Enhanced binding of metabotropic glutamate receptor type 5 (mGluR5) PET tracers in the brain of parkinsonian primates.

The interplay between dopamine and glutamate in the basal ganglia regulates critical aspects of motor learning and behavior. Metabotropic glutamate receptors (mGluR) are increasingly regarded as key modulators of neuroadaptation in these circuits, in normal and disease conditions. Using PET, we demonstrate a significant upregulation of mGluR type 5 in the striatum of MPTP-lesioned, parkinsonian primates, providing the basis for therapeutic exploration of mGluR5 antagonists in Parkinson disease.

Perceived Importance of Information Needs on Breast Cancer among Adults: a Population-Based Survey in the District of Colombo, Sri Lanka

Background: Information needs of Breast Cancer (BC) and its perceived importance has not been adequately assessed in Sri Lanka. The present study aimed to assess cognitive information needs of BC among the adults. Methods: A household survey was conducted among a representative sample (n=1500) of over 18 years of age resident in the district of Colombo not having BC patients in the families. A validated interviewer-administered questionnaire collected information on general and cognitive information needs. Exploratory factor analysis assessed whether any of the aspects of informational needs are redundant and to group the needs. Results: Mean age of the participants was 37.21 (SD = ±9.7) years. Proportion of females was 51.7%, 82.9% were married and 44.1% had been educated up to General Certificate of Education (GCE) Ordinary Level. Exploratory factor analysis revealed all items of the questionnaire to form two groups that were named as "Factual information on BC prevention and early detection (screening and early diagnosis)" and "Factual information on BC diagnosis and treatment". Results indicated that both groups of information needs were considered as highly important and the group "Factual information on BC diagnosis and treatment" (mean score 4.20 ± 0.75) was perceived as more important than the other group. The perceived importance of information needs was shown to be significantly different based on the sex of the adults, marital status, level of education and the employment status of the participants. Conclusion: This study demonstrates that cognitive information needs on BC are viewed as highly important by the general public. The study identified specific informational needs that are perceived as more important and some socio-demographic characteristics that are associated with higher perceived needs. The study recommends taking into account the findings of the study in designing the content and target groups for education on BC.

Longitudinal Association between Selenium Levels and Hypertension in a Rural Elderly Chinese Cohort.

OBJECTIVES: Results from previous studies have been inconsistent on the association between selenium and hypertension, and very few studies on this subject have focused on the elderly population. The purpose of this study is to examine the relationship between selenium level and hypertension in a rural elderly Chinese cohort. DESIGN: A longitudinal study was implemented and data were analyzed using logistic regression models and Cox proportional hazards regression model adjusting for potential confounders. The associations between selenium level and prevalent hypertension at baseline and between selenium and incident hypertension were examined. SETTING: Community-based setting in four rural areas in China. SUBJECTS: A total of 2000 elderly aged 65 years and over (mean 71.9±5.6 years) participated in this study. MEASUREMENTS: Nail selenium levels were measured in all subjects at baseline. Blood pressure measures and self-reported hypertension history were collected at baseline, 2.5 years and 7 years later. Hypertension was defined as systolic blood pressure 140 mmHg or higher, diastolic blood pressure 90 mmHg or higher, or reported use of anti-hypertensive medication. RESULTS: The rate of baseline hypertension was 63.50% in this cohort and the mean nail selenium level is 0.413±0.183µg/g. Multi-covariate adjusted cross-sectional analyses indicated that higher selenium level was associated with higher blood pressure measures at baseline and higher rates of hypertension. For the 635 participants with normal blood pressure at baseline, 360 had developed hypertension during follow-up. The incidence rate for hypertension was 45.83%, 52.27%, 62.50%, 70.48%, and 62.79% from the first selenium quintile to the fifth quintile respectively. Comparing to the lowest quintile group, the hazard ratios were 1.41 (95%CI: 1.03 to1.94), 1.93 (95%CI: 1.40 to 2.67), 2.35 (95%CI: 1.69 to 3.26) and 1.94 (95%CI: 1.36 to 22.77) for the second selenium quintile to the fifth quintile respectively. CONCLUSIONS: Our findings suggest that high selenium may play a harmful role in the development of hypertension. Future studies are needed to confirm our findings and to elucidate a plausible biological mechanism.

