Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a discouraging prognosis. Its aggressive and highly infiltrative nature renders the current standard ...treatment of maximal surgical resection, radiation, and chemotherapy relatively ineffective. Identifying the signaling pathways that regulate GBM migration/invasion and resistance is required to develop more effective therapeutic regimens to treat GBM. Expression of TROY, an orphan receptor of the TNF receptor superfamily, increases with glial tumor grade, inversely correlates with patient overall survival, stimulates GBM cell invasion in vitro and in vivo, and increases resistance to temozolomide and radiation therapy. Conversely, silencing TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in a preclinical intracranial xenograft model. Here, we have identified for the first time that TROY interacts with JAK1. Increased TROY expression increases JAK1 phosphorylation. In addition, increased TROY expression promotes STAT3 phosphorylation and STAT3 transcriptional activity that is dependent upon JAK1. TROY-mediated activation of STAT3 is independent of its ability to stimulate activity of NF-κB. Inhibition of JAK1 activity by ruxolitinib or knockdown of JAK1 expression by siRNA significantly inhibits TROY-induced STAT3 activation, GBM cell migration, and decreases resistance to temozolomide. Taken together, our data indicate that the TROY signaling complex may represent a potential therapeutic target with the distinctive capacity to exert effects on multiple pathways mediating GBM cell invasion and resistance.
Glioblastoma (GBM) is the most common primary malignant brain cancer in adults. A hallmark of GBM is aggressive invasion of tumor cells into the surrounding normal brain. Both the current standard of ...care and targeted therapies have largely failed to specifically address this issue. Therefore, identifying key regulators of GBM cell migration and invasion is important. The leukemia-associated Rho guanine nucleotide exchange factor (LARG) has previously been implicated in cell invasion in other tumor types; however, its role in GBM pathobiology remains undefined. Herein, we report that the expression levels of LARG and ras homolog family members C (RhoC), and A (RhoA) increase with glial tumor grade and are highest in GBM. LARG and RhoC protein expression is more prominent in invading cells, whereas RhoA expression is largely restricted to cells in the tumor core. Knockdown of LARG by siRNA inhibits GBM cell migration in vitro and invasion ex vivo in organotypic brain slices. Moreover, siRNA-mediated silencing of RhoC suppresses GBM cell migration in vitro and invasion ex vivo, whereas depletion of RhoA enhances GBM cell migration and invasion, supporting a role for LARG and RhoC in GBM cell migration and invasion. Depletion of LARG increases the sensitivity of GBM cells to temozolomide treatment. Collectively, these results suggest that LARG and RhoC may represent unappreciated targets to inhibit glioma invasion.
In June 2019 a stratospheric eruption occurred at Raikoke (48∘ N, 153∘ E). Satellite observations show the injection of ash and SO2 into the lower stratosphere and an early entrainment of the plume ...into a cyclone. Following the Raikoke eruption, stratospheric aerosol optical depth (sAOD) values increased in the whole Northern Hemisphere and tropics and remained enhanced for more than 1 year, with peak values at 0.040 (short-wavelength, high northern latitudes) to 0.025 (short-wavelength, Northern Hemisphere average). Discrepancies between observations and global model simulations indicate that ash may have influenced the extent and evolution of the sAOD. Top of the atmosphere radiative forcings are estimated at values between −0.3 and -0.4Wm-2 (clear-sky) and of −0.1 to -0.2Wm-2 (all-sky), comparable to what was estimated for the Sarychev eruption in 2009. Almost simultaneously two significantly smaller stratospheric eruptions occurred at Ulawun (5∘ S, 151∘ E) in June and August. Aerosol enhancements from the Ulawun eruptions mainly had an impact on the tropics and Southern Hemisphere. The Ulawun plume circled the Earth within 1 month in the tropics. Peak shorter-wavelength sAOD values at 0.01 are found in the tropics following the Ulawun eruptions and a radiative forcing not exceeding −0.15 (clear-sky) and −0.05 (all-sky). Compared to the Canadian fires (2017), Ambae eruption (2018), Ulawun (2019) and the Australian fires (2019/2020), the highest sAOD and radiative forcing values are found for the Raikoke eruption.
Abstract
The underwater Hunga Tonga-Hunga Ha-apai volcano erupted in the early hours of 15th January 2022, and injected volcanic gases and aerosols to over 50 km altitude. Here we synthesise ...satellite, ground-based, in situ and radiosonde observations of the eruption to investigate the strength of the stratospheric aerosol and water vapour perturbations in the initial weeks after the eruption and we quantify the net radiative impact across the two species using offline radiative transfer modelling. We find that the Hunga Tonga-Hunga Ha-apai eruption produced the largest global perturbation of stratospheric aerosols since the Pinatubo eruption in 1991 and the largest perturbation of stratospheric water vapour observed in the satellite era. Immediately after the eruption, water vapour radiative cooling dominated the local stratospheric heating/cooling rates, while at the top-of-the-atmosphere and surface, volcanic aerosol cooling dominated the radiative forcing. However, after two weeks, due to dispersion/dilution, water vapour heating started to dominate the top-of-the-atmosphere radiative forcing, leading to a net warming of the climate system.
