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Abstract PurposeThe use of face masks has been proposed to cause or exacerbate the symptoms of dry eye disease (DED), which has been widely discussed under the term mask-associated dry eye (MADE). However, no studies have systematically investigated tear film parameters during the use of different face masks. Therefore, the objective of the present study was to investigate clinically relevant parameters of the tear film before and during the short-time use of face masks in dry and normal eyes.MethodsIn a prospective study, the tear film parameters of 42 DED patients and 42 healthy volunteers were examined while wearing different types of face masks in a randomized order. This included measurements of non-invasive tear break-up time (NIBUT), lipid layer thickness, tear meniscus height, and bulbar redness after 30 min of wearing no mask, a surgical face mask or an FFP2/K95 mask. The equivalence of the means was assessed using the two one-sided t-test (TOST) method.ResultsIn healthy volunteers’ lipid layer thickness, NIBUT and tear meniscus height were not significantly altered by 30 min of surgical or FFP2 mask wear (p > 0.016). The use of either type of mask was significantly associated with decreased bulbar redness (p < 0.001) in healthy eyes. In patients with DED, none of the tear film parameters or bulbar redness were significantly altered by 30 min of mask wear (p > 0.016).ConclusionsBased on these results, the short-term wearing of face masks, regardless of type, did not produce a significant difference in tear film parameters of lipid layer thickness, NIBUT, and tear meniscus in healthy or dry eyes, while bulbar redness was reduced after mask wear only in healthy volunteers.

Physicians’ letters are the optimal source of diagnoses for registries. However, most registries demand for diagnosis codes such as ICD-10. We herein describe an algorithm that infers ICD-10 codes from German ophthalmologic physicians’ letters. We assess the method in three German eye hospitals. Our algorithm is based on the nearest-neighbor method as well as on a large thesaurus for ICD-10 codes. This thesaurus was embedded into a Word2Vec space created from anonymized physicians’ reports of the first hospital. For evaluation, each of the three hospitals sent all diagnoses taken from 100 letters. The inferred ICD-10 codes were evaluated for correctness by the senders. A total of 3332 natural language terms had been sent in (812 hospital one, 1473 hospital two, 1047 hospital three). A total of 526 non-diagnoses were excluded upfront. 2806 ICD-10 codes were inferred (771 hospital one, 1226 hospital two, 809 hospital three). In the first hospital, 98% were fully correct and 99% correct at the level of the superordinate disease concept. The percentages in hospital two were 69% and 86%. The respective numbers for hospital three were 69% and 91%. Our simple method is capable of inferring ICD-10 codes for German natural language diagnoses, especially when the embedding space has been built with physicians’ letters from the same hospital. The method may yield sufficient accuracy for many tasks in the multi-centric setting and can easily be adapted to other languages/specialities.

Nuclear factor of activated T cells 1 (NFAT1) expression has been associated with increased migratory/invasive properties of mammary tumor-derived cell lines in vitro . It is unknown, however, if NFAT activation actually occurs in breast cancer cases and whether the calcineurin/NFAT pathway is important to mammary tumorigenesis. Using a cohort of 321 diagnostic cases of the major subgroup of breast cancer, we found Cn/NFAT pathway activated in ER − PR − HER2 − triple-negative breast cancer subtype, whereas its prevalence is less in other subgroups. Using a small hairpin RNA-based gene expression silencing approach in murine mammary tumor cell line (4T1), we show that not only NFAT1 but also NFAT2 and their upstream activator Cn are essential to the migratory and invasive properties of mammary tumor cells. We also demonstrate that Cn, NFAT1 and NFAT2 are essential to the tumorigenic and metastatic properties of these cells in mice, a phenotype which coincides with increased apoptosis in vivo . Finally, global gene expression analyses identified several NFAT-deregulated genes, many of them being previously associated with mammary tumorigenesis. In particular, we identified the gene encoding a disintegrin and metalloproteinase with thrombonspondin motifs 1, as being a potential direct target of NFAT1. Thus, our results show that the Cn/NFAT pathway is activated in diagnostic cases of breast cancers and is essential to the tumorigenic and metastatic potential of mammary tumor cell line. These results suggest that pharmacological inhibition of the Cn/NFAT pathway at different levels could be of therapeutical interest for breast cancer patients.

