Ground deformation reveals the scale-invariant conduit dynamics driving explosive basaltic eruptions.

The mild activity of basaltic volcanoes is punctuated by violent explosive eruptions that occur without obvious precursors. Modelling the source processes of these sudden blasts is challenging. Here, we use two decades of ground deformation (tilt) records from Stromboli volcano to shed light, with unprecedented detail, on the short-term (minute-scale) conduit processes that drive such violent volcanic eruptions. We find that explosive eruptions, with source parameters spanning seven orders of magnitude, all share a common pre-blast ground inflation trend. We explain this exponential inflation using a model in which pressure build-up is caused by the rapid expansion of volatile-rich magma rising from depth into a shallow (<400 m) resident magma conduit. We show that the duration and amplitude of this inflation trend scales with the eruption magnitude, indicating that the explosive dynamics obey the same (scale-invariant) conduit process. This scale-invariance of pre-explosion ground deformation may usher in a new era of short-term eruption forecasting.

Analysis of the immune landscape of small bowel neuroendocrine tumors.

Immune checkpoint inhibitors have shown promising results in different cancers, and correlation between immune infiltration, expression of programmed death-ligand 1 (PD-L1) by tumor cells and response to immunotherapy has been reported. There is limited knowledge regarding the immune microenvironment of small bowel (SB) neuroendocrine tumors (NETs). This work was aimed at characterizing the immune landscape of SB NETs. Expression of PD-L1 and programmed death-1 (PD-1) was evaluated by immunohistochemistry in 102 surgically resected, primary NETs of the duodenum, jejunum and ileum. Extent and characteristics of the tumor-associated immune infiltrate were also assessed and investigated in their prognostic potential. We detected the expression of PD-L1 in ≥1 and ≥50% of tumor cells in 40/102 (39%; 95% CI, 30-49%) and 14/102 (14%; 95% CI, 8-22%) cases respectively. Intratumor host immune response was apparently absent in 35/102 cases (34%; 95% CI, 25-44%), mild to moderate in 46/102 samples (45%, 95% CI, 35-55%), intense in 21/102 tumors (21%, 95% CI, 13-30%). Expression of PD-L1 and extent of immune infiltration were significantly higher in duodenal NETs as compared with jejunal/ileal NETs. A marked peritumoral host response was organized as ectopic lymph node-like structures in 18/102 cases (18%; 95% CI, 11-26%). Neither PD-L1 expression nor the degree of immune infiltration showed any prognostic significance. Overall, the immune landscape of SB NETs is heterogeneous, with adaptive immune resistance mechanisms prevailing in duodenal NETs. Clinical trials of immune checkpoint inhibitors should take into account the immune heterogeneity of SB NETs.

A phase II study of axitinib in advanced neuroendocrine tumors.

Neuroendocrine tumors (NETs) are highly vascular neoplasms overexpressing vascular endothelial growth factor (VEGF) as well as VEGF receptors (VEGFR). Axitinib is a potent, selective inhibitor of VEGFR-1, -2 and -3, currently approved for the treatment of advanced renal cell carcinoma. We performed an open-label, two-stage design, phase II trial of axitinib 5mg twice daily in patients with progressive unresectable/metastatic low-to-intermediate grade carcinoid tumors. The primary end points were progression-free survival (PFS) and 12-month PFS rate. The secondary end points included time to treatment failure (TTF), overall survival (OS), overall radiographic response rate (ORR), biochemical response rate and safety. A total of 30 patients were enrolled and assessable for toxicity; 22 patients were assessable for response. After a median follow-up of 29months, we observed a median PFS of 26.7months (95% CI, 11.4-35.1), with a 12-month PFS rate of 74.5% (±10.2). The median OS was 45.3 months (95% CI, 24.4-45.3), and the median TTF was 9.6months (95% CI, 5.5-12). The best radiographic response was partial response (PR) in 1/30 (3%) and stable disease (SD) in 21/30 patients (70%); 8/30 patients (27%) were unevaluable due to early withdrawal due to toxicity. Hypertension was the most common toxicity that developed in 27 patients (90%). Grade 3/4 hypertension was recorded in 19 patients (63%), leading to treatment discontinuation in six patients (20%). Although axitinib appears to have an inhibitory effect on tumor growth in patients with advanced, progressive carcinoid tumors, the high rate of grade 3/4 hypertension may represent a potential impediment to its use in unselected patients.

Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors.

Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60 mg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60 mg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response.

The LVD signals during the early-mid stages of the L'Aquila seismic sequence and the radon signature of some aftershocks of moderate magnitude.

The L'Aquila seismic swarm culminated with the mainshock of April 6, 2009 (ML = 5.9). Here, we report and analyze the Large Volume Detector (LVD, used in neutrinos research) low energy traces (∼0.8 MeV), collected during the early-mid stages of the seismic sequence, together with the data of a radon monitoring experiment. The peaks of LVD traces do not correlate with the evolution and magnitude of earthquakes, including major aftershocks. Conversely, our radon measurements obtained by utilizing three automatic stations deployed along the regional NW-SE faulting system, seem to be, in one case, more efficient. In fact, the timeseries collected on the NW-SE Paganica fracture recorded marked variations and peaks that occurred during and prior moderate aftershocks (with ML > 3). The Paganica monitoring station (PGN) seems to better responds to active seismicity due to the fact that the radon detector was placed directly within the bedrock of an active fault. It is suggested that future networks for radon monitoring of active seismicity should preferentially implement this setting.

Could feeding habit and migratory behaviour be the causes of different toxicological hazard to cetaceans of Gulf of California (Mexico)?

In this work, a suite of diagnostic biomarkers was applied to seven cetacean species to evaluate the role of the feeding habits and migratory behavior in the toxicological status of these species from the Gulf of California, Mexico. We investigate the interspecific differences in cytochrome P450 1A1 and 2B (CYP1A1 and CYP2B, respectively), aryl hydrocarbon receptor and E2F transcription factor 1 and the contaminants levels [organochlorine compounds, polybrominated diphenyl ethers (PBDEs) and polycyclic aromatic hydrocarbons (PAHs)] in four odontocete species (common bottlenose dolphin, long-beaked common dolphin, sperm whale and killer whale) and three mysticete species (blue whale, fin whale, and Bryde's whale) using skin biopsy. Differences in contaminant levels and molecular biomarker responses between the odontocete and mysticete species have been pointed out. The canonical discriminant analysis on principal component analysis factors, performed to reveal clustering variables, shows that odontocete are characterised by the highest levels of lipophilic contaminants compared to the mysticete, with the highest levels of polychlorinated biphenyls, dichlorodiphenyltrichloroethanes and PBDEs detected in killer whale and the lowest levels in Bryde's whale. The biomarker data show interspecific differences amongst the seven species, revealing highest CYP1A and CYP2B protein levels in the mysticete fish-eating species (Bryde's whale). In conclusion, three main factors seem to regulate the biomarker responses in these species: (a) the inductive ability of persistent organic pollutants and PAHs; (b) the different evolutionary process of the two CYPs related to the different feeding habits of the species; (c) the migratory/resident behaviour of the mysticete species in this area.

Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERα in breast cancer.

Despite the clinical success of tamoxifen, its resistance remains a major challenge in breast cancer. Here we show that Aurora-A determines tamoxifen sensitivity by regulation of oestrogen receptor (ER)α. Ectopic expression of Aurora-A decreases and depletion of Aurora-A enhances tamoxifen sensitivity in ERα-positive breast cancer. Elevated Aurora-A was significantly associated with the recurrence of ERα-positive tumours. Notably, Aurora-A inhibitor MLN8237, which is currently in clinical trial, synergizes with tamoxifen and overcomes tamoxifen resistance. Furthermore, Aurora-A interacts with and phosphorylates ERα on serine-167 and -305, leading to increase in ERα DNA-binding and transcriptional activity. Elevated levels of Aurora-A are significantly associated with disease-free survival in ERα-positive but not ERα-negative breast cancers. These data suggest that Aurora-A has a pivotal role in tamoxifen resistance and ERα is a bona fide substrate of Aurora-A. Thus, Aurora-A represents a prognostic marker in ERα-positive tumour and a critical therapeutic target in tamoxifen-resistant breast cancer, and Aurora-A inhibitor could be used as either an independent or concurrent agent in tamoxifen-resistant tumour.

Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer.

MicroRNA-155 (miR-155) is frequently upregulated in various types of human cancer; however, its role in cancer angiogenesis remains unknown. Here, we demonstrate the role of miR-155 in angiogenesis through targeting von Hippel-Lindau (VHL) tumour suppressor in breast cancer. Ectopic expression of miR-155 induced whereas knockdown of miR-155 inhibited human umbilical vein endothelial cell network formation, proliferation, invasion and migration. Furthermore, mammary fat pad xenotransplantation of ectopically expressed miR-155 resulted in extensive angiogenesis, proliferation, tumour necrosis and recruitment of pro-inflammatory cells such as tumour-associated macrophages. Expression of VHL abrogated these miR-155 effects. Moreover, miR-155 expression inversely correlates with VHL expression level and is associated with late-stage, lymph node metastasis and poor prognosis, as well as triple-negative tumour in breast cancer. These findings indicate that miR-155 has a pivotal role in tumour angiogenesis by downregulation of VHL, and provide a basis for miR-155-expressing tumours to embody an aggressive malignant phenotype, and therefore miR-155 is an important therapeutic target in breast cancer.

The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis.

BACKGROUND AND PURPOSE: The non-psychotropic cannabinoid cannabichromene is known to activate the transient receptor potential ankyrin-type1 (TRPA1) and to inhibit endocannabinoid inactivation, both of which are involved in inflammatory processes. We examined here the effects of this phytocannabinoid on peritoneal macrophages and its efficacy in an experimental model of colitis. EXPERIMENTAL APPROACH: Murine peritoneal macrophages were activated in vitro by LPS. Nitrite levels were measured using a fluorescent assay; inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2) and cannabinoid (CB1 and CB2 ) receptors were analysed by RT-PCR (and/or Western blot analysis); colitis was induced by dinitrobenzene sulphonic acid (DNBS). Endocannabinoid (anandamide and 2-arachidonoylglycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry. Colonic inflammation was assessed by evaluating the myeloperoxidase activity as well as by histology and immunohistochemistry. KEY RESULTS: LPS caused a significant production of nitrites, associated to up-regulation of anandamide, iNOS, COX-2, CB1 receptors and down-regulation of CB2 receptors mRNA expression. Cannabichromene significantly reduced LPS-stimulated nitrite levels, and its effect was mimicked by cannabinoid receptor and TRPA1 agonists (carvacrol and cinnamaldehyde) and enhanced by CB1 receptor antagonists. LPS-induced anandamide, iNOS, COX-2 and cannabinoid receptor changes were not significantly modified by cannabichromene, which, however, increased oleoylethanolamide levels. In vivo, cannabichromene ameliorated DNBS-induced colonic inflammation, as revealed by histology, immunohistochemistry and myeloperoxidase activity. CONCLUSION AND IMPLICATIONS: Cannabichromene exerts anti-inflammatory actions in activated macrophages - with tonic CB1 cannabinoid signalling being negatively coupled to this effect - and ameliorates experimental murine colitis.

An electroolfactogram study of odor response patterns from the mouse olfactory epithelium with reference to receptor zones and odor sorptiveness.

