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Five-Gene Expression Signature Associated With Acquired FOLFIRI Resistance and Survival in Metastatic Colorectal Cancer
Get PDFFOLFIRI, a combination of folinic acid, 5-fluorouracil, and irinotecan, is one of the recommended first-line chemotherapeutic treatments for metastatic colorectal cancer. Unfortunately, acquired FOLFIRI resistance represents a common obstacle in the treatment of metastatic colorectal cancer patients. Thus, we aimed to identify mechanisms, gene alterations, and gene expression signatures contributing to acquired FOLFIRI resistance by mimicking this problem in a cell culture model and subsequent translation in clinical data sets. Three FOLFIRI-resistant colorectal cancer (CRC) cell lines were established by continuous FOLFIRI treatment. Comparative mutation screening (161 genes) and transcriptomics (pathway and differential expression analyses) were performed in parental and resistant cells. Data reconciliation was performed in GSE62322, a clinical FOLFIRI responder data set (intrinsic resistance). Relapse-free survival (RFS) associations of identified differentially expressed genes and potential gene signatures were investigated in 8 clinical CRC data sets. No mutual genetic alterations were found in FOLFIRI-resistant derivatives. Resistant cell lines displayed activation of mitogen-activated protein kinase, immune response, and epithelial-mesenchymal transition pathways. Twelve differentially expressed genes, significantly differentially expressed in at least 2 of the 3 resistant cell lines, were identified. Comparison with GSE62322 and subsequent survival analyses revealed a 5-gene FOLFIRI signature comprised of CAV2, TNC, TACSTD2, SERPINE2, and PERP that was associated with RFS in multiple data sets including the cancer genome atlas CRC (hazard ratio [HR] =2.634, P = 4.53 × 10−6), in pooled samples of all data sets (all stages [N = 1981]: HR = 1.852, P = 6.44 × 10−13; stage IV [N = 260]: HR = 2.462, P = 5.22 × 10−9). A multivariate Cox regression analysis identified the 5-gene signature as an independent prognostic factor in the cancer genome atlas data set (HR = 1.89, P = .0202). Our analyses revealed a 5-gene FOLFIRI resistance signature associated with RFS that may help predict FOLFIRI resistance and thus avoid unnecessary ineffective treatment. Signature members might also represent targets to fight FOLFIRI resistance
Mechanical properties of 3D printed denture base polymers
No full textStatement of problem
Studies on the mechanical properties of 3-dimensionally (3D) printed denture base polymers with appropriate test methods are lacking.
Purpose
The purpose of this in vitro study was to determine the flexural strength (σf), elastic modulus (E), fracture toughness (KIC), work of fracture (ωe), and Martens hardness (HM) of 3D printed denture base polymers and to compare them with an injection molded material.
Material and methods
Three resins for additive (Lucitone Digital Print, LDP; Flexcera Base, FCB and an experimental material, EXP) and 1 for injection molding (IvoBase Hybrid, IBH) fabrication were analyzed. Standardized specimens were fabricated, polished, tempered, and thermal cycled (5 °C to 55 °C) before testing for σf, E, KIC, ωe, and HM. The results were explored by global analysis (α=.05). The Kolmogorov-Smirnov test was used to test for data distribution. Parametric and nonparametric tests followed by pairwise comparison were applied to test for differences between groups.
Results
The σf, E, and HM of 3D printed polymers were significantly lower than those of the injection molded, both for the tempered and aged groups. The σf was lowest for FCB and highest for IBH in the tempered state. The KIC and ωe of the tempered EXP and IBH groups were lower compared with those of FCB and LDP. After aging, EXP, FCB, and IBH presented KIC in the same range, but it was lower than for LDP. Compared with the printable polymers, the control group IBH was not affected by artificial aging.
Conclusions
The σf, E, and HM of printable polymers were lower than those of the control group, and specimens did not fracture in bend testing. In contrast, KIC and ωe were the highest for a printable polymer. Therefore, tension tests should be considered when testing ductile materials
Very volatile and volatile organic compounds (VVOCs/VOCs) and endotoxins in the indoor air of German schools and apartments (LUPE10)
No full textPeople, including sensitive population groups such as children, spend over 90 % of their time indoors and are exposed to volatile and very volatile organic compounds (VOCs/VVOCs) and endotoxins. We measured 34 VVOCs, 69 VOCs, two organic acids, and endotoxins in the indoor air of 34 apartments and 27 classrooms using four different sampling techniques and analytical methods. Our study aimed to provide a comprehensive overview of a broad spectrum of substances rarely measured in indoor air. The following substance classes showed the highest sum medians in classrooms and apartments: alcohols 249 μg/m3 and 518 μg/m3, aldehydes/acetone 81.6 μg/m3 and 121 μg/m3 and organic acids 61 μg/m3 and 82 μg/m3. The individual substances with the highest medians were ethanol > acetic acid > acetone > decamethylcyclopentasiloxane > formaldehyde > acetaldehyde. The median of the total volatile organic compounds as the sum of the VOCs of C6-C16 was 253 μg/m3 (range: 638–3369 μg/m3) in the apartments and 277 μg/m3 (61–900 μg/m3) in the classrooms. The median (95th percentile) levels of endotoxins in the classrooms and apartments were 5.8 EU/m3 (15.3 EU/m3) and 0.26 EU/m3 (0.91 EU/m3), respectively. Concentrations in apartments are significantly lower than in schools. According to current knowledge, levels pose no health risk.