HSV-1 as a novel therapy for breast cancer meningeal metastases.

Meningeal metastasis is a fatal complication of breast cancer that affects 5-8% of patients. When cancer cells seed in the meninges, their subsequent growth results in severe neurological complications involving the cranial nerves, cerebrum and spinal cord, limiting life expectancy to less than 4 months. The incidences of meningeal metastases increase with prolonged lifespan resulting from treatment advances for primary breast cancer and their metastases. Currently, there is no cure. Aggressive multimodal therapies such as radiation and chemotherapy (intra-cerebrospinal fluid (CSF) and systemic) are ineffective. Therapeutic agents are often quickly cleared from the CSF, while higher doses that can achieve a therapeutic response are highly toxic. The secure guarding of the subarachnoid space by the blood-brain barrier on one side and the blood-CSF barrier on the other prevents chemotherapy from reaching cancer cells in the meninges. These challenges with treating meningeal metastases highlight the urgent need for a new therapeutic modality. An ideal treatment would be an agent that avoids rapid clearance, remains within the CSF, reaches the meninges and selectively destroys tumor cells. Replication conditional oncolytic herpes simplex virus type 1 (HSV-1) may be effective in this regard. Viral oncolysis, the destruction of cancer cells by replicating virus, is under clinical investigation for cancers that are unresponsive to current therapies. It is based on the model of multiple cycles of lytic virus replication in cancer cells that amplify the injected dose. The therapeutic potential of oncolytic HSV-1 for breast cancer meningeal metastases is discussed here. HSV-1 could be a potential novel treatment for meningeal metastases that can be translated to the clinic.

Concurrent chemotherapy inhibits herpes simplex virus-1 replication and oncolysis.

Herpes simplex virus-1 (HSV-1) replication in cancer cells leads to their destruction (viral oncolysis) and has been under investigation as an experimental cancer therapy in clinical trials as single agents, and as combinations with chemotherapy. Cellular responses to chemotherapy modulate viral replication, but these interactions are poorly understood. To investigate the effect of chemotherapy on HSV-1 oncolysis, viral replication in cells exposed to 5-fluorouracil (5-FU), irinotecan (CPT-11), methotrexate (MTX) or a cytokine (tumor necrosis factor-α (TNF-α)) was examined. Exposure of colon and pancreatic cancer cells to 5-FU, CPT-11 or MTX in vitro significantly antagonizes both HSV-1 replication and lytic oncolysis. Nuclear factor-κB (NF-κB) activation is required for efficient viral replication, and experimental inhibition of this response with an IκBα dominant-negative repressor significantly antagonizes HSV-1 replication. Nonetheless, cells exposed to 5-FU, CPT-11, TNF-α or HSV-1 activate NF-κB. Cells exposed to MTX do not activate NF-κB, suggesting a possible role for NF-κB inhibition in the decreased viral replication observed following exposure to MTX. The role of eukaryotic initiation factor 2α (eIF-2α) dephosphorylation was examined; HSV-1-mediated eIF-2α dephosphorylation proceeds normally in HT29 cells exposed to 5-FU, CPT-11 or MTX. This report demonstrates that cellular responses to chemotherapeutic agents provide an unfavorable environment for HSV-1-mediated oncolysis, and these observations are relevant to the design of both preclinical and clinical studies of HSV-1 oncolysis.

