Biomaterial challenges and approaches to stem cell use in bone reconstructive surgery

As life expectancy increases, so does the need to treat large bone defects. New biomaterials combined with osteogenic cells are now being developed as an alternative to autogenous bone grafts. The goal is to make the stem cells adhere to the scaffold, and then grow to differentiate into functional osteogenic cells and organize into healthy bone as the scaffold degrades. Decisive improvements have been made in the fields of stem cell biology, 3-D scaffold fabrication and tissue engineering, but the ideal bone substitute that fulfils all functional and safety requirements has yet to be developed.     

Structure-activity relationships of histamine H1-receptor agonists

Significant progress in the development of potent and selective histamine H1-receptor agonists has been achieved since 1990. Optimisation of the class of 2-phenylhistamines has furnished 2-[3-(trifluoromethyl)phenyl]histamine and its Nalpha-methyl derivative. The discovery of histaprodifen (2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) and the novel lead compound suprahistaprodifen (Nalpha-2-[(1H-imidazol-4-yl)ethyl]histaprodifen) represents additional milestones in the H1-receptor agonist field.     

New macrolides from the sponge Chondrosia corticata

Three new oxazole-containing metabolites, neohalichondramide (5), (19Z)-halichondramide (6), and secohalichondramide (7), along with four previously reported compounds of the same structural class were isolated from the marine sponge Chondrosia corticata collected from Guam. The structures of novel compounds were determined on the basis of combined spectroscopic analyses. These compounds exhibited significant cytotoxicity and antifungal activity toward the human leukemia cell-line K562 and Candida albicans, respectively.     

Altered metastatic behavior of human breast cancer cells after experimental manipulation of matrix metalloproteinase 8 gene expression

Previous work in our laboratory led to the cloning, from the same parent tumor cell line (MDA-MB-435), of two human breast cancer cell lines (M-4A4 and NM-2C5) with opposite metastatic phenotypes. Additional investigations revealed that the nonmetastatic cell line NM-2C5 overexpressed the neutrophil collagenase, matrix metalloproteinase (MMP)-8, relative to its partner. Because other studies have implicated the MMP family in promoting tumor metastasis, we investigated the apparently paradoxical expression of MMP-8 in these cell lines. By genetic engineering, we inverted its relative levels of expression in the two partners and studied the effects on the behavior of the tumors that they generated in athymic mice. Knock-down of expression in NM-2C5 cells by transduction with a sequence encoding a specific ribozyme and overexpression of MMP-8 in M-4A4 cells by retroviral transduction both strikingly changed metastatic performance in opposite directions, indicating that this gene plays a role in the regulation of tumor metastasis.     

Neoexpression of N-cadherin in E-cadherin positive colon cancers

In our study, we aimed to investigate the expression of N-cadherin and E-cadherin and their dependency on epithelial-mesenchymal transition regulators SNAI1, SIP1 and TWIST in human colon cancer. Expression of E-cadherin and N-cadherin was examined by immunohistochemistry in 80 colon carcinomas by using paraffin embedded and formalin fixed tissues. Those cases were partly analyzed for mRNA expression of N-cadherin (42 cases), TWIST (18 cases), SNAI1 (25 cases) and SIP1 (25 cases) by real-time quantitative RT-PCR. Additionally, colon carcinomas that showed amplification of 20q13, the localization of the human SNAI1 gene, were examined. We found cytoplasmic and/or membrane-associated immunoreactivity of N-cadherin in 35/80 (44%) of the cases. However, there was no correlation to upregulated TWIST mRNA levels, as we have shown previously for diffuse-type gastric cancers with abnormal N-cadherin expression. Reduced and/or cytoplasmic E-cadherin immunoreactivity was detected in 19% (15/80) of the cases. Expression of SNAI1 or SIP1 mRNA was not seen in any of the 25 cases analyzed. There was no correlation between amplification of 20q13 and SNAI1 mRNA expression. Remarkably, N-cadherin was almost exclusively expressed in those cases showing normal E-cadherin immunoreactivity, suggesting a mutual exclusion between abnormal E-cadherin reduction and upregulation of N-cadherin. For the first time, we postulate a role for N-cadherin in primary colon cancer progression, which may be similar to the effect discovered by others in breast cancer cell lines, where coexpressed N-cadherin can exert a dominant function over E-cadherin's adhesive function and thus promote tumor invasiveness.     

