Down-regulation of the inhibitor of growth 1 (ING1) tumor suppressor sensitizes p53-deficient glioblastoma cells to cisplatin-induced cell death

Impaired tumor suppressor functions, such as deficient p53, are characteristic for glioblastoma multiforme (GBM) and can cause resistance to DNA-damaging agents like cisplatin. We have recently shown that the INhibitor of Growth 1 (ING1) tumor suppressor is down-regulated in malignant gliomas and that the decrease of ING1 expression correlates with histological grade of malignancy, suggesting a role for ING1 in the pathogenesis and progression of malignant gliomas. Based on this background, the purpose of our current study was to examine the potential impact of ING1 protein levels on DNA-damage response in GBM. Using LN229 GBM cells, which express ING1 proteins and harbor mutant TP53, we are the first to show that DNA damage by cisplatin or ionizing radiation differentially induced the two major ING1 splicing isoforms. The p47 ^ING1a isoform, that promotes deacetylation of histones, thus formation of heterochromatic regions of DNA, which are less susceptible to DNA damage, was preferentially induced by >50-fold. This might represent a response to protect DNA from damage. Also, ING1 knockdown by siRNA accelerated transit of cells through G₁ phase, consistent with ING1 serving a tumor suppressor function, and caused cells to enter apoptosis more rapidly in response to cisplatin. Our results indicate that malignant gliomas may down-regulate ING1 to allow more efficient tumor growth and progression. Also, ING1 down-regulation may sensitize GBM cells with deficient p53 to treatment with cisplatin. U. G. Tallen and M. Truss contributed equally to this work.     

Overexpression Of GPR7 In Schwann Cells From Patients With Peripheral Neuropathies

The identification of regulated gene products that play a role in Schwann cell-axon contact after nerve injuries may have important implications for pain mechanisms and nerve repair processes. Schwann cell-intrinsic defects have been recently shown to cause neuropathies associated with pain (Gillespie et al., 2000). The 7TM GPR7, originally described by O'Dowd et al. (1995) as a likely G-protein coupled receptor, is a human orphan receptor expressed in the nervous system with sequence similarity to both somatostatin and opioid receptors. Using real time quantitative PCR^TM we evaluated the expression of GPR7 in sural nerve biopsies from patients with different kinds of peripheral neuropathies. We observed that GPR7 expression was significantly (p < 0.001) increased in sural nerves when an epineurial and endoneurial perivascular inflammatory infiltration was present. The overexpression was particularly noted in patients with painful peripheral neuropathies with an inflammatory, immuno and vasculitic etiology. In order to confirm changes in GPR7 expression at the protein level, we performed immunofluorescence staining on sections of neuropathic human sural nerves. A comparative analysis of rat injured sciatic nerves was also performed. We observed that GPR7 receptor is expressed by Schwann cells and that the amount of Schwann cell-staining in both human and rat nerve is increased in conditions of inflammatory neuropathy. In addition, we observed that the expression of GPR7 was significantly decreased in severe axonal neuropathies, suggesting that GPR7 expression is axon dependent. Immunofluorescence staining in rat cultured Schwann cells suggested that the expression GPR7 increased during Schwann-axon interaction. Taken together these results suggest that molecules such as GPR7 whose expression in Schwann cells varies under pathological conditions may play a role in the pathogenesis of human neuropathies. Altered GPR7 expression may disrupt myelination leading to progression of the neuropathy. Alternatively, GPR7 may play a role in Schwann cell-axon signaling and thereby influence axonal function in neuropathies leading to a painful phenotype.     

Perioperative Outcomes Following Surgical Resection of Renal Cell Carcinoma with Inferior Vena Cava Thrombus Extending Above the Hepatic Veins: A Contemporary Multicenter Experience

Background

Surgery for renal cell carcinoma (RCC) patients with inferior vena cava (IVC) thrombus above the hepatic veins is technically complex and associated with an increased risk of perioperative morbidity and mortality. However, minimal data exist that describe contemporary perioperative outcomes at major referral centers or the prognostic factors associated with poor outcomes.

Objective

To determine the preoperative predictors of major complications and 90-d mortality after surgery in RCC patients who have IVC thrombus above the hepatic veins.

Design, setting, and participants

We reviewed medical records of all RCC patients who had IVC tumor thrombus above hepatic veins and had had surgery between January 2000 and December 2012 at the Mayo Clinic, M.D. Anderson Cancer Center, University of Texas Southwestern Medical Center, and the University of Wisconsin Hospital.

Outcome measurement and statistical analysis

Major complications recorded were defined as ≥3A according to the Clavien-Dindo system within 90 d of surgery. Univariate and multivariate analyses were used to evaluate associations of preoperative variables with risk of major complications or 90-d mortality.

Results and limitations

A total of 162 patients were identified for study (level 3, 4 in 69, 93 patients, respectively, according to the Neves classification). Cardiopulmonary bypass was used in 60 of 162 patients (37.5%), and 40 patients (24.7%) had preoperative angioembolization. Major complications were reported in 55 patients (34.0%), with the most common being respiratory, cardiac, and hematologic issues. After multivariate analysis, preoperative systemic symptoms and level 4 thrombus were independently associated with increased risk of major complications. Mortality was reported in 17 patients (10.5%) within 90 d after surgery. After multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status (PS) and low serum albumin were preoperative factors independently associated with increased risk of 90-d mortality.

