Phase I and II randomized clinical trial of an oral therapeutic vaccine targeting human papillomavirus for treatment of cervical intraepithelial neoplasia 2 and 3.

BACKGROUND: Although many human papillomavirus (HPV)-targeted therapeutic vaccines have been examined for efficacy in clinical trials, none have been translated into clinical use. These previous agents were mostly administered by intramuscular or subcutaneous injection to induce systemic immunity. We investigated the safety and therapeutic efficacy of an HPV-16 E7-expressing lacticaseibacillus-based oral vaccine. METHODS: In a double-blind, placebo-controlled, randomized trial, a total of 165 patients with HPV-16-positive high-grade cervical intraepithelial neoplasia 2 and 3 were assigned to orally administered placebo or low, intermediate, or high doses of IGMKK16E7 (lacticaseibacillus paracasei expressing cell surface, full-length HPV-16 E7). In the 4 groups, IGMKK16E7 or placebo was administered orally at weeks 1, 2, 4, and 8 postenrollment. The primary outcomes included histopathological regression and IGMKK16E7 safety. RESULTS: In per-protocol analyses, histopathological regression to normal (complete response) occurred in 13 (31.7%) of 41 high-dose recipients and in 5 (12.5%) of 40 placebo recipients (rate difference = 19.2, 95% confidence interval [CI] = 0.5 to 37.8). In patients positive for HPV-16 only, the clinical response rate was 40.0% (12 of 30) in high-dose recipients and 11.5% (3 of 26) in recipients of placebo (rate difference = 28.5, 95% CI = 4.3 to 50.0). There was no difference in adverse events that occurred in the high-dose and placebo groups (P = .83). The number of HPV-16 E7-specific interferon-γ producing cells within peripheral blood increased with level of response (stable disease, partial, and complete responses; P = .004). The regression to normal (complete response) rates among recipients with high levels of immune response were increased in a dose-dependent manner. CONCLUSION: This trial demonstrates safety of IGMKK16E7 and its efficacy against HPV-16-positive cervical intraepithelial neoplasia 2 and 3. IGMKK16E7 is the first oral immunotherapeutic vaccine to show antineoplastic effects. TRIAL REGISTRATION: jRCT2031190034.

An autopsy case of sudden unexpected death with Barlow's disease.

A 45-year-old man was clinically diagnosed with mitral valve regurgitation 2 years before death. The autopsy showed left ventricular hypertrophy and mitral valve prolapse of the bileaflet with billowing valve and excessively thickened leaflet, the findings of which were consistent with Barlow's disease. Microscopically, destruction of the 3-layer structure of the mitral valve and advanced interstitial fibrosis of the left ventricular wall were evident. Additionally, a marked but limited reduction in conduction fibers was found in the branching point of the left and right branches, as seen in cases of idiopathic complete atrioventricular block. Genetic investigation using whole-exome sequencing showed some genetic variants with uncertain significance. In patients with Barlow's disease, a marked reduction of conduction fibers might be a subtype of sudden cardiac death. The overlap of some arrhythmogenic substrate in the heart may increase the risk of sudden cardiac death with asymptomatic Barlow's disease.

National Registry of Designated Intractable Diseases in Japan: Present Status and Future Prospects.

Japan promotes research related to intractable diseases and financially supports patients with these diseases. Intractable diseases are designated as those that fulfill the following criteria: (1) rarity (affecting less than 0.1% of the population in Japan), (2) unknown etiology, (3) lack of effective treatment, (4) necessity of long-term treatment, and (5) existence of objective diagnostic criteria and not necessarily equal to rare diseases in other countries. The construction of a national database is required to promote research to clarify the pathogenesis of these diseases and to develop pharmaceutical products and medical devices. The Ministry of Health, Labor, and Welfare launched an online registration system in 2001, but many problems associated with gathering and utilizing information on patients with intractable diseases remain. In this paper, we describe the present status of the national registry of designated intractable diseases in Japan and discuss future prospects.

Model carcinogen adsorption dynamics of DNA gel.

We have derived theoretical equations describing the adsorption of carcinogen to gels in an immersion medium containing carcinogens. The theory was developed for a cylindrical boundary condition under the assumption of a carcinogen diffusion-limited process combined with the "moving boundary picture (Furusawa et al., 2007)". The time course of the adsorbed carcinogen layer thickness and that of the carcinogen concentration in an immersion medium were expressed by a set of scaled variables, and the asymptotic behavior in the initial stage was derived. Experiments based on the theory were performed using a DNA gel sandwiched between a set of coverglasses in a medium containing acridine orange (AO). The boundary between the AO-adsorbed gel layer and AO-nonadsorbed gel layer was traced during the immersion. The time courses of the AO-adsorbed gel layer thickness and the AO concentration in the immersion medium were well explained by the theory, and the number ratio of the total AO molecules to the adsorption sites in the DNA gel was determined.

Management evaluation about introduction of electric medical record in the national hospital organization.

