julilili42/papers huggingface dataset:
P01.013 Long-term analyses of the NOA-08 randomized phase III trial of temozolomide versus radiotherapy for elderly patients with malignant astrocytomas
2018-09-01

While the NOA-08 trial and the NORDIC Elderly trial suggested an O6-methylguanine DNA-methyl transferase (MGMT) status-tailored use of radiotherapy (RT) and temozolomide (TMZ), recent data from the NCIC CE.6/EORTC 26062 showed that hypofractionated RT plus TMZ was superior to RT for unselected elderly patients with an impact of MGMT for the effect of TMZ. This is the long-term update of the NOA-08 trial (German Cancer Trials Registry ID 386 and NCT01502241) that compared efficacy and safety of RT alone to TMZ alone in elderly patients with anaplastic astrocytoma (AA) or glioblastoma (GB), both isocitrate dehydrogenase wildtype, using overall survival (OS) as primary endpoint and event-free survival (EFS) as well as efficacy according to MGMT status as major secondary endpoints. NOA-08 had randomized patients (N=412; 39 AA, 373 GB) > 65 years with a Karnofsky performance score ≥ 60 in electronically generated blocks of variable length without stratification to receive standard RT to 60 Gy in 30 x 2 Gy fractions or TMZ dosed according to tolerance in a one week on/one week off schedule with tolerability dependent dosing. The trial finished enrolment Nov 2 2009 and demonstrated non-inferiority of TMZ compared with RT (p=0·033). In the long-term analysis with a data cut-off Apr 1 2018 median OS was 8·2 [7·0–10·0] months for TMZ treatment versus 9·4 [8·1–10·4] months for RT; hazard ratio (HR)=0·93 (95% CI: 0·76-1·15)] of TMZ versus RT did not differ between both arms. Also, median EFS [3·4 [3·2–4·1] months versus 4·6 [4·2–5·0] months did not differ with a HR=1·02 (0·83-1·25)]. MGMT promoter methylation tested in tumor tissue (82/221 patients, 37·1%) was associated with prolonged OS [13·6 [10·1–16·5] versus 8·0 [6·9-9·9] months; HR=0·53 (0·40-0·70), p<0·0001]. Patients with MGMT promoter methylation had longer OS and EFS when treated with TMZ (18·4 [13·9–24·4] months and 8·5 [6·9–13·3] months) versus RT (9·6 [6·4–13·7] months and 4·8 [4·3–6·2] months, HR 0·44 [0.27–0.70], p<0·001 for OS and 0·46 [0.29–0.73], p=0·001 for EFS). Patients without MGMT promoter methylation had shorter EFS and a shorter OS with the usual testing not significant when treated with TMZ (6·7 [5·6–8·2] months and 3·0 [2·6-3·3] months) versus with RT (10·2 [8·0–12·0] months and 4·6 [3·7-6·4] months), HR 1·33 [0·95-1·87], p=0·099 for OS and 1·86 [1·32-2·62], p<0·001 for EFS). Also in the long-term analyses, NOA-08 confirms the non-inferiority of TMZ compared with RT in the treatment of elderly patients with WHO grade III or IV astrocytic gliomas. To improve OS and EFS, MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ and offers unexpectedly favorable long-term outcome with initial TMZ monotherapy.
Patients with congenital heart defect and their families support genetic heart research
2018-09-01

The motivation to provide biological samples is high reflecting the need for genetic research to unravel the pathomechanism of CHD. A future aim should be to offer an individual risk assessment for each patient based on the underlying genetics.
Human V4 Activity Patterns Predict Behavioral Performance in Imagery of Object Color
2018-09-01

