Breast cancer: Pretreatment drug resistance parameters (GSH-system, ATase, P-glycoprotein) in tumor tissue and their correlation with clinical and prognostic characteristics

Background: The identification of new factors predicting relapse, outcome and response to systemic therapy in breast cancer is warranted. The measurement of biological markers such as drug resistance parameters (DRPs), which are part of the phenotype of malignant cells and contribute to resistance to anti-cancer drugs may be a possibility, which may ultimately lead to improvement of therapeutic results. Patients and methods: The level of glutathione (GSH), activities of glutathione-S-transferase (GST), glutathione-peroxidase (GPx), 06-alkylguanine-DNA-alkyltransferase (ATase), and P-glycoprotein (PGP) were measured in tumor and adjacent tumor free tissue samples from 89 consecutive, untreated females with breast cancer and correlated with clinical and prognostic factors. Early breast cancer (EBC) was diagnosed in 56 patients, 22 patients had locally advanced (LABC) and 11 patients metastatic breast cancer. Results: All DRPs showed significantly higher expression in tumor than in tumor free tissues. GPx was positively correlated with GST (r = 0.3, P = 0.0048) and with GSH (r = 0.5, P = 0.0001) in tumor as well as in normal tissue. GST activity was significantly higher in EBC than in LABC or metastatic breast cancer (P = 0.02). GSH level was significantly higher in grade I than in grade 2 or grade 3 tumors (P = 0.01). When clinical characteristics were related to the level of DRP, ‘high' GSH was associated with age >60 years (P = 0.01) in EBC, and with grade 1-2 tumors (P = 0.05) in LABC. No differences in OS were apparent between groups of ‘high' and ‘low' DRP-expression. However, the four-year estimated disease-free survival of EBC tended to be higher in patients with ‘high' GST (P = 0.10) and of LABC in patients with ‘high' GPx levels (P = 0.06). Conclusion: We conclude that ‘high' levels of DRP in tumor tissue of breast cancer patients are part of the initial phenotype of the malignant cells. Due to its high prevalence (83% in EBC, 100% in primarily metastatic breast cancer), PGP did not add to prognostic information. High levels of GSH, GST and and GPx were associated with favorable clinical characteristics and good prognosis, whereas low levels of GSH and GST activity were associated with more aggressive or more advanced diseas

Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast

Summary Background: Axl, a member of a family of receptor tyrosine kinases characterized by an extracellular domain resembling cell adhesion molecules and an intracellular conserved tyrosine kinase domain has been reported to induce cell proliferation and transformation. In mice, axl is expressed in the normal mammary gland and over-expressed in aggressive mammary tumors. Patients and methods: We have investigated the expression of axl immunohistochemically in 23 normal human breast samples and in 111 consecutive breast carcinomas. Expression of axl was correlated with tumour characteristics (lymph node involvement, stage, grade) and immunohistochemical expression of ER, PR, Ki-67 and c-erbB-2. Results: In normal tissue, axl localizes to the membrane of breast epithelial cells. Axl protein shows membrane associated staining in high correlation (P = 0.004) with the expression of the estrogen receptor (ER). Axl expression was found in a subset of breast carcinomas and was also correlated with high significance (P < 0.0001) with the presence of ER. Conclusion: Our results suggest that axl may serve as a mediator of estrogen stimulation preventing the completion of the breast epithelial life cycle and that estrogen induced axl expression may give a survival signal to cancerous cells, preventing them from dying through apoptosi

Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts

The photosensitizing properties of m-tetrahydroxyphenylchlorin (mTHPC) and polyethylene glycol-derivatized mTHPC (pegylated mTHPC) were compared in nude mice bearing human malignant mesothelioma, squamous cell carcinoma and adenocarcinoma xenografts. Laser light (20 J/cm2) at 652 nm was delivered to the tumour (surface irradiance) and to an equal-sized area of the hind leg of the animals after i.p. administration of 0.1 mg/kg body weight mTHPC and an equimolar dose of pegylated mTHPC, respectively. The extent of tumour necrosis and normal tissue injury was assessed by histology. Both mTHPC and pegylated mTHPC catalyse photosensitized necrosis in mesothelioma xenografts at drug-light intervals of 1–4 days. The onset of action of pegylated mTHPC seemed slower but significantly exceeds that of mTHPC by days 3 and 4 with the greatest difference being noted at day 4. Pegylated mTHPC also induced significantly larger photonecrosis than mTHPC in squamous cell xenografts but not in adenocarcinoma at day 4, where mTHPC showed greatest activity. The degree of necrosis induced by pegylated mTHPC was the same for all three xenografts. mTHPC led to necrosis of skin and underlying muscle at a drug-light interval of 1 day but minor histological changes only at drug-light intervals from 2–4 days. In contrast, pegylated mTHPC did not result in histologically detectable changes in normal tissues under the same treatment conditions at any drug-light interval assessed. In this study, pegylated mTHPC had advantages as a photosensitizer compared to mTHPC

