Low levels of cathepsin D are associated with a poor prognosis in endometrial cancer

Total cytosolic cathepsin D (Cat D) levels were estimated by an immunoradiometric assay in a series of 156 consecutive patients with surgical stages I–III primary endometrial adenocarcinoma. Simultaneously, the tissue content of both oestrogen (ER) and progesterone (PR) receptors, and p185HER-2/neu, DNA content (ploidy), and the fraction of S-phase cells (S-phase) were also estimated. Tumoral Cat D content ranged from 0 to 243 pmol mg−1 protein (median 44 pmol mg−1 protein) and was not associated with any of the established clinicopathological and biological prognostic variables, with the exception of a weak positive correlation with the tumoral p185HER-2/neu levels. Univariable analysis performed on a subset of 97 patients, followed for a minimum of 2 years or until death, showed that patient age at diagnosis, high histological grade, advanced surgical stage, vascular invasion, positive peritoneal cytology, low levels of Cat D, negative ER and PR status, aneuploidy, and high S-phase were predictive of the presence of persistent or recurrent disease. However, multivariable analysis revealed that only histological grade, surgical stage, Cat D and PR were significantly associated with the patient's outcome. From these findings, we conclude that Cat D is an independent prognostic factor in endometrial adenocarcinoma, its low levels being associated with a worse clinical outcome. © 1999 Cancer Research Campaig

Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolising enzyme inducing immune tolerance. The present study aimed to investigate IDO expression and its prognostic significance in endometrial cancer. Indoleamine 2,3-dioxygenase expression in endometrial cancer tissues (n=80) was immunohistochemically scored as four groups (IDO−, 1+, 2+, and 3+). The high IDO expression (IDO2+ or 3+) in tumour cells was found in 37 (46.3%) of the 80 cases, and was positively correlated with surgical stage, myometrial invasion, lymph-vascular space involvement, and lymph node metastasis, but not with the histological grade. Patients with high IDO expression had significantly impaired overall survival and progression-free survival (PFS) (P=0.002 and P=0.001, respectively) compared to patients with no or weak expression of IDO (IDO− or 1+). The 5-year PFS for IDO−/1+, 2+, and 3+ were 97.7, 72.9, and 36.4%, respectively. Even in patients with early-stage disease (International Federation of Gynecology and Obstetrics I/II, n=64), the PFS for IDO2+/3+ was significantly poor (P=0.001) compared to that for IDO−/1+. On multivariate analysis, IDO expression was an independent prognostic factor for PFS (P=0.020). These results indicated that the high IDO expression was involved in the progression of endometrial cancer and correlated with the impaired clinical outcome, suggesting that IDO is a novel and reliable prognostic indicator for endometrial cancer

Critical Role of NADPH Oxidase in Neuronal Oxidative Damage and Microglia Activation following Traumatic Brain Injury

BACKGROUND: Oxidative stress is known to play an important role in the pathology of traumatic brain injury. Mitochondria are thought to be the major source of the damaging reactive oxygen species (ROS) following TBI. However, recent work has revealed that the membrane, via the enzyme NADPH oxidase can also generate the superoxide radical (O(2)(-)), and thereby potentially contribute to the oxidative stress following TBI. The current study thus addressed the potential role of NADPH oxidase in TBI. METHODOLOGY/PRINCIPAL FINDINGS: The results revealed that NADPH oxidase activity in the cerebral cortex and hippocampal CA1 region increases rapidly following controlled cortical impact in male mice, with an early peak at 1 h, followed by a secondary peak from 24-96 h after TBI. In situ localization using oxidized hydroethidine and the neuronal marker, NeuN, revealed that the O(2)(-) induction occurred in neurons at 1 h after TBI. Pre- or post-treatment with the NADPH oxidase inhibitor, apocynin markedly inhibited microglial activation and oxidative stress damage. Apocynin also attenuated TBI-induction of the Alzheimer's disease proteins β-amyloid and amyloid precursor protein. Finally, both pre- and post-treatment of apocynin was also shown to induce significant neuroprotection against TBI. In addition, a NOX2-specific inhibitor, gp91ds-tat was also shown to exert neuroprotection against TBI. CONCLUSIONS/SIGNIFICANCE: As a whole, the study demonstrates that NADPH oxidase activity and superoxide production exhibit a biphasic elevation in the hippocampus and cortex following TBI, which contributes significantly to the pathology of TBI via mediation of oxidative stress damage, microglial activation, and AD protein induction in the brain following TBI

The Effects of Posttraumatic Hypothermia on Diffuse Axonal Injury Following Parasagittal Fluid Percussion Brain Injury in Rats

Previous investigations have demonstrated the beneficial effects of mild hypothermia following different types of traumatic brain injury (TBI). In some models, early cooling following TBI has been shown to reduce the frequency of axonal damage, a major consequence of head injury. The purpose of this study was to evaluate the effects of post-traumatic hypothermia in a model that has been shown to be sensitive to temperature manipulations in the early injury setting. Animals underwent moderate parasagittal fluid percussion (FP) brain injury and were then either randomized into normothermic or hypothermic groups. In the hypothermic groups, brain temperature was reduced to either 30°C or 33°C 5 minutes after trauma and maintained for a 3-hour period. Normothermic or sham-operated animals were held under normal temperature conditions. At 3 days after TBI, animals were perfusion-fixed for a quantitative assessment of beta amyloid precursor protein (β-APP) immunohistochemistry and silver staining. Traumatic injury led to a significant increase in the frequency of β-APP immunoreactive profiles within both the corpus callosum, external capsule, and the internal capsule. While early cooling revealed a trend for protection, no significant differences were shown between normothermic and hypothermic animals in terms of the frequency of injured axons at 3 days post-trauma. These results emphasize that axonal pathology is a major consequence of brain injury using this particular model. It is concluded that longer periods of post-traumatic hypothermia may be required to chronically protect axon populations undergoing a progressive injury

Assessing the Impact of Mailing Self-Sampling Kits for Human Papillomavirus Testing to Unscreened Non-Responder Women in Manitoba

Background: CervixCheck, Manitoba’s cervical cancer screening program, conducted a pilot study to assess whether screening participation could be improved in unscreened women by offering a mailed self-sampling kit for human papillomavirus (HPV) testing instead of a Pap test. Methods: In a prospective cohort study design, a sample of unscreened women (n = 1052) who had been sent an invitation letter from CervixCheck in the past but who did not respond were randomized to either an intervention group or a control group. The intervention group received a mailed HPV self-sampling kit; the control group received no additional communication. Returned HPV self-sampling swabs were analyzed by a provincial laboratory. After 6 months, screening participation in the two study groups was compared using a logistic regression model adjusted for age and area of residence (urban or rural). Secondary outcomes included HPV positivity, specimen inadequacy, compliance with follow-up, and time to colposcopy. Results: Screening participation was significantly higher in the intervention group than in the control group (n = 51, 9.6%, vs. n = 13, 2.5%; odds ratio: 4.7; 95% confidence interval: 2.56 to 8.77). Geographic area of residence (urban or rural) and age were not statistically significant. Conclusions: The study demonstrated that HPV self-sampling kits can enhance screening participation in unscreened non-responder women in the setting of an organized screening program. Next steps should include additional research to determine the best implementation strategy for HPV self-sampling in Manitoba