The Effect of N-nitrosodimethylamine (NDMA) on Bax and Mcl-1 Expression in Human Neutrophils

In the present study we examined a role of pro-apoptotic Bax and anti-apoptotic Mcl-1 proteins, participating in the regulation of intrinsic apoptosis pathway in human neutrophils (PMNs) exposed to N-nitrosodimethylamine (NDMA), the environmental xenobiotic. For the purpose comparison, the same studies were conducted in autologous peripheral blood mononuclear cells (PBMCs). The production of cytochrome c by PMNs was also determined. A deficit of anti-apoptotic Mcl-1 and overexpression of the pro-apoptotic protein Bax suggest that the apoptosis process in human neutrophils exposed to NDMA is dependent on changes in the expression of these proteins. PMNs were more sensitive to NDMA than PBMCs

Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer: A phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy

<p>Abstract</p> <p>Background</p> <p>In recent years, preoperative volume reduction of locally advanced breast cancers, resulting in higher rates of breast-conserving surgery (BCS), has become increasingly important also in postmenopausal women. Clinical interest has come to center on the third-generation nonsteroidal aromatase inhibitors (AIs), including letrozole, for such neoadjuvant endocrine treatment. This usually lasts 3–4 months and has been extended to up to 12 months, but optimal treatment duration has not been fully established.</p> <p>Methods</p> <p>This study was designed as a multicenter, open-label, single-arm, exploratory phase IIb/III clinical trial of letrozole 2.5 mg, one tablet daily, for 4–8 months. The primary objective was to investigate the effect of neoadjuvant treatment duration on tumor regression and BCS eligibility to identify optimal treatment duration. Tumor regression (by clinical examination, mammography, and ultrasound), shift towards BCS eligibility, and safety assessments were the main outcome measures. Standard parametric and nonparametric descriptive statistics were performed.</p> <p>Results</p> <p>Letrozole treatment was received by 32 of the enrolled 33 postmenopausal women (median (range): 67.0 (56–85) years) with unilateral, initially BCS-ineligible primary breast cancer (clinical stage ≥ T2, N0, M0). Letrozole treatment duration in the modified intent-to-treat (ITT; required 4 months' letrozole treatment) analysis population (29 patients) was 4 months in 14 patients and > 4 months in 15 patients. The respective per-protocol (PP) subgroup sizes were 14 and 11. The majority of partial or complete responses were observed at 4 months, though some beneficial responses occurred during prolonged letrozole treatment. Compared with baseline, median tumor size in the ITT population was reduced by 62.5% at Month 4 and by 70.0% at final study visit (Individual End). Similarly, in the PP population, respective reductions were 64.0% and 67.0%. Whereas initially all patients were mastectomy candidates, letrozole treatment enabled BCS (lumpectomy) in 22 ITT (75.9%) and 18 PP (72.0%) patients.</p> <p>Conclusion</p> <p>Over half of patients become BCS-eligible within 4 months of preoperative letrozole treatment. While prolonged treatment for up to 8 months can result in further tumor volume reduction in some patients, there is no clear optimum for treatment duration. Letrozole has a favorable overall safety and tolerability profile.</p> <p>Trial registration</p> <p>ClinicalTrials.gov identifier NCT00535418.</p

Clinical map document based on XML (cMDX): document architecture with mapping feature for reporting and analysing prostate cancer in radical prostatectomy specimens

<p>Abstract</p> <p>Background</p> <p>The pathology report of radical prostatectomy specimens plays an important role in clinical decisions and the prognostic evaluation in Prostate Cancer (PCa). The anatomical schema is a helpful tool to document PCa extension for clinical and research purposes. To achieve electronic documentation and analysis, an appropriate documentation model for anatomical schemas is needed. For this purpose we developed cMDX.</p> <p>Methods</p> <p>The document architecture of cMDX was designed according to Open Packaging Conventions by separating the whole data into template data and patient data. Analogue custom XML elements were considered to harmonize the graphical representation (e.g. tumour extension) with the textual data (e.g. histological patterns). The graphical documentation was based on the four-layer visualization model that forms the interaction between different custom XML elements. Sensible personal data were encrypted with a 256-bit cryptographic algorithm to avoid misuse. In order to assess the clinical value, we retrospectively analysed the tumour extension in 255 patients after radical prostatectomy.</p> <p>Results</p> <p>The pathology report with cMDX can represent pathological findings of the prostate in schematic styles. Such reports can be integrated into the hospital information system. "cMDX" documents can be converted into different data formats like text, graphics and PDF. Supplementary tools like cMDX Editor and an analyser tool were implemented. The graphical analysis of 255 prostatectomy specimens showed that PCa were mostly localized in the peripheral zone (Mean: 73% ± 25). 54% of PCa showed a multifocal growth pattern.</p> <p>Conclusions</p> <p>cMDX can be used for routine histopathological reporting of radical prostatectomy specimens and provide data for scientific analysis.</p