The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression

Genes of the polycomb group function by silencing homeotic selector genes that regulate embryogenesis. In mice, downregulation of one of the polycomb genes, bmi-1, leads to neurological alterations and severe proliferative defects in lymphoid cells, whilst bmi-1 overexpression, together with upregulation of myc-1, induces lymphoma. An oncogenic function has been further supported in primary fibroblast studies where bmi-1 overexpression induces immortalization due to repression of p16/p19ARF, and where together with H-ras, it readily transforms MEFs. It was the aim of this study to assess the expression of bmi-1 in resectable non-small cell lung cancer (NSCLC) in association with p16 and p14ARF (=human p19ARF). Tumours (48 resectable NSCLC (32 squamous, 9 adeno-, 2 large cell, 4 undifferentiated carcinomas and 1 carcinoid); stage I, 29, II, 7, III, 12; T1, 18, T2, 30; differentiation: G1 12, G2 19, G3 17) were studied by immunohistochemistry for protein expression and by comparative multiplex PCR for gene amplification analysis. In tumour-free, normal lung tissue from patients, weak – moderate bmi-1 staining was seen in some epithelial cells, lymphocytes, glandular cells and in fibroblasts, whereas blood, endothelial, chondrocytes, muscle cells and adipocytes did not exhibit any bmi-1 expression. In tumours, malignant cells were negative/weakly, moderately and strongly positive in 20, 22 and 6 cases, respectively. As assessed by multiplex PCR, bmi-1 gene amplification was not the reason for high-level bmi-1 expression. Tumours with moderate or strong bmi-1 expression were more likely to have low levels of p16 and p14ARF (P = 0.02). Similarly, tumours negative for both, p16 and p14ARF, exhibit moderate–strong bmi-1 staining. 58% of resectable NSCLC exhibit moderate–high levels of bmi-1 protein. The inverse correlation of bmi-1 and the INK4 locus proteins expression (p16/p14ARF) supports a possible role for bmi-1 misregulation in lung carcinogenesis. © 2001 Cancer Research Campaign www.bjcancer.co

The atomic structure of large-angle grain boundaries Σ5\Sigma 5 and Σ13\Sigma 13 in YBa2Cu3O7−δ{\rm YBa_2Cu_3O_{7-\delta}} and their transport properties

We present the results of a computer simulation of the atomic structures of large-angle symmetrical tilt grain boundaries (GBs) $\Sigma 5$ (misorientation angles \q{36.87}{^{\circ}} and \q{53.13}{^{\circ}}), $\Sigma 13$ (misorientation angles \q{22.62}{^{\circ}} and \q{67.38}{^{\circ}}). The critical strain level $\epsilon_{crit}$ criterion (phenomenological criterion) of Chisholm and Pennycook is applied to the computer simulation data to estimate the thickness of the nonsuperconducting layer ${\rm h_n}$ enveloping the grain boundaries. The ${\rm h_n}$ is estimated also by a bond-valence-sum analysis. We propose that the phenomenological criterion is caused by the change of the bond lengths and valence of atoms in the GB structure on the atomic level. The macro- and micro- approaches become consistent if the $\epsilon_{crit}$ is greater than in earlier papers. It is predicted that the symmetrical tilt GB $\Sigma5$ \theta = \q{53.13}{^{\circ}} should demonstrate a largest critical current across the boundary.Comment: 10 pages, 2 figure

Garden and landscape-scale correlates of moths of differing conservation status: significant effects of urbanization and habitat diversity

Moths are abundant and ubiquitous in vegetated terrestrial environments and are pollinators, important herbivores of wild plants, and food for birds, bats and rodents. In recent years, many once abundant and widespread species have shown sharp declines that have been cited by some as indicative of a widespread insect biodiversity crisis. Likely causes of these declines include agricultural intensification, light pollution, climate change, and urbanization; however, the real underlying cause(s) is still open to conjecture. We used data collected from the citizen science Garden Moth Scheme (GMS) to explore the spatial association between the abundance of 195 widespread British species of moth, and garden habitat and landscape features, to see if spatial habitat and landscape associations varied for species of differing conservation status. We found that associations with habitat and landscape composition were species-specific, but that there were consistent trends in species richness and total moth abundance. Gardens with more diverse and extensive microhabitats were associated with higher species richness and moth abundance; gardens near to the coast were associated with higher richness and moth abundance; and gardens in more urbanized locations were associated with lower species richness and moth abundance. The same trends were also found for species classified as increasing, declining and vulnerable under IUCN (World Conservation Union) criteria