16-DNA/p16 status. After a median follow-up of 48 months (range: 4100 months), OS at 4 years was 46.5% for the entire cohort. In multivariate analysis, high CD8 expression was confirmed as an independent prognostic parameter for OS (p = 0.002), LPFS (p = 0.004) and DMFS (p = 0.006), while CD3 expression lacked significance. In multivariate analysis HPV16 DNA positivity was associated with improved OS (p = 0.025) and LPFS (p = 0.013) and p16-positive patients showed improved DMFS (p = 0.008). Interestingly, high CD8 expression was a prognostic parameter for the clinical outcome in both HPV16 DNA-positive and HPV16 DNA-negative patients. Similar findings were observed in the multivariate analysis for the combined HPV16 DNA/p16 status. Altogether, CD8+ TILs constitute an independent prognostic marker in SCCHN patients treated with adjuvant chemoradiotherapy. These data indicate that CD8-positive TILs have antitumour activity and could be used for treatment stratification. Further validation of the prognostic value of CD8+ TILs as a biomarker and its role in the immune response in SCCHN patients after adjuvant chemoradiotherapy is warranted and will be performed in the prospective DKTK-ROG study.
Self-regulation of circumscribed brain activity modulates spatially selective and frequency specific connectivity of distributed resting state networks
2015-07-14

The mechanisms of learning involved in brain self-regulation have still to be unveiled to exploit the full potential of this methodology for therapeutic interventions. This skill of volitionally changing brain activity presumably resembles motor skill learning which in turn is accompanied by plastic changes modulating resting state networks. Along these lines, we hypothesized that brain regulation and neurofeedback would similarly modify intrinsic networks at rest while presenting a distinct spatio-temporal pattern. High-resolution electroencephalography preceded and followed a single neurofeedback training intervention of modulating circumscribed sensorimotor low β-activity by kinesthetic motor imagery in eleven healthy participants. The participants were kept in the deliberative phase of skill acquisition with high demands for learning self-regulation through stepwise increases of task difficulty. By applying the corrected imaginary part of the coherency function, we observed increased functional connectivity of both the primary motor and the primary somatosensory cortex with their respective contralateral homologous cortices in the low β-frequency band which was self-regulated during feedback. At the same time, the primary motor cortex-but none of the surrounding cortical areas-showed connectivity to contralateral supplementary motor and dorsal premotor areas in the high β-band. Simultaneously, the neurofeedback target displayed a specific increase of functional connectivity with an ipsilateral fronto-parietal network in the α-band while presenting a de-coupling with contralateral primary and secondary sensorimotor areas in the very same frequency band. Brain self-regulation modifies resting state connections spatially selective to the neurofeedback target of the dominant hemisphere. These are anatomically distinct with regard to the cortico-cortical connectivity pattern and are functionally specific with regard to the time domain of coherent activity consistent with a Hebbian-like sharpening concept.
Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy
2015-07-14

INTRODUCTION: Somatostatin receptors (SSTR) are widely distributed in well-differentiated neuroendocrine neoplasms (NEN) and serve as primary targets for diagnostics and treatment. An overexpression of the chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. Comparative data are still lacking, however, for neuroendocrine carcinomas (NEC). METHODS: SSTR subtype (1, 2A, 3, 5) and CXCR4 expression was evaluated in G1 (n = 31), G2 (n = 47), and low (G3a; Ki-67: 21–49%; n = 21) and highly proliferative (G3b; Ki-67: >50%, n = 22) G3 (total n = 43) gastroenteropancreatic NEN samples by performing immunohistochemistry with monoclonal rabbit anti-human anti-SSTR and anti-CXCR4 antibodies, respectively, and was correlated with clinical data. RESULTS: Both CXCR4 and SSTR were widely expressed in all tumors investigated. CXCR4 expression differed significantly between the G1 and G3 specimens and within the G3 group (G3a to G3b), and was positively correlated with Ki-67 expression. SSTR2A, in contrast, exhibited an inverse association with Ki-67. SSTR2A was highly expressed in G1 and G2 tumors, but was significantly less abundant in G3 carcinomas. Additionally, SSTR1 expression was higher in G3a than in G3b tumors. CONCLUSION: We observed an elevation in CXCR4 and a decrease in SSTR2A expression with increasing malignancy. Interestingly, 23% of the G3 specimens had strong SSTR2A expression. Because CXCR4 was strongly expressed in highly proliferative G3 carcinomas, it is an interesting new target and needs to be validated in larger studies.
Challenging the understanding of significant improvement and outcome in schizophrenia – the concept of reliable and clinically significant change methods
2015-07-14

