Ice sheet response to sub-shelf melt rates in coupled and uncoupled peri-Antarctic ice-sheet model simulations

Sub-shelf melting is the main driver of Antarctica's ice sheet mass loss. However, sub-shelf melt rate parameterizations for standalone ice models lack the capability to capture complex ocean circulation within ice shelf cavities. To overcome drawbacks of standalone models and to improve melt parameterizations, high resolution coupling of ice sheet and ocean models are capable of hindcasting past decennia and be compared to observations.Here, we present first results of a hindcast (1985-2018) of the new circumpolar coupled Southern Ocean – Antarctic ice sheet configuration, developed within the framework of the PARAMOUR project. The configuration is based on the ocean and sea ice model NEMO3.6-LIM3 and the ice sheet model f.ETISh v1.7. The coupling routine facilitates exchange of monthly sub-shelf melt rates (from ocean to ice model) and evolving ice shelf cavity geometry (from ice to ocean model).We investigate the impact of the coupling frequency (more precisely, the frequency of updating the ice shelf cavity geometry within the ocean model) on the sub-shelf melt rates and its feedback on the ice dynamics. We further compare the sub-shelf melt rates of the coupled setup to those of the standalone ice sheet model with different sub-shelf melt rate parametrizations (ISMIP6, plume, PICO, PICOP) and investigate the sensitivity of the response of the ice sheet for the different basal melt rate patterns on decadal time scales

Role of cancer stem cell markers ALDH1, BCL11B, BMI-1, and CD44 in the prognosis of advanced HNSCC

PURPOSE Cancer stem cells (CSCs) are held accountable for the progress of head and neck squamous cell carcinoma (HNSCC). In the presented study, the authors evaluated the prognostic value of CSC markers in two particular HNSCC cohorts. METHODS This two cohort study consisted of 85~patients with advanced stage HNSCC, treated with primary radio(chemo)therapy (pRCT), and 95~patients with HNSCC, treated with surgery and partially adjuvant radio(chemo)therapy. Overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) were assessed. Samples were assessed for the expression of different molecular stem cell markers (ALDH1, BCL11B, BMI\hbox-1, and CD44). RESULTS In the pRCT cohort, none of the baseline patient and tumor features exhibited a~statistically significant relation with survival in either the cohort or the human papillomavirus (HPV)-stratified subcohorts. High expression of BMI\hbox-1 significantly decreased OS and DFS, while high expression of CD44 decreased all modes of survival. Multivariate analysis showed significant prognostic influence for all tested CSC markers, with high BMI\hbox-1 and CD44 decreasing survival (BMI-1: OS, DFS, DSS; CD44: OS, DFS) and high ALDH1 and BCL11B showing a~beneficial effect on survival (ALDH1: OS, DFS; BCL11B: OS, DSS). In the surgical cohort, classical prognosticators such as HPV status, R1 resection, and nodal status in HPV-negative HNSCC played a~significant role, but the tested CSC markers showed no significant effect on prognosis. CONCLUSION Although validation in independent cohorts is still needed, testing for CSC markers in patients with advanced or late stage HNSCC might be beneficial, especially if many comorbidities exist or disease is irresectable. The findings might guide the development and earlier use of targeted therapies in the future

Die revidierte Version des »Screeninginstruments zur Vorhersage des Gewaltrisikos« (SVG-5): Darstellung relativer und absoluter Rückfallraten

