Comparison of Four Carbapenems; Imipenem-Cilastatin, Panipenem-Betamipron, Meropenem, and Biapenem with Review of Clinical Trials in Japan

The development of carbapenem gives a revolutionary impact to the chemotherapy of infectious diseases. The bacteriological and clinical efficacies of carbapenems, including imipenem/cilastatin, panipenem/betamipron, meropenem and biapenem, were evaluated. All four carbapenems were potent against gram-positive and gram-negative bacteria except Stenotrophomonas maltophilia. The antimicrobial activities of meropenem against Enterobacteriaceae were slightly superior to other carbapenems. Imipenem and panipenem were slightly more active against gram-positive bacteria than meropenem and biapenem. Biapenem was the most potent against Acinetobacter anitratus. The in vitro activity of imipenem was compared between 1990 and 1992 in Nagasaki University Hospital. The resistance rate of S. aureus, whose MIC is higher than 25 mg/l, increased from 3% to 22%, S. pneumoniae, whose MIC is higher than 0.05 mg/l, increased from 9% to 30% and P. aeruginosa, whose MIC is higher than 5 mg/l, increased from 20% to 32%. The isolation rates of S. maltophilia from sputum increased gradually from 0.9% in 1984 to 3.5% in 1991. The clinical efficacy rates of imipenem/cilastatin and panipenem/betamipron were 79% and 77%, and the rates of meropenem and biapenem 100% and 96.2% for the treatment of respiratory infection in our department, respectively. The efficacy rates of imipenem/cilastatin decreased from 79% to 67.7% after being commercialized. This decline was due to administration to patients with severe underlying diseases and with infection caused by resistant strains such as P. aeruginosa and S. aureus. The phase II and III trials of carbapenems in internal medicine, which were performed separately in Japan, showed that the clinical efficacy rates were 73%, 79%, 86% and 89%, and the rates of adverse reaction were 4.7%, 3.3%, 1.8% and 2.2% in imipenem /cilastatin, panipenembetamipron, meropenem and biapenem, respectively. Newly develope

Randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer

Background Chemotherapy-induced peripheral neuropathy is commonly observed in patients treated with nanoparticle albumin–bound paclitaxel (nab-PTX). We conducted a multicenter randomized controlled study to evaluate the optimal dose of nab-PTX. Methods We compared three different doses of q3w nab-PTX (Standard: 260 mg/m2 [SD260] vs Medium: 220 mg/m2 [MD220] vs Low: 180 mg/m2 [LD180]) in patients with HER2-negative metastatic breast cancer (MBC). Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses were estimated using the logistic regression model. The optimal dose was selected in two steps. Initially, if the hazard ratio (HR) for PFS was 1.33, the inferior dose was excluded, and we proceeded with the non-inferior dose. Then, if the estimated incidence rate of grade 3/4 neurotoxicity exceeded 10%, that dose was also excluded. Results One hundred forty-one patients were randomly assigned to SD260 (n = 47), MD220 (n = 46), and LD180 (n = 48) groups, and their median PFS was 6.66, 7.34, and 6.82 months, respectively. The HRs were 0.73 (95% confidence interval [CI]: 0.42–1.28) in MD220 vs SD260, 0.77 (95% CI 0.47–1.28) in LD180 vs SD260, and 0.96 (95% CI 0.56–1.66) in LD180 vs MD220. SD260 was inferior to MD220 and was excluded. The estimated incidence rate of grade 3/4 neurotoxicity was 29.5% in SD260, 14.0% in MD220, and 5.9% in LD180. The final selected dose was LD180. Conclusions Intravenous administration of low-dose nab-PTX at 180 mg/m2 q3w may be the optimal therapy with meaningful efficacy and favorable toxicity in patients with MBC

Association of Genetic Polymorphism with Taxane-induced Peripheral Neuropathy: Sub-analysis of a Randomized Phase II Study to Determine the Optimal Dose of 3-week Cycle Nab-Paclitaxel in Metastatic Breast Cancer Patients

Chemotherapy-induced peripheral neuropathy (CIPN) is an important clinical challenge that threatens patients’ quality of life. This sub-study of the ABROAD trial investigated the influence of single nucleotide polymorphisms (SNPs) on CIPN, using genotype data from a randomized study to determine the optimal dose of a 3-week-cycle regimen of nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2). Five SNPs (EPHA4-rs17348202, EPHA5-rs7349683, EPHA6-rs301927, LIMK2-rs5749248, and XKR4-rs4737264) were analyzed based on the results of a previous genome-wide association study. Per-allele SNP associations were assessed by a Cox regression to model the cumulative dose of nab-PTX up to the onset of severe or worsening sensory neuropathy. A total of 141 patients were enrolled in the parent study; 91(65%) were included in this sub-study. Worsening of CIPN was significantly greater in the cases with XKR4 AC compared to those with a homozygote AA (HR 1.86, 95%CI: 1.00001−3.46, p=0.049). There was no significant correlation of CIPN with any other SNP. A multivariate analysis showed that the cumulative dose of nab-PTX was most strongly correlated with CIPN (p<0.01)