Elastofibroma dorsi – differential diagnosis in chest wall tumours

BACKGROUND: Elastofibromas are benign soft tissue tumours mostly of the infrascapular region between the thoracic wall, the serratus anterior and the latissimus dorsi muscle with a prevalence of up to 24% in the elderly. The pathogenesis of the lesion is still unclear, but repetitive microtrauma by friction between the scapula and the thoracic wall may cause the reactive hyperproliferation of fibroelastic tissue. METHODS: We present a series of seven cases with elastofibroma dorsi with reference to clinical findings, further clinical course and functional results after resection, as well as recurrence. Data were obtained retrospectively by clinical examination, phone calls to the patients' general practitioners and charts review. Follow-up time ranged from four months to nine years and averaged 53 months. RESULTS: The patients presented with swelling of the infrascapular region or snapping scapula. In three cases, the lesion was painful. The ratio men/women was 2/5 with a mean age of 64 years. The tumor sizes ranged from 3 to 13 cm. The typical macroscopic aspect was characterized as poorly defined fibroelastic soft tissue lesion with a white and yellow cut surface caused by intermingled remnants of fatty tissue. Microscopically, the lesions consisted of broad collagenous strands and densely packed enlarged and fragmented elastic fibres with mostly round shapes. In all patients but one, postoperative seroma (which had to be punctuated) occurred after resection; however, at follow-up time, no patient reported any decrease of function or sensation at the shoulder or the arm of the operated side. None of the patients experienced a relapse. CONCLUSION: In differential diagnosis of soft tissue tumors located at this specific site, elastofibroma should be considered as likely diagnosis. Due to its benign behaviour, the tumor should be resected only in symptomatic patients

Occipital peripheral nerve stimulation in the management of chronic intractable occipital neuralgia in a patient with neurofibromatosis type 1: a case report

<p>Abstract</p> <p>Introduction</p> <p>Occipital peripheral nerve stimulation is an interventional pain management therapy that provides beneficial results in the treatment of refractory chronic occipital neuralgia. Herein we present a first-of-its-kind case study of a patient with neurofibromatosis type 1 and bilateral occipital neuralgia treated with occipital peripheral nerve stimulation.</p> <p>Case presentation</p> <p>A 42-year-old Caucasian woman presented with bilateral occipital neuralgia refractory to various conventional treatments, and she was referred for possible treatment with occipital peripheral nerve stimulation. She was found to be a suitable candidate for the procedure, and she underwent implantation of two octapolar stimulating leads and a rechargeable, programmable, implantable generator. The intensity, severity, and frequency of her symptoms resolved by more than 80%, but an infection developed at the implantation site two months after the procedure that required explantation and reimplantation of new stimulating leads three months later. To date she continues to experience symptom resolution of more than 60%.</p> <p>Conclusion</p> <p>These results demonstrate the significance of peripheral nerve stimulation in the management of refractory occipital neuralgias in patients with neurofibromatosis type 1 and the possible role of neurofibromata in the development of occipital neuralgia in these patients.</p

Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages in zebrafish spinal cord regeneration

Spinal cord injury leads to a massive response of innate immune cells in non-regenerating mammals, but also in successfully regenerating zebrafish. However, the role of the immune response in successful regeneration is poorly defined. Here we show that inhibiting inflammation reduces and promoting it accelerates axonal regeneration in spinal-lesioned zebrafish larvae. Mutant analyses show that peripheral macrophages, but not neutrophils or microglia, are necessary for repair. Macrophage-less irf8 mutants show prolonged inflammation with elevated levels of Tnf-α and Il-1β. Inhibiting Tnf-α does not rescue axonal growth in irf8 mutants, but impairs it in wildtype animals, indicating a pro-regenerative role of Tnf-α. In contrast, decreasing Il-1β levels or number of Il-1β+ neutrophils rescue functional regeneration in irf8 mutants. However, during early regeneration, interference with Il-1β function impairs regeneration in irf8 and wildtype animals. Hence, inflammation is dynamically controlled by macrophages to promote functional spinal cord regeneration in zebrafish

