Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy

The immune response to cancer is critically determined by the way in which tumor cells die. As necrotic, stress-associated death can be associated with activation of antitumor immunity, whole tumor cell antigen loading strategies for dendritic cell (DC)-based vaccination have commonly used freeze-thaw "necrotic" lysates as an immunogenic source of tumor-associated antigens. In this study, the effect of such lysates on the ability of DCs to mature in response to well-established maturation stimuli was examined, and methods to enhance lysate-induced DC activation explored. Freeze-thaw lysates were prepared from murine tumor cell lines and their effects on bone marrow-derived DC maturation and function examined. Unmodified freeze-thaw tumor cell lysates inhibited the toll-like receptor-induced maturation and function of bone marrow-derived DCs, preventing up-regulation of CD40, CD86, and major histocompatibility complex class II, and reducing secretion of inflammatory cytokines [interleukin (IL)-12 p70, tumor necrosis factor-alpha, and IL-6]. Although IL-10 secretion was increased by lysate-pulsed DCs, this was not responsible for the observed suppression of IL-12. Although activation of the nuclear factor-kappaB pathway remained intact, the kinase activity of phosphorylated p38 mitogen-activated protein kinase was inhibited in lysate-pulsed DCs. Lysate-induced DC suppression was partially reversed in vitro by induction of tumor cell stress before lysis, and only DCs loaded with stressed lysates afforded protection against tumor challenge in vivo. These data suggest that ex vivo freeze-thaw of tumor cells does not effectively mimic in vivo immunogenic necrosis, and advocates careful characterization and optimization of tumor cell-derived vaccine sources for cancer immunotherapy.     

Hereditary nonpolyposis colorectal cancer (Lynch syndrome): molecular pathogenesis and clinical approaches to diagnosis and management for nurses

Hereditary nonpolyposis colorectal cancer (HNPCC), also referred to as Lynch syndrome, is the most common form of hereditary colorectal cancer and is responsible for 2% to 4% of all colorectal cancers in the Western hemisphere. Generally characterized by early-onset colorectal carcinoma with a mean age of presentation of 40 to 45 years, it can also manifest with extracolonic adenocarcinomas and cancers of the endometrium, ovaries, stomach, pancreas, small intestine, hepatobiliary tract, upper uroepithelial tract, brain, and skin. HNPCC is autosomal dominant and carries an 80% lifetime risk of cancer development. This review addresses the molecular underpinnings of HNPCC while providing a concise approach to clinical detection, diagnosis, and management of patients who may or may not test positive for an HNPCC-causing mutation. Although applicable to any patient-care setting in which cancer may be observed, this review specifically addresses the role of nurses in detecting, diagnosing, and clinically managing HNPCC.     

Multifidus size and symmetry among chronic LBP and healthy asymptomatic subjects

Previous studies have provided evidence of multifidus muscle atrophy in people with low back pain (LBP). In cases of acute LBP, these studies have shown that the pattern of atrophy is both vertebral level and side specific. For chronic LBP, there are conflicting reports about the extent and location of muscle atrophy. The purpose of this study was to compare chronic LBP patients and asymptomatic subjects on measures of multifidus size (cross-sectional area; CSA) and symmetry (proportional difference of relatively larger side to smaller side). Data were obtained from 40 asymptomatic subjects without a prior history of LBP (13 females, 27 males), and a retrospective audit was undertaken of records from 50 chronic low back pain patients (27 females, 23 males) presenting to a back pain clinic. Results of the analysis showed that chronic LBP patients had significantly smaller multifidus CSAs than asymptomatic subjects at the lowest two vertebral levels. Males were found to have significantly larger multifidus CSAs than females at all vertebral levels except L5, the most common symptomatic level as determined by manual examination. The greatest asymmetry between sides was seen at the L5 vertebral level in patients with unilateral pain presentations. The smaller multifidus CSA was ipsilateral to the reported side of pain in all cases. The results of this study support previous findings that the pattern of multifidus muscle atrophy in chronic LBP patients is localized rather than generalized. Furthermore, between side asymmetry may be seen in chronic LBP patients presenting with a unilateral pain distribution.     

Drotrecogin alfa (activated): real-life use and outcomes for the UK

Introduction  

In March 2001, the results of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study were published, which indicated a 6.1% absolute reduction in 28-day mortality. Drotrecogin alfa (activated; DrotAA) was subsequently approved for use in patients with severe sepsis.     

Neuroticism and introversion are associated with salivary cortisol patterns in adolescents

Previous studies have yielded equivocal findings on the relationship between personality and cortisol activity. The present study examined associations between personality and cortisol activity in a large, diverse adolescent sample, while partialling the effects of relevant demographic and health-related covariates. A subsample of 230 participants (57% of whom reported elevated neuroticism) was selected from a larger sample of 16-18-year olds involved in a study on risk factors for emotional disorders. Subsample participants completed a battery of personality questionnaires, and saliva collection was requested several months later on three consecutive days at six time points per day, from wakeup to bedtime. Associations between personality and cortisol rhythms were examined using multilevel growth curve modeling. Neuroticism (N) and introversion (I) were significantly and differentially associated with features of diurnal cortisol patterns. Specifically, a significant N x gender interaction was observed, demonstrating flatter cortisol rhythms across the waking day among male participants with higher N. Elevated I, however, was associated with lower cortisol awakening responses for both male and female participants, and higher cortisol at the time of waking for male participants only. The present study supports personality as a significant predictor of diurnal cortisol patterns in late adolescence, after accounting for the effects of demographic and health covariates, and suggests that gender plays a role in moderating associations between personality and cortisol.     

Cortical α-synuclein load is associated with amyloid-β plaque burden in a subset of Parkinson’s disease patients

Amyloid-β (Aβ) peptide pathology in Alzheimer’s disease (AD) comprises extracellular plaques and cerebral amyloid angiopathy (CAA). In Parkinson’s disease (PD), α-synuclein forms intraneuronal Lewy bodies (LBs), and cortical LBs are thought to play a major role in cognitive decline designated as PD with dementia. As there is increasing evidence that Aβ may also promote α-synuclein fibrillization, we assessed the relationship between LB pathology and Aβ deposition in 40 cases of PD and 20 age-matched controls. In five cortical areas, we established the severity of Aβ plaque load using an approach similar to that recommended by CERAD in AD. LB densities were determined using a morphometric approach. CAA was graded using previously described scales. The APOE genotype was established in 38 PD and 19 control cases. We have found that the overall Aβ plaque burden and, in particular, the diffuse plaque load shows a statistically significant ‘large’ correlation with the overall cortical LB burden. The strength of this correlation further increases in PD cases (about 50% of the cases) with moderate to high Aβ plaque load. The APOE ε4 allele is over-represented in this subgroup. Our data indicate a strong association between pathologically identifiable Aβ plaque burden and α-synuclein load in cerebral cortex and provide indirect evidence that Aβ pathology is likely to be an important factor contributing to cognitive decline in a subgroup of PD patients.