The lysine methyltransferase Smyd1 with its characteristic catalytic SET-domain is highly enriched in the embryonic heart and skeletal muscles, participating in cardiomyogenesis, sarcomere assembly and chromatin remodeling. Recently, significant Smyd1 levels were discovered in endothelial cells (ECs) that responded to inflammatory cytokines. Based on these biochemical properties, we hypothesized that Smyd1 is involved in inflammation-triggered signaling in ECs and therefore, investigated its role within the LPS-induced signaling cascade. Human endothelial cells (HUVECs and EA.hy926 cells) responded to LPS stimulation with higher intrinsic Smyd1 expression. By transfection with expression vectors containing gene inserts encoding either intact Smyd1, a catalytically inactive Smyd1-mutant or Smyd1-specific siRNAs, we show that Smyd1 contributes to LPS-triggered expression and secretion of IL-6 in EA.hy926 cells. Further molecular analysis revealed this process to be based on two signaling pathways: Smyd1 increased the activity of NF-kappa B and promoted the trimethylation of lysine-4 of histone-3 (H3K4me3) within the IL-6 promoter, as shown by ChIP-RT-qPCR combined with IL-6-promoter-driven luciferase reporter gene assays. In summary, our experimental analysis revealed that LPS-binding to ECs leads to the up-regulation of Smyd1 expression to transduce the signal for IL-6 up-regulation via activation of the established NF-κB pathway as well as via epigenetic trimethylation of H3K4.

Simple Summary: Although the survival rate has improved over the past decades, the prognosis of oral squamous cell carcinoma (OSCC) is still poor, and new treatment strategies are required. The aim of this study was to evaluate estrogen receptor alpha (ERa) expression in OSCC in a large patient cohort as a potential prognostic marker and therapeutic target. The findings indicated a rare expression of ERa that, however, was associated with a dramatic decrease of overall survival in male patients. In ERα-positive OSCC patients, an ER-based therapeutic (adjuvant) approach in the future might be conceivable based on the findings of this study.

Abstract: Introduction: Several studies suggest an estrogen receptor alpha (ERα)-mediated influence on the pathogenesis of oral squamous cell carcinoma (OSCC), as described for other malignancies that are not considered to be primarily hormone-dependent. Recently, an association between ERα expression and improved survival in oropharyngeal squamous cell carcinoma (OPSCC) has been found. However, the prognostic relevance of ERα in OSCC has not been proven to date. Therefore, the aim of this study was to evaluate ERα expression in OSCC in a large patient cohort and analyze its influence on survival and recurrence.

Material and methods: A total of 316 patients with primary OSCC who received initial surgical therapy were included in this analysis. The expression of ERα was evaluated on tissue microarrays by immunohistochemistry in the primary tumor and/or primary lymph node metastases. The expression level was quantified by light microscopy using the immunoreactive score (IRS) for estrogen receptor detection. An IRS equal to or greater than 2 was considered positive. The 5-year overall survival (OS) and relapse-free survival (RFS) were examined by the Kaplan-Meier method and log-rank test.

Results: A total of 316 patients (111 females; 205 males) with a mean age of 61.3 years (range 27-96 years) were included in this study. In 16 patients (5.1%; 6 females and 10 males), positive ERα expression was found in the primary tumor (n = 11; 11/302) or lymph node metastases (n = 5; 5/52). Patients with positive ERα expression in primary tumors/primary lymph node metastases had a significantly lower OS and RFS (p = 0.012; p = 0.0053) compared to ERα-negative patients. Sub-group analysis in relation to gender revealed a highly significant influence of ERα expression on OS and RFS in males but not in females, both for the ERα-positive primary tumor cohort (males: p = 0.0013; p < 0.0001; females: p = 0.56; p = 0.89) and the ERα-positive primary tumor/primary lymph node metastasis cohort (males: p < 0.0001; p < 0.0001; females: p = 0.95; p = 0.96). In multivariate cox regression analysis, the ERα IRS of primary tumors (dichotomized; ERα+ vs. ERα-) was an independent risk factor for OS (HR = 4.230; 95%CI 1.616-11.076; p = 0.003) and RFS (HR = 12.390; 95%CI 4.073-37.693; p < 0.001) in the male cohort. There was a significant difference (p = 0.006) of ERα positivity with regard to the localization of the primary tumor. ERα positivity in the primary tumor was significantly associated (p = 0.026) with UICC stage, with most of the cases being diagnosed in stage IV. Furthermore, there was a significantly (p = 0.049) higher rate of bone infiltration in ERα-positive patients.