High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas

Contains fulltext : 80487.pdf (publisher's version ) (Open Access)BACKGROUND: The diagnosis of benign renal oncocytomas (RO) and chromophobe renal cell carcinomas (RCC) based on their morphology remains uncertain in several cases. METHODS: We have applied Affymetrix GeneChip Mapping 250 K NspI high-density oligoarrays to identify small genomic alterations, which may occur beyond the specific losses of entire chromosomes, and also Affymetrix GeneChip HG-U133 Plus2.0 oligoarrays for gene expression profiling. RESULTS: By analysing of DNA extracted from 30 chRCCs and 42 ROs, we have confirmed the high specificity of monosomies of chromosomes 1, 2, 6, 10, 13, 17 and 21 in 70-93% of the chRCCs, while ROs displayed loss of chromosome 1 and 14 in 24% and 5% of the cases, respectively. We demonstrated that chromosomal gene expression biases might correlate with chromosomal abnormalities found in chromophobe RCCs and ROs. The vast majority genes downregulated in chromophobe RCC were mapped to chromosomes 2, 6, 10, 13 and 17. However, most of the genes overexpressed in chromophobe RCCs were located to chromosomes without any copy number changes indicating a transcriptional regulation as a main event. CONCLUSION: The SNP-array analysis failed to detect recurrent small deletions, which may mark loci of genes involved in the tumor development. However, we have identified loss of chromosome 2, 10, 13, 17 and 21 as discriminating alteration between chromophobe RCCs and ROs. Therefore, detection of these chromosomal changes can be used for the accurate diagnosis in routine histology

Optimizing Metapopulation Sustainability through a Checkerboard Strategy

The persistence of a spatially structured population is determined by the rate of dispersal among habitat patches. If the local dynamic at the subpopulation level is extinction-prone, the system viability is maximal at intermediate connectivity where recolonization is allowed, but full synchronization that enables correlated extinction is forbidden. Here we developed and used an algorithm for agent-based simulations in order to study the persistence of a stochastic metapopulation. The effect of noise is shown to be dramatic, and the dynamics of the spatial population differs substantially from the predictions of deterministic models. This has been validated for the stochastic versions of the logistic map, the Ricker map and the Nicholson-Bailey host-parasitoid system. To analyze the possibility of extinction, previous studies were focused on the attractiveness (Lyapunov exponent) of stable solutions and the structure of their basin of attraction (dependence on initial population size). Our results suggest that these features are of secondary importance in the presence of stochasticity. Instead, optimal sustainability is achieved when decoherence is maximal. Individual-based simulations of metapopulations of different sizes, dimensions and noise types, show that the system's lifetime peaks when it displays checkerboard spatial patterns. This conclusion is supported by the results of a recently published Drosophila experiment. The checkerboard strategy provides a technique for the manipulation of migration rates (e.g., by constructing corridors) in order to affect the persistence of a metapopulation. It may be used in order to minimize the risk of extinction of an endangered species, or to maximize the efficiency of an eradication campaign

Oxalic acid, versatile peroxidase secretion and chelating ability of Bjerkandera fumosa in rich and limited culture conditions

Efficient ligninolytic systems of wood-degrading fungi include not only oxidizing enzymes, but also low-molecular-weight effectors. The ability of Bjerkandera fumosa to secrete oxalic acid and versatile peroxidase (VP) in nitrogen-rich and nitrogen-limited media was studied. Higher activity of VP was determined in the nitrogen-limited media but greater concentration of oxalic acid was observed in the cultures of B. fumosa without nitrogen limitation. Ferric ions chelating ability of Bjerkandera fumosa studied in ferric ions limited media was correlated with the increased level of oxalic acid. The presence of hydroxamate-type siderophores in B. fumosa media were also detected. Oxalate decarboxylase was found to be responsible for regulation of oxalic acid concentration in the tested B. fumosa cultures

Staphylococcus aureus Panton-Valentine Leukocidin Contributes to Inflammation and Muscle Tissue Injury

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) threatens public health worldwide, and epidemiologic data suggest that the Panton-Valentine Leukocidin (PVL) expressed by most CA-MRSA strains could contribute to severe human infections, particularly in young and immunocompetent hosts. PVL is proposed to induce cytolysis or apoptosis of phagocytes. However, recent comparisons of isogenic CA-MRSA strains with or without PVL have revealed no differences in human PMN cytolytic activity. Furthermore, many of the mouse studies performed to date have failed to demonstrate a virulence role for PVL, thereby provoking the question: does PVL have a mechanistic role in human infection? In this report, we evaluated the contribution of PVL to severe skin and soft tissue infection. We generated PVL mutants in CA-MRSA strains isolated from patients with necrotizing fasciitis and used these tools to evaluate the pathogenic role of PVL in vivo. In a model of necrotizing soft tissue infection, we found PVL caused significant damage of muscle but not the skin. Muscle injury was linked to induction of pro-inflammatory chemokines KC, MIP-2, and RANTES, and recruitment of neutrophils. Tissue damage was most prominent in young mice and in those strains of mice that more effectively cleared S. aureus, and was not significant in older mice and mouse strains that had a more limited immune response to the pathogen. PVL mediated injury could be blocked by pretreatment with anti-PVL antibodies. Our data provide new insights into CA-MRSA pathogenesis, epidemiology and therapeutics. PVL could contribute to the increased incidence of myositis in CA-MRSA infection, and the toxin could mediate tissue injury by mechanisms other than direct killing of phagocytes