HLA-DR15-derived self-peptides are involved in increased autologous T cell proliferation in multiple sclerosis

The HLA-DR15 haplotype confers the largest part of the genetic risk to develop multiple sclerosis, a prototypic CD4+ T cell-mediated autoimmune disease. The mechanisms how certain HLA-class II molecules functionally contribute to autoimmune diseases are still poorly understood, but probably involve shaping an autoimmune-prone T cell repertoire during central tolerance in the thymus and subsequently maintaining or even expanding it in the peripheral immune system. Self-peptides that are presented by disease-associated HLA-class II molecules most likely play important roles during both processes. Here, we examined the functional involvement of the HLA-DR15 haplotype in autologous proliferation in multiple sclerosis and the contribution of HLA-DR15 haplotype-derived self-peptides in an in vitro system. We observe increased autologous T cell proliferation in patients with multiple sclerosis in relation to the multiple sclerosis risk-associated HLA-DR15 haplotype. Assuming that the spectrum of self-peptides that is presented by the two HLA-DR15 allelic products is important for sustaining autologous proliferation we performed peptide elution and identification experiments from the multiple sclerosis-associated DR15 molecules and a systematic analysis of a DR15 haplotype-derived self-peptide library. We identify HLA-derived self-peptides as potential mediators of altered autologous proliferation. Our data provide novel insights about perturbed T cell repertoire dynamics and the functional involvement of the major genetic risk factor, the HLA-DR15 haplotype, in multiple sclerosi

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.info:eu-repo/semantics/publishedVersio

DIMEimmune: Robust estimation of infiltrating lymphocytes in CNS tumors from DNA methylation profiles

The interaction of CNS tumors with infiltrating lymphocytes plays an important role in their initiation and progression and might be related to therapeutic responses. Gene expression-based methods have been successfully used to characterize the tumor microenvironment. However, methylation data are now increasingly used for molecular diagnostics and there are currently only few methods to infer information about the microenvironment from this data type. Using an approach based on differential methylation and principal component analysis, we developed DIMEimmune (Differential Methylation Analysis for Immune Cell Estimation) to estimate CD4+ and CD8+ T cell abundance as well as tumor-infiltrating lymphocytes (TILs) scores from bulk methylation data. Well-established approaches based on gene expression data and immunohistochemistry-based lymphocyte counts were used as benchmarks. The comparison of DIMEimmune to the previously published MethylCIBERSORT and MeTIL algorithms showed an improved correlation with both gene expression-based and immunohistological results across different brain tumor types. Further, we applied our method to large datasets of glioma, medulloblastoma, atypical teratoid/rhabdoid tumors (ATRTs) and ependymoma. High-grade gliomas showed higher scores of tumor-infiltrating lymphocytes than lower-grade gliomas. There were overall only few tumor-infiltrating lymphocytes in medulloblastoma subgroups. ATRTs were highly infiltrated by lymphocytes, most prominently in the MYC subgroup. DIMEimmune-based estimates of TILs were a significant prognostic factor in the overall cohort of gliomas and medulloblastomas, but not within methylation-based diagnostic subgroups. To conclude, DIMEimmune allows for robust estimates of TIL abundance and might contribute to establishing them as a prognostic or predictive factor in future studies of CNS tumors

Initial clinical status and spot sign are associated with intraoperative aneurysm rupture in patients undergoing surgical clipping for aneurysmal subarachnoid hemorrhage

Objective To assess clinical and radiographic risk factors for intraoperative aneurysm rupture (ioAR) during surgical clipping after aneurysmal subarachnoid hemorrhage (aSAH) and to analyze its influence on patient outcome. Methods Patient selection was based on a retrospective analysis of our prospective subarachnoid hemorrhage patient database including consecutive patients between January 2008 and August 2012 with aSAH undergoing microsurgical clipping. Demographic data, cardiovascular risk factors, preoperative radiologic aneurysm characteristics, as well as timing of surgery and preoperative severity grades (Hunt and Hess [HH], Fisher, World Federation of Neurological Societies [WFNS]), were collected from hospital charts and surgery videos and compared between patients with and without ioAR. Results Of 100 patients (38 men, 62 women) with a median age of 57.4 years (range: 23-85 years), ioAR occurred in 34 cases (34%). Univariate analyses showed that severity grades were significantly higher in the ioAR group (Fisher p = 0.012; HH p = 0.002; WFNS p = 0.023). IoAR was significantly associated with intracerebral hemorrhage (ICH) (23% versus 47%; p = 0.013) and the spot sign as an indicator of active bleeding within the ICH (0% vs 44%; p = 0.007). Multivariate analysis showed that HH was the only significant predictor of ioAR (p = 0.03; odds ratio: 2.3; 95% confidence interval, 1.1-5.0). With a mean follow-up of 17.6 months ( ± 16.6), Glasgow Outcome Scale score, mortality rate (12% versus 15%; p = 0.82), delayed cerebral ischemia (36% versus 38%; p = 0.51), and shunt dependency (32% versus 44%; p = 0.23) were comparable between the non-ioAR and ioAR group. Conclusions Initial clinical status and spot sign were associated with ioAR during microsurgical clipping of ruptured aneurysms. However, there was no difference regarding clinical outcome and complications of the two groups

