Increased fibrosis and impaired intratumoral accumulation of macromolecules in a murine model of pancreatic cancer co-administered with FGF-2

Pancreatic cancer is notorious for its poor prognosis. The histopathologic characteristic of pancreatic ductal adenocarcinoma (PDAC), which is the most common type of pancreatic cancer, is fibrosis within tumor tissue. Although fibrosis within tumor tissue is thought to impede drug therapy by interfering with the intratumoral accumulation of anti-tumor drugs, this hypothesis has yet to be proven directly in preclinical models. Here, we evaluated the effect of enhanced fibrosis on intratumoral accumulation of macromolecular drugs by increasing fibrosis in a murine tumor model of subcutaneously xenografted BxPC-3, a human PDAC cell line. When fibroblast growth factor-2 (FGF-2) was co-administered upon BxPC-3 inoculation, stromal fibrotic area was increased and was characterized by augmented murine collagen accumulation compared to inoculation of BxPC-3 alone, which correlated with increased monocyte/macrophage contents in the tumor tissues. We further discovered that the intratumoral accumulation of intravenously administrated fluorescein isothiocyanate-dextran of 2,000,000 Da (2 MDa) was significantly reduced in the FGF-2 co-administered tumors despite unaltered hyaluronan accumulation and pericyte coverage of the tumor neovasculature and increased lymphangiogenesis. Finally, we found that FGF-2 co-administered tumors are more refractory to macromolecular drug therapy using nab-paclitaxel (Abraxane). The model established and analyzed in this study, characterized by increased fibrotic component, provides a preclinical animal model suited to predict the intratumoral accumulation of macromolecular drugs and to evaluate the efficacy of drugs targeting the tumor stroma

Localization of Liv2 as an Immature Hepatocyte Marker in EB Outgrowth

The objective of this study was to establish Liv2, a surface marker of mouse immature hepatocytes (hepatoblasts), as a selection tool for embryonic stem (ES) cell–derived immature hepatocytes by acquiring basic data on Liv2 in normal mouse embryos and by confirming Liv2 expression in mouse ES-derived cells. The estimated molecular weight of Liv2 was 4045 kDa, and immunoreactivity was definitively detected in the cell membrane of fetal hepatocytes on embryonic day (E) 9.5, declined gradually until E12.5, and subsequently became undetectable. Liv2 was localized on and close to the cell membrane. Embryoid bodies (EB) were formed from mouse ES cells whose undifferentiated state was confirmed with immunostaining of Nanog by the hanging drop method. A few Liv2-positive cells occurred as a cluster in EB outgrowth on day 7, but only some of these were albumin (ALB)-positive on day 13. These cells had the same pattern of immunoreactivity, i.e., localization on the cell membrane, as immature hepatocytes in the developing liver, although there were other types of cells with a different pattern of immunoreactivity that were seen only as a granular pattern in the cytoplasm and without ALB or the neuronal marker nestin. These results suggest that Liv2 may be useful as a surface marker for immature hepatocytes derived from ES cells. This application would allow for the sole selection of immature hepatocytes and provide a useful tool for regenerative medicine

NC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo

Drug release rate is an important factor in determining efficacy and toxicity of nanoscale drug delivery systems. However, optimization of the release rate in polymeric micellar nanoscale drug delivery systems has not been fully investigated. In this study NC-6301, a poly(ethylene glycol)-poly(aspartate) block copolymer with docetaxel (DTX) covalently bound via ester link, was synthesized with various numbers of DTX molecules bound to the polymer backbone. The number of DTX molecules was determined up to 14 to achieve an optimal release rate, based upon the authors’ own pharmacokinetic model using known patient data. Efficacy and toxicity of the formulation was then tested in animals. When administered three times at 4-day intervals, the maximum tolerated doses of NC-6301 and native DTX were 50 and 10 mg/kg, respectively, in nude mice. Tissue distribution studies of NC-6301 in mice at 50 mg/kg revealed prolonged release of free DTX in the tumor for at least 120 hours, thus supporting its effectiveness. Furthermore, in cynomolgus monkeys, NC-6301 at 6 mg/kg three times at 2-week intervals showed marginal toxicity, whereas native DTX, at 3 mg/kg with the same schedule, induced significant decrease of food consumption and neutrophil count. NC-6301 at 50 mg/kg in mice also regressed a xenografted tumor of MDA-MB-231 human breast cancer. Native DTX, on the other hand, produced only transient and slight regression of the same tumor xenograft. NC-6301 also significantly inhibited growth of OCUM-2MLN human scirrhous gastric carcinoma in an orthotopic mouse model. Total weight of metastatic lymph nodes was also reduced. In conclusion, NC-6301 with an optimized release rate improved the potency of DTX while reducing its toxicity