Comparison of intravenous versus intraperitoneal administration of oncolytic herpes simplex virus 1 for peritoneal carcinomatosis in mice.

hrR3 is an oncolytic herpes simplex virus 1 (HSV-1) mutant that replicates preferentially in tumors compared with normal tissues. Portal venous administration of hrR3 in mice bearing diffuse colorectal carcinoma liver metastases significantly reduces tumor burden and prolongs animal survival. In this study, we compared survival benefit and biodistribution of hrR3 following intravenous (i.v.) administration versus intraperitoneal (i.p.) administration in immunocompetent mice bearing colon carcinoma peritoneal metastases. Mice bearing peritoneal metastases received 1 x 10(8) plaque-forming units hrR3 or mock-infected media every other day for three doses and were randomized to have the viruses administered by either an i.p. or i.v. route. Biodistribution was assessed by PCR amplification of HSV-1-specific sequences from tumor and normal tissues including the small bowel, liver, spleen, kidney, lung, heart and brain. LD(50) for i.p. administration was compared with the LD(50) for i.v. administration. In subsequent experiments, animals were monitored for survival. The frequency of HSV-1 detection in peritoneal tumors was similar in mice randomized to either i.p. or i.v. administration. However, i.p. administration resulted in a more restricted systemic biodistribution, with a reduced frequency of virus detected in the kidney, lung and heart. The LD(50) associated with i.p. administration was higher than that with i.v. administration. Tumor burden was more effectively reduced with i.p. compared with i.v. administration. Median survival following i.p. administration was approximately twice that observed with i.v. administration. I.p. administration of an HSV-1 oncolytic mutant is associated with a more restricted biodistribution, less toxicity and greater efficacy against peritoneal metastases compared with i.v. administration.

Microvascular architecture of hepatic metastases in a mouse model.

Development of effective treatment for hepatic metastases can be initiated by a better understanding of tumour vasculature and blood supply. This study was designed to characterise the microvascular architecture of hepatic metastases and observe the source of contributory blood supply from the host. Metastases were induced in mice by an intrasplenic injection of colon carcinoma cells (10(6) cells/ml.) Vascularization of tumours was studied over a three week period by scanning electron microscopy of microvascular corrosion casts. Metastatic liver involvement was observed initially within a week post induction, as areas approximately 100 microns in diameter not perfused by the casting resin. On histology these spaces corresponded to tumour cell aggregates. The following weeks highlighted the angiogenesis phase of these tumours as they received a vascular supply from adjacent hepatic sinusoids. Direct sinusoidal supply of metastases was maintained throughout tumour growth. At the tumour periphery most sinusoids were compressed to form a sheath demarcating the tumour from the hepatic vasculature. No direct supply from the hepatic artery or the portal vein was observed. Dilated vessels termed vascular lakes dominated the complex microvascular architecture of the tumours, most tapering as they traversed towards the periphery. Four vascular branching patterns could be identified as true loops, bifurcations and trifurcations, spirals and capillary networks. The most significant observation in this study was the direct sinusoidal supply of metastases, together with the vascular lakes and the peripheral sinusoidal sheaths of the tumour microculature.

Tamoxifen inhibits colorectal cancer metastases in the liver: a study in a murine model.