Black men are disproportionately affected by type 2 diabetes (T2D) and experience higher diabetes-related complications than non-Hispanic White men. To address the complex barriers in diabetes ...self-management for Black men, we implemented a 3-month peer-led and empowerment-based Diabetes Self-Management Education (DSME) and Support (DSMS) intervention in Metro Detroit. Twenty-five Black men ≥55 years of age with self-reported T2D were randomized to the intervention group (n=12)—10 hr of DSME and 9 hr of DSMS—or enhanced usual care (EUC) group (n=13)—10 hr of DSME. Peer leaders (n = 3) were trained by certified diabetes care and education specialists (CDCESs) to cofacilitate the support sessions. Outcomes (hemoglobin A1c HbA1c, diabetes self-care activities, and diabetes distress) were assessed preintervention and postintervention. In the intervention and EUC groups, mean HbA1c decreased by 0.20% (p = .52, SD = 0.99) and 0.13% (p = .68), respectively. General diet (p = .03, M change: 1.32, SD = 1.71) and blood glucose monitoring (p < .05, M change: 0.50, SD = 0.74) scores improved among those in the intervention group. General diet scores also improved in the EUC group: mean change: 1.77, p = .08, although changes were not statistically significant. Changes in diabetes distress scores differed based on the number of sessions attended, with a significant decrease in those attending 7 to 12 sessions (n = 7), >50%, (p = .003, M change: −5.71, SD = 3.20). Implementing a peer-led DSMS program for Black men was feasible, adopted, and led to positive changes in outcomes. Scaling up the intervention and assessing sustainability is warranted.
Glioblastoma multiforme (GBM) is the most common type of malignant brain tumors in adults and has a dismal prognosis. The highly aggressive invasion of malignant cells into the normal brain ...parenchyma renders complete surgical resection of GBM tumors impossible, increases resistance to therapeutic treatment, and leads to near-universal tumor recurrence. We have previously demonstrated that TROY (TNFRSF19) plays an important role in glioblastoma cell invasion and therapeutic resistance. However, the potential downstream effectors of TROY signaling have not been fully characterized. Here, we identified PDZ-RhoGEF as a binding partner for TROY that potentiated TROY-induced nuclear factor kappa B activation which is necessary for both cell invasion and survival. In addition, PDZ-RhoGEF also interacts with Pyk2, indicating that PDZ-RhoGEF is a component of a signalsome that includes TROY and Pyk2. PDZ-RhoGEF is overexpressed in glioblastoma tumors and stimulates glioma cell invasion via Rho activation. Increased PDZ-RhoGEF expression enhanced TROY-induced glioma cell migration. Conversely, silencing PDZ-RhoGEF expression inhibited TROY-induced glioma cell migration, increased sensitivity to temozolomide treatment, and extended survival of orthotopic xenograft mice. Furthermore, depletion of RhoC or RhoA inhibited TROY- and PDZ-RhoGEF–induced cell migration. Mechanistically, increased TROY expression stimulated Rho activation, and depletion of PDZ-RhoGEF expression reduced this activation. Taken together, these data suggest that PDZ-RhoGEF plays an important role in TROY signaling and provides insights into a potential node of vulnerability to limit GBM cell invasion and decrease therapeutic resistance.
Glioblastoma is the most frequent primary brain tumor in adults and a highly lethal malignancy with a median survival of about 15 months. The aggressive invasion of the surrounding normal brain makes ...complete surgical resection impossible, increases the resistance to radiation and chemotherapy, and assures tumor recurrence. Thus, there is an urgent need to develop innovative therapeutics to target the invasive tumor cells for improved treatment outcomes of this disease. Expression of TROY (TNFRSF19), a member of the tumor necrosis factor (TNF) receptor family, increases with increasing glial tumor grade and inversely correlates with patient survival. Increased expression of TROY stimulates glioblastoma cell invasion
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and increases resistance to temozolomide and radiation therapy. Conversely, silencing TROY expression inhibits glioblastoma cell invasion, increases temozolomide sensitivity, and prolongs survival in an intracranial xenograft model. Here, a novel complex is identified between TROY and EGFR, which is mediated predominantly by the cysteine-rich CRD3 domain of TROY. Glioblastoma tumors with elevated TROY expression have a statistically positive correlation with increased EGFR expression. TROY expression significantly increases the capacity of EGF to stimulate glioblastoma cell invasion, whereas depletion of TROY expression blocks EGF stimulation of glioblastoma cell invasion. Mechanistically, TROY expression modulates EGFR signaling by facilitating EGFR activation and delaying EGFR receptor internalization. Moreover, the association of EGFR with TROY increases TROY-induced NF-κB activation. These findings substantiate a critical role for the TROY-EGFR complex in regulation of glioblastoma cell invasion.
