Changes in markers of neuronal and glial plasticity after cortical injury induced by food restriction

The regenerative capacity of the adult central nervous system is limited. We investigated whether short-term food restriction (FR; 50% of the daily food intake lasting 3 months) modulates processes of brain plasticity after cortical injury. Quantitative changes of growth-associated protein 43 (GAP-43) and synaptophysin (SYP) mRNA levels in the ipsilateral cortex of the adult rat during the recovery period (from 2 to 28 days) after injury were investigated by real-time RT-PCR. Using Western blot and immunohistochemical analyses we examined the levels and localization of proteins involved in neuronal plasticity, SYP and GAP-43, as well as glial fibrillary acidic protein (GFAP), a marker of glial plasticity. A marked rise in GAP-43 and SYP immunoreactivity observed in the FR group on the 7th day after injury pointed to increases in axonal branching and synapses in the cortex surrounding the lesion. The appearance of reactive astrocytes was accompanied by the absence of immunoreactivity for GAP-43 and SYP in ad libitum fed animals. This finding supports the hypothesis that morphological hypertrophy of astrocytes associated with GFAP synthesis is responsible either directly or indirectly for the inhibitory role of activated glia on axonal regeneration. Examination of the effects of FR on serum corticosterone and glucose concentrations and GAP-43, SYP and GFAP expression revealed that FR facilitated recovery of the injured region by attenuating reactive astrogliosis and enhancing the expression of neuronal plasticity markers.     

Humanized SCID mice models of SLE

The pathological DNA-specific B cells in Systemic lupus erythematosus are a logical target for a selected therapeutic intervention. It has been recently shown that complement receptor type 1 on human B and T-lymphocytes has suppressive activity. The co-crosslinking of this receptor with the B-cell receptor (BCR) inhibits B cell activation and proliferation and it could be an attractive new target for negative signal delivery. Experimental therapy in humans is limited by many restrictions. Severe combined immunodeficiency (SCID) mice, which lack both T and B lymphocytes and accept xenogenic cells have been used for human cell transfer for evaluating the pathogenesis of human SLE. We hypothesize that it may be possible to re-establish tolerance to native DNA in humanized SCID mice with cells transferred from SLE patients by administering to them a chimeric molecule, containing a monoclonal antibody against human inhibitory complement receptor type 1 coupled to a decapeptide DWEYSVWLSN that mimics DNA antigenically. These protein-engineered molecules are able to co-crosslink selectively the antigen receptors of B-cells possessing anti-native DNA specificity with the inhibitory surface receptors, thus delivering a strong suppressive signal.     

Submicroscopic bone marrow involvement in isolated extramedullary relapses in childhood acute lymphoblastic leukemia: a more precise definition of "isolated" and its possible clinical implications, a collaborative study of the Resistant Disease Committee of the International BFM study group

This study investigates the extent of bone marrow (BM) involvement at diagnosis of apparent isolated extramedullary (AIEM) relapses of childhood acute lymphoblastic leukemia (ALL) and its relation to prognosis. Sixty-four children with first AIEM relapse treated in Germany, Czech Republic, or France were included. Real-time quantitative polymerase chain reaction using T-cell receptor and immunoglobulin gene rearrangements provided a sensitive measure of submicroscopic BM involvement, which was detectable at a level of 10(-4) or higher in 46 patients and less than 10(-4) in 11 patients, and was nondetectable (sensitivity: 10(-4)) in 7 patients. In the total cohort, the probability of event-free survival (pEFS) for children with BM involvement of 10(-4) or higher was 0.30 (0.09 +/- SE) versus 0.60 (+/- 0.12) for those with less than 10(-4) (P = .13). The cumulative incidence of subsequent relapse was 0.24 (+/- 0.01) for patients with BM involvement less than 10(-4) and 0.65 (+/- 0.01) for those with 10(-4) or higher (P = .012). Restricted to central nervous system (CNS) relapses, pEFS was 0.11 (+/- 0.09) for patients with BM involvement 10(-4) or higher and 0.63 (+/- 0.17) for those with less than 10(-4) (P = .053). CNS relapses were associated with a higher (> or = 10(-4): 80%) submicroscopic BM involvement than testicular relapses (> or = 10(-4): 57%, P = .08). In summary, we show marked heterogeneity of submicroscopic BM involvement at first AIEM relapse diagnosis in children with ALL, and demonstrate its possible prognostic relevance.     

