Fibrillar extracellular matrix produced by pericyte-like cells facilitates glioma cell dissemination.

Gliomagenesis induces profound changes in the composition of the extracellular matrix (ECM) of the brain. In this study, we identified a cellular population responsible for the increased deposition of collagen I and fibronectin in glioblastoma. Elevated levels of the fibrillar proteins collagen I and fibronectin were associated with the expression of fibroblast activation protein (FAP), which is predominantly found in pericyte-like cells in glioblastoma. FAP+ pericyte-like cells were present in regions rich in collagen I and fibronectin in biopsy material and produced substantially more collagen I and fibronectin in vitro compared to other cell types found in the GBM microenvironment. Using mass spectrometry, we demonstrated that 3D matrices produced by FAP+ pericyte-like cells are rich in collagen I and fibronectin and contain several basement membrane proteins. This expression pattern differed markedly from glioma cells. Finally, we have shown that ECM produced by FAP+ pericyte-like cells enhances the migration of glioma cells including glioma stem-like cells, promotes their adhesion, and activates focal adhesion kinase (FAK) signaling. Taken together, our findings establish FAP+ pericyte-like cells as crucial producers of a complex ECM rich in collagen I and fibronectin, facilitating the dissemination of glioma cells through FAK activation.

Fibroblast activation protein as a potential theranostic target in brain metastases of diverse solid tumours.

Brain metastases are a very common and serious complication of oncological diseases. Despite the vast progress in multimodality treatment, brain metastases significantly decrease the quality of life and prognosis of patients. Therefore, identifying new targets in the microenvironment of brain metastases is desirable. Fibroblast activation protein (FAP) is a transmembrane serine protease typically expressed in tumour-associated stromal cells. Due to its characteristic presence in the tumour microenvironment, FAP represents an attractive theranostic target in oncology. However, there is little information on FAP expression in brain metastases. In this study, we quantified FAP expression in samples of brain metastases of various primary origin and characterised FAP-expressing cells. We have shown that FAP expression is significantly higher in brain metastases in comparison to non-tumorous brain tissues, both at the protein and enzymatic activity levels. FAP immunopositivity was localised in regions rich in collagen and containing blood vessels. We have further shown that FAP is predominantly confined to stromal cells expressing markers typical of cancer-associated fibroblasts (CAFs). We have also observed FAP immunopositivity on tumour cells in a portion of brain metastases, mainly originating from melanoma, lung, breast, and renal cancer, and sarcoma. There were no significant differences in the quantity of FAP protein, enzymatic activity, and FAP+ stromal cells among brain metastasis samples of various origins, suggesting that there is no association of FAP expression and/or presence of FAP+ stromal cells with the histological type of brain metastases. In summary, we are the first to establish the expression of FAP and characterise FAP-expressing cells in the microenvironment of brain metastases. The frequent upregulation of FAP and its presence on both stromal and tumour cells support the use of FAP as a promising theranostic target in brain metastases.

DNA Fragility and Repair: Some Personal Recollections.

In this autobiographical article, I reflect on my Swedish background. Then I discuss endogenous DNA alterations and the base excision repair pathway and alternative repair strategies for some unusual DNA lesions. Endogenous DNA damage, such as loss of purine bases and cytosine deamination, is proposed as a major source of cancer-causing mutations.

Deglacial variability of South China hydroclimate heavily contributed by autumn rainfall.

The deglacial hydroclimate in South China remains a long-standing topic of debate due to the lack of reliable moisture proxies and inconsistent model simulations. A recent hydroclimate proxy suggests that South China became wet in cold stadials during the last deglaciation, with the intensification proposed to be contributed mostly by the East Asian summer monsoon (EASM). Here, based on a deglacial simulation in a state-of-the-art climate model that well reproduces the evolution of EASM, winter monsoon (EAWM) and the associated water isotopes in East Asia, we propose that the intensified hydroclimate in South China is also contributed heavily by the rainfall in autumn, during the transition between EASM and EAWM. The excessive rainfall in autumn results from the convergence between anomalous northerly wind due to amplified land-sea thermal contrast and anomalous southerly wind associated with the anticyclone over Western North Pacific, both of which are, in turn, forced by the slowdown of the Atlantic thermohaline circulation. Regardless the rainfall change, however, the modeled δ18Op remains largely unchanged in autumn. Our results provide new insights to East Asia monsoon associated with climate change in the North Atlantic.

Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis.

Fibroblast activation protein (FAP) is a membrane-bound protease that is upregulated in a wide range of tumours and viewed as a marker of tumour-promoting stroma. Previously, we demonstrated increased FAP expression in glioblastomas and described its localisation in cancer and stromal cells. In this study, we show that FAP+ stromal cells are mostly localised in the vicinity of activated CD105+ endothelial cells and their quantity positively correlates with glioblastoma vascularisation. FAP+ mesenchymal cells derived from human glioblastomas are non-tumorigenic and mostly lack the cytogenetic aberrations characteristic of glioblastomas. Conditioned media from these cells induce angiogenic sprouting and chemotaxis of endothelial cells and promote migration and growth of glioma cells. In a chorioallantoic membrane assay, co-application of FAP+ mesenchymal cells with glioma cells was associated with enhanced abnormal angiogenesis, as evidenced by an increased number of erythrocytes in vessel-like structures and higher occurrence of haemorrhages. FAP+ mesenchymal cells express proangiogenic factors, but in comparison to normal pericytes exhibit decreased levels of antiangiogenic molecules and an increased Angiopoietin 2/1 ratio. Our results show that FAP+ mesenchymal cells promote angiogenesis and glioma cell migration and growth by paracrine communication and in this manner, they may thus contribute to glioblastoma progression.

Abrupt Heinrich Stadial 1 cooling missing in Greenland oxygen isotopes.

Abrupt climate changes during the last deglaciation have been well preserved in proxy records across the globe. However, one long-standing puzzle is the apparent absence of the onset of the Heinrich Stadial 1 (HS1) cold event around 18 ka in Greenland ice core oxygen isotope δ18 O records, inconsistent with other proxies. Here, combining proxy records with an isotope-enabled transient deglacial simulation, we propose that a substantial HS1 cooling onset did indeed occur over the Arctic in winter. However, this cooling signal in the depleted oxygen isotopic composition is completely compensated by the enrichment because of the loss of winter precipitation in response to sea ice expansion associated with AMOC slowdown during extreme glacial climate. In contrast, the Arctic summer warmed during HS1 and YD because of increased insolation and greenhouse gases, consistent with snowline reconstructions. Our work suggests that Greenland δ18 O may substantially underestimate temperature variability during cold glacial conditions.

Trends and outcomes for non-elective neurosurgical procedures in Central Europe during the COVID-19 pandemic.

The world currently faces the novel severe acute respiratory syndrome coronavirus 2 pandemic. Little is known about the effects of a pandemic on non-elective neurosurgical practices, which have continued under modified conditions to reduce the spread of COVID-19. This knowledge might be critical for the ongoing second coronavirus wave and potential restrictions on health care. We aimed to determine the incidence and 30-day mortality rate of various non-elective neurosurgical procedures during the COVID-19 pandemic. A retrospective, multi-centre observational cohort study among neurosurgical centres within Austria, the Czech Republic, and Switzerland was performed. Incidence of neurosurgical emergencies and related 30-day mortality rates were determined for a period reflecting the peak pandemic of the first wave in all participating countries (i.e. March 16th-April 15th, 2020), and compared to the same period in prior years (2017, 2018, and 2019). A total of 4,752 emergency neurosurgical cases were reviewed over a 4-year period. In 2020, during the COVID-19 pandemic, there was a general decline in the incidence of non-elective neurosurgical cases, which was driven by a reduced number of traumatic brain injuries, spine conditions, and chronic subdural hematomas. Thirty-day mortality did not significantly increase overall or for any of the conditions examined during the peak of the pandemic. The neurosurgical community in these three European countries observed a decrease in the incidence of some neurosurgical emergencies with 30-day mortality rates comparable to previous years (2017-2019). Lower incidence of neurosurgical cases is likely related to restrictions placed on mobility within countries, but may also involve delayed patient presentation.

