Persistent activation of the signal transducer and activator of transcription 3 (STAT3) signalling has been linked to oncogenesis and the development of chemotherapy resistance in glioblastoma and other cancers. Inhibition of the STAT3 pathway thus represents an attractive therapeutic approach for cancer. In this study, we investigated the inhibitory effects of a small molecule compound known as LLL-3, which is a structural analogue of the earlier reported STAT3 inhibitor, STA-21, on the cell viability of human glioblastoma cells, U87, U373, and U251 expressing constitutively activated STAT3. We also investigated the inhibitory effects of LLL-3 on U87 glioblastoma cell growth in a mouse tumour model as well as the impact it had on the survival time of the treated mice. We observed that LLL-3 inhibited STAT3-dependent transcriptional and DNA binding activities. LLL-3 also inhibited viability of U87, U373, and U251 glioblastoma cells as well as induced apoptosis of these glioblastoma cell lines as evidenced by increased poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavages. Furthermore, the U87 glioblastoma tumour-bearing mice treated with LLL-3 exhibited prolonged survival relative to vehicle-treated mice (28.5 vs 16 days) and had smaller intracranial tumours and no evidence of contralateral invasion. These results suggest that LLL-3 may be a potential therapeutic agent in the treatment of glioblastoma with constitutive STAT3 activation.

Glioblastoma multiforme (GBM) accounts for the majority of primary malignant brain tumors and remains virtually incurable despite extensive surgical resection, radiotherapy, and chemotherapy. Treatment difficulty is due to its exceptional infiltrative nature and proclivity to integrate into normal brain tissue. Long-term survivors are rare, and median survival for patients is about 1 year. Use of adult stem cells as cellular delivery vehicles for anticancer agents is a novel attractive therapeutic strategy. We hypothesized that adipose-derived stem cells (ADSCs) possess the ability to home and deliver myxoma virus to glioma cells and experimental gliomas. We infected ADSCs with vMyxgfp and found them to be permissive for myxoma virus replication. ADSCs supported single and multiple rounds of replication leading to productive infection. Further, we observed no significant impact on ADSC viability. We cocultured fluorescently labeled GBM cells with myxoma virus-infected ADSCs in three-dimensional assay and observed successful cross infection and concomitant cell death almost exclusively in GBM cells. In vivo orthotopic studies injected with vMyxgfp-ADSCs intracranially away from the tumor demonstrated that myxoma virus was delivered by ADSCs resulting in significant survival increase. Our data suggest that ADSCs are promising new carriers of oncolytic viruses, specifically myxoma virus, to brain tumors.

These findings demonstrate that chronic nicotine produces a stable, long-lasting, mechanical hypersensitivity that exacerbates mechanical sensitivity resulting from peripheral nerve injury. The mechanism of this may involve an increase in spinal neuronal activity and apoptosis.

OBJECTIVE The objective of this study was to investigate the neurovascular and anatomical differences in patients with lumbosacral transitional vertebrae (LSTV) and the associated risk of neurovascular injury in minimally invasive spine surgery. METHODS The authors performed a retrospective study of CT and MR images of the lumbar spine obtained at their institution between 2010 and 2014. The following characteristics were evaluated: level of the iliac crest in relation to the L4–5 disc space, union level of the iliac veins and arteries in relation to the L4–5 disc space, distribution of the iliac veins and inferior vena cava according to the different Moro zones (A, I, II, III, IV, P) at the L4–5 disc space, and the location of the psoas muscle at the L4–5 disc space. The findings were compared with findings on images obtained in 28 age- and sex-matched patients without LSTV who underwent imaging studies during the same time period. RESULTS Twenty-eight patients (12 male, 16 female) with LSTV and the required imaging studies were identified; 28 age- and sex-matched patients who had undergone CT and MRI studies of the thoracic and lumbar spine imaging but did not have LSTV were selected for comparison (control group). The mean ages of the patients in the LSTV group and the control group were 52 and 49 years, respectively. The iliac crest was located at a mean distance of 12 mm above the L4–5 disc space in the LSTV group and 4 mm below the L4–5 disc space in the controls. The iliac vein union was located at a mean distance of 8 mm above the L4–5 disc space in the LSTV group and 2.7 mm below the L4–5 disc space in the controls. The iliac artery bifurcation was located at a mean distance of 23 mm above the L4–5 disc space in the LSTV group and 11 mm below the L4–5 disc space in controls. In patients with LSTV, the distribution of iliac vein locations was as follows: Zone A, 7.1%; Zone I only, 78.6%; Zone I encroaching into Zone II, 7.1%; and Zone II only, 7.1%. In the control group, the distribution was as follows: Zone A only, 17.9%; Zone A encroaching into Zone I, 75%; and Zone I only, 7.1%. There were no iliac vessels in Zone II in the control group. The psoas muscle was found to be rising away laterally and anteriorly from the vertebral body more often in patients with LSTV, resulting in the iliac veins being found in the “safe zone” only 14% of the time, greatly increasing the risk of vascular injury. CONCLUSIONS In patients with LSTV, the iliac crest is more likely to be above the L4–5 disc space, which increases the technical challenges of a lateral approach. The location of the psoas muscle rising away laterally and ventrally in patients with LSTV compared with controls and with the union of the iliac veins occurring more often above the L4–5 disc space increases the risk for iatrogenic vascular injury at the L4–5 level in this patient population.

OBJECTIVETraumatic vertebral artery injuries (TVAIs) are a common finding in cervical spine trauma and can predispose patients to posterior circulation infarction. While extensive research has been conducted regarding the management and criteria for imaging in patients with suspected blunt vascular injury, little research has been conducted highlighting these injuries in the geriatric population.METHODSThe authors performed a retrospective review of all patients evaluated at a level 1 trauma center and found to have TVAIs between January 1, 2010, and January 1, 2018. Biometric, clinical, and imaging data were obtained from a trauma registry database. Patients were divided into 2 groups on the basis of age, a geriatric group (age ≥ 65 years) and an adult group (age 18 to < 65 years). Variables evaluated included type of trauma, mortality, Injury Severity Score (ISS), and ICU length of stay. The Student t-test was used for continuous variables, and Pearson’s chi-square test was used for categorical variables.RESULTSOf the 2698 of patients identified with traumatic cervical spine injuries, 103 patients demonstrated evidence of TVAI. Of these patients, 69 were < 65 and 34 were ≥ 65 years old at the time of their trauma. There was no difference in the incidence of TVAIs between the 2 groups. The ICU length of stay (4.71 vs 4.32 days, p > 0.05), hospital length of stay (10.71 vs 10.72 days, p > 0.05), and the ISS (21.50 vs 21.32, p > 0.05) did not differ significantly between the 2 groups. Mortality was significantly higher in the geriatric group, occurring in 9 of 34 patients (26.5%) compared with only 3 of 69 patients (4.4%) in the adult group (p < 0.001). Ground-level falls were the most common inciting event in the geriatric group (44% vs 14.5%, p < 0.001), whereas motor vehicle accidents were the most common etiology in the younger population (72.5% vs 38.2%, p < 0.001). Incidence of ischemic stroke did not vary significantly between the 2 groups (p > 0.05).CONCLUSIONSTVAI in the older adult population is associated with a significantly greater risk of mortality than in the younger adult population, despite the 2 groups having similar ISSs. Additionally, low-velocity mechanisms of injury, such as ground-level falls, are a greater risk factor for acquired TVAI in older adults than in younger adults, in whom it is a significantly less common etiology.