Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines

Multiple myeloma (MM) is an incurable hematological disorder characterized by dysregulated proliferation of terminally differentiated plasma cells. Aberrant histone acetylation has been observed in the development of numerous malignancies. Histone deacetylase inhibitors such as valproic acid (VPA) are promising drugs for cancer therapy since they have been reported to have antiproliferative effects and to induce differentiation in carcinoma and leukemic cells. Considering the advantage of being already in clinical use for epilepsy treatment, valproic acid might be a promising therapeutic candidate drug in the management of multiple myeloma. In this study, we show that the short fatty acid VPA has a time and dose-dependent cytotoxic effect on the MM cell lines OPM2, RPMI and U266. The influence of VPA on cell cycle and apoptosis have been evaluated by flow cytometry. Our results show that the three cell lines are blocked in G0/G1 phase. The observed sensitivity to VPA can be partially explained by late apoptosis. Since caspase 3 is activated in all tested cell lines after VPA treatment, a caspase-dependent pathway seems to be involved but not activated by the classic apoptotic pathways. We have also studied another mechanism of cell death, the senescence-like phenotype, but did not find any evidence for its implication. Thus, treatment with VPA may imply other alternative cell death mechanisms.     

Phase-contrast magnetic resonance angiography measurements of global cerebral blood flow in the neonate

Cerebral blood flow (CBF) alterations are important in pathogenesis of neonatal ischemic/hemorrhagic brain damage. In clinical practice, estimation of neonatal CBF is mostly based on Doppler-measured blood flow velocities in major intracranial arteries. Using phase-contrast magnetic resonance angiography (PC-MRA), global CBF can be estimated, but there is limited neonatal experience. The objective of this study was to gain experience with PC-MRA for the determination of global CBF in neonates. In infants eligible for MRI, PC-MRA global CBF was determined by measuring volume blood flow in both internal carotid arteries (ICAs) and basilar artery (BA). Thirty newborns (GA, 25.7-42.1 wk; weight, 1050-5858 g; postconceptional age, 225-369 d) were investigated. Total PC-MRA CBF ranged from 27 to 186 mL/min. Significant correlations between PC-MRA CBF and postconceptional age and weight were detected. When calculating PC-MRA measured CBF per kilogram body weight, brain perfusion was about stable over the range of postconceptional ages and ranged between 11 and 48 mL/min/kg (median, 25 mL/min/kg). In conclusion, neonatal PC-MRA CBF seems to be a useful technique to estimate noninvasive CBF.     

Deficiency of tenascin-X causes abnormalities in dermal elastic fiber morphology

Deficiency of the extracellular matrix protein tenascin-X (TNX) was recently described as the molecular basis of a new, recessive type of Ehlers-Danlos syndrome. Here we report gross abnormalities of the elastic fibers and microfibrils in the dermis of these patients, and reduced dermal collagen content, as determined by quantitative image analysis. The ascending, fine elastic fibers in the papillary dermis were absent or inconspicuous and had few branches. The coarse elastic fibers of the reticular dermis were fragmented and clumped. At the ultrastructural level, irregular and immature elastin fibers and fibers devoid of microfibrils were observed. In TNX-deficient patients the dermal collagen density was reduced, but no structural abnormalities in the collagen fibrils were found. These findings suggest that both elastic fiber abnormalities and reduced collagen content contribute to the observed phenotype in TNX-deficient patients.     

Pain catastrophizing: a dimensional concept analysis

Title.  Pain catastrophizing: a dimensional concept analysis.
Aim.  This paper is a report of a concept analysis of pain catastrophizing.
Background.  The importance of pain catastrophizing in the experience of pain and development of chronic pain has been demonstrated. It has been described as a tendency to have a fixation about pain and to feel unable to deal with pain.
Data sources.  Fifty-one papers containing the keyword 'pain catastrophizing' were selected from the Medline, Embase and Psycinfo indexes between 1996 and 2008. Dimensional analysis methodology was used to make explicit the ways in which the concept is constructed and used. The themes of this approach seem to contribute to the understanding of both nurse and client perspectives.
Results.  The literature on 'pain catastrophizing' seems to reach a level of middle-range explanatory theory. The focus is on specifying relationships between pain catastrophizing and two or more concepts, and on validating the theoretical hypotheses of 'communal coping' as opposed to 'hypervigilance'. The predominance of correlational and cross-sectional studies testifies to this. The concept's definition includes the curative and preventive approaches. However, only the professional perspective seems to be reflected in the concept's terminology.
Conclusion.  Nursing theories and qualitative research seem to be avenues for the comprehension of the phenomenon and the broadening of perspectives. They may bring not only a new but also a unique perspective. Nevertheless, the current state of knowledge on pain catastrophizing is important to nurses as they could influence greatly the timing of interventions and prevention of chronic pain.     