Role of eruption season in reconciling model and proxy responses to tropical volcanism.

The response of the El Niño/Southern Oscillation (ENSO) to tropical volcanic eruptions has important worldwide implications, but remains poorly constrained. Paleoclimate records suggest an "El Niño-like" warming 1 year following major eruptions [Adams JB, Mann ME, Ammann CM (2003) Nature 426:274-278] and "La Niña-like" cooling within the eruption year [Li J, et al. (2013) Nat Clim Chang 3:822-826]. However, climate models currently cannot capture all these responses. Many eruption characteristics are poorly constrained, which may contribute to uncertainties in model solutions-for example, the season of eruption occurrence is often unknown and assigned arbitrarily. Here we isolate the effect of eruption season using experiments with the Community Earth System Model (CESM), varying the starting month of two large tropical eruptions. The eruption-year atmospheric circulation response is strongly seasonally dependent, with effects on European winter warming, the Intertropical Convergence Zone, and the southeast Asian monsoon. This creates substantial variations in eruption-year hydroclimate patterns, which do sometimes exhibit La Niña-like features as in the proxy record. However, eruption-year equatorial Pacific cooling is not driven by La Niña dynamics, but strictly by transient radiative cooling. In contrast, equatorial warming the following year occurs for all starting months and operates dynamically like El Niño. Proxy reconstructions confirm these results: eruption-year cooling is insignificant, whereas warming in the following year is more robust. This implies that accounting for the event season may be necessary to describe the initial response to volcanic eruptions and that climate models may be more accurately simulating volcanic influences than previously thought.

Fibroblast activation protein alpha is expressed by transformed and stromal cells and is associated with mesenchymal features in glioblastoma.

Glioblastomas are deadly neoplasms resistant to current treatment modalities. Fibroblast activation protein (FAP) is a protease which is not expressed in most of the normal adult tissues but is characteristically present in the stroma of extracranial malignancies. FAP is considered a potential therapeutic target and is associated with a worse patient outcome in some cancers. The FAP localization in the glioma microenvironment and its relation to patient survival are unknown. By analyzing 56 gliomas and 15 non-tumorous brain samples, we demonstrate increased FAP expression in a subgroup of high-grade gliomas, in particular on the protein level. FAP expression was most elevated in the mesenchymal subtype of glioblastoma. It was neither associated with glioblastoma patient survival in our patient cohort nor in publicly available datasets. FAP was expressed in both transformed and stromal cells; the latter were frequently localized around dysplastic blood vessels and commonly expressed mesenchymal markers. In a mouse xenotransplantation model, FAP was expressed in glioma cells in a subgroup of tumors that typically did not express the astrocytic marker GFAP. Endogenous FAP was frequently upregulated and part of the FAP+ host cells coexpressed the CXCR4 chemokine receptor. In summary, FAP is expressed by several constituents of the glioblastoma microenvironment, including stromal non-malignant mesenchymal cells recruited to and/or activated in response to glioma growth. The limited expression of FAP in healthy tissues together with its presence in both transformed and stromal cells suggests that FAP may be a candidate target for specific delivery of therapeutic agents in glioblastoma.

Intraventricular and lumbar intrathecal administration of antibiotics in postneurosurgical patients with meningitis and/or ventriculitis in a serious clinical state.