Impact of the surgical strategy on the incidence of C5 nerve root palsy in decompressive cervical surgery - Fig 2

<p>Sagittal schematic of the surgical spine to illustrate C5 palsy rate of two level hybrid constructs, i.e. combination of corpectomy and ACDF, for the levels C4-7 (A) and C3-6 (B). Statistical values are summarized in C, including overall C5 incidence rate for hybrid constructs on all levels around the vulnerable level of C4/C5. Additional information on other possible surgical constructs around the level of C4/C5 is presented in D, allowing for the direct comparison of C5 palsy rate of the different surgical strategies. Statistical analysis applied routine cross tables and chi² testing.</p

Influence of microbiological diagnosis on the clinical course of spondylodiscitis

Purpose!#!This study sought to recognize differences in clinical disease manifestations of spondylodiscitis depending on the causative bacterial species.!##!Methods!#!We performed an evaluation of all spondylodiscitis cases in our clinic from 2013-2018. 211 patients were included, in whom a causative bacterial pathogen was identified in 80.6% (170/211). We collected the following data; disease complications, comorbidities, laboratory parameters, abscess occurrence, localization of the infection (cervical, thoracic, lumbar, disseminated), length of hospital stay and 30-day mortality rates depending on the causative bacterial species. Differences between bacterial detection in blood culture and intraoperative samples were also recorded.!##!Results!#!The detection rate of bacterial pathogens through intraoperative sampling was 66.3% and could be increased by the results of the blood cultures to a total of 80.6% (n = 170/211). S. aureus was the most frequently detected pathogen in blood culture and intraoperative specimens and and was isolated in a higher percentage cervically than in other locations of the spine. Bacteremic S. aureus infections were associated with an increased mortality (31.4% vs. overall mortality of 13.7%, p = 0.001), more frequently developing complications, such as shock, pneumonia, and myocardial infarction. Comorbidities, abscesses, length of stay, sex, and laboratory parameters all showed no differences depending on the bacterial species.!##!Conclusion!#!Blood culture significantly improved the diagnostic yield, thus underscoring the need for a structured diagnostic approach. MSSA spondylodiscitis was associated with increased mortality and a higher incidence of complications

Carbon fiber–reinforced PEEK versus titanium implants: an in vitro comparison of susceptibility artifacts in CT and MR imaging

Artifacts in computed tomography (CT) and magnetic resonance imaging (MRI) due to titanium implants in spine surgery are known to cause difficulties in follow-up imaging, radiation planning, and precise dose delivery in patients with spinal tumors. Carbon fiber-reinforced polyetheretherketon (CFRP) implants aim to reduce these artifacts. Our aim was to analyze susceptibility artifacts of these implants using a standardized in vitro model. Titanium and CFRP screw-rod phantoms were embedded in 3% agarose gel. Phantoms were scanned with Siemens Somatom AS Open and 3.0-T Siemens Skyra scanners. Regions of interest (ROIs) were plotted and analyzed for CT and MRI at clinically relevant localizations. CT voxel-based imaging analysis showed a significant difference of artifact intensity and central overlay between titanium and CFRP phantoms. For the virtual regions of the spinal canal, titanium implants (ti) presented - 30.7 HU vs. 33.4 HU mean for CFRP (p &amp;lt; 0.001), at the posterior margin of the vertebral body 68.9 HU (ti) vs. 59.8 HU (CFRP) (p &amp;lt; 0.001) and at the anterior part of the vertebral body 201.2 HU (ti) vs. 70.4 HU (CFRP) (p &amp;lt; 0.001), respectively. MRI data was only visually interpreted due to the low sample size and lack of an objective measuring system as Hounsfield units in CT. CT imaging of the phantom with typical implant configuration for thoracic stabilization could demonstrate a significant artifact reduction in CFRP implants compared with titanium implants for evaluation of index structures. Radiolucency with less artifacts provides a better interpretation of follow-up imaging, radiation planning, and more precise dose delivery

Inverse Perfusion Requirements of Supra- and Infratentorial Brain Metastases Formation

Background and Aims: Vascular border zones and the gray-white matter junction are preferred sites for the development of brain metastases (BM), whereas microvascular lesions are known to be a protective factor. In this proof of concept study, we aim to study the relationship of blood perfusion and the spatial distribution of BM.Materials and Methods: An average CT perfusion atlas of 107 healthy patients was created. Voxel-wise reference perfusion values were extracted from BM-negative and BM-positive regions in a second cohort of 100 untreated patients harboring 809 BM confirmed by MRI. A comparison of regional perfusion values was performed using the independent t-test.Results: In contrast to supratentorial BM that develop preferably in areas with lower CBV/CBF and longer MTT/TTP compared to the average regional perfusion (p &lt; 0.001), infratentorial BM showed a higher CBV/CBF and shorter MTT/TTP (p &lt; 0.001).Conclusion: Our results imply differing pathophysiological mechanisms underlying supra- and infratentorial BM spreading. The inverse perfusion patterns may result from differences in vascular supply, hemodynamic requirements, and/or production of pro-angiogenic factors

Bacterial adhesion characteristics on implant materials for intervertebral cages: titanium or PEEK for spinal infections?

Purpose!#!Surgical intervention with intercorporal stabilisation in spinal infections is increasingly needed. Our aim was to compare titanium and polyetheretherketon (PEEK) cages according to their adhesion characteristics of different bacteria species in vitro.!##!Methods!#!Plates made from PEEK, polished titanium (Ti), two-surface-titanium (TiMe) (n = 2-3) and original PEEK and porous trabecular structured titanium (TiLi) interbody cages (n = 4) were inoculated in different bacterial solutions, S.aureus (MSSA, MRSA), S.epidermidis and E.coli. Growth characteristics were analysed. Biofilms and bacteria were visualised using confocal- and electron microscopy.!##!Results!#!Quantitative adherence of MSSA, MRSA, S.epidermidis and E.coli to Ti, TiMe and PEEK plates were different, with polished titanium being mainly advantageous over PEEK and TiMe with significantly less counts of colony forming units (CFU) for MRSA after 56 h compared to TiMe and at 72 h compared to PEEK (p = 0.04 and p = 0.005). For MSSA, more adherent bacteria were detected on PEEK than on TiMe at 32 h (p = 0.02). For PEEK and TiLi cages, significant differences were found after 8 and 72 h for S.epidermidis (p = 0.02 and p = 0.008) and after 72 h for MSSA (p = 0.002) with higher bacterial counts on PEEK, whereas E.coli showed more CFU on TiLi than PEEK (p = 0.05). Electron microscopy demonstrated enhanced adhesion in transition areas.!##!Conclusion!#!For S.epidermidis, MSSA and MRSA PEEK cages showed a higher adherence in terms of CFU count, whereas for E.coli PEEK seemed to be advantageous. Electron microscopic visualisation shows that bacteria did not adhere at the titanium mesh structure, but at the border zones of polished material to rougher parts

Edema is not a reliable diagnostic sign to exclude small brain metastases

<div><p>No prior systematic study on the extent of vasogenic edema (VE) in patients with brain metastases (BM) exists. Here, we aim to determine 1) the general volumetric relationship between BM and VE, 2) a threshold diameter above which a BM shows VE, and 3) the influence of the primary tumor and location of the BM in order to improve diagnostic processes and understanding of edema formation. This single center, retrospective study includes 173 untreated patients with histologically proven BM. Semi-manual segmentation of 1416 BM on contrast-enhanced T1-weighted images and of 865 VE on fluid-attenuated inversion recovery/T2-weighted images was conducted. Statistical analyses were performed using a paired-samples t-test, linear regression/generalized mixed-effects model, and receiver-operating characteristic (ROC) curve controlling for the possible effect of non-uniformly distributed metastases among patients. For BM with non-confluent edema (n = 545), there was a statistically significant positive correlation between the volumes of the BM and the VE (P < 0.001). The optimal threshold for edema formation was a diameter of 9.4 mm for all BM. The primary tumors as interaction term in multivariate analysis had a significant influence on VE formation whereas location had not. Hence VE development is dependent on the volume of the underlying BM and the site of the primary neoplasm, but not from the location of the BM.</p></div