Robotic Renal Autotransplantation: A Feasibility Study in a Porcine Model

We investigated the feasibility of robotic renal autotransplantation (RAT) in a porcine model to reduce invasiveness of RAT. Five pigs underwent robotic RAT using the da Vinci® robotic system. A robotic left nephrectomy was performed in all cases. Robotic RAT was performed on the left side in all but one case. Four ports were used. In 3 cases, the kidney was taken out through the GelPort® and irrigated on ice with Ringer’s solution. In 2 cases, a complete intracorporeal robotic RAT was performed. An end-to-side anastomosis was performed between the renal vein and the external iliac vein and between the renal artery and the external iliac artery. Ureteroneocystostomy was also performed in 2 cases. All cases were performed robotically without open conversion. The median (IQR) console time was 3.1 (0.7) h, and the operative time was 3.8 (1.1) h. The estimated blood loss was 30 (0) ml. The warm ischemia time was 4.0 (0.2) min, and the cold ischemia time was 97 (17) min. Intracorporeal transarterial hypothermic renal perfusion was feasible in the 2 complete intracorporeal robotic RAT cases by using a perfusion catheter through a laparoscopic port. Robotic RAT has the potential to be a new minimally invasive substitute for conventional open surgery

A Report on Overseas Teaching Practicum by Graduate Students in Elementary/Secondary Schools in the United States (Ⅶ)

The present reports is on the 7th overseas teaching practicum in the United States by 15 graduate students of Hiroshima University, Japan, partly organized by Hiroshima University Global Partnership School Center since 2007. The group was comprised of 13 elementary school and 2 secondary school education major graduate students. They planned and conducted lessons in English in three local public schools in North Carolina. The expected outcomes of this project were: 1) to self-develop practical instructional competence by teaching pupils with diverse backgrounds in the U.S.; 2) to enhance the abilities in developing teaching materials through hands-on teaching experiences in English; and 3) to acquire the abilities to design, implement and evaluate programs for promoting global partnership. In addition, the teaching experience was followed by cross-cultural study visits to Raleigh, NC and Washington, D.C. It helped to boost our group motivation that the local media, newspaper and TV, and the city Board of Education covered our visit. It is hoped that this project will enhance the students’ teaching competence in designing quality materials/lessons and classroom communication skills in English

JASMINE: Near-infrared astrometry and time-series photometry science

The Japan Astrometry Satellite Mission for INfrared Exploration (JASMINE) is a planned M-class science space mission by the Institute of Space and Astronautical Science, the Japan Aerospace Exploration Agency. JASMINE has two main science goals. One is Galactic archaeology with a Galactic Center survey, which aims to reveal the Milky Way’s central core structure and formation history from Gaia-level (∼25 ${\mu}$as) astrometry in the near-infrared (NIR) Hw band (1.0–1.6 ${\mu}$m). The other is an exoplanet survey, which aims to discover transiting Earth-like exoplanets in the habitable zone from NIR time-series photometry of M dwarfs when the Galactic Center is not accessible. We introduce the mission, review many science objectives, and present the instrument concept. JASMINE will be the first dedicated NIR astrometry space mission and provide precise astrometric information on the stars in the Galactic Center, taking advantage of the significantly lower extinction in the NIR. The precise astrometry is obtained by taking many short-exposure images. Hence, the JASMINE Galactic Center survey data will be valuable for studies of exoplanet transits, asteroseismology, variable stars, and microlensing studies, including discovery of (intermediate-mass) black holes. We highlight a swath of such potential science, and also describe synergies with other missions

EphA7+perivascular cells as myogenic and angiogenic precursors improving skeletal muscle regeneration in a muscular dystrophic mouse model. （EphA7陽性周細胞は、筋ジストロフィーマウスモデルにおいて、骨格筋再生能を改善する）