Conclusions

Contemporary perioperative mortality and major complication rates for RCC patients who have upper-level thrombus are 10% and 34%, respectively. Patients who have ECOG PS >1 or low serum albumin have increased risk for perioperative mortality.     

Accuracy of three cone-beam CT devices and two software systems in the detection of vertical root fractures

Objectives :The aim of this study was to compare the accuracy of vertical root fracture (VRF) detection using three tomography devices and two software systems in teeth with different endodontic fillings.Methods:The sample consisted of 45 premolars divided into 3 groups: No filling (NF, n=15); Gutta percha (GP, n=15) and Metallic Post (MP, n=15). Cone-beam computed tomography (CBCT) images were acquired in Kodak 9000 3D, Orthopantomography 300 (OP300) and PreXion 3D devices, before and after induced root fractures. Two oral radiologists analyzed all images using InVivoDental and e-Vol DX software systems. The analysis was repeated after 15 days in 30% of the sample. Data analysis compared receiver operating characteristic (ROC) curves, as well the areas under the ROC curves. Accuracy, sensitivity, specificity, positive and negative predictive value were calculated according to each tomographic device and software. Intra- and interexaminer reliability were tested using the Kappa coefficient.Results:The highest accuracy was seen in the image set from the PreXion 3D, using InVivo (0.96) or e-Vol DX (0.92) in image analysis. The OP300 device presented a similar performance of the PreXion 3D in teeth with different endodontic fillings. When using e-Vol DX, the accuracy of Kodak 9000 3D improved from 0.62 to 0.74.Conclusions:The PreXion 3D device is the most accurate when detecting VRF, with a performance similar to the OP300 in endodontic filled teeth. Kodak 9000 3D is indicated for teeth without fillings, with better accuracy using e-Vol DX software.     

The Impact of Migraine on Health Status

Problems.-What is the effect of migraine on health status, defined as the patient's physical, psychological, and social functioning? And, suppose that the health status of migraine sufferers appears to be impaired, to what extent is this a consequence of migraine-associated comorbidity rather than of migraine itself? Methods.-A group of 846 migraineurs, selected from the general population following IHS criteria, and a control group were surveyed with the Medical Outcomes Study 36-item Short-Form Health Survey, Nottingham Health Profile, EuroQol instrument, end the COOP/WONCA charts. Questions on demographic characteristics and comorbidity were included. Results.-The health status of migraineurs appeared to be significantly impaired in comparison to the control group. Because statistical significance is distinct from relevance, effect size estimators were employed. Although the direction of the differences indicated consistently a worse health status of the migraineurs, regardless of the instrument used, the sizes of the differences were small to medium. Self-reported comorbidity, especially depression, was more prevalent in the migraine group. However, this offered only a partial explanation for the impaired health status of the migraine group. Conclusions.-Migraine has an independent moderately deteriorating effect on the daily functioning of individuals.     

NHP or SIP—A comparative study in renal insufficiency associated anemia

In this study we compared the feasibility, internal structure and psychometric characteristics (internal consistency, test-retest reliability, construct validity) of two widely used generic health status measures, i.e. the Nottingham Health Profile (NHP) and the Sickness Impact Profile (SIP) when employed among a sample of patients on renal dialysis (n=63). The NHP was found to be more feasible, i.e. shorter and less difficult, than the SIP. The NHP scales showed somewhat higher levels of internal consistency (mean =0.67, range=0.39–0.80) than the SIP scales (mean =0.65, range=0.14–0.82). Test-retest reliability with a 24-hour interval was acceptable for most NHP scales (not available for the SIP in this study). Intercorrelations between the NHP scales were somewhat weaker than those for the SIP, and the expected patterns of scale intercorrelations were largely confirmed. The overall pattern of correlations between NHP scales and SIP scales was consistent with expectations, although the correlations were generally rather weak. Correlations between NHP scales and SIP scales and instruments measuring mainly physical functioning (ADL, Karnofsky) were largely as expected. Similarly, correlations between NHP scales and SIP scales and instruments measuring mainly psychological functioning [STAI (anxiety), SDS-Zung (depression)] were also as expected, although here the correlations were weaker for the SIP when compared with the NHP. The Index of Well-being exhibited intra-class correlations >0.3 with one SIP scale and with five out of six NHP scales. Common factor analysis, yielding a two-factor solution with a physical and a mental factor of equal importance, showed the SIP scales to load more on the physical factor, while the NHP scales loaded more on the mental factor. The NHP generally performed better than the SIP in terms of feasibility and internal consistency. Physical functioning is emphasized in the SIP, whereas the emphasis of the NHP lies on mental functioning. The analysis confirmed to some extent the intentions of the constructors of NHP and SIP respectively, i.e. the NHP to be a measure of perceived health and the SIP to be a more functional measure.