Preventive medical services not covered by public health insurance started in the Daiko Medical Center of Nagoya University in June, 2004. Those services included:(1) Helicobacter pylori (H. pylori) diagnosis and eradication treatments, for which CYP2C19 genotyping was introduced in November 2005;(2) smoking cessation support with genotype tests of CYP1A1 Ile462Val, GSTM1 present/null, GSTT1 present/null, and NQO1 Pro187Ser;(3) advice on alcohol consumption with genotype tests of ADH Arg47His and ALDH2 Glu487Lys;(4) advice on folate-associated diseases with a genotype test of MTHFR C677T;(5) advice on a tumor marker CA19-9 with genotype tests of Lewis and Secretor genes; and (6) raloxifene prescription aimed to prevent breast cancer for high-risk postmenopausal women. A total of 683 patients visited the Center until it closed in March 2011. Those given diagnoses and eradication treatments for H. pylori numbered 567, followed by 44 for smoking cessation support, 35 for advice on folate-associated diseases, 26 for advice on alcohol consumption, 8 for CA19-9, and 3 for raloxifene prescription. Around 2004, public interest in H. pylori was relatively high, but thereafter patient numbers dropped markedly. The Center closed in March 2011 due to the reduction in patient visits. Our unique trial showed that continuing to provide uninsured preventive services at a clinic was difficult in Japan without the affiliation of hospitals/clinics providing medical services covered by public health insurance.

BACKGROUND Recombinant KSAC and L110f are promising Leishmania vaccine candidates. Both antigens formulated in stable emulsions (SE) with the natural TLR4 agonist MPL® and L110f with the synthetic TLR4 agonist GLA in SE protected BALB/c mice against L. major infection following needle challenge. Considering the virulence of vector-transmitted Leishmania infections, we vaccinated BALB/c mice with either KSAC+GLA-SE or L110f+GLA-SE to assess protection against L. major transmitted via its vector Phlebotomus duboscqi. METHODS Mice receiving the KSAC or L110f vaccines were challenged by needle or L. major-infected sand flies. Weekly disease progression and terminal parasite loads were determined. Immunological responses to KSAC, L110f, or soluble Leishmania antigen (SLA) were assessed throughout vaccination, three and twelve weeks after immunization, and one week post-challenge. RESULTS Following sand fly challenge, KSAC-vaccinated mice were protected while L110f-vaccinated animals showed partial protection. Protection correlated with the ability of SLA to induce IFN-γ-producing CD4(+)CD62L(low)CCR7(low) effector memory T cells pre- and post-sand fly challenge. CONCLUSIONS This study demonstrates the protective efficacy of KSAC+GLA-SE against sand fly challenge; the importance of vector-transmitted challenge in evaluating vaccine candidates against Leishmania infection; and the necessity of a rapid potent Th1 response against Leishmania to attain true protection.

BACKGROUND Babesia bovis is an apicomplexan intraerythrocytic protozoan parasite that induces babesiosis in cattle after transmission by ticks. During specific stages of the apicomplexan parasite lifecycle, such as the sporozoites of Plasmodium falciparum and tachyzoites of Toxoplasma gondii, host cells are targeted for invasion using a unique, active process termed "gliding motility". However, it is not thoroughly understood how the merozoites of B. bovis target and invade host red blood cells (RBCs), and gliding motility has so far not been observed in the parasite. METHODOLOGY/PRINCIPAL FINDINGS Gliding motility of B. bovis merozoites was revealed by time-lapse video microscopy. The recorded images revealed that the process included egress of the merozoites from the infected RBC, gliding motility, and subsequent invasion into new RBCs. The gliding motility of B. bovis merozoites was similar to the helical gliding of Toxoplasma tachyzoites. The trails left by the merozoites were detected by indirect immunofluorescence assay using antiserum against B. bovis merozoite surface antigen 1. Inhibition of gliding motility by actin filament polymerization or depolymerization indicated that the gliding motility was driven by actomyosin dependent process. In addition, we revealed the timing of breakdown of the parasitophorous vacuole. Time-lapse image analysis of membrane-stained bovine RBCs showed formation and breakdown of the parasitophorous vacuole within ten minutes of invasion. CONCLUSIONS/SIGNIFICANCE This is the first report of the gliding motility of B. bovis. Since merozoites of Plasmodium parasites do not glide on a substrate, the gliding motility of B. bovis merozoites is a notable finding.

Owing to new developments in Internet technologies, the amount of available oncology information is growing. Both patients and caregivers are increasingly using the Internet to obtain medical information. However, while it is easy to provide information, ensuring its quality is always a concern. Thus, many instruments for evaluating the quality of health information have been created, each with its own advantages and disadvantages. The increasing importance of online search engines such as Google warrants the examination of the correlation between their rankings and medical quality. The Internet also mediates the exchange of information from one individual to another. Mailing lists of advocate groups and social networking sites help spread information to patients and caregivers. While text messages are still the main medium of communication, audio and video messages are also increasing rapidly, accelerating the communication on the Internet. Future health information developments on the Internet include merging patients' personal information on the Internet with their traditional health records and facilitating the interaction among patients, caregivers and health-care providers. Through these developments, the Internet is expected to strengthen the mutually beneficial relationships among all stakeholders in the field of medicine.