Background Metaplastic breast cancer (MBC) is a rare form of breast cancer characterized by an aggressive clinical presentation, with a poor response to standard chemotherapy. MBCs are typically triple-negative breast cancers (TNBCs), frequently with alterations to genes of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. The objective of this study was to determine the response to PI3K and MAPK pathway inhibitors in patient-derived xenografts (PDXs) of MBCs with targetable alterations. Methods We compared survival between triple-negative MBCs and other histological subtypes, in a clinical cohort of 323 TNBC patients. PDX models were established from primary breast tumors classified as MBC. PI3K-AKT-mTOR and RTK-MAPK pathway alterations were detected by targeted next-generation sequencing (NGS) and analyses of copy number alterations. Activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways was analyzed with reverse-phase protein arrays (RPPA). PDXs carrying an activating mutation of PIK3CA and genomic changes to the RTK-MAPK signaling pathways were treated with a combination consisting of a PI3K inhibitor and a MEK inhibitor. Results In our clinical cohort, the patients with MBC had a worse prognosis than those with other histological subtypes. We established nine metaplastic TNBC PDXs. Three had a pathogenic mutation of PIK3CA and additional alterations to genes associated with RTK-MAPK signaling. The MBC PDXs expressed typical EMT and stem cell genes and were of the mesenchymal or mesenchymal stem-like TNBC subtypes. On histological analysis, MBC PDXs presented squamous or chondroid differentiation. RPPA analysis showed activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. In vivo, the combination of PI3K and MAPK inhibitors displayed marked antitumor activity in PDXs carrying genomic alterations of PIK3CA , AKT1 , BRAF , and FGFR4 . Conclusion The treatment of metaplastic breast cancer PDXs by activation of the PI3K-AKT-mTOR and RTK-MAPK pathways at the genomic and protein levels with a combination of PI3K and MEK inhibitors resulted in tumor regression in mutated models and may therefore be of interest for therapeutic purposes.

The transition of ductal carcinoma in situ (DCIS) to invasive breast carcinoma requires tumor cells to cross the basement membrane (BM). However, mechanisms underlying BM transmigration are poorly understood. Here, we report that expression of membrane-type 1 (MT1)-matrix metalloproteinase (MMP), a key component of the BM invasion program, increases during breast cancer progression at the in situ to invasive breast carcinoma transition. In the intraductal xenograft model, MT1-MMP is required for BM transmigration of MCF10DCIS.com breast adenocarcinoma cells and is overexpressed in cell clusters overlying focal BM disruptions and at the invasive tumor front. Mirrored upregulation of p63 and MT1-MMP is observed at the edge of MCF10DCIS.com xenograft tumors and p63 is required for induction of MT1-MMP-dependent invasive program in response to microenvironmental signals. Immunohistochemistry and analysis of public database reveal that p63 and MT1-MMP are upregulated in human basal-like breast tumors suggesting that p63/MT1-MMP axis contributes to progression of basal-like breast cancers with elevated p63 and MT1-MMP levels.

Maize arabinoxylans (AX) and proteins (maize gluten meal, MGM) can partially replace gluten in gluten-free (GF) breads by forming polymer networks. This study investigated how non-covalent interactions (hydrophobic, electrostatic, or hydrogen (H) forces) influenced viscoelasticity, gas retention and enzymatic AX–protein cross-linking in simplified GF model batters using two maize AX extracts (commercial MAX; xylanase-extracted M-XEAX). Batter stability strongly depended on AX structure and formulation type. MGM-only controls were mainly governed by hydrophobic and electrostatic forces, while AX-based batters relied primarily on H-bonds and electrostatic interactions. Combining MGM and AX increased batter stiffness, dominated by electrostatic and H-interactions. Enzymatic coupling reinforced the AX–protein network when both H and electrostatic forces were present, whereas hydrophobic interactions partly hindered these associations. Changes in viscoelasticity (G′) did not fully align with gas retention behaviour. In MGM-containing batters, gas retention was predominantly governed by H and electrostatic interactions. AX-based batters showed extract-dependent responses: electrostatic or H-interactions hindered gas stabilisation in M-XEAX, while their suppression supported gas-holding in enzyme-treated MAX batters. AX-MGM systems generally showed reduced gas expansion, indicating the contribution of multiple non-covalent interactions. Overall, batter stability strongly depended on AX structure, MGM addition, the balance of non-covalent interactions and the resulting network strength.

Background: RSPO ligands, activators of the Wnt/ β -catenin pathway, are overexpressed in different cancers. The objective of this study was to investigate the role of RSPOs in breast cancer (BC). Methods: Expression of RSPO and markers of various cancer pathways were measured in breast tumours and cell lines by qRT–PCR. The effect of RSPO on the Wnt/ β -catenin pathway activity was determined by luciferase assay, western blotting, and qRT–PCR. The effect of RSPO2 inhibition on proliferation was determined by using RSPO2 siRNAs. The effect of IWR-1, an inhibitor of the Wnt/ β -catenin pathway, was examined on the growth of an RSPO2 -positive patient-derived xenograft (PDX) model of metaplastic triple-negative BC. Results: We detected RSPO2 and RSPO4 overexpression levels in BC, particularly in triple-negative BC (TNBC), metaplastic BC, and triple-negative cell lines. Various mechanisms could account for this overexpression: presence of fusion transcripts involving RSPO , and amplification or hypomethylation of RSPO genes. Patients with RSPO2 -overexpressing tumours have a poorer metastasis-free survival ( P =3.6 × 10 −4 ). RSPO2 and RSPO4 stimulate Wnt/ β -catenin pathway activity. Inhibition of RSPO expression in a TN cell line inhibits cell growth, and IWR-1 significantly inhibits the growth of an RSPO2- overexpressing PDX. Conclusions: RSPO overexpression could therefore be a new prognostic biomarker and therapeutic target for TNBC.