In addition to the classic VOCs, VVOCs should also be measured to a greater extent, as considerable exposure to substances from this group is expected indoors. These results underline the urgent need for further research to improve indoor air quality and protect public health
From inconsistent annotations to ground truth: Aggregation strategies for annotations of proximal carious lesions in dental imagery
Get PDFObjectives
Annotating carious lesions on images is challenging. For artificial intelligence (AI) applications, the aggregation of heterogeneous multi-examiner annotations into one single annotation (e.g. via majority voting, MV) is usually needed. We assessed different aggregation strategies for multi-examiner annotations of primary proximal carious lesions on orthoradial radiographs and Near-Infrared Light Transillumination (NILT) images.
Methods
A total of 1007 proximal surfaces from 522 extracted posterior teeth were assessed by five dentists. Histological analysis provided the gold standard. Surfaces were classified as (1) sound, (2) enamel lesion or (3) dentin lesion. Four label aggregation strategies - MV, Weighted Majority Voting (WMV), Dawid-Skene (DS), and multi-annotator competence estimation (MACE) - were applied to unimodal (radiographs, NILT) and multimodal (combined) datasets. The area under the receiver operating characteristic curve (AUROC) was the primary outcome metric.
Results
According to the gold standard, 637 (63 %) surfaces were sound, 280 (28 %) showed carious lesions limited to the enamel, and 90 (9 %) showed lesions extending into the dentin. For radiographs, aggregation using MACE outperformed MV, WMV and DS significantly across all lesion depths (p < 0.002). For NILT, MACE significantly outperformed MV across all lesion depths (p < 0.001) and DS for enamel and dentin lesions (p ≤ 0.002). In the multimodal dataset, DS outperformed the other label aggregation strategies across all lesion depths significantly (p < 0.05).
Conclusions
The commonly applied MV may be suboptimal. There is a need for informed application of specific aggregation strategies, depending on the dataset characteristics.
Clinical significance
Most AI applications for dental image analysis are trained on a single annotation, usually resulting from aggregated multi-examiner annotations of each image. However, since these annotations are usually aggregated in an in vivo setting where no definitive ground truth is available, the choice of aggregation strategy plays a crucial role
Circadian rhythm and sleep in focal epilepsy
No full textAlthough a relationship between sleep, circadian rhythm and the occurrence of epileptic seizures was first postulated over a hundred years ago, few studies, mainly with a small number of seizures were published.
In this study we analyzed all partial seizures determined by continuous EEG-monitoring to reevaluate previous results and to provide a first step towards creating chronotypes in epilepsy.
Data were collected at the epilepsy monitoring unit of the Department of Neurology, LMU University Hospital in Munich from 715 patients undergoing pre-surgical long-term Video-EEG-monitoring. Only seizures with a single focal seizure onset zone were considered and were divided into five groups: frontal, temporal, parietal, occipital and central region.
A total of 3950 seizures were included in the final analysis (temporal: 2055; frontal: 1512; central: 181; parietal: 90; occipital: 112).
C
osinor analysis revealed a periodicity in the occurrence of seizures regarding the temporal (p = 0.019), occipital (p = 0.045) und frontal lobe (p = 0.034) whereas parietal and central region seizures did not show a 24 h periodicity.
Temporal lobe seizures showed a peak at 10 am, whereas frontal lobe seizures peaked at 4 am and occipital lobe seizures at 4 pm.
Most seizures occurred in the awake state (in total 64.56 %) regardless of the seizure onset zone.