PETREL: Platform for Extra and Terrestrial Remote Examination with LCTF

A small satellite ”PETREL” for UV astronomy and remote sensing with ”tunable” multi-spectral cameras conducted by an academia-industrial collaboration is presented. This project was originally proposed by an astronomer who desired a satellite for exploration of explosive objects in ultraviolet. To avoid the earthshine the astronomical observations are scheduled only in the nighttime. To utilize the daytime more electively we conceived a plan of ”satellite sharing” with the industrial collaborators, that can also reduce the developing cost drastically. The daytime mission is spectroscopy that is one of the potential fields in terms of data business, because that can provide chemical and biological information on the surface of the earth. We employ multi-spectral cameras making use of liquid crystal tunable filters (LCTFs) that enable adaptive observations at the optimized wave-bands for each targets. In 2020, this remote-sensing project and ultraviolet astronomy mission were accepted as a small satellite project of JAXA’s Innovative Satellite Technology Demonstration program and as an ISAS/JAXA’s small-scale program, respectively. This satellit

Development of Radiation Hard N+-on-P Silicon Microstrip Sensors for Super LHC

Radiation tolerance up to 1015 1-MeV neq/cm2 is required for the silicon microstrip sensors to be operated at the Super LHC experiment. As a candidate for such sensors, we are investigating non-inverting n+-on-p sensors. We manufactured sample sensors of 1 times 1 cm in 4" and 6" processes with implementing different interstrip electrical isolation structures. Industrial high resistive p-type wafers from FZ and MCZ growth are tested. They are different in crystal orientations lang100rang and lang111rang with different wafer resistivities. The sensors were irradiated with 70-MeV protons and characterized in views of the leakage current increase, noise figures, electrical strip isolation, full depletion voltage evolution, and charge collection efficiency

ABCA1 gene-physical activity interaction for HDL-C

Few studies have investigated the interactions between HDL-C-related SNPs identified by genome-wide association (GWA) study and physical activity (PA) on HDL-C. First, we conducted a sex-stratified GWA study in a discovery sample (2,231 men and 2,431 women) and replication sample (2,599 men and 3,109 women) to identify SNPs influencing log-transformed HDL-C in Japanese participants in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. We also replicated previously reported HDL-C-related SNPs in a combined (discovery plus replication) sample (4,830 men and 5,540 women). We then analyzed the interactions of the HDL-C-related SNPs with PA on HDL-C. The sex-stratified GWA analyses identified 11 and 10 HDL-C-related SNPs in men and women as targets for an interaction analysis. Among these, only one interaction of ABCA1 rs1883025 with PA was statistically significant in men, after Bonferroni correction [P-interaction = 0.001 (α = 0.05/21 = 0.002)]. The per-major-allele (C allele) increase in log-transformed HDL-C was lost in men with low PA (β = 0.008) compared with those with medium (β = 0.032) or high PA (β = 0.034). These findings suggest that the benefit of carrying a C allele of ABCA1 rs1883025 on enhancing HDL-C may be attenuated in inactive men

A genome-wide association study on meat consumption in a Japanese population : the Japan Multi-Institutional Collaborative Cohort study

Recent genome-wide association studies (GWAS) on the dietary habits of the Japanese population have shown that an effect rs671 allele was inversely associated with fish consumption, whereas it was directly associated with coffee consumption. Although meat is a major source of protein and fat in the diet, whether genetic factors that influence meat-eating habits in healthy populations are unknown. This study aimed to conduct a GWAS to find genetic variations that affect meat consumption in a Japanese population. We analysed GWAS data using 14 076 participants from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. We used a semi-quantitative food frequency questionnaire to estimate food intake that was validated previously. Association of the imputed variants with total meat consumption per 1000 kcal energy was performed by linear regression analysis with adjustments for age, sex, and principal component analysis components 1–10. We found that no genetic variant, including rs671, was associated with meat consumption. The previously reported single nucleotide polymorphisms that were associated with meat consumption in samples of European ancestry could not be replicated in our J-MICC data. In conclusion, significant genetic factors that affect meat consumption were not observed in a Japanese population

Cyclical and Patch-Like GDNF Distribution along the Basal Surface of Sertoli Cells in Mouse and Hamster Testes

BACKGROUND AND AIMS: In mammalian spermatogenesis, glial cell line-derived neurotrophic factor (GDNF) is one of the major Sertoli cell-derived factors which regulates the maintenance of undifferentiated spermatogonia including spermatogonial stem cells (SSCs) through GDNF family receptor α1 (GFRα1). It remains unclear as to when, where and how GDNF molecules are produced and exposed to the GFRα1-positive spermatogonia in vivo. METHODOLOGY AND PRINCIPAL FINDINGS: Here we show the cyclical and patch-like distribution of immunoreactive GDNF-positive signals and their close co-localization with a subpopulation of GFRα1-positive spermatogonia along the basal surface of Sertoli cells in mice and hamsters. Anti-GDNF section immunostaining revealed that GDNF-positive signals are mainly cytoplasmic and observed specifically in the Sertoli cells in a species-specific as well as a seminiferous cycle- and spermatogenic activity-dependent manner. In contrast to the ubiquitous GDNF signals in mouse testes, high levels of its signals were cyclically observed in hamster testes prior to spermiation. Whole-mount anti-GDNF staining of the seminiferous tubules successfully visualized the cyclical and patch-like extracellular distribution of GDNF-positive granular deposits along the basal surface of Sertoli cells in both species. Double-staining of GDNF and GFRα1 demonstrated the close co-localization of GDNF deposits and a subpopulation of GFRα1-positive spermatogonia. In both species, GFRα1-positive cells showed a slender bipolar shape as well as a tendency for increased cell numbers in the GDNF-enriched area, as compared with those in the GDNF-low/negative area of the seminiferous tubules. CONCLUSION/SIGNIFICANCE: Our data provide direct evidence of regionally defined patch-like GDNF-positive signal site in which GFRα1-positive spermatogonia possibly interact with GDNF in the basal compartment of the seminiferous tubules