Im Anschluss an eine frühere Studie (MschrKrim 2010, 346-360) wird die Fortentwicklung eines statistischen Prognoseinstrumentariums zur Einschätzung des Gewaltrisikos bei verurteilten Gewalttätern dargestellt. Die erweiterte Stichprobe besteht nun aus 307 männlichen und 2001 bis 2003 in Österreich entlassenen Gewalttätern, deren Rückfallrisiko mit einer revidierten Fassung (SVG-5 statt SVG-10, da nur noch fünf Items) eingestuft wird. Im fünfjährigen Beobachtungszeitraum wurde etwa jeder zweite Proband der beiden Hochrisikokategorien rückfällig. Die Reduktion auf die Items Deliktfrequenz, psychische Auffälligkeiten, Alter bei erstem Gewaltdelikt, jemals Tötungsdelikt, Anzahl früherer Gewaltdelikte führt zu einer Verbesserung der als sehr gut bewerteten Prognosegüte. Es wird darauf hingewiesen, dass der SVG-5 (wie auch schon das Vorgängermodell) kein Instrument zur Erfassung des individuellen Risikos ist

Real‐life effectiveness of biological therapies on symptoms in severe asthma with comorbid CRSwNP

Background We aimed to evaluate the effectiveness of different antibody therapies on nasal polyp symptoms in patients treated for severe asthma. Methods We performed a retrospective analysis of patients with severe asthma and comorbid CRSwNP who were treated with anti-IgE, anti-IL-5/R or anti-IL-4R. CRSwNP symptom burden was evaluated before and after 6 months of therapy. Results Fifty patients were included hereof treated with anti-IgE: 9, anti-IL-5/R: 26 and anti-IL-4R: 15 patients. At baseline median SNOT-20 was similar among groups (anti-IgE: 55, anti-IL-5/R: 52 and anti-IL-4R: 56, p = 0.76), median visual analogue scale (VAS) for nasal symptoms was 4, 7 and 8 (p = 0.14) and VAS for total symptoms was higher in the anti-IL-4R group (4, 5 and 8, p = 0.002). After 6 months SNOT-20 improved significantly in all patient groups with median improvement of anti-IgE: −8 (p < 0.01), anti-IL-5/R: −13 (p < 0.001) and anti-IL-4R: −18 (p < 0.001), with larger improvement in the anti-IL-4R group than in anti-IgE (p < 0.001) and anti-IL-5/R (p < 0.001) groups. VAS nasal symptoms improved by median anti-IgE: 0 (n.s.), anti-IL-5/R: −1 (p < 0.01) and anti-IL-4R: −3 (p < 0.001), VAS total symptoms by anti-IgE: −1 (n.s.), anti-IL-5/R: −2 (p < 0.001) and anti-IL-4R: −2 (p < 0.001). Conclusions Treatment by all antibodies showed effectiveness in reducing symptoms of CRSwNP in patients with severe asthma, with the largest reduction observed in anti-IL-4R-treated patients

Cancer stem cell markers in adenocarcinoma of the salivary glands - reliable prognostic markers?

PURPOSE Adenocarcinoma of the salivary glands is of low incidence and a broad range of histopathological subtypes. Cancer stem cell markers (CSC) might serve as novel prognostic parameters. To date, only a few studies examined the expression of CSC in adenocarcinoma of the salivary glands with diverging results. To further investigate the reliability in terms of prognostic value, a histopathological analysis of CSCs on a cohort of patients with adenocarcinomas of the major salivary glands was performed. METHODS Tumor samples of 40 consecutive patients with adenocarcinoma of the major salivary gland treated with curative intend at one tertiary center were stained with the CSCs ALDH1, BMI-1, CD44, Nanog, and SOX2. Expression of these markers was correlated with clinicopathological parameters and survival estimates. RESULTS Correlation of high expression of ALDH1 with higher grading (p < 0.001) and high expression of CD44 with the localization of the neoplasm (p = 0.05), larger tumor size (p = 0.006), positive pN-category (p = 0.023), and advanced UICC stage (p = 0.002) was found. Furthermore, high expression of SOX2 correlated with a negative perineural invasion (p = 0.02). No significant correlation of any investigated marker with survival estimates was observed. CONCLUSION In conclusion, our study did not find a significant correlation of the investigated CSCs with survival estimates in adenocarcinoma of the major salivary glands. Recapitulating the results of our study in conjunction with data in the literature, the CSCs ALDH1, BMI-1, CD44, Nanog, and SOX2 do not seem to serve as reliable prognostic parameters in the treatment of adenocarcinoma of the salivary glands