Abstract Significant changes of schizophrenia patients during inpatient treatment were evalutaed and compared to established outcome criteria. The concept of reliable and clinically significant change methods was applied to three hundred and ninety‐six patients suffering from a schizophrenia spectrum disorder. First, information on whether or not the change of the patient's condition is sufficient in order to declare that it is beyond a measurement error or random effect (= reliable change) was evaluated and in a second step it was observed if the reliable change was clinically meaningful (= clinically significant change). Different Positive and Negative Syndrome Scale for Schizophrenia (PANSS) thresholds were applied to define the clinically significant change (40, 45 and 50 points). These changes were then compared to established outcome criteria such as response and remission. Seventy‐nine of the 396 patients (20%) showed a reliable improvement of symptoms, whereas 70% improved without achieving a reliable change of their condition. Of the 79 patients achieving a reliable change during treatment 8‐15% concurrently showed a clinically significant change depending on the respective PANSS threshold. In contrast, 56% of the patients achieved response and 60% were in remission at discharge when applying established outcome criteria. Our results showed that a rather small number of schizophrenia patients were found to reliably change during inpatient treatment, with even less patients achieving a clinically significant change. The concept of reliable and clinically significant changes revealed to be a lot more stringent than today's established outcome criteria and should be critically evaluated regarding its use in schizophrenia patients. Copyright © 2015 John Wiley &amp; Sons, Ltd.
The Feasibility of Using Acoustic Markers of Speech for Optimizing Patient Outcomes during Randomized Amplitude Variation in Deep Brain Stimulation: A Proof of Principle Methods Study
2015-07-14

Intra-individual changes in speech were detected as a response to modified amplitude; however, no clear pattern was observed across patients as a group. The use of objective acoustic measures allows for quantification of speech changes during DBS optimization protocols, even when those changes are subtle and potentially difficult to detect perceptually.
Requirement of Cell Wall Remodeling for Cell–Cell Communication and Cell Differentiation in Filamentous Cyanobacteria of the OrderNostocales
2015-07-14

Cyanobacteria of the order Nostocales form filaments of hundreds of interacting cells exchanging metabolites and signal molecules, similar to multicellular eukaryotes. Here, we show a structural requisite for intrafilament communication: perforation of a single layered septal cell wall by an array of nanopores. An autolytic enzyme was identified in two heterocyst-forming strains, Nostoc punctiforme ATCC 29133 and Anabaena sp. PCC 7120, with similarities to the AmiC protein of the divisome from E. coli. Mutations of the cyanobacterial AmiC-orthologs abolished nanopore formation, cell–cell communication, and differentiation. Through this, we identified a novel function for a cell wall amidase: it transforms the cell-separating septum into a framework for cell-joining structures with approximately 150 pores 20 nm wide, which together constitute a novel bacterial organelle, establishing multicellularity in a filamentous prokaryote.
The Need to Distinguish Between Quantity and Quality in Research on Parental Involvement: The Example of Parental Help With Homework
2015-07-15

Parental involvement research has greatly expanded over the past decade, but findings are mixed, reflecting in part the conceptual and methodological limitations of many studies. On the basis of longitudinal questionnaire data from 1,685 sixth-grade students, the authors studied parental help with homework because it is the most common and most controversial type of parental involvement. Distinguishing between the quantity and quality of parental homework involvement, the research shows that completely different conclusions about the effectiveness of parental homework involvement will be reached if its quantity is assessed instead of its quality: How often parents helped with homework was negatively associated with the development of achievement, whereas homework help that was perceived as supportive had positive predictive effects, and homework help perceived as intrusive had negative effects. Moreover, the results show that effect sizes would be overestimated if students' prior achievement and family background were not controlled.
On the dependence of the X-ray continuum variations with luminosity in accreting X-ray pulsars
2015-07-15

Using RXTE/ASM archival data, we investigate the behaviour of the spectral\\nhardness ratio as a function of X-ray luminosity in a sample of six transient\\nX-ray pulsars (EXO 2030+375, GX 304-1, 4U 0115+63, V 0332+63, A 0535+26 and MXB\\n0656-072). In all sources we find that the spectral hardness ratio defined as\\n increases with the ASM flux\\n(1.33--12 keV) at low luminosities and then saturates or even slightly\\ndecreases above some critical X-ray luminosity falling into the range\\n ~erg~s . Two-dimensional structure of accretion\\ncolumns in the radiation-diffusion limit is calculated for two possible\\ngeometries (filled and hollow cylinder) for mass accretion rates \\nranging from to 1.2 ~g s . The observed spectral\\nbehaviour in the transient X-ray pulsars with increasing can be\\nreproduced by a Compton saturated sidewall emission from optically thick\\nmagnetized accretion columns with taking into account the emission reflected\\nfrom the neutron star atmosphere. At above some critical value ~g~s , the hight of the column becomes\\nsuch that the contribution of the reflected component to the total emission\\nstarts decreasing, which leads to the saturation and even slight decrease of\\nthe spectral hardness. Hollow-cylinder columns have a smaller height than the\\nfilled-cylinder ones, and the contribution of the reflected component in the\\ntotal emission does not virtually change with (and hence the hardness\\nof the continuum monotonically increases) up to higher mass accretion rates\\nthan for the filled columns.\\n
Death Dilemma and Organism Recovery in Ecotoxicology
2015-07-15

