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.
Comprehensive, accessible, and grounded in case law, Occupational Health Law has been an established authority in the field for over thirty years, and continues to provide practical coverage of ...occupational health, incorporating changes in the legal framework to reflect the very latest developments. The sixth edition of this indispensable reference work includes substantial new information on European law, the legal and ethical duties of occupational health professionals, medical records and confidentiality, data protection, compensation for work-related injury, the gig economy, the Equality Act and disability discrimination, and much more. Covers the provision of occupational health services, the legal liability of occupational health professionals, confidentiality, health surveillance, compensation and equal opportunity legislation Includes extensively revised content which aligns with current legislation and case law Contains new chapter summaries and highlighted key information boxes throughout Occupational Health Law, Sixth Edition, is the definitive resource for occupational health and safety professionals, from nurses, physicians and safety officers to HR managers, policy makers, risk managers, and employment lawyers.
To examine whether risk factor profile, baseline features, and outcome of cervical artery dissection (CEAD) differ according to the dissection site.
We analyzed 982 consecutive patients with CEAD ...included in the Cervical Artery Dissection and Ischemic Stroke Patients observational study (n = 619 with internal carotid artery dissection ICAD, n = 327 with vertebral artery dissection VAD, n = 36 with ICAD and VAD).
Patients with ICAD were older (p < 0.0001), more often men (p = 0.006), more frequently had a recent infection (odds ratio OR = 1.59 95% confidence interval (CI) 1.09-2.31), and tended to report less often a minor neck trauma in the previous month (OR = 0.75 0.56-1.007) compared to patients with VAD. Clinically, patients with ICAD more often presented with headache at admission (OR = 1.36 1.01-1.84) but less frequently complained of cervical pain (OR = 0.36 0.27-0.48) or had cerebral ischemia (OR = 0.32 0.21-0.49) than patients with VAD. Among patients with CEAD who sustained an ischemic stroke, the NIH Stroke Scale (NIHSS) score at admission was higher in patients with ICAD than patients with VAD (OR = 1.17 1.12-1.22). Aneurysmal dilatation was more common (OR = 1.80 1.13-2.87) and bilateral dissection less frequent (OR = 0.63 0.42-0.95) in patients with ICAD. Multiple concomitant dissections tended to cluster on the same artery type rather than involving both a vertebral and carotid artery. Patients with ICAD had a less favorable 3-month functional outcome (modified Rankin Scale score >2, OR = 3.99 2.32-6.88), but this was no longer significant after adjusting for baseline NIHSS score.
In the largest published series of patients with CEAD, we observed significant differences between VAD and ICAD in terms of risk factors, baseline features, and functional outcome.
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.
Objective: A significant number of patients with obsessive–compulsive disorder (OCD) fail to benefit sufficiently from treatments. This study aimed to evaluate whether certain OCD symptom dimensions ...were associated with cognitive‐behavioral therapy (CBT) outcome.
Method: Symptoms of 104 CBT‐treated in‐patients with OCD were assessed with the clinician‐rated Yale‐Brown Obsessive–Compulsive Scale symptom checklist. Logistic regression analyses examined outcome predictors.
Results: The most frequent OCD symptoms were aggressive and contamination obsessions, and compulsive checking and cleaning. Patients with hoarding symptoms at baseline (n = 19) were significantly less likely to become treatment responders as compared to patients without these symptoms. Patients with sexual and religious obsessions tended to respond less frequently, although this failed to reach statistical significance (P = 0.07). Regression analyses revealed that higher scores on the hoarding dimension were predictive of non‐response, even after controlling for possible confounding variables.
Conclusion: Our results strongly indicate that in‐patients with obsessive–compulsive hoarding respond poorly to CBT.
Objective: To examine whether thrombolysis for stroke attributable to cervical artery dissection (CeADStroke) affects outcome and major haemorrhage rates.
Methods: We used a multicentre CeADStroke ...database to compare CeADStroke patients treated with and without thrombolysis. Main outcome measures were favourable 3‐month outcome (modified Rankin Scale 0–2) and ‘major haemorrhage’ any intracranial haemorrhage (ICH) and major extracranial haemorrhage. Adjusted odds ratios OR (95% confidence intervals) were calculated on the whole database and on propensity‐matched groups.