Liver metastases account for over 70% of deaths resulting from colorectal carcinoma, with survival rates varying between 6-18 months. At present, surgical resection offers the only hope for a cure, while chemotherapy, focal destructive techniques and selective internal radiation offer palliative care. Tamoxifen, a non-steroidal anti-oestrogen is primarily known for treating oestrogen receptor (ER)-positive breast cancer. Some studies suggest that tamoxifen may have beneficial effects in malignancies other than breast cancer. These inhibitory effects, which have been shown to be independent of the ER, highlight new mechanisms of therapeutic action. Using an intrasplenic animal model we report the efficacy of tamoxifen on experimental liver metastases. In this model, a dimethyl hydrazine-induced colon carcinoma cell suspension is introduced into the portal circulation via the spleen, which results in secondary tumour deposits in the liver in virtually all animals. Tamoxifen was administered at a dose of 1 mg/kg suspended in 1.0% methyl cellulose. The control group received an equal volume of the vehicle. The reagents were administered s.c. on the day of metastases induction and were continued daily over a 4 week period. The effect of tamoxifen on tumour growth was assessed by stereology and bromodeoxyuridine immunohistochemistry at selected time points. Data were assessed by a multiple analysis of variance where P < 0.05 was considered significant. In the control group the volume of metastases increased from 44 +/- 41 mm3 at day 10 to 517 +/- 380 mm3, 1394 +/- 598 mm3 and 2082 +/- 675 mm3 by days 16, 22 and 28, respectively. Daily administration of tamoxifen exerted an inhibitory effect on tumour growth during the first 3 weeks, recording a volume of 421 +/- 299 mm3 by day 22 compared with the control group at that time point (P = 0.00004). The inhibitory effect diminished by the fourth week recording a tumour volume of 1344 +/- 674 mm3 by day 28. Inhibition of tumour growth at day 22 coincides with a reduction of cells in the S phase of the cell cycle. The percentage of brdU-positive nuclear profiles in metastases of tamoxifen-treated mice at 3 weeks was 35.87 +/- 5.60% compared with 48.01 +/- 3.96% in the control group (P = 0.001). These data suggest that tamoxifen has a potent inhibitory action on colorectal liver metastases by exerting an effect on cell proliferation.

Characterization of an animal model of hepatic metastasis.

The experimental study of possible therapies for control of the growth of liver metastases requires the availability of a model which is technically feasible and appears to exhibit growth characteristics similar to human tumours. We report on the development of an intrasplenic injection model of liver metastases, and describe the histology, growth pattern and blood flow demonstrated by light microscopy, stereology and laser Doppler flowmetry. The hepatic metastases were induced in mice by intrasplenic injection of dimethylhydrazine (DMH) induced primary colonic carcinoma cells (10(6) cells in 1 mL). The growth and development of metastases was studied over a period of 3 weeks at predetermined time points. Tumour cells were visible in the hepatic sinusoids by day 7 by light microscopy. Macroscopically visible tumours with a diameter of 0.18 +/- 0.02 cm (mean +/- s.d.) were seen by day 10. By this time the tumours had derived a blood supply from the hepatic sinusoids adjacent to the tumour periphery. With further vascularization the tumours reached a diameter of 0.96 +/- 0.50 cm by day 22. Metastatic growth was quantitated by stereological analysis of tumour volume in relation to non-diseased hepatic tissue. Normal mouse liver had a mean volume of 1.13 +/- 0.14 cm3. Tumour growth occurred in three phases. During the initial slow phase the volume of metastases increased from 0.03 +/- 0.02 cm3 at day 10 to 0.22 +/- 0.24 cm3 by day 16. Rapid tumour growth, occurring over the next 3 days, constituted the intermediate phase with metastatic volume reaching 1.21 +/- 0.74 cm3 by day 19 (P = 0.0003 compared with day 16). This growth was followed by a plateau phase when the metastatic volume was 1.40 +/- 0.55 cm3 at day 22. The volume of total liver and of tumour necrosis followed a similar growth pattern. A necrotic tumour volume of 0.004 +/- 0.006 cm3 first seen on day 10 increased to 0.05 +/- 0.06 cm3 by day 16, and to 0.25 +/- 0.20 cm3 by day 22 (P = 0.0022 compared with day 16). The blood flow in metastases measured by laser Doppler flowmetry was lower compared to the non-diseased liver. Tumour blood flow, expressed as a percentage of normal liver blood flow, was 63.31 +/- 26.28% at day 10 and diminished to 27.91 +/- 8.99% by day 22, with an increase in tumour size and age. The decrease in flow was significant between days 13 and 16 (P = 0.0015). This intrasplenic mouse model of metastases is reproducible and should prove useful in the study of treatment of hepatic metastases.