The TROY-EGFR signaling complex emerges as a potential therapeutic target to inhibit glioblastoma cell invasion.
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During an extended volcanic unrest starting in 2017, two main moderate stratospheric eruptions occurred at the Ambae volcano (15°S and 167°E), Vanuatu, in April and July 2018. Observations from a ...geostationary orbit show that the April and July eruptions injected a volcanic plume into the lower stratosphere. While aerosol enhancements from the April eruption have only had an impact on the Southern Hemisphere, the plume from the July eruption was distributed within the lower branch of the Brewer–Dobson circulation to both hemispheres. Satellite, ground‐based and in situ observations show that the background aerosol is enhanced throughout the year after the July eruption on a global scale. A volcanic‐induced perturbation of the global stratospheric aerosol optical depth up to 0.011 is found, in the ultraviolet/visible spectral range. This perturbation is comparable to that of recent moderate stratospheric eruptions like from Kasatochi, Sarychev, and Nabro. Top of the atmosphere radiative forcing values are estimated between −0.45 and −0.6 W/m2 for this event, showing that the Ambae eruption had the strongest climatic impact of the year 2018. Thus, the Ambae eruption in 2018 has to be taken into account when studying the decadal lower stratospheric aerosol budget and in climate studies.
Key Points
Two stratospheric eruptions occurred at the Ambae volcano in 2018, in April and July
Various satellite data reveal a significant impact on the global stratosphere
A significant radiative forcing is found for the eruption of July 2018
Glioblastoma (GB) is the most common and lethal type of primary brain tumor. Clinical outcome remains poor and is essentially palliative due to the highly invasive nature of the disease. A more ...thorough understanding of the molecular mechanisms that drive glioma invasion is required to limit dispersion of malignant glioma cells.
We investigated the potential role of differential expression of microRNAs (miRNA) in glioma invasion by comparing the matched large-scale, genome-wide miRNA expression profiles of migrating and migration-restricted human glioma cells. Migratory and migration-restricted cell populations from seven glioma cell lines were isolated and profiled for miRNA expression. Statistical analyses revealed a set of miRNAs common to all seven glioma cell lines that were significantly down regulated in the migrating cell population relative to cells in the migration-restricted population. Among the down-regulated miRNAs, miR-23b has been reported to target potential drivers of cell migration and invasion in other cell types. Over-expression of miR-23b significantly inhibited glioma cell migration and invasion. A bioinformatics search revealed a conserved target site within the 3' untranslated region (UTR) of Pyk2, a non-receptor tyrosine kinase previously implicated in the regulation of glioma cell migration and invasion. Increased expression of miR-23b reduced the protein expression level of Pyk2 in glioma cells but did not significantly alter the protein expression level of the related focal adhesion kinase FAK. Expression of Pyk2 via a transcript variant missing the 3'UTR in miR-23b-expressing cells partially rescued cell migration, whereas expression of Pyk2 via a transcript containing an intact 3'UTR failed to rescue cell migration.
Reduced expression of miR-23b enhances glioma cell migration in vitro and invasion ex vivo via modulation of Pyk2 protein expression. The data suggest that specific miRNAs may regulate glioma migration and invasion to influence the progression of this disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:To examine the import of prior cervical trauma (PCT) in patients with cervical artery dissection (CeAD).
METHODS:In this observational study, the presence of and the type of PCT were ...systematically ascertained in CeAD patients using 2 different populations for comparisons1) age- and sex-matched patients with ischemic stroke attributable to a cause other than CeAD (non–CeAD-IS), and 2) healthy subjects participating in the Cervical Artery Dissection and Ischemic Stroke Patients Study. The presence of PCT within 1 month was assessed using a standardized questionnaire. Crude odds ratios (ORs) with 95% confidence intervals (CIs) and ORs adjusted for age, sex, and center were calculated.
RESULTS:We analyzed 1,897 participants (n = 966 with CeAD, n = 651 with non–CeAD-IS, n = 280 healthy subjects). CeAD patients had PCT in 40.5% (38.2%–44.5%) of cases, with 88% (344 of 392) classified as mild. PCT was more common in CeAD patients than in non–CeAD-IS patients (ORcrude 5.6 95% CI 4.20–7.37, p < 0.001; ORadjusted 7.6 95% CI 5.60–10.20, p < 0.001) or healthy subjects (ORcrude 2.8 95% CI 2.03–3.68, p < 0.001; ORadjusted 3.7 95% CI 2.40–5.56, p < 0.001). CeAD patients with PCT were younger and presented more often with neck pain and less often with stroke than CeAD patients without PCT. PCT was not associated with functional 3-month outcome after adjustment for age, sex, and stroke severity.
CONCLUSION:PCT seems to be an important environmental determinant of CeAD, but was not an independent outcome predictor. Because of the characteristics of most PCTs, the term mechanical trigger event rather than trauma may be more appropriate.
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