Among the multitude of elements making up visual experience, color stands out in that it can specify both subjective experience and objective properties of the outside world. Whereas most neuroimaging research on human color vision has focused on external stimulation, the present study addressed this duality by investigating how externally elicited color vision is linked to subjective color experience induced by object imagery. We recorded fMRI activity while showing our participants abstract color stimuli that were either red, green, or yellow in half of the runs ("real-color runs") and asked them to produce mental images of colored objects corresponding to the same three categories in the remaining half ("imagery runs"). To make sure that participants were engaged in visual imagery, they performed a 1-back same/different color judgment task on the imagined objects. We trained color classifiers using MVPA to distinguish between fMRI responses to the three color stimuli and cross-validated them on data from real-color or imagery runs. Although real-color percepts could be predicted from all retinotopically mapped visual areas, only color decoders trained on hV4 responses could additionally predict the color category of an object that was being imagined. This suggests that sensory-driven and self-induced colors share a common neural code in hV4. Using a hierarchical drift diffusion model, we furthermore demonstrated that the decoding accuracy in hV4 was predictive of performance in the color judgment task on a trial-by-trial basis. The commonality between neural representations of perceived and imagined object color, in combination with the behavioral modeling evidence, hence identifies area hV4 as a "perceptual bridge" linking externally triggered color vision with color in self-generated object imagery. Meeting abstract presented at VSS 2018
Silicone-based Chip-in-Foil System
2018-09-01

Abstract Aiming at devices for bioelectronic medicine, this paper proposes a die embedding process for the fabrication of flexible smart implants. By combining thinned bare dies with a polymeric encapsulation, completely flexible implants can be designed. The dies are encapsulated using a flip-chip process and a backfilling with silicone rubber. A completely even surface without detectable edge between the chip and the surrounding polymer substrate is achieved by gluing the chips face-down onto a polyimide-covered substrate. The backside is coated with silicone rubber and a second carrier substrate is attached. Removing the first substrate subsequent to curing of the silicone leads to chips located under a continuous polyimide layer, enabling the use of microtechnology for further processing steps. A custom-made test chip is proposed that enables the evaluation of the mechanical and chemical stability of the system.
Interaction between form and motion processing contributes to habituation to distortions of the natural visual world
2018-09-01

Spatial geometric distortions, such as image skew, recurrently occur in the visual world when using spectacles like progressive additional lenses. Image skew alters form information as well as motion direction statistics of the natural world. The visual system seems to compensate for these alterations during habituation to distoritons of spectacles. Here, we tested whether the interaction between form and motion cortical processing contributes to habituation to distortions of the natural visual world. A motion direction adaptation aftereffect (MAE), induced by distorted form and motion features of ecological stimuli, was psychophysically evaluated with a constant stimulus procedure in 10 observers. MAE was tested with two types of adapting stimuli; type 1: skewed dynamic natural image sequences (both form and motion features), type 2: skewed static natural images (only form feature). After exposure to either of the adapting stimuli, observers identified if the direction of coherently moving random dots was either diagonally up or diagonally down. The aftereffect was quantified by the point of subjective equality (PSE), i.e. the direction of the moving dots percieved as horizontal. After exposure to both types of the adapting stimuli, the PSE significantly shifted to the adapting skew direction, p< 0.05. The reported perceptual adjustment in motion perception after exposure to distortion induced alterations of form feature in static natural images reveals interaction between form and motion visual processing. Thus, cortical interactions in form-motion processing possibly partakes in the process of habituation to geometric distortions of the natural environment. Meeting abstract presented at VSS 2018
Micro Electron Beam Welding of the hybrid material combination Nitinol and stainless steel without filler material
2018-09-01

Nitinol, which consists of 50 at.-% nickel and 50 at.-% titanium, and stainless steels. These materials are widely used in medical engineering. Due to the versatile properties of Nitinol, for example shape memory and superelasticity, it finds application in implants and medical instruments. Because of its high-cost and poor machinability, there is a high demand for dissimilar welding of Nitinol components to stainless steel. During welding of titanium-containing alloys, like Nitinol, to ferrous metals like stainless steel, intermetallic phases between titanium and iron are formed. These phases are very brittle and lead to cracks and reduced mechanical properties of the joint. This publication intends to demonstrate the feasibility of producing weld seams with good quality by the use of Micro Electron Beam Welding. Due to a very accurate beam alignment and fast beam deflection, the composition and the level of dilution in the weld metal can be precisely controlled, resulting in a significantly reduced amount of intermetallic phases. Another aim of this paper is to show that the electron-optical monitoring can be used for quality assurance.
Where am I? In terms of my physical and of my perceived body
2018-09-01