Why do some individuals survive after exposure to chemicals while others die? Either, the tolerance threshold is distributed among the individuals in a population, and its exceedance leads to certain death, or all individuals share the same threshold above which death occurs stochastically. The previously published General Unified Threshold model of Survival (GUTS) established a mathematical relationship between the two assumptions. According to this model stochastic death would result in systematically faster compensation and damage repair mechanisms than individual tolerance. Thus, we face a circular conclusion dilemma because inference about the death mechanism is inherently linked to the speed of damage recovery. We provide empirical evidence that the stochastic death model consistently infers much faster toxicodynamic recovery than the individual tolerance model. Survival data can be explained by either, slower damage recovery and a wider individual tolerance distribution, or faster damage recovery paired with a narrow tolerance distribution. The toxicodynamic model parameters exhibited meaningful patterns in chemical space, which is why we suggest toxicodynamic model parameters as novel phenotypic anchors for in vitro to in vivo toxicity extrapolation. GUTS appears to be a promising refinement of traditional survival curve analysis and dose response models.
Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy
2015-07-15

Summary Partial deletions of the RBFOX 1 gene encoding the neuronal splicing regulator have been reported in a range of neurodevelopmental diseases including idiopathic/genetic generalized epilepsy ( IGE / GGE ), childhood focal epilepsy, and self‐limited childhood benign epilepsy with centrotemporal spikes ( BECTS , rolandic epilepsy), and autism. The protein regulates alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. Herein, we examined whether structural deletions affecting RBFOX 1 exons confer susceptibility to common forms of juvenile and adult focal epilepsy syndromes. We screened 807 unrelated patients with sporadic focal epilepsy, and we identified seven hemizygous exonic RBFOX 1 deletions in patients with sporadic focal epilepsy (0.9%) in comparison to one deletion found in 1,502 controls. The phenotypes of the patients carrying RBFOX 1 deletions comprise magnetic resonance imaging ( MRI )–negative epilepsy of unknown etiology with frontal and temporal origin (n = 5) and two patients with temporal lobe epilepsy with hippocampal sclerosis. The epilepsies were largely pharmacoresistant but not associated with intellectual disability. Our study extends the phenotypic spectrum of RBFOX 1 deletions as a risk factor for focal epilepsy and suggests that exonic RBFOX 1 deletions are involved in the broad spectrum of focal and generalized epilepsies.
Nifurtimox reduces N-Myc expression and aerobic glycolysis in neuroblastoma
2015-07-15

Neuroblastoma is one of the most common solid tumors in childhood and usually accompanied with poor prognosis and rapid tumor progression when diagnosed with amplification of the proto-oncogene N-Myc. The amplification of N-Myc has major influence on the maintenance of aerobic glycolysis, also known as the Warburg effect. This specific switch in the conversion of pyruvate to lactate instead of the conversion of pyruvate to acetyl-coenzyme A even in the presence of oxygen has important benefits for the tumor, e.g. increased production of enzymes and enzyme substrates that are involved in tumor progression, angiogenesis and inhibition of apoptosis. The antiprotozoal drug nifurtimox, which is generally used for the treatment of infections with the parasitic protozoan Trypanosoma cruzi, has been reported to have cytotoxic properties in the therapy of neuroblastoma. However, its action of mechanism has not been described in detail yet. The presented in vitro study on the neuroblastoma cell lines LA-N-1, IMR-32, LS and SK-N-SH shows an increased production of oxidative stress, a reduced lactate dehydrogenase enzyme activity and reduced lactate production after nifurtimox treatment. Furthermore, nifurtimox leads to reduced mRNA and protein levels of the proto-oncogene protein N-Myc. Thus, the current work gives new insights into the effect of nifurtimox on tumor metabolism revealing a shifted glucose metabolism from production of lactate to oxidative phosphorylation and a reduced expression of the major molecular prognostic factor in neuroblastoma N-Myc, presenting nifurtimox as a possible adjuvant therapeutic agent against (high risk) neuroblastoma.
Reversible Increase of Central Choroidal Thickness During High-Altitude Exposure
2015-07-15

A small but significant increase in choroidal thickness was observed upon acute altitude exposure to 4559 m. This increase in choroidal blood flow was not related to AMS and was fully reversible after return to low altitude.
Ant Abundance along a Productivity Gradient: Addressing Two Conflicting Hypotheses
2015-07-15