OBJECT: To date, reports on the clinical efficacy of intraventricularly and intrathecally administered antibiotics for the treatment of neurosurgical ventriculitis and meningitis in adults are limited. The authors aimed to evaluate the efficacy and safety of the intraventricular (IVT) and lumbar intrathecal (IT) administration of antibiotics in critically ill neurosurgical patients. METHODS: Thirty-four postneurosurgical patients with meningitis and ventriculitis were studied. Intraventricular/lumbar intrathecal antibiotics were administered due to positive CSF cultures persisting despite the use of intravenous antibiotics. The time period until CSF sterilization, changes in clinical state, and efficacy of different routes of antibiotic administration were evaluated. RESULTS: The mean time necessary to obtain CSF sterilization was 2.9 ± 2.7 days (range 1-12 days). The CSF cultures became negative within 24 hours after the administration of IVT/IT antibiotics in 17 patients (50%) and up to 48 hours in a further 6 patients (18%). The clinical outcome of patients assessed by the modified Rankin Scale improved in 17 patients (50%), stayed unchanged in 10 patients (29%), and was impaired in 1 patient (3%). Six patients (18%) died; however, 2 of them died due to reasons not directly related to meningitis or ventriculitis, so the overall mortality rate for meningitis and/or ventriculitis was 11.8% in this group of patients. All patients with ventriculitis (n = 4) were treated by antibiotics administered via the IVT route. The average time to CSF sterilization was 6.5 days in the patients with ventriculitis. Thirty patients had clinical signs of meningitis without ventriculitis. Despite the higher ratio of unfavorable Gram-negative meningitis in the subgroup of patients treated via lumbar drainage, the mean duration of CSF sterilization was 2.2 days compared with 2.6 days in the subgroup treated via external ventricular drainage, a difference that was not statistically significant (p = 0.3). Adverse effects of IVT/IT antibiotics appeared in 3 of 34 patients and were of low clinical significance. CONCLUSIONS: Intraventricular/lumbar intrathecal antibiotics can lead to very quick CSF sterilization in postneurosurgical patients with meningitis and ventriculitis. The relapse rate of meningitis and/or ventriculitis is also very low among patients treated by IVT/IT antibiotics. Intraventricular/lumbar intrathecal administration of antibiotics appears to be an effective and safe treatment for infections of the CNS caused by multidrug-resistant organisms. In patients with signs of ventriculitis, the authors prefer the IVT route of antibiotics. This study did not prove a lower efficacy of administration of antibiotics via lumbar drainage compared with the ventricular route in patients with meningitis.

[The use of modern microneurosurgical methods and state of the art technologies in the treatment of brain tumors and neurovascular diseases]. / Aplikace moderní mikroneurochirurgie a soucasných technologií pri resení nádorových a cévních onemocnení mozku.

Brain tumors and neurovascular diseases represent the most frequent and serious areas of intracranial neurosurgery. The recent advances in microneurosurgery aim at the complete treatment of the lesions (i.e. radical removal of the tumor, total occlusion of the vascular malformation) while respecting the minimal invasivity for the patient and avoiding risks and morbidity of the surgical procedure. The main tools used in order to accomplish this end are partly meticulous application of recent microneurosurgical principles that enable to treat complicated and deep lesions with minimal retraction and risk of injury to nerves and vascular structures, partly the use of contemporary technologies. Neuronavigation and functional neuronavigation facilitate exact preoperative planning and intraoperative orientation, methods based on fluorescence help to display intravascular blood flow or residual tumor in the operative field and intraoperative magnetic resonance allows exact morphological imaging of the intracranial structures during surgical procedure and increases accuracy of navigation. Electrophysiological monitoring helps to increase the safety of the procedure by continuous tracking of selected brain and nerve functions. Tailored combination and cooperation of aforementioned methods maximizes effect for the uneventful outcome. We present review paper on application of these methods and our experiences in the neurosurgical department Na Homolce hospital and show illustrative cases.

Direct repair (nerve grafting), neurotization, and end-to-side neurorrhaphy in the treatment of brachial plexus injury.