Conclusion: Expression of ERα is rare in OSCC; however, it is associated with a dramatic decrease in OS in male patients. Further studies are necessary to confirm our results and to evaluate the exact mechanism underlying this observation. Hence, ERα-positive OSCC patients might benefit from an ER-based therapeutic (adjuvant) approach in the future.

Simple Summary: Solid tumor cells can lose or heterogeneously express antigens to become resistant to chimeric antigen receptor (CAR) T cell therapy. Here, we explore whether epigenetic manipulation to unleash antigen-independent killing mechanisms can overcome this hurdle. KDM1A is overexpressed in many cancers and removes lysine methylation on histones that keeps the DNA firmly packed to selectively activate or repress gene activity, depending on the specific lysine target. KDM1A also regulates the expression of nonhistone proteins. We inhibited KDM1A in the childhood tumor, neuroblastoma, to increase FAS expression on tumor cells. The FAS receptor can be triggered to induce cell death when bound by the FAS ligand on CAR and other activated T cells present in the tumor environment, even if the tumor cells lack the target antigen. FAS upregulation via KDM1A inhibition sensitized neuroblastoma cells to FAS-FASL-mediated killing and augmented CAR T cell therapy against antigen-poor or even antigen-negative neuroblastoma.

Abstract: Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising treatment strategy, however, therapeutic success against solid tumors such as neuroblastoma remains modest. Recurrence of antigen-poor tumor variants often ultimately results in treatment failure. Using antigen-independent killing mechanisms such as the FAS receptor (FAS)-FAS ligand (FASL) axis through epigenetic manipulation may be a way to counteract the escape achieved by antigen downregulation. Analysis of public RNA-sequencing data from primary neuroblastomas revealed that a particular epigenetic modifier, the histone lysine demethylase 1A (KDM1A), correlated negatively with FAS expression. KDM1A is known to interact with TP53 to repress TP53-mediated transcriptional activation of genes, including FAS. We showed that pharmacologically blocking KDM1A activity in neuroblastoma cells with the small molecule inhibitor, SP-2509, increased FAS cell-surface expression in a strictly TP53-dependent manner. FAS upregulation sensitized neuroblastoma cells to FAS-FASL-dependent killing and augmented L1CAM-directed CAR T cell therapy against antigen-poor or even antigen-negative tumor cells in vitro. The improved therapeutic response was abrogated when the FAS-FASL interaction was abolished with an antagonistic FAS antibody. Our results show that KDM1A inhibition unleashes an antigen-independent killing mechanism via the FAS-FASL axis to make tumor cell variants that partially or totally suppress antigen expression susceptible to CAR T cell therapy.

Background: The tumor microenvironment (TME) mainly comprises tumor cells and tumor-infiltrating immune cells mixed with stromal components. Latestresearch hasdisplayed that tumor immune cell infiltration (ICI) is associated with the clinical outcome of patients with osteosarcoma (OS). This work aimed to build a gene signature according to ICI in OS for predicting patient outcomes.

Methods: The TARGET-OS dataset was used for model training, while the GSE21257 dataset was taken forvalidation. Unsupervised clustering was performed on the training cohort based on the ICI profiles. The Kaplan-Meier estimator and univariate Cox proportional hazards models were used to identify the differentially expressed genes between clusters to preliminarily screen for potential prognostic genes. We incorporated these potential prognostic genes into a LASSO regression analysis and produced a gene signature, which was next assessed with the Kaplan-Meier estimator, Cox proportional hazards models, ROC curves, IAUC, and IBS in the training and validation cohorts. In addition, we compared our signature to previous models. GSEAswere deployed to further study the functional mechanism of the signature. We conducted an analysis of 22 TICsfor identifying the role of TICs in the gene signature's prognosis ability.

Results: Data from the training cohort were used to generate a nine-gene signature. The Kaplan-Meier estimator, Cox proportional hazards models, ROC curves, IAUC, and IBS validated the signature's capacity and independence in predicting the outcomes of OS patients in the validation cohort. A comparison with previous studies confirmed the superiority of our signature regarding its prognostic ability. Annotation analysis revealed the mechanism related to the gene signature specifically. The immune-infiltration analysis uncoveredkey roles for activated mast cells in the prognosis of OS.

