Mechanisms in the development of limbic status epilepticus and hippocampal neuron loss: an experimental study in a model of status epilepticus induced by kindling-like electrical stimulation of the deep prepyriform cortex in rats.

A new model of status epilepticus (SE), which was induced by intermittent electrical stimulation (20 Hz for 20 sec every min for 180 min) of the deep prepyriform cortex, has been developed in the conscious rat. SE was induced in 9 of 16 rats in the drug-free group. The number of stimulation trains required to induce SE in this status subgroup was 125.6 +/- 12.7 (mean +/- SEM) and the mean duration of self-sustained seizure activity (SSSA) occurring after cessation of the stimulation session was 295.4 +/- 111.4 min. Some animals showed secondary generalized seizures. Significant cell loss was observed in the hippocampal CA3 pyramidal cell layer ipsilateral to the stimulation site and bilateral CA1 areas in the status subgroup compared with the group subjected to sham operation. In addition, there was a significant negative correlation between the duration of SSSA subsequent to the stimulation session and the total number of intact pyramidal neurons observed in the bilateral CA1 and ipsilateral CA3 subfields of the status subgroup. There were significant differences between the status and non-status subgroups with respect to the number of afterdischarges (ADs) and the total AD duration during the stimulation session. Pretreatment with phenobarbital (30 mg/kg) prevented the development of SE and hippocampal cell loss completely. Pretreatment with MK-801, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist (0.25 or 1 mg/kg), also prevented hippocampal cell loss, although it did not block SE generation completely, which suggests dissociation of the mechanisms underlying the development of SE and hippocampal damage. These results indicate that prolonged SSSA actually causes hippocampal damage and it is critically dependent upon NMDA receptor participation.</p

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

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

Clinical results on liver, rectum, and pancreas

NIRS−USMS Joint Seminar on Carbon Ion Therap

Carbon-ion Therapy For Patients With Locally Recurrent Rectal Cancer

Purpose/Objective: To improve long-term local control and survival of locally recurrent rectal cancer, we have initiated a radiation dose-escalation trial using carbon ion beams. The purpose of this study is to evaluate the tolerance for and effectiveness of carbon ion radiotherapy in patients locally recurrent rectal cancer Materials/Methods: Between April 2001 and August 2012, 198 lesions at 189 patients were enrolled onto this study. Criteria for trial eligibility were confirmation of locally recurrent rectal cancers without distant metastases based on CT, MRI and PET findings and ECOG performance score 0,1,2. Contraindications for trial entry included pelvic bone destruction. Carbon beams of 290, 350 and 400 MeV/nucleon energy were generated in the HIMAC synchrotron. The dose was determined as 67.2GyE and escalated to 70.4GyE, 73.6GyE. Of the 189 eligible patients, 132 were male and 57 female. Median age was 61.5 years. The predominant sites of relapse were 75 presacral , 77 lymph nodes, 28 perineal and 9 anastomosis. Toxicities on organs were assessed according to the NCI-CTC classification. Tumor response was defined by the RESIST scoring system. Local recurrence was defined in terms of lesions occurring in the tumor bed. Survival curves were estimated by the Kaplan and Meier method.Results: Ten patients received radiation dose at 67.2GyE, 18(+3) at 70.4GyE and 161(+6) at 73.6GyE. All toxicities in the 198 lesions at 189 patients were relatively few and mild in these patients. No grade 3 to 5 acute toxicity was observed. The local control rates in 197 lesions are 94% at three year and 89% at five years. Local control rates at 5 year were 97% at 73.6GyE. In terms of symptomatic response within 3 months after treatment, pain improved in 97% of the symptomatic cases. Pain relief was maintained at one year in 67%, 91% and 100% of the patients treated with 67.2GyE ,, 70.4GyE and 73.6GyE, respectively. The three and five year overall survival rate in 188 patients were 72% and 47% respectively. Survival rates at 5 year were 20% at 67.2GyE, 24% at 70.4GyE and 51% at 73.6GyE. In the literature, the reported five-year survival rates for locally recurrent rectal cancer treated with resection were 20 to 40%.Conclusions: Carbon ion radiotherapy seems to be a safe and effective modality in the management of locally recurrent rectal cancer, providing good local control and offering a survival advantage without acceptable morbidity.American Society for Radiation Oncology (ASTRO) Annual Meetin

Carbon Ion Radiotherapy for Patients with Locally Recurrent Rectal Cancer and Pancreas Cancer

NIRS-Mayo Clinic Joint Symposium 2013 on Carbon Ion Therap

Carbon-Ion Radiotherapy for Pancreatic Cancer

Abstract：Pancreatic cancer is the fifth leading cause of cancer death and is considered to be one of the most lethal cancers in Japan. Complete surgical resection is the only curative treatment. Even if curative resection is performed, the disease usually recurs, and 5-year survival rates are less than 20 %. Chemotherapy or chemoradiotherapy is selected as a standard treatment for unresectable pancreatic cancer. However, since pancreatic cancer is often resistant to chemotherapy and radiotherapy, the local control and survival rates are very low. We conducted a phase I/II clinical trial using carbon ion radiotherapy (C-ion RT) for patients with operable and locally advanced pancreatic cancer. This was delivered preoperatively in 8 fractions over 2 weeks, was well tolerated, and resulted in excellent local control and survival rates. C-ion RT for patients with locally advanced pancreatic cancer was also well tolerated, even when concomitantly administered with the highest dose of gemcitabine (1,000 mg/m2), and likewise resulted in a good survival rate. We discuss current treatment methods and the results of C-ion RT for pancreatic cancer at the National Institute of Radiological Sciences