The value of the Van Nuys Prognostic Index in ductal carcinoma in situ of the breast: a retrospective analysis

The Van Nuys Prognostic Index 1996 (VNPI), based upon tumor size, pathological grade and tumor margins, is a guideline for the treatment of ductal carcinoma in situ (DCIS). It was thought to strongly decrease overtreatment. In 2003, age was added to the index as a fourth prognostic factor. We examined changes in treatment modality after applying the VNPI retrospectively and investigated if the addition of age to the Index causes a shift in treatment. The influence of each prognostic factor on disease-free survival (DFS) was calculated. We performed a retrospective file study of DCIS patients treated between 1985 and 2003 at the University Hospital, Antwerp. Patients were assigned a Van Nuys Score 1996 and 2003. The influence of tumor size, pathological grade, tumor margins and age on DFS was calculated with the Kaplan-Meier method and the log-rank test. We identified 104 DCIS cases with a median follow-up of 36 months. Twelve patients showed recurrence (11.5%), of whom seven were invasive (58%). Seventeen of the 29 women diagnosed before 1997 were undertreated according to the VNPI 1996 and six of them showed recurrence. The remaining three recurrences were correctly treated. Seventy-five patients diagnosed after 1997 were all treated according to the VNPI 1996 and only three had a recurrence. The introduction of age caused no significant shift in treatment modalities. Significant differences in DFS were seen between large (>41 mm) and small (<15 mm) tumors (p = 0.0074), old (>60 years) and young (<40 years) patients (p = 0.024) and Van Nuys Subgroup 2 and 3 (p = 0.04). Tumor margins and pathological grade showed no significant difference in DFS. The VNPI can be a useful tool in the treatment of DCIS. However, this Index is not evidence-based, using a relatively small retrospective series of patients. The validity of the modified VNPI must be prospectively confirmed with large numbers of DCIS patients.     

Identification of epigenetically silenced genes in tumor endothelial cells

Tumor angiogenesis requires intricate regulation of gene expression in endothelial cells. We recently showed that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors directly repress endothelial cell growth and tumor angiogenesis, suggesting that epigenetic modifications mediated by DNMTs and HDAC are involved in regulation of endothelial cell gene expression during tumor angiogenesis. To understand the mechanisms behind the epigenetic regulation of tumor angiogenesis, we used microarray analysis to perform a comprehensive screen to identify genes down-regulated in tumor-conditioned versus quiescent endothelial cells, and reexpressed by 5-aza-2'-deoxycytidine (DAC) and trichostatin A (TSA). Among the 81 genes identified, 77% harbored a promoter CpG island. Validation of mRNA levels of a subset of genes confirmed significant down-regulation in tumor-conditioned endothelial cells and reactivation by treatment with a combination of DAC and TSA, as well as by both compounds separately. Silencing of these genes in tumor-conditioned endothelial cells correlated with promoter histone H3 deacetylation and loss of H3 lysine 4 methylation, but did not involve DNA methylation of promoter CpG islands. For six genes, down-regulation in microdissected human tumor endothelium was confirmed. Functional validation by RNA interference revealed that clusterin, fibrillin 1, and quiescin Q6 are negative regulators of endothelial cell growth and angiogenesis. In summary, our data identify novel angiogenesis-suppressing genes that become silenced in tumor-conditioned endothelial cells in association with promoter histone modifications and reactivated by DNMT and HDAC inhibitors through reversal of these epigenetic modifications, providing a mechanism for epigenetic regulation of tumor angiogenesis.     

Toxicity assessment of contaminated soils from an antitank firing range

Explosives are released into the environment at production and processing facilities, as well as through field use. These compounds may be toxic at relatively low concentrations to a number of ecological receptors. A toxicity assessment was carried out on soils from an explosive-contaminated site at a Canadian Forces Area Training Center. Toxicity studies on soil organisms using endpoints such as microbial processes (potential nitrification activity, dehydrogenase activity, substrate-induced respiration, basal respiration), plant seedling and growth (Lactuca sativa and Hordeum vulgare), and earthworm (Eisenia andrei) growth and reproduction were carried out. Results showed that 1,3,5,7-tetranitro-1,3,5,7-tetrazacyclooctane (HMX) was the principal polynitro-organic compound measured in soils. Soils from the contaminated site decreased microbial processes and earthworm reproduction; whereas plant growth was not significantly reduced. Toxicity to aquatic organisms and genotoxicity were also assessed on soil elutriates using Microtox (Vibrio fischeri), growth inhibition of algae (Selenastrum capricornutum), and SOS Chromotest (Escherichia coli). Results indicated that soil elutriates were generally not toxic to bacteria (Microtox) and algae. However, genotoxicity was found in a number of soil elutriate samples. Thus, the explosive-contaminated soils from the antitank firing range may represent a hazard for the soil organisms. Nevertheless, the global toxicity might have partially resulted from HMX as well as from other (not identified) contaminants such as heavy metals.     

Fine-needle aspiration cytology of sarcomatoid renal cell carcinoma: A morphologic and immunocytochemical study of 15 cases

Sarcomatoid renal cell carcinoma (SRCC), which accounts for 5% of all renal cell carcinomas (RCC), has a worse prognosis than conventional nonsarcomatoid RCC. making accurate diagnosis important. This study reports on the morphologic and immunocytochemical features of 15 cases of SRCC (9 primary tumors and 6 metastases) diagnosed by fine-needle aspiration (FNA) biopsy. All but three cases showed a dimorphic cell population consisting of varying proportions of a high-grade epithelial component, either clear or granular-cell type and a spindle cell (sarcomatoid) component, of either fibrosarcomatous, malignant fibrous histiocytoma (MFH), or unclassified types. The sarcomatoid component in the biphasic and monophasic tumors stained positively for cytokeratin in 12 of 14 (85%) cases, for vimentin in 10 of 11 (91 %) cases, and for muscle-specific action in 4 of 11 (36%) cases. Of note, the three cases that demonstrated a purely sarcomatoid morphology stained positively for cytokeratin. Unlike in studies performed on surgically resected specimens, neither the proportion of the sarcomatoid component nor the presence of necrosis had prognostic significance, the discrepancy most likely being related to the sampling. We conclude that SRCC, both primary and metastatic, can be accurately diagnosed by FNA when cytologic features are evaluated in conjunction with immunocytochemical findings.