Olfactory sensory neuron (OSN) responses to odors, measured at the population level, tend to be spatially heterogeneous in the vertebrates that have been studied. These response patterns vary between odors but are similar across subjects for a given stimulus. However, few species have been studied making functional interpretation of these patterns problematic. One proximate explanation for the spatial heterogeneity of odor responses comes from evidence that olfactory receptor (OR) genes in rodents are expressed in OSN populations that are spatially restricted to a few zones in the olfactory epithelium (OE). A long-standing functional explanation for response anisotropy in the OE posits that it is the signature of a supplementary mechanism for quality coding, based on the sorptive properties of odor molecules. These theories are difficult to assess because most mapping studies have utilized few odors, provided little replication, or involved but a single species (rat). In fact, to our knowledge, a detailed olfactory response "map" has not been reported for mouse, the species used in most studies of gene localization. Here we report the results of a study of mouse OE response patterns using the electroolfactogram (EOG). We focused on the medial aspect of olfactory turbinates that are accessible in the midsagittal section. This limited approach still allowed us to test predictions derived from the zonal distribution of OSN types and the sorption hypothesis. In 3 separate experiments, 290 mice were used to record EOGs from a set of standard locations along each of 4 endoturbinates utilizing 11 different odors resulting in over 4,400 separate recordings. Our results confirmed a marked spatial heterogeneity in odor responses that varied with odor, as seen in other species. However, no discontinuities were found in the odor-specific response patterns across the OE as might have been predicted given the existence of classical receptor zones nor did we find clear support for the hypothesis that OE response patterns, presumably a reflection of OSN distribution, have been shaped through natural selection by the relative sorptive properties of odors. We propose that receptor zones may be an epiphenomenon of a contingent evolutionary process. In this formulation, constraints on developmental programs for distributing OSN classes within the OE may be minimally related to the odor ligands of specific class members. Further, we propose that odor sorptiveness, which appears to be correlated with the inherent response patterns in the OE of larger species, may be of minimal effect in mice owing to scaling issues.

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

BACKGROUND: Mutations in genes for hereditary non-polyposis colorectal cancer (HNPCC) in ovarian cancer patients remains poorly defined. We sought to estimate the frequency and characteristics of HNPCC gene mutations in a population-based sample of women with epithelial ovarian cancer. METHODS: The analysis included 1893 women with epithelial ovarian cancer ascertained from three population-based studies. Full-germline DNA sequencing of the coding regions was performed on three HNPCC genes, MLH1, MSH2 and MSH6. Collection of demographic, clinical and family history information was attempted in all women. RESULTS: Nine clearly pathogenic mutations were identified, including five in MSH6, two each in MLH1 and MSH2. In addition, 28 unique predicted pathogenic missense variants were identified in 55 patients. Pathogenic mutation carriers had an earlier mean age at diagnosis of ovarian cancer, overrepresentation of cancers with non-serous histologies and a higher number of relatives with HNPCC-related cancers. CONCLUSIONS: Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations. This represents a lower-range estimate due to the large number of predicted pathogenic variants in which pathogenicity could not definitively be determined. Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women.

Developments in real-time radon monitoring at Stromboli volcano.

We present the results of one year of continuous radon monitoring at Stromboli volcano collected at two automated real-time stations. These were deployed on the NE flank (at 520 m a.s.l.) and within the summit area (900 m a.s.l.). Higher daily emissions at the lower station approached 4,200 Bq/m³, with bulk averages around 1,800 (±980) Bq/m³; whereas the summit station reached peak values of 23,000 Bq/m³ and bulk averages of 12,500 Bq/m³ (±4,000). Negative correlations are observed between radon emissions, soil temperature and, to a lesser extent, atmospheric pressure. In contrast, increases in radon concentrations were observed during periods of higher rainfall conditions. Therefore, trends in radon concentrations may be decoupled from those of other geochemical parameters (CO2 fluxes and CO2/SO2 plume ratios) during periods of heavy to moderate rainfalls. Multiple Linear Regression statistics (including the effects of soil temperature, atmospheric pressure and tidal forces) led us to compute the residuals given by the difference of measured and calculated ²²²Rn concentrations. The cross-check between the daily measured radon activities and the absolute variations in radon residuals, for the data collected at the summit station, give us the opportunity to suggest a methodological approach that can be used in the attempt of predicting some major changes in volcanic activity.

Correlation between COX-2 and APC expression in left versus right-sided human colon cancer.