We investigated the following three questions: 1) Where do people locate themselves on their body? 2) How precisely can people locate their body parts? and 3) Do people locate themselves differently in terms of their perceived compared to their physical body dimensions? Alsmith and Longo (2014) asked participants to point directly to themselves with a physical pointer. They found pointing to be to two distinct locations, upper face and upper torso. To investigate the robustness of their findings, we used virtual reality (VR), because this allows for systematic control over experimental variables and easy manipulation of visual information. In a VR headset and on a large-scale immersive display, participants rotated a pointer in their sagittal plane instructed to "Point directly to you", but also to nine of their body parts (feet, knees, hips, waist, shoulders, chin, nose, eyes and top of the head) previously measured for their physical heights. From the pointed-to body parts a perceived body was constructed, to which the self-locations were alternatively scaled/normalized. Pointing to self relative to the physical body was frequently found for all body regions above mid-torso, as well as above the head (Supplement, left graph). Participants pointed precisely to many body parts, but not to feet and knees, nor to the top of the head. Relative to the perceived body, pointing to self resembled more the results from the earlier physical setup, that is participants pointed mainly to upper torso and the face (Supplement, right graph). These results suggest, that a) people do not have one specific location where they locate themselves, and b) people do not accurately point to their entire body in the vertical plane. Alsmith, A. J. T. & Longo, M. R. (2014). Where exactly am I? Self-location judgements distribute between head and torso. Consciousness and Cognition, 24, 70-74. Meeting abstract presented at VSS 2018
B04 Environment-dependent modulation of striatal gene expression in the BACHD RAT model
2018-09-01

<h3>Background</h3> Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in exon 1 of the huntingtin (HTT) gene that results in progressive brain neurodegeneration with highest damage in striatum. Evidence from both human and mouse model studies suggests that (i) transcriptional dysregulation may represent a major factor underlying mutant HTT (mHTT) activity and (ii) the environment can affect HD features, although the underlying mechanisms are unclear. <h3>Aims</h3> The aim of this study was to examine HD related early life gene-environment interactions in the BACHD rat model. <h3>Methods/techniques</h3> We applied maternal separation (MS) and environmental enrichment (EE) during development in BACHD rats and examined the effects on striatal gene expression, using RNA sequencing. To relate environmental effects with disease progression, we integrated our results with striatal consensus modules defined on HTT-CAG length and age-dependent co-expression gene networks. <h3>Results/outcome</h3> Our results show that while most gene expression changes were determined by mHTT, both environmental treatments modulated the mHTT induced alterations with distinctive and opposing effects of MS and EE on striatal consensus modules. <h3>Conclusions</h3> The opposite modulatory action of MS and EE in this study, may explain their antithetic effects observed on disease phenotypes in animal models of HD and other neurodegenerative disorders.
B07 Metabolic characteristics of primary neuron cultures from bachd rats compared to induced lesion models
2018-09-01

<h3>Background</h3> The BACHD rat is by now a well characterized animal model of Huntington's disease (HD), presenting several disease relevant symptoms and pathologies. The BACHD rat represents one of the few animal models that overexpresses the full length human mutant huntingtin (mHTT) and is thus of great value for HD research. <h3>Aims</h3> The aim of this study was to compare the metabolic properties of primary striatal, hypothalamic and cortical neurons of BACHD rats with the l-glutamate or MPP+ induced rat striatal lesion models to establish BACHD primary cells as valuable <i>in vitro</i> HD model. <h3>Methods</h3> BACHD rat pups, as well as wildtype pups, were dissected at embryonic day 19 and primary neurons of the striatum, hypothalamus and cortex were cultivated. Cells were analyzed after 1, 7 and 14 days <i>in vitro</i>. For the lesion models, primary striatal embryonic day 19 rat neurons were cultivated for 15 days and lesioned with l-glutamate or MPP+ for 24 hours. All samples were analyzed with the MTT- and LDH-assay. <h3>Results</h3> Our data show that primary neurons of embryonic BACHD rats show a significantly decreased metabolic activity in the striatum and hypothalamus. These results are comparable with data obtained by l-glutamate or MTT+ lesions in primary striatal neurons of wildtype rats. <h3>Conclusions</h3> We conclude that the BACHD rat model is a valuable tool for the <i>in vitro</i> evaluation of HD-related metabolic properties.
OS2.1 Objective responses to chemotherapy in recurrent glioma do not predict better survival: A prospective analysis from the German Glioma Network
2018-09-01

