Detection of hepatocyte growth factor/scatter factor receptor (c-Met) in axillary drainage after operations for breast cancer using reverse transcriptase–polymerase chain reaction

BACKGROUND: The diverse biological effects of hepatocyte growth factor/scatter factor (HGF/SF) are mediated by c-Met, which is preferentially expressed on epithelial cells. Met signaling has a role in normal cellular activities, and may be associated with the development and progression of malignant processes. In this study we examined whether Met can be detected in the axillary drainage from patients who underwent conservative operations for breast cancer, and its prognostic significance. METHODS: Thirty-one consecutive patients with invasive ductal carcinoma of the breast suitable for breast-conserving treatment were studied. The output of the drain that had been placed in the axilla during the operation was collected, and the presence of Met and β-actin were assessed by reverse transcriptase–polymerase chain reaction (RT–PCR) assays. The data were compared with the pathological features of the tumor and the axillary lymph nodes, and with the estrogen receptor and progesterone receptor status. RESULTS: RT–PCR of the axillary lymphatic drainage was positive for Met in 23 (74.2%) of the patients. Positive assays were correlated with increasing tumor size and grade, with capillary and lymphatic invasion, and with lymph node metastasis (P < 0.02, for all comparisons). All 12 patients with axillary lymph node metastases had positive assays for Met, compared with 57.9% of patients without lymph node metastases. All five patients with tumor involvement in the margins of the resection had positive assays for Met in their lymphatic fluid, compared with 18 of 26 positive assays (69.2%) for patients without involved margins (P < 0.04). Finally, Met showed negative correlations with positivity for estrogen receptor and progesterone receptor (P < 0.02). CONCLUSION: Met can be detected in the axillary fluids of patients with breast cancer and its expression in the axillary drainage may have potential as a prognostic factor. This finding might be relevant to therapeutic considerations, because a positive assay for Met in histologically node-negative patients might point to the need to search for node microinvasion or involvement of the excision margins with tumor

Interactions of strings and D-branes from M theory

We discuss the relation between M theory and type II string theories. We show that, assuming ``natural'' interactions between membranes and fivebranes in M theory, the known interactions between strings and D-branes in type II string theories arise in appropriate limits. Our discussion of the interactions is purely at the classical level. We remark on issues associated with the M theory approach to enhanced gauge symmetries, which deserve further investigation.Comment: 19 pages, 3 figures, uses harvmac.tex and epsf.tex. Added a discussion of Kaluza-Klein monopoles and some minor change

The effect of a high-polyphenol Mediterranean diet (Green-MED) combined with physical activity on age-related brain atrophy: The Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT PLUS)

Background: The effect of diet on age-related brain atrophy is largely unproven. Objectives: We aimed to explore the effect of a Mediterranean diet (MED) higher in polyphenols and lower in red/processed meat (Green-MED diet) on age-related brain atrophy. Methods: This 18-mo clinical trial longitudinally measured brain structure volumes by MRI using hippocampal occupancy score (HOC) and lateral ventricle volume (LVV) expansion score as neurodegeneration markers. Abdominally obese/dyslipidemic participants were randomly assigned to follow 1) healthy dietary guidelines (HDG), 2) MED, or 3) Green-MED diet. All subjects received free gym memberships and physical activity guidance. Both MED groups consumed 28 g walnuts/d (+440 mg/d polyphenols). The Green-MED group consumed green tea (3-4 cups/d) and Mankai (Wolffia-globosa strain, 100 g frozen cubes/d) green shake (+800 mg/d polyphenols). Results: Among 284 participants (88% men; mean age: 51 y; BMI: 31.2 kg/m2; APOE-ε4 genotype = 15.7%), 224 (79%) completed the trial with eligible whole-brain MRIs. The pallidum (-4.2%), third ventricle (+3.9%), and LVV (+2.2%) disclosed the largest volume changes. Compared with younger participants, atrophy was accelerated among those ≥50 y old (HOC change: -1.0% ± 1.4% compared with -0.06% ± 1.1%; 95% CI: 0.6%, 1.3%; P Conclusions: A Green-MED (high-polyphenol) diet, rich in Mankai, green tea, and walnuts and low in red/processed meat, is potentially neuroprotective for age-related brain atrophy.This trial was registered at clinicaltrials.gov as NCT03020186

Diffusion MRI of Structural Brain Plasticity Induced by a Learning and Memory Task

Background: Activity-induced structural remodeling of dendritic spines and glial cells was recently proposed as an important factor in neuroplasticity and suggested to accompany the induction of long-term potentiation (LTP). Although T1 and diffusion MRI have been used to study structural changes resulting from long-term training, the cellular basis of the findings obtained and their relationship to neuroplasticity are poorly understood. Methodology/Principal Finding: Here we used diffusion tensor imaging (DTI) to examine the microstructural manifestations of neuroplasticity in rats that performed a spatial navigation task. We found that DTI can be used to define the selective localization of neuroplasticity induced by different tasks and that this process is age-dependent in cingulate cortex and corpus callosum and age-independent in the dentate gyrus. Conclusion/Significance: We relate the observed DTI changes to the structural plasticity that occurs in astrocytes and discuss the potential of MRI for probing structural neuroplasticity and hence indirectly localizing LTP