Introduction of Electronic Medical Record (EMR) into a hospital was started from 1999 in Japan. Then, most of all EMR company said that EMR improved efficacy of the management of the hospital. National Hospital Organization (NHO) has been promoting the project and introduced EMR since 2004. NHO has 143 hospitals, 51 hospitals offer acute-phase medical care services, the other 92 hospitals offer medical services mainly for chronic patients. We conducted three kinds of investigations, questionnaire survey, checking the homepage information of the hospitals and analyzing the financial statements of each NHO hospital. In this financial analysis, we applied new indicators which have been developed based on personnel costs. In 2011, there are 44 hospitals which have introduced EMR. In our result, the hospital with EMR performed more investment of equipment/capital than personnel expenses. So, there is no advantage of EMR on the financial efficacy.

Lessons learned from the Great East Japan Earthquake: impact on child and adolescent health.

The Great East Japan Earthquake (the Tohoku Earthquake) was one of the most devastating natural disasters ever to hit Japan, and its social impact was so enormous that Japan may never be the same again. This was an unprecedented triple disaster: an earthquake followed by a devastating tsunami and, finally, the destruction of a major nuclear power plant with the leaking of large amounts of radiation. The destruction occurred despite the presence of a 10-m protection wall and the effects of the tsunami were seen as high as 40 m above sea level. About 78,000 residents from areas within a 20-km radius of the Fukushima Daiichi Nuclear Power Plant were evacuated together with another 10,000 residents from areas with elevated levels of radiation. In the afflicted area, 30% of the population was older than 60 years of age, but more than 60% of the deaths were in this age cohort. Children and adolescents younger than 19 years accounted for 6.5% of the deaths, and there were 229 survivors younger than 18 years who lost both their parents in the disaster and 1295 who lost one of their parents. The long-term psychological effects on children and adolescents remain uncertain.

Distinct relations among plasma concentrations required for different pharmacological effects in oxycodone, morphine, and fentanyl.

Several clinical reports showed that adverse effect profiles are not the same in morphine, oxycodone, and fentanyl. The authors investigated whether the relationship between plasma concentrations for antinociceptive effect and for various pharmacological effects differed among oxycodone, morphine, and fentanyl under controlled experimental setting using animal models. Oxycodone induced constipation and an antinociceptive effect in a similar concentration-dependent manner, whereas morphine required approximately 9-fold higher plasma concentration for antinociceptive effect compared with that for constipation when 50% effective plasma concentration (EC(50)) levels were compared. The EC(50) values for inhibition of behavioral activity were 2.1-, 2.7-, and 1.3-fold higher than those for antinociceptive effect in oxycodone, morphine, and fentanyl, respectively. Respiratory inhibition was observed even at higher plasma concentrations in all three opioids, and the differences in the EC(50) values compared with those for antinociceptive effects were 234.5-fold (oxycodone), 233.1-fold (morphine), or 104.2-fold (fentanyl). These results showed that oxycodone, morphine, and fentanyl exhibited unique patterns of plasma concentrations required for different pharmacological effects. The different adverse effect profiles observed in a clinical setting appear to be resulted from, at least in part, distinct intrinsic pharmacological profiles among these µ-opioid receptor agonists.

Dynamics in the process of formation of anisotropic chitosan hydrogel.

To control the dynamics of dialysis-induced anisotropic gel formation, we have derived a theoretical expression for the development of the gel layer for a simple case where no cross-link sites for cross-linking agents exists and the inflow and the outflow of low molecular weight components through the dialysis membrane modify the state of polymer molecules to meet the gelation condition. A series of experiments using chitosan solution were done as a model case. The experimental results were compared with asymptotic expressions of the time development equation predicted by theory, and the compatibility of the theoretical picture was examined.

Thymosin-beta4 regulates motility and metastasis of malignant mouse fibrosarcoma cells.

We identified a thymosin-beta4 gene overexpression in malignant mouse fibrosarcoma cells (QRsP-30) that were derived from clonal weakly tumorigenic and nonmetastatic QR-32 cells by using a differential display method. Thymosin-beta4 is known as a 4.9-kd polypeptide that interacts with G-actin and functions as a major actin-sequestering protein in cells. All of the six malignant fibrosarcoma cell lines that have been independently converted from QR-32 cells expressed high levels of thymosin-beta4 mRNA and its expression in tumor cells was correlated with tumorigenicity and metastatic potential. Up-regulation of thymosin-beta4 in QR-32 cells (32-S) transfected with sense thymosin-beta4 cDNA converted the cells to develop tumors and formed numerous lung metastases in syngeneic C57BL/6 mice. In contrast, antisense thymosin-beta4 cDNA-transfected QRsP-30 (30-AS) cells reduced thymosin-beta4 expression, and significantly lost tumor formation and metastases to distant organs. Vector-alone transfected cells (32-V or 30-V cells) behaved like their parental cells. We observed that tumor cell motility, cell shape, and F-actin organization is regulated in proportion to the level of thymosin-beta4 expression. These findings indicate that thymosin-beta4 molecule regulates fibrosarcoma cell tumorigenicity and metastasis through actin-based cytoskeletal organization.