By knowing the peaks of seizure occurrence chronotypes can be identified and antiseizure medication can be adjusted accordingly. This might help to enhance seizure control and reduce seizure associated risk
Geographical patterns in the Bavarian dialects of Austria and South Tyrol. A real-time comparison using dialectometric methods
No full textThis paper presents a comparative real-time study of phonological variation in Bavarian dialects in Austria and South Tyrol, using a dialectometric approach. Drawing on historical data from the ‘Dictionary of Bavarian Dialects in Austria’ (Wörterbuch der bairischen Mundarten in Österreich) and contemporary data from the project ‘Variation and Change of Dialect Varieties in Austria (in Real and Apparent Time)’, supplemented by data from the project ‘German Dialects in South Tyrol’ (Deutsche Dialekte in Südtirol), we investigate geographic patterns of dialectal variation over time. The study addresses three central research questions: (1) What geolinguistic patterns emerge from historical and contemporary datasets? (2) How do these patterns align with traditional qualitative dialect classifications? (3) Can language change be identified through diachronic comparison? By analyzing a consistent set of 31 phonological variables using techniques such as multidimensional scaling and cluster analysis, we find a strong overall correspondence between historical and contemporary dialect classifications, which also align well with traditional qualitative dialect classifications. Our results highlight the persistence of major dialect divisions, particularly between (South) Central Bavarian and South Bavarian. At the same time, we identify more localized changes, such as the retreat of South Bavarian in southeastern Austria, increasing regionalization, and shifts in east-west variation patterns. In sum, the study demonstrates that real-time comparisons using dialectometric methods are feasible, despite certain methodological challenges
Infinitival Constructions in the German Dialects of Austria: On Variation, Constraints, and Change of a Prominent Syntactic Feature
Get PDFInfinitival constructions (ICs) have received considerable attention from syntacticians and typologists, but less so from variationist linguistics. Based on new data from a comprehensive dialect survey, this study investigates the variation and change of ICs in Austrian dialects. The results reveal clear geographical patterns for different IC variants in Austria. Regarding linguistic factors, several constraints are identified, most importantly with respect to the IC’s syntactical function and governing element (e.g., phase verbs). Moreover, an apparent-time analysis shows that one variant (zum + infinitive) has been grammaticalized and spread at the expense of all other variants, presumably due to both dialect leveling and dialect-standard advergence
The role of the epithelium in intraocular lens and corneal power calculation
No full textPurpose:
To investigate the influence of the corneal epithelium on corneal power, particularly in special cases such as post-refractive surgery and keratoconus.
Methods:
A retrospective observational study. Measurement data were obtained from a high-resolution anterior segment analyser (CSO MS-39). Corneal curvature and power data, as well as surface height data, were organised in a cylindrical coordinate system. Calculations considered one, two and three refractive surfaces, examining the role of epithelial thickness and stromal curvature.
Results:
The effect of the epithelium on corneal power was minimal (<0.1 D) in normal corneas, but it was considerable in keratoconus and post-refractive surgery cases, with differences up to 0.9 D. The effect decreased for larger measurement zones.
Conclusion:
Incorporating epithelial thickness and stromal curvature into corneal power calculations is a crucial next step in accurate corneal power and intraocular lens calculation in eyes with previous refractive surgery or keratoconus. This study highlights the need for advanced diagnostic and calculation methods in complex cases
Unraveling pH Regulation of TMEM175, an Endolysosomal Cation Channel With a Role in Parkinson's Disease
Get PDFTransmembrane protein 175 (TMEM175) is an endolysosomal cation channel, which has attracted much attention recently from academics and the pharmaceutical industry alike since human mutations in TMEM175 were found to be associated with the development of Parkinson's disease (PD). Thus, gain-of-function mutations were identified, which reduce and loss-of-function mutations, which increase the risk of developing PD. After having been characterized as an endolysosomal potassium channel initially, soon after TMEM175 was claimed to act as a proton channel. In fact, recent evidence suggests that depending on the conditions, TMEM175 can act as either a potassium or proton channel, without acting as an antiporter or exchanger. A recent work has now identified amino acid H57 to be directly involved in gating, increasing proton conductance of the channel while leaving the potassium conductance unaffected. We review here the current knowledge of TMEM175 function, pharmacology, physiology, and pathophysiology. We discuss the potential of this ion channel as a novel drug target for the treatment of neurodegenerative diseases such as PD, and we discuss the discovery of H57 as proton sensor
Qandle: Accelerating State Vector Simulation Using Gate-Matrix Caching and Circuit Splitting
No full textTo address the computational complexity associated with state-vector simulation for quantum circuits, we propose a combination of advanced techniques to accelerate circuit execution. Quantum gate matrix caching reduces the overhead of repeated applications of the Kronecker product when applying a gate matrix to the state vector by storing decomposed partial matrices for each gate. Circuit splitting divides the circuit into sub-circuits with fewer gates by constructing a dependency graph, enabling parallel or sequential execution on disjoint subsets of the state vector. These techniques are implemented using the PyTorch machine learning framework. We demonstrate the performance of our approach by comparing it to other PyTorch-compatible quantum state-vector simulators. Our implementation, named Qandle, is designed to seamlessly integrate with existing machine learning workflows, providing a user-friendly API and compatibility with the OpenQASM format. Qandle is an open-source project hosted on GitHub and PyPI