Nuclear magnetic resonance spectroscopy in pancreatic disorders

Nuclear magnetic resonance spectroscopy (NMRS) is a powerful technique that enables continuous monitoring of biochemical processes in tissues and organs in a non-invasive manner. A model of isolated perfused rat pancreas, suitable for NMRS studies, was developed. Acute pancreatitis was induced by injections of either 0.5 ml 5% sodium taurocholate (TC) into the bile duets, or 1.0 ml 10% TC injections into the pancreatic parenchyma. Phosphorous (31P) NMRS of experimental pancreatitis were characterized by a transient signal at -0.18±0.04 ppm which was assigned as solubilized lecithin, and can be used as an indicator of the early phases of the discase. Depletion of the high energy phosphorous compounds, phosphocreatine and ATP, were also found during acute pancreatitis, and paralleled the extension of the pathological damage. The role of NMRS in pancreatic cancer diagnosis and its treatment were assessed in three models of pancreatic neoplasms. Perfused MIA PaCa-2 human pancreatic cancer cells, subcutancously implanted pancreatic tumors in hamsters, and pancreatic tumors induced in-situ in rats by direct appiication of the carcinogen 7,12-dimethyl benzanthracene, were studied by phosphorous (31P), sodium (23Na) and proton (¹H) NMRS. 31P spectra of pancreatic cancer were qualitatively similar to those of intact organs. However, 31P NMRS was found to be useful for monitoring the effects of treatment. Total (infra- and extracellular) sodium concentrations, measured in the solid tumors, were similar in both the normal pancreas and the pancreatic tumors (39-40 mmol/g wet weight). Proton spectra of perchloric acid extracts revealed several differences between tumors and control pancreases. The principal findings were elevated levels of the amino acid taurine, from I.17±O.39 mmol/g wet weight in healthy pancreases, to 2.79±0.71 mmol/g wet weight in pancreatic carcinoma in rats, and lactate levels which increased from 0.92±0.2 to 6.19±1.93 mmol/g wet weight, respectively. On the other hand, creatine and glutamate were higher in the normal pancreases. These studies demonstrated that NMRS is a useful technique for studying fundamental biochemical and metabolic events of acute pancreatitis and pancreatic cancer, and for the development of therapeutical modalitie

HGF/SF Activates Glycolysis and Oxidative Phosphorylation in DA3 Murine Mammary Cancer Cells

Hepatocyte growth factor/scatter factor (HGF/SF) is a paracrine growth factor which increases cellular motility and has also been implicated in tumor development and progression and in angiogenesis. Little is known about the metabolic alteration induced in cells following Met-HGF/SF signal transduction. The hypothesis that HGF/SF alters the energy metabolism of cancer cells was investigated in perfused DA3 murine mammary cancer cells by nuclear magnetic resonance (NMR) spectroscopy, oxygen and glucose consumption assays and confocal laser scanning microscopy (CLSM). (31)P NMR demonstrated that HGF/SF induced remarkable alterations in phospholipid metabolites, and enhanced the rate of glucose phosphorylation (P < .05). (13)C NMR measurements, using [(13)C(1)]-glucose-enriched medium, showed that HGS/SF reduced the steady state levels of glucose and elevated those of lactate (P < .05). In addition, HGF/SF treatment increased oxygen consumption from 0.58±0.02 to 0.71±0.03 µmol/hour per milligram protein (P < .05). However, it decreased CO(2) levels, and attenuated pH decrease. The mechanisms of these unexpected effects were delineated by CLSM, using NAD(P)H fluorescence measurements, which showed that HGF/SF increased the oxidation of the mitochondrial NAD system. We propose that concomitant with induction of ruffling, HGF/SF enhances both the glycolytic and oxidative phosphorylation pathways of energy production

Heparanase Expression in Malignant Salivary Gland Tumors Inversely Correlates with Long-Term Survival

BACKGROUND: Upregulation of the endo-β-d-glucuronidase, heparanase, was noted in an increasing number of human malignancies. Heparanase expression correlated with enhanced local and distant metastatic spread, increased vascular density, and reduced postoperative survival. PATIENTS AND METHODS: We analyzed heparanase expression in 60 patients (aged 59 ± 17 years) with malignant salivary tumors (39 males and 21 females) using immunohisto-chemistry. We applied antiheparanase antibody 733, which has previously been shown to preferentially recognize a 50-kDa active heparanase subunit over a 65-kDa latent enzyme. Thus, immunostaining can directly be correlated with enzymatic activity. RESULTS: Heparanase staining was positive (> 0) in 70% of tumors (42 of 60 patients) and was negative (0) in the remaining 30% (18 patients). The cumulative survival of patients diagnosed as heparanase-negative (n = 18) at 300 months was 70% (95% confidence interval = 35–88). In contrast, the cumulative survival of patients diagnosed as heparanase-positive (n = 42) at 300 months was 0% (statistically significant difference, P = .035). CONCLUSIONS: Heparanase expression levels inversely correlate with the survival rates of salivary gland cancer patients, clearly indicating that heparanase is a reliable prognostic factor for this malignancy and an attractive target for anticancer drug development