Outside of clinical trials, the occurrence of objective responses (OR) to chemotherapy in patients with recurrent gliomas is poorly characterized. Further, the predictive value of OR for progression-free survival (PFS) and overall survival (OS) in glioma patients is unclear. We screened the German Glioma Network Database for patients who had received any chemotherapy for recurrent glioma from 2004–2008. Patients with a prior gross total resection of the recurrent tumor, patients receiving additional radiotherapy for the recurrent tumor and patients with spinal gliomas were excluded. As PFS was not available for a large number of patients we used the composite endpoint time-to-treatment-failure (progressive disease, start of a new therapy or death). We included 485 patients who received 646 chemotherapy regimens for treatment of recurrent glioma. Of these, only 32 chemotherapies in 32 patients resulted in an objective response (30 PR, 2 CR) after central neuroradiological review according to RANO criteria. OR rates were 2.8%, 11.0% and 10.6% for glioblastoma, anaplastic glioma WHO grade III and diffuse glioma WHO grade II, respectively. Temozolomide (n=232) resulted in ORs in 7.8% of the patients, while nitrosourea (n=212) and imatinib (n=27) resulted in ORs in 6.1% and 3.7%, respectively. Overall, responders showed a significantly improved OS compared to non-responders (median OS 33.3 versus 15 months, p=0.054). Yet, a Cox regression analysis adjusted for diagnosis (including WHO grade) and age did not reveal a significant association of objective responses with overall survival (relative risk 0.8, p=0.391). In addition, we generated a 1:3 cohort (n=96) of non-responders matched for histology and WHO grade. There was no relevant difference in OS comparing responders to the matched cohort (median OS 33.3 versus 25.6 months, p=0.929). When comparing non-responders with longer time-to-treatment-failure (>14 weeks, assumed stable disease as best response) with responders (n=32) the difference in outcome was lost (median OS 24.3 versus 33.3 months, p=0.86). In contrast, non-responders with shorter time-to-treatment-failure (<14 weeks, assumed progressive disease as best response) had dramatically shorter survival (median OS 6.4 versus 33.3 months, p<0.05). In this large, prospective study objective responses to chemotherapy in the recurrent setting were rare in glioma patients. Notably, when comparing responders with a matched cohort or patients with assumed stable disease as best response, objective responses do not seem to be associated with improved survival.
OS2.2 Highly personalized peptide vaccination for patients with newly diagnosed glioblastoma: the GAPVAC trial
2018-09-01

There is a need for treatment personalization as every cancer is molecularly unique. In addition glioblastoma (GB) are immunologically regarded as resistant, “cold” tumor with few targetable antigens available from mutations, thus demanding new personalized immunotherapies. So far outside Neuro-Oncology, T cells orchestrate impressive anti-tumor effects with checkpoint inhibitors, but also vaccines. The GAPVAC consortium established an immunotherapy, for which personalized selection of 2 peptide-based actively personalized vaccines (APVAC) per patient for treatment of newly diagnosed GB was based not only on whole-exome sequencing but also on human leukocyte antigen (HLA)-ligandome analyses providing insight into the actual presentation of relevant epitopes in the tumor. GAPVAC-101 (NCT02149225) enrolled 16 patients in a European phase I feasibility, safety and immunogenicity trial integrated into standard of care. For APVAC1, up to 7 peptides were selected from a trial specific warehouse based on individual biomarker data. Vaccination (i.d.) with GM-CSF and poly-ICLC in 15 patients started with the 1st adjuvant cycle of temozolomide (TMZ). For APVAC2, analyses revealed a median of 36 somatic, non-synonymous mutations in the patients’ tumors. From the 4th TMZ cycle, 11 patients received APVAC2 with usually 2 de novo antigens per patient selected according to mutation, actual or putative HLA presentation and immunogenicity. Overall 20 APVAC2 antigens incl. 14 mutated were vaccinated. Adverse events were largely reversible injection site reactions and two anaphylactic reactions and one increase in cerebral edema. Short, non-mutated APVAC1 antigens induced sustained CD8 responses with memory phenotype. Mutated APVAC2 antigens induced predominantly CD4 responses of favorable TH1 type. Median PFS and OS were 14.2 and 29 months from diagnosis, respectively, in patients that received ≥1 APVAC vaccination (N=15). Overall, GAPVAC displayed expected safety profiles and high biological activity indicating further development.
A23 Calpastatin ablation aggravates the molecular phenotype in cell and animal models of huntington disease
2018-09-01