The number of individuals within a population or community and their body size can be associated with changes in resource supply. While these relationships may provide a key to better understand the role of abiotic vs. biotic constraints in animal communities, little is known about the way size and abundance of organisms change along resource gradients. Here, we studied this interplay in ants, addressing two hypotheses with opposite predictions regarding variation in population densities along resource gradients- the 'productivity hypothesis' and the 'productivity-based thinning hypothesis'. The hypotheses were tested in two functional groups of ground-dwelling ants that are directly primary consumers feeding on seeds: specialized seed-eaters and generalist species. We examined variations in colony density and foraging activity (a size measurement of the forager caste) in six ant assemblages along a steep productivity gradient in a semi-arid region, where precipitation and plant biomass vary 6-fold over a distance of 250km. An increase in the density or foraging activity of ant colonies along productivity gradients is also likely to affect competitive interactions among colonies, and consequently clinal changes in competition intensity were also examined. Ant foraging activity increased with productivity for both functional groups. However, colony density revealed opposing patterns: it increased with productivity for the specialized seed-eaters, but decreased for the generalist species. Competition intensity, evaluated by spatial partitioning of species at food baits and distribution of colonies, was uncorrelated with productivity in the specialized seed-eaters, but decreased with increasing productivity in the generalists. Our results provide support for two contrasting hypotheses regarding the effect of resource availability on the abundance of colonial organisms- the 'productivity hypothesis' for specialized seed-eaters and the 'productivity-based thinning hypothesis' for generalist species. These results also stress the importance of considering the role of functional groups in studies of community structure.
Prospects for regenerative medicine approaches in women's health
2015-07-15

Abstract Novel regenerative strategies, stem cell‐based therapies or the development of advanced human cell‐based in vitro ‐manufactured preclinical test systems offer great potential to generate advances in clinical practice in the field of women's health. This review aims to provide a brief overview of the current advances in the field.
GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo
2015-07-16

A large body of evidence from in vitro studies suggests that GABA is depolarizing during early postnatal development. However, the mode of GABA action in the intact developing brain is unknown. Here we examine the in vivo effects of GABA in cells of the upper cortical plate using a combination of electrophysiological and Ca(2+)-imaging techniques. We report that at postnatal days (P) 3-4, GABA depolarizes the majority of immature neurons in the occipital cortex of anaesthetized mice. At the same time, GABA does not efficiently activate voltage-gated Ca(2+) channels and fails to induce action potential firing. Blocking GABA(A) receptors disinhibits spontaneous network activity, whereas allosteric activation of GABA(A) receptors has the opposite effect. In summary, our data provide evidence that in vivo GABA acts as a depolarizing neurotransmitter imposing an inhibitory control on network activity in the neonatal (P3-4) neocortex.
Immunoliposomes for Targeted Delivery of an Antifibrotic Drug
2015-07-16

Excessive extracellular matrix formation in organs and tissues arises from an imbalance between the synthesis and degradation of matrix proteins, especially collagen. This condition interferes with proper wound healing and regeneration, and to date, no specific treatment is available. In the present study, we propose a targeted drug delivery system consisting of cell-specific immunoliposomes (ILs) loaded with deferoxamine (DFO) as an antifibrotic drug. ILs were functionalized with polyethylene glycol (PEG) to improve the steric stability and prolong their half-life. In addition, a single-chain Fv (scFv) antibody fragment that specifically targets fibroblast activation protein (FAP) was incorporated. An in vitro fibrosis model was employed to test this construct. This model consisted of highly activated pro-fibrotic fibroblasts with 2- to 6-fold induction of selected fibrosis markers: cell/matrix deposited collagen I, total soluble collagen, and α smooth muscle actin. The activation was accompanied by a significant and cell-specific elevation of FAP expression and activity, thereby confirming that FAP is an adequate target for antifibrotic drug delivery. Purified anti-FAP scFv was shown to bind specifically to these cells without influencing the FAP enzymatic activity. DFO was demonstrated to have a dose-dependent antifibrotic activity as quantified by collagen deposition. Specific binding and intracellular uptake of DiI-labeled ILs into the activated fibroblasts were shown by flow cytometry and microscopy. Finally, DFO-loaded ILs targeted to FAP caused a significant reduction in the collagen deposition, whereas no effect was observed using liposomes that lacked the targeting antibody fragment. These results suggest that the FAP-specific scFv-conjugated liposomes have considerable potential for cell-specific targeting applicable as a therapy for excessive collagen deposition during fibrosis. In general, through liposome encapsulation, bioactive molecules, such as DFO, that have broad effects and poor cell penetration can be converted into cell-specific composites for targeted drug delivery.