Conclusion: We identified a robust nine-gene signature (ZFP90, UHRF2, SELPLG, PLD3, PLCB4, IFNGR1, DLEU2, ATP6V1E1, and ANXA5) that can predict OS outcome precisely and is strongly linked to activated mast cells.

Salomon Neumann (1819-1908) is one of the outstanding representatives of 19th century social medicine. As a medical reformer, statistician and city councilor, he made a significant contribution to improving social and hygienic conditions in Berlin. His most famous work was published in 1847 under the title "Die oeffentliche Gesundheitspflege und das Eigenthum" [Public Health and Property]. From 1859 to 1905, Neumann was active in the Berlin City Council for the improvement of the living conditions of the population. He was involved in the construction of municipal hospitals, supported the modernisation of sewage disposal, organised the Berlin censuses of 1861 and 1864 and was active in the field of health and social statistics. Not only was Neumann exposed to anti-Semitic reprisals during his lifetime, a foundation he founded to promote the science of Judaism was dissolved by the National Socialists in 1940. On the occasion of his 200th birthday, this article commemorates the life and work of the democratically minded and socially committed doctor and health politician. Salomon Neumann has rendered great services to social medicine in Germany.

An investigation of pulsed-laser-ablated Zn, Cd and Hg metal atom reactions with HCN under excess argon during co-deposition with laser-ablated Hg atoms from a dental amalgam target also provided Hg emissions capable of photoionization of the CN photo-dissociation product. A new band at 1933.4 cm−1 in the region of the CN and CN+ gas-phase fundamental absorptions that appeared upon annealing the matrix to 20 K after sample deposition, and disappeared upon UV photolysis is assigned to (Ar)nCN+, our key finding. It is not possible to determine the n coefficient exactly, but structure calculations suggest that one, two, three or four argon atoms can solvate the CN+ cation in an argon matrix with C−N absorptions calculated (B3LYP) to be between 2317.2 and 2319.8 cm−1. Similar bands were observed in solid krypton at 1920.5, in solid xenon at 1935.4 and in solid neon at 1947.8 cm−1. H13CN reagent gave an 1892.3 absorption with shift instead, and a 12/13 isotopic frequency ratio–nearly the same as found for 13CN+ itself in the gas phase and in the argon matrix. The CN+ molecular ion serves as a useful infrared probe to examine Ng clusters. The following ion reactions are believed to occur here: the first step upon sample deposition is assisted by a focused pulsed YAG laser, and the second step occurs on sample annealing: (Ar)2++CN→Ar+CN+→(Ar)nCN+.

We explore the effects of Libya's administrative division into Tripolitania, Cyrenaica, and Fezzan on the onset of the Libyan conflict. We argue that Tripolitania and Cyrenaica, in particular, followed two different and distinct paths of political development and socioeconomic transformation. While Tripolitania and its elites are connected to the core of Libyan statehood and the legacies of Italian colonization, Cyrenaica is defined by localized political autonomy and economic autarky with respect to natural resources. Furthermore, the Qadhafi regime marginalized Cyrenaica politically, despite its major significance for the Libyan economy, because of its strong royalist inclinations. By offering an overview of Libya's political evolution and socioeconomic development, we indicate that the current conflict has largely been due to the asymmetric and artificial dominance of Tripolitania over the other two regions, particularly Cyrenaica.

Background: Subarachnoid hemorrhage (SAH) caused by rupture of an intracranial aneurysm, is a life-threatening emergency that is associated with substantial morbidity and mortality. Emerging evidence suggests involvement of the innate immune response in secondary brain injury, and a potential role of neutrophil extracellular traps (NETs) for SAH-associated neuroinflammation. In this study, we investigated the spatiotemporal patterns of NETs in SAH and the potential role of the RNase A (the bovine equivalent to human RNase 1) application on NET burden.