PURPOSE: This phase 1 study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of linifanib in Japanese patients with advanced solid tumors. METHODS: Patients were assigned to one of four sequential cohorts (0.05, 0.10, 0.20, or 0.25 mg/kg) of oral, once-daily linifanib on a 21-day cycle. Adverse events (AEs) were assessed per common terminology criteria for adverse events v3.0; tumor responses were assessed by response evaluation criteria in solid tumors. RESULTS: Eighteen patients were enrolled. Eleven (61%) received ≥3 prior therapies. Dose-limiting toxicities were Grade 3 ALT increase (0.10 mg/kg linifanib) and Grade 1 T-wave inversion (0.25 mg/kg linifanib) requiring dose interruption for >7 days and discontinuation on day 29. The most common linifanib-related AE was hypertension. Other significant treatment-related AEs included proteinuria, fatigue, and palmar-plantar erythrodysaesthesia. Linifanib pharmacokinetics were dose-proportional across 0.10-0.25 mg/kg. Two patients (11.1%) had confirmed partial responses, 12 had a best response of stable disease (11 had stable disease for ≥12 weeks), and four patients were not evaluable due to incomplete data. Four patients (lung cancer, breast cancer, thymic cancer, sarcoma) have continued linifanib for ≥48 weeks (range, 48-96+ weeks). CONCLUSION: Linifanib was well tolerated with promising preliminary clinical activity in Japanese patients. Later-phase global studies examining linifanib efficacy will include Japanese patients.

BACKGROUND The availability of molecular-targeted therapies for the treatment of melanoma has emphasised the need to identify mutations in target genes such as BRAF and KIT. Circulating tumour cells (CTC) are present in the peripheral blood of a significant proportion of cancer patients. METHODS High molecular weight melanoma-associated antigen (HMW-MAA) was used to isolate melanoma cells from peripheral blood as it is selectively expressed at high levels on melanomas. The HMW-MAA-positive cells were isolated using immunomagnetic beads. After removing CD45(+) cells, CTC were identified by staining with MART-1- and gp100-specific antibodies (HMW-MAA(+), CD45(-), MART-1/gp100(+)). Single, isolated CTC were then subjected to BRAF and KIT mutational analysis. RESULTS CTC (HMW-MAA(+), CD45(-), MART-1/gp100(+)) were isolated from the blood of 11 patients and BRAF and KIT were sequenced in nine and four patients, respectively. The BRAF sequences identified in the CTC were inconsistent with those identified in autologous melanoma tumours in three patients and the KIT sequences were inconsistent in three patients. In addition, polyclonal BRAF mutations were identified in one patient and concomitant mutations in BRAF and KIT were identified in another patient. CONCLUSION Melanoma cells show clonal heterogeneity. Therefore, CTC genotyping may be crucial for successful molecular-targeted therapy.

EGCG [(-)-epigallocatechin-3-O-gallate], the major polyphenol of green tea, has cancer chemopreventive and chemotherapeutic activities. EGCG selectively inhibits cell growth and induces apoptosis in cancer cells without adversely affecting normal cells; however, the underlying molecular mechanism in vivo is unclear. In the present study, we show that EGCG-induced apoptotic activity is attributed to a lipid-raft clustering mediated through 67LR (67 kDa laminin receptor) that is significantly elevated in MM (multiple myeloma) cells relative to normal peripheral blood mononuclear cells, and that aSMase (acid sphingomyelinase) is critical for the lipid-raft clustering and the apoptotic cell death induced by EGCG. We also found that EGCG induces aSMase translocation to the plasma membrane and PKCδ (protein kinase Cδ) phosphorylation at Ser664, which was necessary for aSMase/ceramide signalling via 67LR. Additionally, orally administered EGCG activated PKCδ and aSMase in a murine MM xenograft model. These results elucidate a novel cell-death pathway triggered by EGCG for the specific killing of MM cells.

Objectives: The objective of this study was to identify clinical and dosimetric factors for the development of radiation pneumonitis (RP) among patients with oesophageal cancer treated with three-dimensional radiotherapy without prophylactic nodal irradiation.Methods: 125 patients with oesophageal cancer had undergone dose-volume histogram (DVH) metrics and received chemoradiotherapy. Several clinical and dosimetric factors with regard to the lung were evaluated as predictive factors for the development of symptomatic RP.Results: 26 patients (20.8%) developed symptomatic RP classified as ≥ grade 2. By univariate analysis, body weight loss, tumour length, stage IV, response to treatment and all DVH parameters proved to be significant factors for the development of RP (p<0.05). By multivariate analysis, stage IV and all dosimetric factors were independent predictive factors for the development of symptomatic RP (p<0.05). Recursive partitioning analysis indicated that V10 values of 24.8% or more and stage IV were associated with higher development of RP (odds ratio 6.53).Conclusions: Our study demonstrated that severe RP was also developed in patients treated with the minimal radiation field. Stage IV and the dosimetric factors were identified as independent predictive factors for symptomatic RP in oesophageal cancer patients treated with CRT without prophylactic nodal irradiation.

OBJECTIVE: For long-term preservation of ventriculo-peritoneal (VP) shunt function, it is essential to place the ventricular catheter tip above the foramen of Monro. But the free-hand technique for ventricular catheter passage is not consistent. METHODS: Supposing that a convex of skull matches to a sphere, in which the foramen of Monro is the center, a perpendicular direction from the surface of the sphere to inside always directs toward the center. The authors identified the range of skull where corresponded to the sphere by magnetic resonance imaging assessment and utilized tripod to achieve exactly perpendicular insertion of ventricular catheter. And an optimal length of catheter insertion was investigated by navigation system. RESULTS: The anterior-posterior range of the spherical portion was from coronal suture to 20mm anterior, and the lateral range of it was between 15 and 35mm lateral from sagittal suture. The optimal catheter length for insertion was between 55 and 58mm from the brain surface. Ideal placement of a ventricular catheter tip was achieved in more than 90% of cases (31/34) with this technique. CONCLUSION: Tripod-guided ventricular catheter insertion is a simple and reliable method for VP shunt at any angle of head-rotation.