Systemic therapy of necrobiotic xanthogranuloma: a systematic review

Background Even though a plethora of systemic therapies have been proposed for necrobiotic xanthogranuloma (NXG), there is no systematic review on this topic in literature. Objective To review all existing literature on the systemic therapy of NXG in order to identify the most effective therapies. Methods All reported papers in the literature were screened for systemic treatments of NXG. Papers without proper description of the therapies, papers describing topical therapy, and articles without assessment of effectiveness were excluded. Subsequently, we analyzed 79 papers and a total of 175 cases. Results The most effective treatments for NXG are intravenous immunoglobulins (IVIG), corticosteroids, and combination therapies including corticosteroids. Conclusions Corticosteroids and IVIG should therefore be considered first-line treatments in patients with NXG

GPR4 in the pH ‐dependent migration of melanoma cells in the tumor microenvironment

Due to its high metastatic potential, malignant melanoma is one of the deadliest skin cancers. In melanoma as well as in other cancers, acidification of the tumor microenvironment (=TME, inverse pH-gradient) is a well-known driver of tumor progression and metastasis. Membrane-bound receptors, such as the proton-sensitive GPCR (pH-GPCR) GPR4, are considered as potential initiators of the signalling cascades relevant to malignant transformation. In this study, we investigated the pH-dependent migration of GPR4 wildtype/overexpressing SK-Mel-28 cells using an impedance-based electrical wounding and migration assay and classical Boyden chamber experiments. Migration of GPR4 overexpressing SK-Mel-28 cells was enhanced in a range of pH 6.5–7.5 as compared to controls in the impedance-based electrical wounding and migration assay. In Boyden chamber experiments, GPR4 overexpression only increased migration at pH 7.5 in a Matrigel-free setup, but not at pH 6.5. Results indicate that GPR4 is involved in the migration of melanoma cells, especially in the tumor periphery, and that this process is affected by pH in the TME

Speech Comprehension Difficulties in Chronic Tinnitus and Its Relation to Hyperacusis

Objective: Many tinnitus patients complain about difficulties regarding speech comprehension. In spite of the high clinical relevance little is known about underlying mechanisms and predisposing factors. Here, we performed an exploratory investigation in a large sample of tinnitus patients to (1) estimate the prevalence of speech comprehension difficulties among tinnitus patients, to (2) compare subjective reports of speech comprehension difficulties with behavioral measurements in a standardized speech comprehension test and to (3) explore underlying mechanisms by analyzing the relationship between speech comprehension difficulties and peripheral hearing function (pure tone audiogram), as well as with co-morbid hyperacusis as a central auditory processing disorder. Subjects and Methods: Speech comprehension was assessed in 361 tinnitus patients presenting between 07/2012 and 08/2014 at the Interdisciplinary Tinnitus Clinic at the University of Regensburg. The assessment included standard audiological assessments (pure tone audiometry, tinnitus pitch, and loudness matching), the Goettingen sentence test (in quiet) for speech audiometric evaluation, two questions about hyperacusis, and two questions about speech comprehension in quiet and noisy environments ("How would you rate your ability to understand speech?"; "How would you rate your ability to follow a conversation when multiple people are speaking simultaneously?"). Results: Subjectively-reported speech comprehension deficits are frequent among tinnitus patients, especially in noisy environments (cocktail party situation). 74.2% of all investigated patients showed disturbed speech comprehension (indicated by values above 21.5 dB SPL in the Goettingen sentence test). Subjective speech comprehension complaints (both for general and in noisy environment) were correlated with hearing level and with audiologically-assessed speech comprehension ability. In contrast, co-morbid hyperacusis was only correlated with speech comprehension difficulties in noisy environments, but not with speech comprehension difficulties in general. Conclusion: Speech comprehension deficits are frequent among tinnitus patients. Whereas speech comprehension deficits in quiet environments are primarily due to peripheral hearing loss, speech comprehension deficits in noisy environments are related to both peripheral hearing loss and dysfunctional central auditory processing. Disturbed speech comprehension in noisy environments might be modulated by a central inhibitory deficit. In addition, attentional and cognitive aspects may play a role