The F-GAMMA program is a coordinated effort to investigate the physics of Active Galactic Nuclei (AGNs) via multi-frequency monitoring of Fermi blazars. In the current study we show and discuss the evolution of broad-band radio spectra, which are measured at ten frequencies between 2.64 and 142 GHz using the Effelsberg 100-m and the IRAM 30-m telescopes. It is shown that any of the 78 sources studied can be classified in terms of their variability characteristics in merely 5 types of variability. It is argued that these can be attributed to only two classes of variability mechanisms. The first four types are dominated by spectral evolution and can be described by a simple two-component system composed of: (a) a steep quiescent spectral component from a large scale jet and (b) a time evolving flare component following the \"Shock-in-Jet\" evolutionary path. The fifth type is characterised by an achromatic change of the broad band spectrum, which could be attributed to a different mechanism, likely involving differential Doppler boosting caused by geometrical effects. Here we present the classification, the assumed physical scenario and the results of calculations that have been performed for the spectral evolution of flares.

Although successful needle-free DNA vaccination has been described on several occasions, the true benefit of this delivery technology over needle-based injections for DNA vaccination of dogs has not yet been documented. We conducted a side-by-side comparison of needle-free transdermal plasmid delivery vs. intramuscular vs. intradermal needle-based delivery of the same plasmid in dogs. Our data confirmed the importance of the route of plasmid delivery and further established the unique potential of needle-free transdermal plasmid delivery to elicit strong antigen-specific, hTyr-specific IFNγ T in the dog. Further, this study demonstrated that properly enabled DNA vaccination has the potential to trigger very significant cell-based immune responses in dogs, establishing needle-free transdermal plasmid delivery as a critical technology for successful immunotherapy of cancer and/or chronic infectious diseases in companion animal medicine.

Perceived stress is prevalent in industrial societies, negatively impacting mental health. Smartphone-based stress management interventions provide accessible alternatives to traditional methods, but their efficacy remains modest, potentially due to limited integration of smartphone sensor technology. The primary aim of this study was to evaluate the efficacy of an 18-day smartphone-based stress management intervention, MT-StressLess with integrated heart rate (HR)-based biofeedback using built-in accelerometer sensors, compared to a waitlist control (WLC) condition. Secondary outcomes included emotion regulation skills, depressive symptoms, overall well-being, usbiality and usage data. As exploratory aims, we investigated whether the MT-StressLess version without HR-based biofeedback was also superior to the WLC condition, and whether the version with HR-based biofeedback provided additional benefits compared to the version without. In a three-arm randomized controlled trial, 166 participants were assigned to MT-StressLess with HR-based biofeedback, MT-StressLess , or the WLC condition. Linear mixed-effects models were used to analyze intervention effects over time (baseline, postintervention, and 1-month follow-up). At postintervention, MT-StressLess with HR-based biofeedback showed significantly greater reductions in perceived stress compared to the WLC condition ( d  = 0.41, 95% CI [0.03, 0.79]), whereas the version without biofeedback did not differ significantly ( d  = 0.14, 95% CI [−0.24, 0.51]). No significant differences were observed between the two active conditions ( d  = 0.29, 95% CI [−0.08, 0.66]). Both active conditions, however, led to significant improvements in the secondary outcomes of emotion regulation skills and well-being compared to the WLC (all ds  = −0.58 to −0.27). These patterns persisted at the 1-month follow-up. Usability ratings were high, but overall adherence was moderate. The findings in the main comparison may reflect increased interoceptive awareness and self-regulation. Yet, the limited effects of the core intervention and the biofeedback component also suggest the influence of non-specific factors, such as placebo effects, outcome expectancy and user engagement, which highlights the need to better understand optimal intervention duration, motivation, reinforcement, and more individualized approaches to stress reactivity. Overall, the findings provide preliminary support for the potential of a smartphone-based intervention that includes HR-based biofeedback to reduce perceived stress compared to no intervention. As these interventions are still in their early stages, future research should explore how personalization driven by artificial intelligence and real-time physiological tracking can enhance engagement and efficacy.