Methods: A total number of n=81 male C57Bl/6 mice were operated utilizing a filament perforation model to induce SAH, and Sham operation was performed for the corresponding control groups. To confirm the bleeding and exclude stroke and intracerebral hemorrhage, the animals received MRI after 24h. Mice were treated with intravenous injection of RNase A (42 mu g/kg body weight) or saline solution for the control groups, respectively. Quadruple-immunofluorescence (IF) staining for cell nuclei (DAPI), F-actin (phalloidin), citrullinated H3, and neurons (NeuN) was analyzed by confocal imaging and used to quantify NET abundance in the subarachnoid space (SAS) and brain parenchyma. To quantify NETs in human SAH patients, cerebrospinal spinal fluid (CSF) and blood samples from day 1, 2, 7, and 14 after bleeding onset were analyzed for double-stranded DNA (dsDNA) via Sytox Green.

Results: Neutrophil extracellular traps are released upon subarachnoid hemorrhage in the SAS on the ipsilateral bleeding site 24h after ictus. Over time, NETs showed progressive increase in the parenchyma on both ipsi- and contralateral site, peaking on day 14 in periventricular localization. In CSF and blood samples of patients with aneurysmal SAH, NETs also increased gradually over time with a peak on day 7. RNase application significantly reduced NET accumulation in basal, cortical, and periventricular areas.

Conclusion: Neutrophil extracellular trap formation following SAH originates in the ipsilateral SAS of the bleeding site and spreads gradually over time to basal, cortical, and periventricular areas in the parenchyma within 14days. Intravenous RNase application abrogates NET burden significantly in the brain parenchyma, underpinning a potential role in modulation of the innate immune activation after SAH.

Cardiovascular pathology is often accompanied by changes in relative content and/or ratios of structural extracellular matrix (ECM) proteins within the heart and elastic vessels. Three of these proteins, collagen-I, collagen-III, and elastin, make up the bulk of the ECM proteins in these tissues, forming a microenvironment that strongly dictates the tissue biomechanical properties and effectiveness of cardiac and vascular function. In this review, we aim to elucidate how the ratios of collagen-I to collagen-III and elastin to collagen are altered in cardiovascular diseases and the aged individuum. We elaborate on these major cardiovascular ECM proteins in terms of structure, tissue localization, turnover, and physiological function and address how their ratios change in aging, dilated cardiomyopathy, coronary artery disease with myocardial infarction, atrial fibrillation, aortic aneurysms, atherosclerosis, and hypertension. To the end of guiding in vitro modeling approaches, we focus our review on the human heart and aorta, discuss limitations in ECM protein quantification methodology, examine comparability between studies, and highlight potential in vitro applications. In summary, we found collagen-I relative concentration to increase or stay the same in cardiovascular disease, resulting in a tendency for increased collagen-I/collagen-III and decreased elastin/collagen ratios. These ratios were found to fall on a continuous scale with ranges defining distinct pathological states as well as a significant difference between the human heart and aortic ECM protein ratios.

This Perspective examines a recent surge of information regarding the potential benefits of acid-suppression drugs in the context of COVID-19, with a particular eye on the great variability (and, thus, confusion) that has arisen across the reported findings, at least as regards the popular antacid famotidine. The degree of inconsistency and discordance reflects contradictory conclusions from independent, clinical-based studies that took roughly similar approaches, in terms of both experimental design (retrospective, observational, cohort-based, etc.) and statistical analysis workflows (propensity-score matching and stratification into sub-cohorts, etc.). The contradictions and potential confusion have ramifications for clinicians faced with choosing therapeutically optimal courses of intervention: e.g., do any potential benefits of famotidine suggest its use in a particular COVID-19 case? (If so, what administration route, dosage regimen, duration, etc. are likely optimal?) As succinctly put this March in Freedberg et al. (2021), "…several retrospective studies show relationships between famotidine and outcomes in COVID-19 and several do not." Beyond the pressing issue of possible therapeutic indications, the conflicting data and conclusions related to famotidine must be resolved before its inclusion/integration in ontological and knowledge graph (KG)-based frameworks, which in turn are useful for drug discovery and repurposing. As a broader methodological issue, note that reconciling inconsistencies would bolster the validity of meta-analyses which draw upon the relevant data-sources. And, perhaps most broadly, developing a system for treating inconsistencies would stand to improve the qualities of both 1) real world evidence-based studies (retrospective), on the one hand, and 2) placebo-controlled, randomized multi-center clinical trials (prospective), on the other hand. In other words, a systematic approach to reconciling the two types of studies would inherently improve the quality and utility of each type of study individually.