Essential role of the TNF-TNFR2 cognate interaction in mouse dendritic cell-natural killer cell crosstalk

Dendritic cells (DCs) and natural killer (NK) cells are essential components of the innate immune system and have a central role in initiation and regulation of adaptive immune responses. During the early critical immune activities, DCs and NK cells interact and reciprocally regulate each other via cell-cell contact. The molecular mediators of the DC-NK-cell crosstalk are largely undefined. In the present study, we show in mice that DC stimulation of NK-cell IFN-gamma secretion requires DC membrane-bound but not secreted products; is increased by augmenting the expression of DC transmembrane tumor necrosis factor (tmTNF) and NK-cell transmembrane TNF receptor type 2 (tmTNFR2); is inhibited by blocking TNF or TNFR2 but not TNFR1; is impaired by knocking out DC Tnf or NK-cell Tnfr2 but not DC Tnfr1 or Tnfr2 and NK-cell Tnf or Tnfr1; and is restored in TNF-deficient DCs by reconstituting tmTNF, but cannot be mimicked by soluble TNF. We also demonstrate that DC TNF and NK-cell TNFR2 are required for DC-mediated NK-cell proliferation and amplification of cytotoxic activity. These novel findings provide the first evidence that DC-NK-cell crosstalk mediates enhancement of NK-cell functions via triggering NK-cell tmTNFR2 by DC tmTNF.     

Phyllodes tumors of the breast diagnostic and therapeutic dilemmas

BACKGROUND: This article compares experiences in the diagnosis and treatment of phyllodes tumors from 2 regional institutions with the relevant literature. PATIENTS AND METHODS: From 1991 to 2005, 2,848 breast cancer patients were treated in our institutions, 36 (1.44%) for phyllodes tumors. The average tumor size was 5.1 cm (range 1.4-19.6). Triple assessment was the standard diagnostic algorithm. Wide excision with tumor-free margins was carried out in 29 (80.5%) cases and mastectomy in 7 (19.4%) cases. Axillary lymphadenectomy was performed in patients with positive lymph nodes. RESULTS: Histology showed the phyllodes tumors to be benign in 27 (75.0%), malignant in 6 (16.6%), and borderline in 3 (8.3%) cases. Follow-up was from 5 months to 16 years. In this period, recurrences of 3 (8.3%) malignant and 2 (5.6%) benign phyllodes tumors were diagnosed and treated. 10 (27.7%) patients treated with wide local excision showed deformities in the form of scarring. The steroid receptor status was of no prognostic value in our patients, and chemotherapy was used in only 1 (2.7%) patient. 5-year survival was 86.2%. CONCLUSION: Our study shows that tumor size, margin infiltration, mitotic activity and degree of cellular atypia are important prognostic factors. Problems in diagnosing this condition arise from its similarity to fibroadenoma. Although wide local excision is usually the treatment of choice, tumor recurrence is common. Axillary lymphadenectomy in malignant phyllodes tumors is, in our opinion, still controversial.     

Radiation-induced antitumor properties of vitamin B5 (pantothenic acid) and its effect on mitomycin C activity: experiments in vitro

Vitamin B5 (pantothenic acid) shows a strongly pronounced antitumor effect under the influence of ionizing radiation. In the frame of experiments in vitro (model: Escherichia coli bacteria, AB1157) performed under the exact knowledge of concentration and kind of the free radicals acting in the various aqueous media (pH 7.4) the following was established: (i) vitamin B5 possesses a very intense antitumor property, (ii) it exerts a strong synergistic effect on mitomycin C (MMC), (iii) the oxidizing species (OH*, O2*-) appears to be most important in the initiation of the observed effect. The generated radiolytic products from vitamin B5 very likely also play an important role in this respect.     

Preoperative Serum CA-125 Level As a Predictor for The Extent of Cytoreduction in Patients with Advanced Stage Epithelial Ovarian Cancer

BackgroundOvarian cancer is the seventh most common cancer in women worldwide and the eighth most common cause of cancer death. Due to the lack of effective early detection strategies and the unspecific onset of symptoms, it is diagnosed at an advanced stage in 75% of cases. The cancer antigen (CA) 125 is used as a prognostic marker and its level is elevated in more than 85% of women with advanced stages of epithelial ovarian cancer (EOC). The standard treatment is primary debulking surgery (PDS) followed by adjuvant chemotherapy (ACT), but the later approach is neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). Several studies have been conducted to find out whether preoperative CA-125 serum levels influence treatment choice, surgical resection and survival outcome. The aim of our study was to analyse experience of single institution as Cancer comprehensive center with preoperative usefulness of CA-125.Patients and methodsAt the Institute of Oncology Ljubljana a retrospective analysis of 253 women with stage FIGO IIIC and IV ovarian cancer was conducted. Women were divided into two groups based on their primary treatment. The first group was the NACT group (215 women) and the second the PDS group (38 women). The differences in patient characteristics were compared using the Chi-square test and ANOVA and the Kaplan-Meier method was used for calculating progression-free survival (PFS) and overall survival (OS).ResultsThe median serum CA-125 level was higher in the NACT group than in the PDS group, 972 IU/ml and 499 IU/ ml, respectively. The PFS in the NACT group was 8 months (95% CI 6.4–9.5) and 18 months (95% CI 12.5–23.4) in the PDS group. The median OS was lower in the NACT group than in the PDS group, 25 months (95% CI 20.6–29.5) and 46 months (95% CI 32.9–62.1), respectively.ConclusionsPreoperative CA-125 cut off value of 500 IU/ml is a promising threshold to predict a successful PDS.Key words: ovarian cancer, tumour marker, CA-125, primary debulking surgery, neoadjuvant chemotherapy     

