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Purpose/objective(s) To report results from our phase II study of stereotactic body radiotherapy (SBRT) delivering 36 Gy in 4 fractions for patients with localized prostate cancer. Materials/methods We enrolled 55 patients treated with SBRT delivering 36 Gy in 4 fractions between 2015 to 2018. All patients were categorized as low-risk (n = 4), intermediate-risk (n = 31) or high-risk (n = 20) according to National Comprehensive Cancer Network criteria. Median age was 73 years (range 54–86 years). Two-thirds of patients (n = 37) had received androgen-deprivation therapy for 3–46 months (median, 31 months). Median duration of follow-up was 36 months (range 1–54 months). We used Radiation Therapy Oncology Group and National Cancer Institute—Common Toxicity Criteria version 4 for toxicity assessments. Quality of life (QOL) outcomes were also evaluated using the Expanded Prostate Cancer Index Composite (EPIC). Results Protocol treatments were completed for all patients. Six patients experienced biochemical failures. Among these six patients, three patients experienced clinical failure. One patient showed bone metastasis before biochemical failure. One patient died of gastric cancer. The 3-year biochemical control rate was 89.8%. Acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities were observed in 5 patients (9%) and 6 patients (11%), respectively. No grade 3 or higher acute toxicities were observed. Late grade 2 GU and GI toxicities were observed in 7 patients (13%) and 4 patients (7%), respectively. Late grade 3 GU and GI toxicities were observed in 1 patient (1.8%) each. EPIC scores decreased slightly during the acute phase and recovered within 3 months after treatment. Conclusion Our phase II study showed that SBRT delivering 36 Gy in 4 fractions was safe and effective with favorable QOL outcomes, although this regimen showed slightly more severe toxicities compared to current standards.

We previously designed a modified channelrhodopsin-1 (mVChR1) protein chimera with a broader action than that of Chlamydomonas channelrhodopsin-2 and reported that its transduction into retinal ganglion cells can restore visual function in genetically blind, dystrophic Royal College of Surgeons (RCS) rats, with photostimuli ranging from 486 to 640 nm. In the current study, we sought to investigate the safety and influence of mVChR1 transgene expression. Adeno-associated virus type 2 encoding mVChR1 was administered by intravitreous injection into dystrophic RCS rats. Reverse-transcription PCR was used to monitor virus and transgene dissemination and the results demonstrated that their expression was restricted specifically within the eye tissues, and not in non-target organs. Moreover, examination of the blood, plasma and serum revealed that no excess immunoreactivity was present, as determined using standard clinical hematological parameters. Serum antibodies targeting the recombinant adeno-associated virus (rAAV) capsid increased after the injection; however, no increase in mVChR1 antibody was detected during the observation period. In addition, retinal histological examination showed no signs of inflammation in rAAV-injected rats. In conclusion, our results demonstrate that mVChR1 can be exogenously expressed without harmful immunological reactions in vivo . These findings will aid in studies of AAV gene transfer to restore vision in late-stage retinitis pigmentosa.

Precise understanding of biological functions requires tools comparable in size to the basic components of life 1 , 2 , 3 , 4 . Single molecule studies have revealed molecular behaviors usually hidden in the ensemble- and time-averaging of bulk experiments 5 , 6 . Although most such approaches rely on sophisticated optical strategies to limit the detection volume 7 , 8 , another attractive approach is to perform the assay inside very small containers 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . We have developed a silicone device presenting a large array of micrometer-sized cavities. We used it to tightly enclose volumes of solution, as low as femtoliters, over long periods of time. The microchip insures that the chambers are uniform and precisely positioned. We demonstrated the feasibility of our approach by measuring the activity of single molecules of β-galactosidase and horseradish peroxidase. The approach should be of interest for many ultrasensitive bioassays at the single-molecule level.

Objective: To measure total energy expenditure (TEE) for normal healthy Japanese by the doubly labelled water (DLW), and to compare the physical activity level (PAL) among categories classified by the categories used in daily reference intake (DRI), Japan and the International Physical Activity Questionnaire (IPAQ). Subjects and methods: A total of 150 healthy Japanese men and women aged 20- to 59-year-old living in four districts of Japan. TEE was measured by the DLW method, and the PAL was calculated from TEE divided by basal metabolic rate. Simultaneously with TEE measurement, the PAL was assessed employing the categories used in DRI, Japan and IPAQ. Results: The average TEE and PAL were 10.781.67 MJ/day and 1.720.22 for males and 8.371.30 MJ/day and 1.720.27 for females, respectively. The subjects in the highly active categories assessed by both DRI and IPAQ showed significantly higher PAL compared with less active categories. However, PALs among light and moderate categories by DRI, and insufficient and sufficiently active by IPAQ were not significantly different. Conclusions: In developed countries, highly active subjects could be assessed by a simple questionnaire. However, the questionnaire should be improved to clarify the sedentary to moderately active subjects by assessing carefully very light to moderate physical activity.