Purpose: Subsurface blood vessels in the cerebral cortex have been identified as a bottleneck in cerebral perfusion with the potential for collateral remodeling. However, valid techniques for non-invasive, longitudinal characterization of neocortical microvessels are still lacking. In this study, we validated contrast-enhanced magnetic resonance imaging (CE-MRI) for in vivo characterization of vascular changes in a model of spontaneous collateral outgrowth following chronic cerebral hypoperfusion.

Methods: C57BL/6J mice were randomly assigned to unilateral internal carotid artery occlusion or sham surgery and after 21 days, CE-MRI based on T2*-weighted imaging was performed using ultra-small superparamagnetic iron oxide nanoparticles to obtain subtraction angiographies and steady-state cerebral blood volume (ss-CBV) maps. First pass dynamic susceptibility contrast MRI (DSC-MRI) was performed for internal validation of ss-CBV. Further validation at the histological level was provided by ex vivo serial two-photon tomography (STP).

Results: Qualitatively, an increase in vessel density was observed on CE-MRI subtraction angiographies following occlusion; however, a quantitative vessel tracing analysis was prone to errors in our model. Measurements of ss-CBV reliably identified an increase in cortical vasculature, validated by DSC-MRI and STP.

Conclusion: Iron oxide nanoparticle-based ss-CBV serves as a robust, non-invasive imaging surrogate marker for neocortical vessels, with the potential to reduce and refine preclinical models targeting the development and outgrowth of cerebral collateralization.

Background: Hemispherotomy is an epilepsy surgery procedure applied to cure particularly pharmacorefractory lesional epilepsy due to unihemispheric pathologies. Such a disconnection of an entire hemisphere is followed by reorganizational processes.

Methods: We describe an acute aggravation of behavioral problems following a hemispherotomy in a patient treated with valproic acid, which subsided once valproate was discontinued.

Results: A 9-year-old boy with drug-resistant epilepsy caused by the residua of a perinatal stroke treated for several years with valproic acid and lamotrigine underwent hemispherotomy. Shortly after surgery, minimal preoperative behavioral problems intensified dramatically, and aggression occurred as a new symptom. Assuming a correlation between valproate treatment and the postoperative altered neuronal network, we tapered off valproate. The behavioral problems decreased in intensity with the reduction of valproate dose and disappeared after drug discontinuation.

Conclusion: We describe severe behavioral problems after hemispherotomy that subsided when valproate was tapered off. While we cannot rule out a spontaneous correction of a post-hemispherotomy network dysregulation, our report raises awareness to possible altered effects of the anticonvulsant valproic acid parallel to reorganizational processes after hemispherotomy.

Health-related quality of life (HRQoL) is an essential complementary parameter in the assessment of disease burden and treatment outcome in multiple sclerosis (MS) and can be affected by neuropsychiatric symptoms, which in turn are sensitive to psychological stress. However, until now, the impact of neurobiological stress and relaxation on HRQoL in MS has not been investigated. We thus evaluated whether the activity of neural networks triggered by mild psychological stress (elicited in an fMRI task comprising mental arithmetic with feedback) or by stress termination (i.e., relaxation) at baseline (T0) predicts HRQoL variations occurring between T0 and a follow-up visit (T1) in 28 patients using a robust regression and permutation testing. The median delay between T0 and T1 was 902 (range: 363-1,169) days. We assessed HRQoL based on the Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and accounted for the impact of established HRQoL predictors and the cognitive performance of the participants. Relaxation-triggered activity of a widespread neural network predicted future variations in overall HRQoL (t = 3.68, p(family-wise error [FWE])-corrected = 0.008). Complementary analyses showed that relaxation-triggered activity of the same network at baseline was associated with variations in the HAQUAMS mood subscale on an alpha(FWE) = 0.1 level (t = 3.37, p(FWE) = 0.087). Finally, stress-induced activity of a prefronto-limbic network predicted future variations in the HAQUAMS lower limb mobility subscale (t = -3.62, p(FWE) = 0.020). Functional neural network measures of psychological stress and relaxation contain prognostic information for future HRQoL evolution in MS independent of clinical predictors.

Objective: Extracellular vesicles (EV) are sub-1 μm bilayer lipid coated particles and have been shown play a role in long-term cardiovascular outcome after ischemic stroke. However, the dynamic change of EV after stroke and their implications for functional outcome have not yet been elucidated.