Ganglioneurocytoma of the Third Ventricle

We present a very rare case of an intracranial ganglioneurocytoma. This 57-year-old female patient noticed some concentration difficulties for about 5 months. Visual acuity was 80% on both sides. CT and MRI of her head demonstrated a 3 x 2.5 x 2.8 cm3 lesion within the third ventricle with inhomogenous enhancement of contrast medium. After a right pterional approach the tumor could be removed completely. Postoperatively there was a paresis of the oculomotor nerve on the right side and psychological changes. Histological examination revealed neuronal differentiation with neurocytes and small ganglionic cells and the tumor was graded as a ganglioneurocytoma (WHO grade II). Follow-up examination 6 months after the operation showed improvement of her third nerve paresis and of her neuropsychological deficits. MRI showed no recurrence.     

Elevated cyclooxygenase-2 expression correlates with distant metastases in breast cancer

BACKGROUND: Cyclooxygenase-2 (COX-2) overexpression clearly plays an important role in the pathogenesis of breast cancer. In this study, we analysed the relationship between COX-2 expression and various clinicopathological factors in human breast cancer. MATERIALS AND METHODS: Using immunohistochemistry, we analysed archival specimens of human breast cancer (n=29) using antibodies to COX-2, ER, PgR and HER2 and, from medical records, obtained clinicopathological data. RESULTS: We observed a significant association between COX-2 overexpression and distant metastasis. COX-2 expression was not significantly associated with any other clinical or pathological variable. CONCLUSION: These findings lend support to the hypothesis that COX-2 overexpression represents an adverse prognostic event in human breast cancer and are encouraging for proposed strategies of COX-2 suppression to treat the disease.     

Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene

Melanoma differentiation associated gene-5 (mda-5) was identified by subtraction hybridization as a novel upregulated gene in HO-1 human melanoma cells induced to terminally differentiate by treatment with IFN-beta+MEZ. Considering its unique structure, consisting of a caspase recruitment domain (CARD) and an RNA helicase domain, it was hypothesized that mda-5 contributes to apoptosis occurring during terminal differentiation. We have currently examined the expression pattern of mda-5 in normal tissues, during induction of terminal differentiation and after treatment with type I IFNs. In addition, we have defined its genomic structure and chromosomal location. IFN-beta, a type I IFN, induces mda-5 expression in a biphasic and dose-dependent manner. Based on its temporal kinetics of induction and lack of requirement for prior protein synthesis mda-5 is an early type I IFN-responsive gene. The level of mda-5 mRNA is in low abundance in normal tissues, whereas expression is induced in a spectrum of normal and cancer cells by IFN-beta. Expression of mda-5 by means of a replication incompetent adenovirus, Ad.mda-5, induces apoptosis in HO-1 cells as confirmed by morphologic, biochemical and molecular assays. Additionally, the combination of Ad.mda-5+MEZ further augments apoptosis as observed in Ad.null or uninfected HO-1 cells induced to terminally differentiate by treatment with IFN-beta+MEZ. The mda-5 gene is located on human chromosome 2q24 and consists of 16 exons, without pseudogenes, and is conserved in the mouse genome. Present data documents that mda-5 is a novel type I IFN-inducible gene, which may contribute to apoptosis induction during terminal differentiation and during IFN treatment. The conserved genomic and protein structure of mda-5 in human and mouse will permit analysis of the evolution and developmental aspects of this gene.     

Phyto-oestrogen Intake and Breast Cancer Risk in South Asian Women in England: Findings from a Population-based Case-Control Study

OBJECTIVE: This study investigates whether intake of phyto-oestrogens is associated with breast cancer risk in South Asian women from the Indian subcontinent, whose diet is rich in pulses and vegetables but poor in soyfoods. METHODS: A total of 240 South Asian breast cancer cases living in England and 477 age-matched population-based controls were recruited into the study. Dietary intake was measured using a validated food frequency questionnaire. Conditional logistic regression models were used to estimate the effect of phyto-oestrogen intake on breast cancer risk. RESULTS: After adjustment for known breast cancer risk factors and total energy intake, there was moderate evidence of a dose-effect response in the odds of breast cancer with isoflavone intake (p-value for trend 0.08), with women in the top quartile having approximately half the odds of breast cancer of those in the bottom one (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.33, 1.00) but with no reductions in the odds for women in the second and third quartiles. The ORs for second, third and highest quartiles of total lignan intake compared to the lowest were 0.78 (95% CI 0.48, 1.26), 0.74 (0.46, 1.19) and 0.66 (0.41, 1.07), respectively, again with moderate evidence of a linear dose-effect response (p-value for trend 0.09). Further adjustment for non-startch polysaccharides (NSP) intake slightly weakened the phyto-oestrogens-breast cancer associations. CONCLUSIONS: These findings are consistent with the possibility that high phyto-oestrogen intake may protect against breast cancer, but further research is required to confirm this hypothesis.