Skeletal muscle has a capacity for muscular regeneration mediated by satellite cells (SCs) and non-SCs. Although it is proposed that non-SCs are attractive therapeutic targets for dystrophies, the biological properties of these cells remain unclear. We have recently identified novel multipotent pericytes (PCs), capillary stem cells (CapSCs) derived from the microvasculature. In the present study, we determined if CapSCs contributed to myogenic regeneration using muscular dystrophy mouse model. CapSCs were isolated as EphA7+NG2+PCs from the subcutaneous adipose tissues of GFP-transgenic mice. Co-culture with C2C12 myoblast cells showed that CapSCs effectively enhanced myogenesis as compared to controls including EphA7- PCs and adipose stromal cells (ASCs). CapSCs transplanted in cardiotoxin-injured gastrocnemius muscles were well differentiated into both muscle fibers and microvessels, as compared to controls. At three weeks after cell-transplantation into the limbs of the mdx/utrn-/-mouse, CapSCs increased the number of GFP+myofibers along with dystrophin expression and the area size of myofibers, and also enhanced the muscular mass and its performance, assessed by treadmill test as compared to controls. In conclusion, CapSCs have potent myogenic regeneration capacity and improved the pathological condition in a muscular dystrophy mouse. Thus, CapSCs are an attractive cellular source in regenerative therapy for muscular dystrophy.博士（医学）旭川医科大

The Relationship between Training Cycle-Dependent Fluctuations in Resting Blood Lactate Levels and Exercise Performance in College-Aged Rugby Players

An increase in resting blood lactate (La−) concentration due to metabolic conditions has been reported. However, it is not clear whether resting La− changes with training cycles in athletes. The purpose of this study was to test the hypotheses that (1) the morning resting La− levels are lower in periods of high training compared to periods of low training and (2) these changes in La− concentration are related to athletes’ metabolic capacity during exercise in male college-aged rugby players. Resting La− and blood glucose concentrations were measured in the morning in eight league rugby players during the summer pre-season period (Pre-period), the training and competition season period (TC-period), and the winter post-season period (Post-period). In each period, anaerobic power, La− concentration, and respiratory responses were measured during the 40 s maximal Wingate anaerobic test (WT). The resting La− concentration in the morning was significantly lower in the TC-Period (1.9 ± 0.6 mmol/L) than in the Post-Period (2.3 ± 0.9 mmol/L). The rate of decrease in La− level immediately after the 40 s WT was significantly higher in the TC-Period than in the Post-Period. The resting La− concentration was significantly correlated with the peak oxygen uptake and the carbon dioxide output during the WT. These results support the hypothesis that an athlete’s training cycle (i.e., in season and off season) influences the resting La− levels as well as the metabolic capacity during high-intensity exercise. The monitoring of resting La− fluctuations may provide a convenient indication of the training cycle-dependent metabolic capacity in athletes

A Competitive Sprinter’s Resting Blood Lactate Levels Fluctuate with a One-Year Training Cycle: Case Reports

It has been reported that the variability of resting blood lactate concentration (BLa) is related to metabolic capacity. However, it is unclear whether the resting BLa of athletes can be utilized as a metabolic biomarker. This longitudinal case study tested the hypothesis that resting BLa levels in the morning fluctuate with a 1-year training cycle. The subject was an adult male sprinter, and BLa and blood glucose at the time of waking were measured every day for 1 year. The training cycles were divided into five phases: 1. Basic training: high-intensity and high-volume load; 2. Condition and speed training: high-intensity and low-volume load; 3. Competition training I: track race and high-intensity load; 4. Conditioning for injury; 5. Competition training II. The mean BLa levels in the basic training (1.10 ± 0.32 mmol/L and competition training I (1.06 ± 0.28 mmol/L) phases were significantly lower than in the condition and speed training (1.26 ± 0.40 mmol/L) and conditioning injury (1.37 ± 0.34 mmol/L) phases. The clarified training cycle dependence of resting BLa is suggested to be related to the ability to utilize lactate as an energy substrate with fluctuations in oxidative metabolic capacity. This case report supports the tentative hypothesis that resting BLa may be a biomarker index linked to the metabolic capacity according to the training cycle