Methods: Serial blood samples from 110 subacute ischemic stroke patients enrolled in the prospective BAPTISe study were analyzed. All patients participated in the PHYS-STROKE trial and received 4-week aerobic training or relaxation sessions. Levels of endothelial-derived (EnV: Annexin V+, CD45-, CD41-, CD31+/CD144+/CD146+), leukocyte-derived (LV: Annexin V+, CD45+, CD41-), monocytic-derived (MoV: Annexin V+, CD41-, CD14+), neuronal-derived (NV: Annexin V+, CD41-, CD45-, CD31-, CD144-, CD146-, CD56+/CD171+/CD271+), and platelet-derived (PV: Annexin V+, CD41+) EV were assessed via fluorescence-activated cell sorting before and after the trial intervention. The levels of EV at baseline were dichotomized at the 75th percentile, with the EV levels at baseline above the 75th percentile classified as "high" otherwise as "low." The dynamic of EV was classified based on the difference between baseline and post intervention, defining increases above the 75th percentile as "high increase" otherwise as "low increase." Associations of baseline levels and change in EV concentrations with Barthel Index (BI) and cardiovascular events in the first 6 months post-stroke were analyzed using mixed model regression analyses and cox regression.

Results: Both before and after intervention PV formed the largest population of vesicles followed by NV and EnV. In mixed-model regression analyses, low NV [-8.57 (95% CI -15.53 to -1.57)] and low PV [-6.97 (95% CI -13.92 to -0.01)] at baseline were associated with lower BI in the first 6 months post-stroke. Patients with low increase in NV [8.69 (95% CI 2.08-15.34)] and LV [6.82 (95% CI 0.25-13.4)] were associated with reduced BI in the first 6 months post-stroke. Neither baseline vesicles nor their dynamic were associated with recurrent cardiovascular events.

Conclusion: This is the first report analyzing the concentration and the dynamic of EV regarding associations with functional outcome in patients with subacute stroke. Lower levels of PV and NV at baseline were associated with a worse functional outcome in the first 6 months post-stroke. Furthermore, an increase in NV and LV over time was associated with worse BI in the first 6 months post-stroke. Further investigation of the relationship between EV and their dynamic with functional outcome post-stroke are warranted.

Among trans adolescents, increased psychological distress is reported in the literature. The goal of this study was to examine psychological distress, associated peer relations and parent report congruence among the treatment-seeking sample of the Gender Identity Special Consultation (GISC) for youth at the Charite Berlin. Further, differences between the instruments' binary gender norms were investigated. Retrospectively, we analyzed clinical data derived from the GISC. By initial interviews and using the Youth Self-Report and Child Behavior Checklist, n = 50 trans adolescents aged 12-18 years (M = 15.5) were examined for psychological problems and peer relations. Congruence between self and parent report was analyzed by correlations. Half of the sample reported suicidality, self-harm and bullying. Trans adolescents showed significantly higher internalizing and total problems than the German norm population. The congruence between self and parent report proved to be moderate to high. The level of congruence and poor peer relations were identified as predictors of internalizing problems. Significant differences between the female vs. male gender norms emerged regarding mean scores and the number of clinically significant cases. Data provide valuable implications for intervention on a peer and family level. There are limitations to the suitability of questionnaires that use binary gender norms, and further research on adequate instruments and assessment is needed.

Simple Summary: The prediction of pancreatic neuroendocrine tumor (PNET) aggressiveness is important for treatment planning. The aim of this study was to evaluate the diagnostic performance of magnetic resonance elastography (MRE) with tomoelastography postprocessing (tomoelastography) in differentiating PNET from healthy pancreatic tissue and to correlate PNET stiffness with aggressiveness using asphericity derived from positron emission tomography (PET) as reference. In this prospective study we showed in a group of 13 patients with PNET that tomoelastography detected PNET by increased stiffness (p < 0.01) with a high diagnostic performance (AUC = 0.96). PNET was positively correlated with PET derived asphericity (r = 0.81). Tomoelastography provides quantitative imaging markers for the detection of PNET and the prediction of greater tumor aggressiveness by increased stiffness.