BACKGROUND: Because of clinicopathologic and genetic differences between left-sided colorectal cancer (LSCRC) and right-sided colon cancer (RSCC), cyclooxygenase-2(COX-2) and adenomatous polyposis coli (APC) expression may be of clinical relevance. MATERIALS AND METHODS: Clinicopathologic information for 72 primary colon tumors, 44 left and 28 right, from 72 patients (34 F, 38 M) were analyzed. COX-2 and wild-type APC (W-APC) immunohistochemical expressions were determined for each case. The data were analyzed using the Chi-square test and exact binomial confidence intervals. RESULTS: Overall, 31 out of 44 (70%) LSCRC were W-COX-2 positive vs. 13 out of 28 (46%) RSCC (p-value=0.042). When evaluated independently of the anatomic location, COX-2 expression showed a borderline statistical correlation with the lack of W-APC protein (p-value=0.054). When considering location of tumors, the inverse correlation between COX-2 and W-APC expression became statistically significant (p-value=0.024). CONCLUSION: We report a strong inverse correlation between COX-2 and W-APC expression, with COX-2 being more frequently as expressed in LSCRC. These data may be useful to stratify colorectal cancer patients into right- and left-sided and COX-2 expressor and non-expressor subsets, when evaluating COX-2 inhibitor and other targeted therapies in colon cancer.

Molecular adaptations in haemoglobins of notothenioid fishes.

Since haemoglobins of all animal species have the same haem group, differences in their properties, including oxygen affinity, electrophoretic mobility and pH sensitivity, must result from the interaction of the prosthetic group with specific amino-acid residues in the primary structure. For this reason, fish globins have been the subject of extensive studies in recent years, not only for their structural characteristics, but also because they offer the possibility to investigate the evolutionary history of these ancient molecules in marine and freshwater species living in a great variety of environmental conditions. This review summarizes the current knowledge on the structure, function and phylogeny of haemoglobins of notothenioid fishes. On the basis of crystallographic analysis, the evolution of the Root effect is analysed. Adaptation of the oxygen transport system in notothenioids seems to be based on evolutionary changes, involving levels of biological organization higher than the structure of haemoglobin. These include changes in the rate of haemoglobin synthesis or in regulation by allosteric effectors, which affect the amount of oxygen transported in blood. These factors are thought to be more important for short-term response to environmental challenges than previously believed.

Increased perfusion and angiogenesis in a hindlimb ischemia model with plasmid FGF-2 delivered by noninvasive electroporation.

Gene therapy approaches delivering fibroblast growth factor-2 (FGF-2) have shown promise as a potential treatment for increasing blood flow to ischemic limbs. Currently, effective noninvasive techniques to deliver plasmids encoding genes of therapeutic interest, such as FGF-2, are limited. We sought to determine if intradermal injection of plasmid DNA encoding FGF-2 (pFGF) followed by noninvasive cutaneous electroporation (pFGFE+) could increase blood flow and angiogenesis in a rat model of hindlimb ischemia. pFGFE+ or control treatments were administered on postoperative day 0. Compared to injection of pFGF alone (pFGFE-), delivery of pFGFE+ significantly increased FGF-2 expression for 10 days. Further, the increase in FGF-2 expression with pFGFE+ was sufficient to significantly increase ischemic limb blood flow, measured by laser Doppler perfusion imaging, beginning on postoperative day 3. Ischemic limb blood flow in the pFGFE+ treatment group remained significantly higher than all control groups through the end point of the study, postoperative day 14. Immunohistochemical staining of gastrocnemius cross sections determined there was a twofold increase in capillary density in the pFGFE+ treatment group. Our results suggest that pFGFE+ is a potential noninvasive, nonviral therapeutic approach to increase perfusion and angiogenesis for the treatment of limb ischemia.

Identification of tetracycline- and erythromycin-resistant Gram-positive cocci within the fermenting microflora of an Italian dairy food product.