<h3>Background</h3> Deciphering the molecular pathology of Huntington disease is of particular importance, not only for a better understanding of this neurodegenerative disease, but also to identify potential therapeutic targets. The disease protein huntingtin was shown to undergo proteolysis, resulting in the accumulation of toxic and aggregation-prone fragments. Amongst several classes of proteolytic enzymes responsible for huntingtin cleavage, the group of calcium-activated calpains has been found to significantly mediate disease protein toxicity. <h3>Aims</h3> To confirm the impact of calpain-mediated huntingtin cleavage in Huntington disease, we analyzed effects of depleting or overexpressing the endogenous calpain inhibitor calpastatin in HEK293T cells transfected with wild-type or mutant huntingtin. Moreover, we crossbred two Huntington disease mouse models with calpastatin knockout mice to assess its effect not only on huntingtin cleavage and aggregation but also additional molecular markers. <h3>Methods</h3> Effects of depleting the endogenous inhibitor of calpains on huntingtin fragmentation and aggregation, as well as on other molecular markers of Huntington disease were investigated via western blotting, filter retardation assays and immunocytochemistry or immunohistochemistry. <h3>Results</h3> We demonstrated that reduced or ablated calpastatin expression triggers calpain overactivation and a consequently increased mutant huntingtin cleavage in cells and <i>in vivo</i>. These alterations were accompanied by an elevated formation of predominantly cytoplasmic huntingtin aggregates. Conversely, calpastatin overexpression in cells attenuated huntingtin fragmentation and aggregation. In addition, we observed an enhanced cleavage of DARPP-32, p35 and synapsin-1 in neuronal tissue upon calpain overactivation. <h3>Conclusions</h3> Our results corroborate the important role of calpains in the molecular pathogenesis of Huntington disease and endorse targeting these proteolytic enzymes as a therapeutic approach.
C05 BRCA mutations are associated with higher CAG numbers found in various polyglutamine disorders
2018-09-01

<h3>Background</h3> The CAG repeat expansion in the HTT gene is a dynamic mutation varying in length in tissues and between generations. The mechanisms behind the instability of CAG expansions are polymerase slippage and DNA repair failure. BRCA1 and BRCA2 are well characterized DNA repair genes and mutations increase the risk of developing breast and ovarian cancer for carriers. <h3>Aim</h3> Therefore, in our study we analysed CAG lengths in various polyglutamine containing genes to investigate the potential effect of mutations in the DNA repair genes BRCA1 and BRCA2 on CAG length. <h3>Methods</h3> In a cohort of patients from Department of Obstetrics and Gynecology in Tuebingen carrying BRCA1 or BRCA2 mutations, CAG lengths in 6 different polyglutamine disease genes (HD, SCA1, SCA2, SCA3, SCA6 and SCA7) were determined by fragment length analysis. CAG lengths were classified as non-pathological, intermediate and pathological for each disorder. The findings were compared to data on the general population and to a control group from the Department of Obstetrics and Gynecology in Tuebingen. <h3>Results</h3> We have found no difference in the overall CAG repeat length in patients carrying BRCA1 or BRCA2 mutations. However, the frequency of patients carrying intermediate CAG lengths was higher in patients carrying BRCA1 and BRCA2 mutations in comparison to the general population. <h3>Conclusion</h3> The frequency of intermediate alleles was in our cohort higher than reported for the general population. They further link BRCA mutations to defects in DNA repair possibly contributing to the expansion of the CAG repeats with a mechanism common to different polyglutamine disorders. Further studies are needed in order to evaluate the correlation of specific mutations with CAG size and CAG size with disease prognosis of BRCA1 or BRCA2 mutation carriers.