Abstract: Purpose: To evaluate the diagnostic performance of tomoelastography in differentiating pancreatic neuroendocrine tumors (PNETs) from healthy pancreatic tissue and to assess the prediction of tumor aggressiveness by correlating PNET stiffness with PET derived asphericity. Methods: 13 patients with PNET were prospectively compared to 13 age-/sex-matched heathy volunteers (CTR). Multifrequency MR elastography was combined with tomoelastography-postprocessing to provide high-resolution maps of shear wave speed (SWS in m/s). SWS of pancreatic neuroendocrine tumor (PNET-T) were compared with nontumorous pancreatic tissue in patients with PNET (PNET-NT) and heathy pancreatic tissue (CTR). The diagnostic performance of tomoelastography was evaluated by ROC-AUC analysis. PNET-SWS correlations were calculated with Pearson’s r. Results: SWS was higher in PNET-T (2.02 ± 0.61 m/s) compared to PNET-NT (1.31 ± 0.18 m/s, p < 0.01) and CTR (1.26 ± 0.09 m/s, p < 0.01). An SWS-cutoff of 1.46 m/s distinguished PNET-T from PNET-NT (AUC = 0.89; sensitivity = 0.85; specificity = 0.92) and a cutoff of 1.49 m/s differentiated pancreatic tissue of CTR from PNET-T (AUC = 0.96; sensitivity = 0.92; specificity = 1.00). The SWS of PNET-T was positively correlated with PET derived asphericity (r = 0.81; p = 0.01). Conclusions: Tomoelastography provides quantitative imaging markers for the detection of PNET and the prediction of greater tumor aggressiveness by increased stiffness.

We evaluated a simple semi-quantitative (SSQ) method for determining pulmonary involvement in computed tomography (CT) scans of COVID-19 patients. The extent of lung involvement in the first available CT was assessed with the SSQ method and subjectively. We identified risk factors for the need of invasive ventilation, intensive care unit (ICU) admission and for time to death after infection. Additionally, the diagnostic performance of both methods was evaluated. With the SSQ method, a 10% increase in the affected lung area was found to significantly increase the risk for need of ICU treatment with an odds ratio (OR) of 1.68 and for invasive ventilation with an OR of 1.35. Male sex, age, and pre-existing chronic lung disease were also associated with higher risks. A larger affected lung area was associated with a higher instantaneous risk of dying (hazard ratio (HR) of 1.11) independently of other risk factors. SSQ measurement was slightly superior to the subjective approach with an AUC of 73.5% for need of ICU treatment and 72.7% for invasive ventilation. SSQ assessment of the affected lung in the first available CT scans of COVID-19 patients may support early identification of those with higher risks for need of ICU treatment, invasive ventilation, or death.

Traumatic spinal cord injury (TSCI), commonly caused by high energy trauma in young active patients, is frequently accompanied by traumatic brain injury (TBI). Although combined trauma results in inferior clinical outcomes and a higher mortality rate, the understanding of the pathophysiological interaction of co-occurring TSCI and TBI remains limited. This review provides a detailed overview of the local and systemic alterations due to TSCI and TBI, which severely affect the autonomic and sensory nervous system, immune response, the blood-brain and spinal cord barrier, local perfusion, endocrine homeostasis, posttraumatic metabolism, and circadian rhythm. Because currently developed mesenchymal stem cell (MSC)-based therapeutic strategies for TSCI provide only mild benefit, this review raises awareness of the impact of TSCI-TBI interaction on TSCI pathophysiology and MSC treatment. Therefore, we propose that unravelling the underlying pathophysiology of TSCI with concomitant TBI will reveal promising pharmacological targets and therapeutic strategies for regenerative therapies, further improving MSC therapy.

Simple Summary: Neuroendocrine tumors of the gastrointestinal tract (GEP-NEN) are a rare type of tumor with considerable variability in the course of disease, which makes clinical management particularly challenging. Biomarkers that are able to guide personalized treatment decisions would be of importance, but are not yet available. In this study, we demonstrate that tissue expression, as well as circulating levels of the cytokine Flt3L in advanced and aggressive tumors, predict survival and time to progression. Increased tumoral Flt3L was also associated with upregulation of genes related to immune activation, suggesting Flt3L as a surrogate marker of host anti-tumor immunity. Therefore, Flt3L measurements in serum may hold promise as a biomarker of disease outcome that could support personalized treatment decisions in GEP-NEN patients, potentially guiding researchers towards viable immunotherapies.

Background: The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features. Methods: We evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN. Results: We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients' progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue. Conclusions: We propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions.