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Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1 +  myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies. The tumour microenvironment counteracts immune therapy in Glioblastomas. Authors show here, using spatially resolved and single cell transcriptomics, that dysfunctional T cells are induced by a myeloid cell subset via Interleukin-10 signalling, and inhibition of the downstream JAK/STAT pathway might restore glioblastoma immune therapy responsiveness.

Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFβ, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses. Astrocytes play important roles in neuroinflammatory diseases. Here the authors characterize human glioblastoma-associated astrocytes by gene expression and demonstrate their immunosuppressive role promoted by interactions with tumor and microglia cells in an organotypic model.

ObjectiveSpinal cerebrospinal fluid (CSF) leaks cause spontaneous intracranial hypotension (SIH). Microsurgery can sufficiently seal spinal CSF leaks. Yet, some patients suffer from residual symptoms. Aim of the study was to assess predictors for favorable outcome after surgical treatment of SIH.MethodsWe included consecutive patients with SIH treated surgically from January 2013 to May 2020. Subjects were surveyed by a questionnaire. Primary outcome was resolution of symptoms as rated by the patient. Secondary outcome was postoperative headache intensity on the numeric rating scale (NRS). Association between variables and outcome was assessed using univariate and multivariate regression. A cut-off value for continuous variables was calculated by a ROC analysis.ResultsSixty-nine out of 86 patients (80.2%) returned the questionnaire and were analyzed. Mean age was 46.7 years and 68.1% were female. A significant association with the primary and secondary outcome was found only for preoperative symptom duration (p = 0.001 and p < 0.001), whereby a shorter symptom duration was associated with a better outcome. Symptom duration remained a significant predictor in a multivariate model (p = 0.013). Neither sex, age, type of pathology, lumbar opening pressure, nor initial presentation were associated with the primary outcome. ROC analysis yielded treatment within 12 weeks as a cut-off for better outcome.ConclusionShorter duration of preoperative symptoms is the most powerful predictor of favorable outcome after surgical treatment of SIH. While an initial attempt of conservative treatment is justified, we advocate early definitive treatment within 12 weeks in case of persisting symptoms.

Abstract BACKGROUND Spinal cerebrospinal fluid (CSF) leaks are the cause of spontaneous intracranial hypotension (SIH). OBJECTIVE To propose a surgical strategy, stratified according to anatomic location of the leak, for sealing all CSF leaks around the 360° circumference of the dura through a single tailored posterior approach. METHODS All consecutive SIH patients undergoing spinal surgery were included. The anatomic site of the leak was exactly localized. We used a tailored hemilaminotomy and intraoperative neurophysiological monitoring (IOM) for all cases. Neurological status was assessed before and up to 90 d after surgery. RESULTS Forty-seven SIH patients had an identified CSF leak between the levels C6 and L1. Leaks, anterior to the spinal cord, were approached by a transdural trajectory (n = 28). Leaks lateral to the spinal cord by a direct extradural trajectory (n = 17) and foraminal leaks by a foraminal microsurgical trajectory (n = 2). The transdural trajectory necessitated cutting the dentate ligament accompanied by elevation and rotation of the spinal cord under continuous neuromonitoring (spinal cord release maneuver, SCRM). Four patients had transient defiticts, none had permanent neurological deficits. We propose an anatomic classification of CSF leaks into I ventral (77%, anterior dural sac), II lateral (19%, including nerve root exit, lateral, and dorsal dural sac), and III foraminal (4%). CONCLUSION Safe sealing (with IOM) of all CSF leaks around the 360° surface of the dura is feasible through a single posterior approach. The exact surgical trajectory is selected according to the anatomic category of the leak.

Human adenovirus type 55 (HAdV-55) causes acute respiratory disease of variable severity and has become an emergent threat in both civilian and military populations. HAdV-55 infection is endemic to China and South Korea, but data from other regions and time periods are needed for comprehensive assessment of HAdV-55 prevalence from a global perspective. In this study, we subjected HAdV-55 isolates from various countries collected during 1969-2018 to whole-genome sequencing, genomic and proteomic comparison, and phylogenetic analyses. The results show worldwide distribution of HAdV-55; recent strains share a high degree of genomic homogeneity. Distinct strains circulated regionally for several years, suggesting persistent local transmission. Several cases of sporadic introduction of certain strains to other countries were documented. Among the identified amino acid mutations distinguishing HAdV-55 strains, some have potential impact on essential viral functions and may affect infectivity and transmission.

Background Recently, there is increasing evidence that the proportion of odontogenic brain abscesses is greater than previously known. In this study, we aim to differentiate the oral infections as triggers more precisely and to classify them in the clinical setting. Methods For analysis, we conducted a retrospective single center study. We reviewed patients with brain abscesses who have undergone treatment in the University Hospital of Freiburg, Germany in the period between 2000–2021. Inclusion required two main criteria: 1. The brain abscess must not have an other focus than odontogenic. 2. The microbial spectrum identified in the brain abscess must be consistent with an odontogenic origin. Results Of 217 brain abscess patients, 26 met the inclusion criteria. 42% (11 patients) suffered from immunosuppressive conditions. Odontogenic foci were diagnosed in 18 cases (69%). Neurologic deficits included vigilance reduction and hemiparesis. Pathogens of the Streptococcus anginosus group were the most frequent causative agent (21 cases, 81%). Metronidazole (54%) and ceftriaxone (42%) were part of the targeted antibiotic therapy. All brain abscesses were surgically treated. Teeth were extracted in 14 of 17 cases for focus control. 18 cases (72%) showed complete or partial resolution of neurologic symptoms and 3 cases were fatal. Conclusion Apparently silent or chronic oral infections are sufficient to cause bacterial colonization of the brain, especially in immunocompromised patients. Therefore, special care should be taken to maintain good oral health. An interdisciplinary management should become a standard to prevent and treat the occurrence of brain abscesses.

Arboviruses continue to be a significant global health concern. The unbiased metagenomic analyses of mosquito-borne and mosquito-specific viruses are useful to understand viral diversity and for the surveillance of pathogens of medical and veterinary importance. Metagenomic analysis was conducted on 6368 mosquitoes (736 pools), covering 16 species from 18 locations throughout the Republic of Korea (ROK) in 2016. In this report, we describe three viruses detected in a single pool of Aedes vexans nipponii collected at Yongsan U.S. Army Garrison, located in a densely populated district of Seoul, the ROK. The three novel viruses, designated as Yongsan bunyavirus 1 (YBV1), Yongsan picorna-like virus 3 (YPLV3) and Yongsan sobemo-like virus 1 (YSLV1), share sequence and structural characteristics with members belonging to the family Bunyaviridae, order Picornavirales, and family Solemoviridae, with shared RNA-dependent RNA polymerase (RdRp) amino acid identities of 40%, 42% and 86%, respectively. The real-time reverse transcription and polymerase chain reaction (RT-PCR) of 3493 Aedes vexans nipponii (257 pools) showed a high prevalence of YBV1 and YSLV1 viruses, which were present in 65% and 62% of tested pools, respectively. This study highlighted the utility of a metagenomic sequencing approach for arbovirus discovery and for a better understanding of the virome of potential medically relevant vectors.

Glioblastoma (GBM) is a highly aggressive disease and is associated with poor prognosis despite treatment advances in recent years. Surgical resection of tumor remains the main therapeutic option when approaching these patients, especially when combined with adjuvant radiochemotherapy. In the present study, we conducted a comprehensive literature review on the state-of-the-art and future trends of the surgical treatment of GBM, emphasizing topics that have been the object of recent study.

Despite unprecedented global sequencing and surveillance of SARS-CoV-2, timely identification of the emergence and spread of novel variants of concern (VoCs) remains a challenge. Several million raw genome sequencing runs are now publicly available. We sought to survey these datasets for intrahost variation to study emerging mutations of concern. We developed iSKIM (“intrahost SARS-CoV-2 k-mer identification method”) to relatively quickly and efficiently screen the many SARS-CoV-2 datasets to identify intrahost mutations belonging to lineages of concern. Certain mutations surged in frequency as intrahost minor variants just prior to, or while lineages of concern arose. The Spike N501Y change common to several VoCs was found as a minor variant in 834 samples as early as October 2020. This coincides with the timing of the first detected samples with this mutation in the Alpha/B.1.1.7 and Beta/B.1.351 lineages. Using iSKIM, we also found that Spike L452R was detected as an intrahost minor variant as early as September 2020, prior to the observed rise of the Epsilon/B.1.429/B.1.427 lineages in late 2020. iSKIM rapidly screens for mutations of interest in raw data, prior to genome assembly, and can be used to detect increases in intrahost variants, potentially providing an early indication of novel variant spread.

Background Glioblastoma of the corpus callosum (ccGBM) are rare tumors, with a dismal prognosis marked by a rapid clinical deterioration. For a long time, surgical treatment was not considered beneficial for most patients with such tumors. Recent studies claimed an improved survival for patients undergoing extensive resection, albeit without integration of the molecular profile of the lesions. The purpose of this study was to investigate the effect of biopsy and surgical resection on oncological and functional outcomes in patients with IDH wild-type ccGBM. Methods We performed a retrospective analysis of our institution’s database of patients having been treated for high-grade glioma between 2005 and 2017. Inclusion criteria were defined as follows: patients older than 18 years, histopathological, and molecularly defined IDH wild-type glioma, major tumor mass (at least 2/3) invading the corpus callosum in the sagittal plane with a uni- or bilateral infiltration of the adjacent lobules. Surgical therapy (resection vs. biopsy), extent of resection according to the remaining tumor volume and adjuvant treatment as well as overall survival and functional outcome using the Karnofsky Performance Score (KPS) were analyzed. Results Fifty-five patients were included in the study, from which the mean age was 64 years and men ( n  = 34, 61.8%) were more often affected than women ( n  = 21, 38.2%). Thirty (54.5%) patients were treated with stereotactic biopsy alone, while 25 patients received tumor resection resulting in 14.5% ( n  = 8) gross-total resections and 30.9% ( n  = 17) partial resections. The 2-year survival rate after resection was 30% compared to 7% after biopsy ( p  = 0.047). The major benefit was achieved in the group with gross-total resection, while partial resection failed to improve survival. Neurological outcome measured by KPS did not differ between both groups either pre- or postoperatively. Conclusions Our study suggests that in patients with corpus callosum glioblastoma, gross-total resection prolongs survival without negatively impacting neurological outcome as compared to biopsy.