Expression of pH-Sensitive TRPC4 in Common Skin Tumors

TRPCs (transient receptor potential classical or cation channels) play a crucial role in tumor biology, especially in the Ca2+ homeostasis in cancer cells. TRPC4 is a pH-sensitive member of this family of proteins. As solid tumors exhibit an inversed pH-gradient with lowered extracellular and increased intracellular pH, both contributing to tumor progression, TRPC4 might be a signaling molecule in the altered tumor microenvironment. This is the first study to investigate the expression profiles of TRPC4 in common skin cancers such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM) and nevus cell nevi (NCN). We found that all SCCs, NCNs, and MMs show positive TRPC4-expression, while BCCs do only in about half of the analyzed samples. These data render TRPC4 an immunohistochemical marker to distinguish SCC and BCC, and this also gives rise to future studies investigating the role of TRPC4 in tumor progression, and especially metastasis as BCCs very rarely spread and are mostly negative for TRPC4

Isolation and characterization of head and neck cancer-derived peritumoral and cancer-associated fibroblasts

IntroductionHead and neck squamous cell carcinomas (HNSCC) are characterized by strong cellular and molecular heterogeneity and treatment resistance entailing poor survival. Besides cell-intrinsic properties, carcinoma cells receive important cues from non-malignant cells within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a major component of the TME that impact on the molecular make-up of malignant cells and have a decisive function in tumor progression. However, the potential functionality of fibroblasts within tumor-adjacent, macroscopically normal tissue remains poorly explored.MethodsHere, we isolated primary peritumoral fibroblasts (PtFs) from macroscopically normal tissue in vicinity of primary human papillomavirus-negative and -positive oropharyngeal HNSCC and compared their phenotype and functionality with matched CAFs (n = 5 pairs) and with human oral fibroblasts (hOFs).ResultsExpression patterns of CD90, CD73, CD105, smooth muscle actin, Vimentin, and S100A4 were comparable in PtFs, CAFs, and hOFs. Cell proliferation and doubling times of CAFs and PtFs were heterogeneous across patients (n =2 PtF&gt;CAF; n = 1 CAF&gt;PtF; n = 2 CAF=PtF) and reflected inferior growth than hOFs. Furthermore, PtFs displayed an reduced heterogeneity in cell size compared to matched CAFs, which were characterized by the presence of single large cells. Overall, conditioned supernatants from CAFs had more frequently growth-promoting effects on a panel of carcinoma cell lines of the upper aerodigestive tract carcinoma cell lines (Cal27, Cal33, FaDu, and Kyse30), whereas significant differences in migration-inducing effects demonstrated a higher potential of PtFs. Except for Kyse30, CAFs were significantly superior to hOFs in promoting proliferation, while PtFs induced stronger migration than hOFs in all carcinoma lines tested. Analysis of soluble factors demonstrated significantly increased VEGF-A production in CAFs (except in pat.8), and significantly increased PDGF-BB production in PtFs of two patients. Tube formation assays confirmed a significantly enhanced angiogenic potential of conditioned supernatants from CAFs compared to hOFs on human umbilical vascular endothelial cells (HUVECs) in vitro.DiscussionHence, matched CAFs and PtFs present in HNSCC patients are heterogeneous in their proliferation-, migration-, and angiogenesis-promoting capacity. Despite this heterogeneity, CAFs induced stronger carcinoma cell proliferation and HUVEC tube formation overall, whereas PtFs promoted migration of tumor cells more strongly