Pressurization facilitates adenovirus-mediated gene transfer into vein graft

AbstractWe investigated whether application of non-distending hydrostatic pressure facilitates gene transfer into vein grafts. An external jugular vein was placed in a chamber with 100 μl adenovirus solution at a titer of 1010 pfu/ml and was pressurized to up to 8 atm above ambient pressure for 10 min. Histochemical analysis demonstrated a positive transgene expression in all layers of the vessel wall. Gene transfer with 8 atm pressurization resulted in an approximately 50 times higher transgene expression than that without pressurization. Under 8 atm pressurization, the efficiency of gene transfer reached a plateau at 7.5 min. The application of hydrostatic pressure may improve the effectiveness of intraoperative genetic engineering of vein grafts

Lenvatinib for Anaplastic Thyroid Cancer

Background: Lenvatinib has been approved by regulatory agencies in Japan, the United States, and the European Union for treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thyroid cancer, however, is a clinically diverse disease that includes anaplastic thyroid cancer (ATC), the subtype associated with the highest lethality. Effective therapy for ATC is an unmet need. Patients and methods: This phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate. Results: At data cutoff, 17 patients with ATC were enrolled. All experienced >= 1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were decreased appetite (82%), hypertension (82%), fatigue (59%), nausea (59%), and proteinuria (59%). Of note, only one patient required lenvatinib withdrawal because of a TEAE, and this TEAE was considered unrelated to lenvatinib. The median PFS was 7.4 months [95% confidence interval (CI): 1.7-12.9], the median OS was 10.6 months (95% CI: 3.8-19.8), and the objective response rate was 24%. Conclusion: In this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Multi-Agent Simulation for Crisis Management

Traditional crowd simulators are based on a simple numerical analysis of inputs such as the positions of people and structures; they do not consider leadership. Since leaders (in terms of evacuations) are present in many real-world situations, the validity of evacuation simulations can be increased through their introduction. We assess the results of a real-world evacuation experiment to develop more realistic scenarios for simulation. The simulations produced by the improved scenarios are found to closely mimic the experimental results. This work shows that scenariobased agent systems such as FlatWalk and FreeWalk offer excellent promise in simulating evacuations more realistically

Spinal fusion on adolescent idiopathic scoliosis patients with the level of L4 or lower can increase lumbar disc degeneration with sagittal imbalance 35 years after surgery

Introduction: The purpose of this study was to investigate the long-term incidence of lumbar disc degeneration and Modic changes in the non-fused segments of patients with adolescent idiopathic scoliosis (AIS) who previously underwent spinal fusion. Methods: Study subjects consisted of 252 patients with AIS who underwent spinal fusion between 1968 and 1988. Of 252 patients, 35 subjects underwent lumbar spine MRI and whole spine X-ray examination. The mean patient age at the time of follow-up was 49.8 years, with an average follow-up period of 35.1 years. We classified the subjects into two groups based on the lowest fused vertebra: H group whose lowest fused vertebra was L3 or higher levels and L group whose lowest fused vertebra was L4 or lower levels. Results: The L group had significantly advanced disc degeneration on MRI. There was no significant difference between two groups in Modic changes. The L group showed less lumbar lordosis than the H group (H group: 48.1 degrees; and L group: 32.1 degrees) and greater SVA (H group: 1.2 cm; and L group: 5.5 cm). Conclusions: In AIS patients, 35 years after spinal fusion surgery on average, we evaluated lumbar disc degeneration and Modic changes of the non-fused segments. In patients with the lowest fusion level at L4 or lower, there were reduced lumbar lordosis, considerable SVA imbalance, and severe disc degeneration compared with those with the lowest fusion level at L3 or higher. The lowest fusion level at L3 or higher is recommended to reduce disc degeneration in midlife