Enzymatic characterization of recombinant rat DDHD2, a soluble diacylglycerol lipase

学位記番号：医博甲1589

Percutaneous cryoablation for clinical T3a renal cell carcinoma (< 7 cm) with segmental vein involvement or perinephric fat invasion based on preoperative evaluation of high-resolution multidetector computed tomography scan

Purpose　To retrospectively assess the feasibility, safety, renal function, technique efficacy rate, and survival of patients with clinical T3a renal cell carcinoma (RCC). Materials and methods　Sixteen cryoablation sessions were performed in 14 patients (10 men; mean age, 69.8 ± 10.5 years; range, 49–90 years) with 14 clear cell T3a RCCs (mean, 3.3 ± 0.9 cm; range, 1.9–5.2 cm). One patient was on dialysis. Transcatheter arterial embolization was performed before cryoablation in 15 sessions. The primary endpoint was the technique efficacy rate. The secondary endpoints included feasibility, safety, renal function, and survival. Results　Cryoablation was technically successful in all RCC cases. In two RCCs, cryoablation was performed twice because of local tumor progression. No major adverse events were observed. All patients were alive without metastases, with a median follow-up of 45 months (6−93 months). Complete response was achieved by cryoablation in 11 RCCs (78.6%). The primary and secondary technique efficacy rates were 77.1% and 84.4% at 1 year, 57.9% and 73.9% at 3 years, and 57.9% and 73.9% at 5 years, respectively. One patient underwent dialysis given a total contralateral nephrectomy due to another RCC 1 month after initial cryoablation and a total ipsilateral nephrectomy 46 months after initial cryoablation due to local progression. Except for two dialysis patients, of the 12 patients with a median follow-up of 41 months (6–93 months), none were on dialysis. Conclusion　Cryoablation was safe and effective in T3a RCC, which mainly involved the renal venous branches and may represent an alternative treatment for inoperable patients

ErbB2 Dephosphorylation and Anti-Proliferative Effects of Neuregulin-1 in ErbB2-Overexpressing Cells; Re-evaluation of Their Low-Affinity Interaction

Neuregulin-1 binds to ErbB3 and ErbB4 and regulates cancer proliferation and differentiation. Neuregulin-1 had been suggested to also react with ErbB2, but this argument becomes controversial. Here, we re-evaluated the cellular responses and ErbB2 interaction of neuregulin-1 in ErbB2 overexpressing cell lines. In a competitive ligand-binding assay, we detected significant replacement of [35S]-labeled neuregulin-1 with nano molar ranges of cold neuregulin-1 in L929 cells expressing ErbB2 alone and SKOV3 cells carrying sulf-1 cDNA but not in these parental cells. The concentration of neuregulin-1 significantly decreased thymidine incorporation and phosphorylation of ErbB2 (Tyr877, Tyr1396, and Tyr1121) in ErbB2-overexpressing cancer cells as well as in L929 cells expressing ErbB2. A crosslinking assay ascertained the presence of neuregulin-1 immunoreactivity in the ErbB2 immune complexes of L929 expressing ErbB2 alone. These results suggest that the higher concentrations of neuregulin-1 exert an anti-oncogenic activity to attenuate ErbB2 auto-phosphorylation potentially through its low-affinity interaction with ErbB2

Cultivated Grapevines Represent a Symptomless Reservoir for the Transmission of Hop Stunt Viroid to Hop Crops: 15 Years of Evolutionary Analysis

Hop stunt was a mysterious disorder that first emerged in the 1940s in commercial hops in Japan. To investigate the origin of this disorder, we infected hops with natural Hop stunt viroid (HpSVd) isolates derived from four host species (hop, grapevine, plum and citrus), which except for hop represent possible sources of the ancestral viroid. These plants were maintained for 15 years, then analyzed the HpSVd variants present. Here we show that the variant originally found in cultivated grapevines gave rise to various combinations of mutations at positions 25, 26, 54, 193, and 281. However, upon prolonged infection, these variants underwent convergent evolution resulting in a limited number of adapted mutants. Some of them showed nucleotide sequences identical to those currently responsible for hop stunt epidemics in commercial hops in Japan, China, and the United States. Therefore, these results indicate that we have successfully reproduced the original process by which a natural HpSVd variant naturally introduced into cultivated hops was able to mutate into the HpSVd variants that are currently present in commercial hops. Furthermore, and importantly, we have identified cultivated grapevines as a symptomless reservoir in which HSVd can evolve and be transmitted to hop crops to cause epidemics

発症早期ALS患者に対する超高用量メチルコバラミンの有効性・安全性について : ランダム化比較試験

Importance: Post hoc analysis in a phase 2/3 trial indicated ultra-high dose methylcobalamin slowed decline of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score at week 16 as well as at week 182, without increase of adverse events, in patients with amyotrophic lateral sclerosis (ALS) who were enrolled within 1 year from onset. Objective: To validate the efficacy and safety of ultra-high dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design: A multicenter, placebo-controlled, double-blind, randomized phase 3 trial with 12-week observation and 16-week randomized period, conducted from October 2017 to September 2019. Setting: Twenty-five neurology centers in Japan. Participants: Patients with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in ALSFRS-R total score, a percent forced vital capacity over 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulant. The target number was 64 in both methylcobalamin and placebo groups. Of 203 patients enrolled in the observation, 130 patients (age, 61.0 ± 11.7 years; female, 56) met the criteria and were randomly assigned through an electronic web-response system to methylcobalamin or placebo (65 for each). Of these, 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Interventions: Intramuscular injection of methylcobalamin 50 mg or placebo twice weekly for 16 weeks. Main outcomes and measures: The primary endpoint was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: The least-squares mean difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (−2.66 versus −4.63; 95% CI, 0.44–3.50; P = 0.012). The incidence of adverse events was similar between the two groups. Conclusions and relevance: Ultra-high dose methylcobalamin was efficacious in slowing functional decline and safe in the 16-week treatment period in ALS patients in the early stage and with moderate progression rate. Trial registration: UMIN-CTR Identifier: UMIN000029588 (umin.ac.jp/ctr); ClinicalTrials.gov Identifier: NCT03548311 (clinicaltrials.gov

A comparison of the structure and practice of dairy farming in New Zealand and Japan

Japan's production cost for milk is the highest in the world. In contrast, New Zealand's production cost for milk is the lowest in the world. The purpose of this report is to examine the difference in the structure of dairy farming between New Zealand and Hokkaido, Japan. Hokkaido dairy farms account for over 40% of milk production in Japan. New Zealand dairy farming has several things in common with Hokkaido dairy farming. First, New Zealand is a relatively new country and Hokkaido is a new area (Hokkaido has a history of 130 years of development). Second, both have significant areas of grassland. Third, both produce milk of which most parts are supplied to milk processing factories. Finally, both have made remarkable progress in the development of dairy farming. In 1975/76 New Zealand produced 5,403 million litres of milk, and in 1995/96 9,325 million litres of milk. Hokkaido produced 1,447 million kgs of milk in 1975 and in 1996 3,530 million kgs. However, there are many differences in dairy farming between New Zealand and Hokkaido. Differences occur for each of the following: first, the ownership of land, buildings and machinery; second, the use of farmland and the management of cows; third, the treatment of manure; and fourth, the use of labour and the process of farm succession