The purpose of this study was to report the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) for National Comprehensive Cancer Network (NCCN) criteria-defined high-risk (HR) and very high-risk (VHR) prostate cancer. Data from 178 HR (n = 96, 54%) and VHR (n = 82, 46%) prostate cancer patients who underwent 192Ir-HDR brachytherapy and hypofractionated EBRT with long-term ADT between 2003 and 2008 were retrospectively analyzed. The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After five fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administered. All patients initially underwent ≥6 months of neoadjuvant ADT, and adjuvant ADT was continued for 36 months after EBRT. The median follow-up was 61 months (range, 25–94 months) from the start of radiotherapy. The 5-year biochemical non-evidence of disease, freedom from clinical failure and overall survival rates were 90.6% (HR, 97.8%; VHR, 81.9%), 95.2% (HR, 97.7%; VHR, 92.1%), and 96.9% (HR, 100%; VHR, 93.3%), respectively. The highest Radiation Therapy Oncology Group-defined late genitourinary toxicities were Grade 2 in 7.3% of patients and Grade 3 in 9.6%. The highest late gastrointestinal toxicities were Grade 2 in 2.8% of patients and Grade 3 in 0%. Although the 5-year outcome of this tri-modality approach seems favorable, further follow-up is necessary to validate clinical and survival advantages of this intensive approach compared with the standard EBRT approach.

From June to August 2018, the eruption of Kīlauea volcano on the island of Hawai‘i injected millions of cubic meters of molten lava into the nutrient-poor waters of the North Pacific Subtropical Gyre. The lava-impacted seawater was characterized by high concentrations of metals and nutrients that stimulated phytoplankton growth, resulting in an extensive plume of chlorophyll a that was detectable by satellite. Chemical and molecular evidence revealed that this biological response hinged on unexpectedly high concentrations of nitrate, despite the negligible quantities of nitrogen in basaltic lava. We hypothesize that the high nitrate was caused by buoyant plumes of nutrient-rich deep waters created by the substantial input of lava into the ocean. This large-scale ocean fertilization was therefore a unique perturbation event that revealed how marine ecosystems respond to exogenous inputs of nutrients.

We previously identified the mouse and human Glipr1 and GLIPR1/RTVP-1 genes, respectively, as direct p53 targets with proapoptotic activities in various cancer cell lines, including prostate cancer (PCa). Intratumoral injection of an adenoviral vector capable of efficient transduction and expression of Glipr1 (AdGlipr1) yielded promising therapeutic results in an orthotopic, metastatic mouse model of PCa. AdGlipr1-transduced macrophages (Mφ/Glipr1) generated greater surface expression of CD40, CD80 and major histocompatibility complex class II molecules and greater production of interleukin 12 (IL-12) and IL-6 in vitro than control macrophages did. Mechanistic analysis indicated that increased production of IL-12 in Mφ/Glipr1 depends on activation of the p38 signaling cascade. Mφ/Glipr1 injected into orthotopic 178-2BMA tumors in vivo resulted in significantly suppressed prostate tumor growth and spontaneous lung metastases and longer survival relative to those observed in control-treated mice. Furthermore, these preclinical data indicate the generation of systemic natural killer cell activity and tumor-specific cytotoxic T lymphocyte responses. Trafficking studies confirmed that intratumorally injected Mφ/Glipr1 could migrate to draining lymph nodes. Overall, our data suggest that this novel gene-modified cell approach is an effective treatment avenue that induces antitumor immune responses in preclinical studies.

A large-scale production system of cytidine 5'monophospho-N-acetylneuraminic acid (CMP-NeuAc) and sialyloligosaccharides was established by a whole-cell reaction through the combination of recombinant Escherichia coli strains and Corynebacterium ammonia-genes. For the production of CMP-NeuAc, two recombinant E. coli strains were generated that overexpressed the genes of CMP-NeuAc synthetase and CTP synthetase, respectively. C. ammoniagenes contributed to the formation of UTP from orotic acid. CMP-NeuAc was accumulated at 27 mM (17 g/l) after a 27-h reaction starting with orotic acid and N-acetylneuraminic acid. When E. coli cells that overexpressed the alpha-(2-->3)-sialyltransferase gene of Neisseria gonorrhoeae were put into the CMP-NeuAc production system, 3'-sialyllactose was accumulated at 52 mM (33 g/l) after an 11-h reaction starting with orotic acid, N-acetylneuraminic acid, and lactose. Almost no oligosaccharide byproducts other than 3'-sialyllactose were observed after the reaction. The production of 3'-sialyllactose at a 5-l jar fermenter scale was almost the same as that at a beaker scale, which indicated the high potential of the 3'-sialyllactose production on an industrial scale.