AIMS: Microbiological and molecular analysis of antibiotic resistance in Gram-positive cocci derived from the Italian PDO (Protected Designation of Origin) dairy food product Mozzarella di Bufala Campana. METHODS AND RESULTS: One hundred and seven coccal colonies were assigned to Enterococcus faecalis, Lactococcus lactis and Streptococcus bovis genera by ARDRA analysis (amplified ribosomal DNA restriction analysis). Among them, 16 Ent. faecalis, 26 L. lactis and 39 Strep. bovis displayed high minimum inhibitory concentration (MIC) values for tetracycline, while 17 L. lactis showed high MIC values for both tetracycline and erythromycin. Strain typing and molecular analysis of the phenotypically resistant isolates demonstrated the presence of the tet(M) gene in the tetracycline-resistant strains and of tet(S) and erm(B) in the double-resistant strains. Southern blot analysis revealed plasmid localization of L. lactis tet(M), as well as of the erm(B) and tet(S) genes. Genetic linkage of erm(B) and tet(S) was also demonstrated by PCR amplification. Conjugation experiments demonstrated horizontal transfer to Ent. faecalis strain JH2-2 only for the plasmid-borne L. lactis tet(M) gene. CONCLUSIONS: We characterized tetracycline-and erythromycin-resistance genes in coccal species, representing the fermenting microflora of a typical Italian dairy product. SIGNIFICANCE AND IMPACT OF THE STUDY: These results are of particular relevance from the food safety viewpoint, especially in the light of the potential risk of horizontal transfer of antibiotic-resistance genes among foodborne commensal bacteria.

Cyclooxygenase-2 (COX-2) expression in human endometrial carcinoma and precursor lesions and its possible use in cancer chemoprevention and therapy.

In recent years, the design of new antineoplastic agents that can halt the progression of human malignancies with minimal systemic damage has been at the forefront of cancer research, with cyclooxygenase-2 (COX-2) as a major target molecule. With an aim to demonstrate the expression and role of COX-2, the principal putative target of COX-2 inhibitor therapy, in endometrial adenocarcinoma (EACA) and precursor lesions, atypical complex hyperplasia (ACH) and endometrial hyperplasia (EH), an immunohistochemical (IHC) analysis of 22 primary human EACAs and 14 precursor lesions was carried out. Relevant clinicopathological data were tabulated from a random computer-generated sample of 22 primary EACA patients, treated by hysterectomy at our institution. Representative tumor sections including adjacent precursor lesions and normal endometrium (NE) were immunostained with human monoclonal anti-COX-2. Qualitative and semi-quantitative COX-2 IHC staining scores were determined based on the proportion of immunoreactive cells and the intensity of cytoplasmic COX-2 expression. Fisher's exact test and the Wilcoxon Rank Sum test were used for statistical analysis. Mean patient age was 68 years (range 51-93). All 22 EACAs were of endometrioid type, of which ten (45%) were grade I, eight (36%) grade II and four (18%) were grade III. Overall, four out of nine (44%) EHs, four out of five (80%) ACHs, and 18 out of 22 (88%) EACAs were COX-2 positive. The mean COX-2 IHC scores for EH and EACAs were 33 (SD 24.11) and 76 (SD 54.57), respectively (p = 0.022). Strong or moderate COX-2 expression was observed in 17 out of 22 (77%) adenocarcinomas as compared to two out of 14 (14%) of the precursor lesions (EH and ACH). The areas of adenomyosis were COX-2 positive, while myometrial smooth muscle and normal fallopian tube tissues stained negative for COX-2. The demonstration of frequent and strong expression of COX-2 in human EACAs supports a possible role for COX-2 inhibitors. Furthermore, an increasing expression of COX-2 from EH to invasive EACAs suggests potential usefulness of COX-2 inhibition to halt the progression of precursor lesions to invasive endometrial cancers.

Optimization of cutaneous electrically mediated plasmid DNA delivery using novel electrode.

The easy accessibility of skin makes it an excellent target for gene transfer protocols. To take advantage of skin as a target for gene transfer, it is important to establish an efficient and reproducible delivery system. Electroporation is an established technique for enhancing plasmid delivery to many tissues in vivo. A critical component of this technique is the electrode configuration. Electroporation parameters were optimized for transgene expression with minimal tissue damage with a novel electrode. The highest transgene expression and efficiency of individual cell transformation with minimal damage was produced with eight 150 ms pulses at field strength of 100 V/cm. This electrode design offers the potential for easier and more reproducible electrically mediated cutaneous plasmid delivery than the simple electrodes currently commercially available. This electrode can be a valuable tool in determining the applicability of electrically mediated cutaneous gene transfer.