Porencephaly in a Cynomolgus Monkey (Macaca Fascicularis)

Porencephaly was observed in a female cynomolgus monkey (Macaca fascicularis) aged 5 years and 7 months. The cerebral hemisphere exhibited diffuse brownish excavation with partial defects of the full thickness of the hemispheric wall, and it constituted open channels between the lateral ventricular system and arachnoid space. In addition, the bilateral occipital lobe was slightly atrophied. Histopathologically, fibrous gliosis was spread out around the excavation area and its periphery. In the roof tissue over the cavity, small round cells were arranged in the laminae. They seemed to be neural or glial precursor cells because they were positive for Musashi 1 and negative for NeuN and GFAP. In the area of fibrous gliosis, hemosiderin or lipofuscin were deposited in the macrophages, and activated astroglias were observed extensively around the excavation area

A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring human epidermal growth factor receptor 2 amplification (JUPITER trial)

Introduction: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol. Methods/Design: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response. Discussion: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab. Trial registration: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150

Tsunami run-up heights of the 2003 Tokachi-oki earthquake

Tsunami height survey was conducted immediately after the 2003 Tokachi-oki earthquake. Results of the survey show that the largest tsunami height was 4 m to the east of Cape Erimo, around Bansei-onsen, and locally at Mabiro. The results also show that the tsunami height distribution of the 2003 Tokachi-oki earthquake is clearly different from that of the 1952 Tokachi-oki earthquake, suggesting the different source areas of the 1952 and 2003 Tokachioki earthquakes. Numerical simulation of tsunami is carried out using the slip distribution estimated by Yamanaka and Kikuchi (2003). The overall pattern of the observed tsunami height distribution along the coast is explained by the computed ones although the observed tsunami heights are slightly smaller. Large later phase observed at the tide gauge in Urakawa is the edge wave propagating from Cape Erimo along the west coast of the Hidaka area.The 2003 Tokachi-oki earthquak

Targeting Notch-1 positive acute leukemia cells by novel fucose-bound liposomes carrying daunorubicin

Complete remission by induction therapy in acute myelogenous leukemia (AML) can be achieved due to improvements in supportive and optimized therapy. However, more than 20% of patients will still need to undergo salvage therapy, and most will have a poor prognosis. Determining the specificity of drugs to leukemia cells is important since this will maximize the dose of chemotherapeutic agents that can be administered to AML patients. In turn, this would be expected to lead to reduced drug toxicity and its increased efficacy. We targeted Notch-1 positive AML cells utilizing fucose-bound liposomes, since activation of Notch-1 is required for O-fucosylation. Herein, we report that intravenously injected, L-fucose-bound liposomes containing daunorubicin can be successfully delivered to AML cells that express fucosylated antigens. This resulted in efficient tumor growth inhibition in tumor-bearing mice and decreased proliferation of AML patient-derived leukemia cells. Thus, biological targeting by fucose-bound liposomes that takes advantage of the intrinsic characteristics of AML cells could be a promising new strategy for Notch-1 positive-AML treatment

Mining of the Uncharacterized Cytochrome P450 Genes Involved in Alkaloid Biosynthesis in California Poppy Using a Draft Genome Sequence

ハナビシソウゲノムの解読から見えてきたイソキノリンアルカロイド生合成酵素遺伝子の進化 --植物が有用物質生産系を進化させる仕組みの解読--. 京都大学プレスリリース. 2018-01-26.Land plants produce specialized low molecular weight metabolites to adapt to various environmental stressors, such as UV radiation, pathogen infection, wounding and animal feeding damage. Due to the large variety of stresses, plants produce various chemicals, particularly plant species-specific alkaloids, through specialized biosynthetic pathways. In this study, using a draft genome sequence and querying known biosynthetic cytochrome P450 (P450) enzyme-encoding genes, we characterized the P450 genes involved in benzylisoquinoline alkaloid (BIA) biosynthesis in California poppy (Eschscholzia californica), as P450s are key enzymes involved in the diversification of specialized metabolism. Our in silico studies showed that all identified enzyme-encoding genes involved in BIA biosynthesis were found in the draft genome sequence of approximately 489 Mb, which covered approximately 97% of the whole genome (502 Mb). Further analyses showed that some P450 families involved in BIA biosynthesis, i.e. the CYP80, CYP82 and CYP719 families, were more enriched in the genome of E. californica than in the genome of Arabidopsis thaliana, a plant that does not produce BIAs. CYP82 family genes were highly abundant, so we measured the expression of CYP82 genes with respect to alkaloid accumulation in different plant tissues and two cell lines whose BIA production differs to estimate the functions of the genes. Further characterization revealed two highly homologous P450s (CYP82P2 and CYP82P3) that exhibited 10-hydroxylase activities with different substrate specificities. Here, we discuss the evolution of the P450 genes and the potential for further genome mining of the genes encoding the enzymes involved in BIA biosynthesis

Determination of Enantiomeric Purity of Single-Wall Carbon Nanotubes Using Flavin Mononucleotide

Although enantiomeric separation of single-wall carbon nanotubes is possible, their enantiomeric purity (EP) remains an issue due to a lack of effective evaluation methods. In this work, we report the EP of (6,5) carbon nanotube enantiomers using flavin mononucleotide (FMN) as an enantiomer-sensitive dispersant. The enantiomers (6,5) and (11,–5) were separated by a gel column chromatography method and dispersed in a FMN aqueous solution. In these solutions, (6,5) and (11,–5) showed E₁₁ optical transitions at different wavelengths due to handedness-dependent interactions with the FMN molecule, which enabled us to estimate each concentration, namely, the EP. We prepared six intermediate-purity enantiomer samples by mixing the (6,5) and (11,–5) enantiomers and measured their circular dichroism (CD) spectra. The CD signal was confirmed to change linearly with the EP. Using this relationship, we can estimate the EP of any mixture of (6,5) and (11,–5) from its CD intensity

Dose- and time-dependent association of smoking and its cessation with glycemic control and insulin resistance in male patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry.

Cigarette smoking is an important modifiable risk factor for cardiovascular diseases. However, the effect of smoking and its cessation on glycemic control in diabetic patients has not been fully examined yet. The aim of the present study was to examine the association of smoking status with glycemic level and markers of insulin resistance and secretion in patients with type 2 diabetes mellitus.A total of 2,490 Japanese male patients with type 2 diabetes mellitus aged ≥20 years were divided according to smoking status, amount of cigarettes smoked and years since quitting. The associations with glycemic level and markers of insulin resistance and secretion were examined cross-sectionally.HbA1c levels increased progressively with increases in both number of cigarettes per day and pack-years of cigarette smoking compared with never smokers (P for trend = 0.001 and <0.001, respectively), whereas fasting plasma glucose did not. On the other hand, HbA1c, but not fasting plasma glucose, decreased linearly with increase in years after smoking cessation (P for trend <0.001). These graded relationships persisted significantly after controlling for the confounders, including total energy intake, current drinking, regular exercise, depressive symptoms, and BMI. In addition, a homeostasis model assessment of insulin resistance and high-sensitivity C-reactive protein also showed similar trends.Smoking and its cessation showed dose- and time-dependent relationship with glycemic control and insulin resistance in patients with type 2 diabetes mellitus. These findings may highlight the importance of smoking cessation in the clinical management of diabetes mellitus