Results: Among 616 CeADStroke patients, 68 (11.0%) received thrombolysis; which was used in 55 (81%) intravenously. Thrombolyzed patients had more severe strokes (median NIHSS score 16 vs. 3; P < 0.001) and more often occlusion of the dissected artery (66.2% vs. 39.4%; P < 0.001). After adjustment for stroke severity and vessel occlusion, the likelihood for favourable outcome did not differ between the treatment groups ORadjusted 0.95 (95% CI 0.45–2.00). The propensity matching score model showed that the odds to recover favourably were virtually identical for 64 thrombolyzed and 64 non‐thrombolyzed‐matched CeADStroke patients OR 1.00 (0.49–2.00). Haemorrhages occurred in 4 (5.9%) thrombolyzed patients, all being asymptomatic ICHs. In the non‐thrombolysis group, 3 (0.6%) patients had major haemorrhages asymptomatic ICH (n = 2) and major extracranial haemorrhage (n = 1).
Conclusion: As thrombolysis was neither independently associated with unfavourable outcome nor with an excess of symptomatic bleedings, our findings suggest thrombolysis should not be withheld in CeADStroke patients. However, the lack of any trend towards a benefit of thrombolysis may indicate the legitimacy to search for more efficient treatment options including mechanical revascularization strategies.
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Background and purpose
Risk factors for IS in young adults differ between genders and evolve with age, but data on the age‐ and gender‐specific differences by stroke etiology are scare. These ...features were compared based on individual patient data from 15 European stroke centers.
Methods
Stroke etiology was reported in detail for 3331 patients aged 15–49 years with first‐ever IS according to Trial of Org in Acute Stroke Treatment (TOAST) criteria: large‐artery atherosclerosis (LAA), cardioembolism (CE), small‐vessel occlusion (SVO), other determined etiology, or undetermined etiology. CE was categorized into low‐ and high‐risk sources. Other determined group was divided into dissection and other non‐dissection causes. Comparisons were done using logistic regression, adjusting for age, gender, and center heterogeneity.
Results
Etiology remained undetermined in 39.6%. Other determined etiology was found in 21.6%, CE in 17.3%, SVO in 12.2%, and LAA in 9.3%. Other determined etiology was more common in females and younger patients, with cervical artery dissection being the single most common etiology (12.8%). CE was more common in younger patients. Within CE, the most frequent high‐risk sources were atrial fibrillation/flutter (15.1%) and cardiomyopathy (11.5%). LAA, high‐risk sources of CE, and SVO were more common in males. LAA and SVO showed an increasing frequency with age. No significant etiologic distribution differences were found amongst southern, central, or northern Europe.
Conclusions
The etiology of IS in young adults has clear gender‐specific patterns that change with age. A notable portion of these patients remains without an evident stroke mechanism according to TOAST criteria.
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Background and purpose
Most recurrent cervical artery dissection (CeAD) events occur shortly after the acute first CeAD. This study compared the characteristics of recurrent and first CeAD events and ...searched for associations between subsequent events of an individual person.
Methods
Cervical artery dissection patients with a new CeAD event occurring during a 3–6 month follow‐up were retrospectively selected in seven specialized stroke centers. Clinical and vascular characteristics of the initial and the recurrent CeADs were compared.
Results
The study sample included 76 patients. Recurrent CeADs were occlusive in one (1.3%) patient, caused cerebral ischaemia in 13 (17.1%) and were asymptomatic in 39 (51.3%) patients, compared to 29 (38.2%) occlusive, 42 (55.3%) ischaemic and no asymptomatic first CeAD events. In 52 (68.4%) patients, recurrent dissections affected both internal carotid arteries or both vertebral arteries, whilst 24 (31.6%) patients had subsequent dissections in both types of artery. Twelve (28.6%) of 42 patients with an ischaemic first dissection had ischaemic symptoms due to the recurrent CeADs, too. However, only one (1.3%) of 34 patients with a non‐ischaemic first CeAD suffered ischaemia upon recurrence.
Conclusion
Recurrent CeAD typically affects the same site of artery. It causes ischaemic events less often than the first CeAD. The risk that patients who presented with solely non‐ischaemic symptoms of a first CeAD will have ischaemic symptoms in the case of a recurrent CeAD seems very small.
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