OBJECT: The authors present the long-term results of nerve grafting and neurotization procedures in their group of patients with brachial plexus injuries and compare the results of "classic" methods of nerve repair with those of end-to-side neurorrhaphy. METHODS: Between 1994 and 2006, direct repair (nerve grafting), neurotization, and end-to-side neurorrhaphy were performed in 168 patients, 95 of whom were followed up for at least 2 years after surgery. Successful results were achieved in 79% of cases after direct repair and in 56% of cases after end-to-end neurotization. The results of neurotization depended on the type of the donor nerve used. In patients who underwent neurotization of the axillary and the musculocutaneous nerves, the use of intraplexal nerves (motor branches of the brachial plexus) as donors of motor fibers was associated with a significantly higher success rate than the use of extraplexal nerves (81% compared with 49%, respectively, p = 0.003). Because of poor functional results of axillary nerve neurotization using extraplexal nerves (success rate 47.4%), the authors used end-to-side neurorrhaphy in 14 cases of incomplete avulsion. The success rate for end-to-side neurorrhaphy using the axillary nerve as a recipient was 64.3%, similar to that for neurotization using intraplexal nerves (68.4%) and better than that achieved using extraplexal nerves (47.4%, p = 0.19). CONCLUSIONS: End-to-side neurorrhaphy offers an advantage over classic neurotization in not requiring sacrifice of any of the surrounding nerves or the fascicles of the ulnar nerve. Typical synkinesis of muscle contraction innervated by the recipient nerve with contraction of muscles innervated by the donor was observed in patients after end-to-side neurorrhaphy.

Solar influence on climate during the past millennium: results from transient simulations with the NCAR Climate System Model.

The potential role of solar variations in modulating recent climate has been debated for many decades and recent papers suggest that solar forcing may be less than previously believed. Because solar variability before the satellite period must be scaled from proxy data, large uncertainty exists about phase and magnitude of the forcing. We used a coupled climate system model to determine whether proxy-based irradiance series are capable of inducing climatic variations that resemble variations found in climate reconstructions, and if part of the previously estimated large range of past solar irradiance changes could be excluded. Transient simulations, covering the published range of solar irradiance estimates, were integrated from 850 AD to the present. Solar forcing as well as volcanic and anthropogenic forcing are detectable in the model results despite internal variability. The resulting climates are generally consistent with temperature reconstructions. Smaller, rather than larger, long-term trends in solar irradiance appear more plausible and produced modeled climates in better agreement with the range of Northern Hemisphere temperature proxy records both with respect to phase and magnitude. Despite the direct response of the model to solar forcing, even large solar irradiance change combined with realistic volcanic forcing over past centuries could not explain the late 20th century warming without inclusion of greenhouse gas forcing. Although solar and volcanic effects appear to dominate most of the slow climate variations within the past thousand years, the impacts of greenhouse gases have dominated since the second half of the last century.

Dorsal root entry zone (DREZ) localization using direct spinal cord stimulation can improve results of the DREZ thermocoagulation procedure for intractable pain relief.

The dorsal root entry zone (DREZ) thermocoagulation for intractable pain after brachial plexus avulsion was performed in 21 patients. Good results in pain relief (relief of more than 75% of preoperative pain) were achieved in 62% of patients, whereby fair results (relief of 25-75% of preoperative pain) in 38% of patients. There was no patient with poor result (relief of less than 25% of preoperative pain). Complication rate was 14%. The whole patient population was subdivided into two groups (Group 1 and Group 2). Direct spinal cord bipolar stimulation and registration with the goal to localize DREZ was performed in the Group 2 consisting of 12 patients (n=12). The point on the spinal cord surface where no response after stimulus of low intensity was obtained was the site (the posterolateral sulcus) we identified as the most suitable point for the placement of radiofrequency thermocoagulation electrode. Comparing with the Group 1 consisting of nine patients (n=9), where the localization of DREZ by evoked potentials was not performed, significantly better effect of pain relief was recorded (P<0.05, odds ratio 10). There was no statistically significant difference (P>0.7) in complication rate in Group 1 and Group 2. Described electrophysiological technique is very helpful in identifying of DREZ and, in combination with microsurgical technique, can create DREZ thermocoagulation more effective.