Differentially expressed genes in neurofibromatosis 1-associated neurofibromas and malignant peripheral nerve sheath tumors

Neurofibromas represent one of the hallmarks of neurofibromatosis 1 (NF1) patients. Tumor progression of neurofibromas to malignant peripheral nerve sheath tumors (MPNST) is a frequent and life threatening complication. To learn more about processes involved in malignant transformation, we evaluated differential gene expression in plexiform neurofibroma and MPNST from the same NF1 patient. Suppression subtractive hybridization (SSH) yielded 133 differentially expressed genes confirmed by reverse Northern blotting. Virtual Northern blots were employed to validate 23 genes. To independently verify differential expression, immunohistochemical analyses with antibodies to matrix metalloproteinase 13 (MMP13), platelet-derived growth factor receptor alpha (PDGFRA) and fibronectin (FN1) were performed on 9 dermal and 9 plexiform neurofibromas and 16 MPNST from 19 NF1 patients. All three proteins proved to be up-regulated in MPNST. MMP13 expression was observed in 44% of MPNST but was absent in neurofibromas. PDGFRA was expressed in all tumors, but the number of cells expressing it was below 30% in neurofibromas and over 50% in MPNST. Likewise, FN1 was expressed in all tumors, but less than 30% of the cells in neurofibromas and more than 70% of the cells in MPNST exhibited antibody binding. Our data point to several genes not previously recognized to be differentially expressed, and provide a framework for future studies on progression-associated gene expression in low- and high-grade nerve sheath tumors.     

Treatment of Squamous Cell Carcinoma with Interferon

Human natural leukocytic interferon and recombinant HulFN alpha 2c can be used in the therapy of squamous cell carcinoma. The duration of treatment was 3-6 weeks. A single dose was 400,000-5,000,000 units given weekly for 3-6 weeks. Clinically and histologically 19 of 32 patients were cured and tumor cells were not found in the material taken after interferon treatment for the second biopsy. In ten patients tumor size was reduced 25-90%, and in three patients tumor size was not reduced according to clinical findings. With recombinant HulFN alpha 2c therapy given 5 times per week for 4 weeks. Four of ten patients with similar tumors were cured clinically and histologically clinical findings. In five patients tumor size was reduced 25-90%, while in one patient there was no reduction in tumor size. Both types of interferons are effective in the treatment of squamous cell carcinoma. Side reactions were mild.     

Satisfaction with the dentition related to dental functional status and tooth replacement in an adult Bulgarian population: a cross-sectional study

Objectives

The purpose of this study is to assess satisfaction with the dentition in general, dental esthetics, and chewing function related to dental functional status and tooth replacement in subjects, dentate in both jaws.

Materials and methods

Dentitions of subjects (n?=?2,437) aged ≥20 years were categorized in a hierarchical functional classification system, with and without tooth replacements, according to four dental conditions: ‘≥10 teeth in each jaw’, ‘complete anterior regions’, ‘sufficient premolar regions’ (≥3 occluding pairs), and ‘sufficient molar regions’ (bilaterally ≥1 occluding pair). Likelihood ratios (LR) were used to express the ability of these conditions to discriminate between satisfied and not satisfied subjects. Odds ratios (OR) were calculated to evaluate associations between satisfaction, the four dental conditions separately, and tooth replacement.

Results

In the hierarchical system, subjects having ‘<10 teeth’ were more likely of being not satisfied with their dentitions (LR 4.09), esthetics (LR 3.51), and chewing (LR 5.49). As a separate condition, ‘≥10 teeth’ was significantly associated only with satisfaction with chewing. The conditions ‘complete anterior regions’ and ‘sufficient’ premolar and molar regions’ were associated with all satisfaction variables (ORs 1.47–2.96, p values ≤0.012). When dental conditions were determined on the basis of natural teeth only, having teeth replaced was positively correlated with satisfaction; when determined on the basis of natural plus replaced teeth, subjects having teeth replaced tended to be less satisfied than their counterparts with natural teeth only.

Conclusions

Satisfaction was strongly associated with dental functional status.

Clinical relevance

Dental configurations comprising both natural and artificial teeth were less likely to provide the same level of satisfaction as equivalent dental configurations comprising natural teeth only.