Antitumor activity of α-pinene in T-cell tumors

T-cell acute leukemia and lymphoma have a poor prognosis. Although new therapeu-tic agents have been developed, their therapeutic effects are suboptimal. α- Pinene, a monoterpene compound, has an antitumor effect on solid tumors; however, few comprehensive investigations have been conducted on its impact on hematologic ma-lignancies. This report provides a comprehensive analysis of the potential benefits of using α- pinene as an antitumor agent for the treatment of T-cell tumors. We found that α- pinene inhibited the proliferation of hematologic malignancies, especially in T- cell tumor cell lines EL-4 and Molt-4, induced mitochondrial dysfunction and re-active oxygen species accumulation, and inhibited NF-κB p65 translocation into the nucleus, leading to robust apoptosis in EL-4 cells. Collectively, these findings suggest that α- pinene has potential as a therapeutic agent for T-cell malignancies, and further investigation is warranted

血漿ADAMTSは肝硬変患者の予後をChild-PughスコアやMELDスコアと同様に生存率を予測できる可能性がある

Aim:  Decreased plasma ADAMTS13 activity (ADAMTS13:AC) results in accumulation of unusually large von Willebrand factor multimers and platelet thrombi formation. Our aim was to evaluate whether ADAMTS13:AC is a prognostic marker in patients with liver cirrhosis. Methods:  Plasma ADAMTS13:AC and its related parameters were examined in 108 cirrhotic patients. Results:  ADAMTS13:AC decreased as the severity of liver disease increased (means: controls 100%, Child A-cirrhotics 79%, Child B-cirrhotics 63%, and Child C-cirrhotics 31%). ADAMTS13:AC markedly decreased in the cirrhotics with hepatorenal syndrome, refractory ascites and hepatic encephalopathy. The cumulative survival time was the shortest (median: 4.5 months) in the cirrhotics with severe to moderate ADAMTS13:AC deficiency (50%). In contrast, based on the Child-Turcotte-Pugh (CTP) score, Child C-cirrhotics had the worst survival, but the survival probabilities did not differ between Child A and B cirrhotics. Based on the Model for End-Stage Liver Disease (MELD) score, the survival was the worst for the cirrhotics in the fourth quartile, but it was not different among cirrhotics in the first three quartiles. Cox proportional-hazards regression analysis showed that ADAMTS13:AC and serum albumin were independent factors affecting the survival. Conclusions:  ADAMTS13:AC concomitantly decreases as the functional liver capacity decreases. This activity may be a useful prognostic marker that is equal or superior to the CTP score and the MELD score to predict not only the short-term prognosis but also the long-term survival of the cirrhotic patients.博士（医学）・甲613号・平成26年3月17

Salvage living donor liver transplantation after percutaneous transluminal angioplasty for recurrent Budd-Chiari syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>Budd-Chiari syndrome is a very rare pathological entity that ultimately leads to liver failure. Several therapeutic modalities, including percutaneous transluminal angioplasty, have been attempted to save the life of patients with Budd-Chiari syndrome. Few reports have described a salvage living donor liver transplantation performed after percutaneous transluminal angioplasty in a patient with acute Budd-Chiari syndrome.</p> <p>Case presentation</p> <p>A 26-year-old Japanese man developed severe progressive manifestations, such as massive ascites and hematemesis due to rupture of esophageal varices. After making several investigations, we diagnosed the case as Budd-Chiari syndrome. We first performed percutaneous transluminal angioplasty to dilate a short-segment stenosis of his inferior vena cava. The first percutaneous transluminal angioplasty greatly improved the clinical manifestations. However, after a year, re-stenosis was detected, and a second percutaneous transluminal angioplasty failed to open the severe stricture of his inferior vena cava. Since our patient had manifestations of acute liver failure, we decided to perform salvage living donor liver transplantation from his brother. The transplantation was successfully performed and all clinical manifestations were remarkably alleviated.</p> <p>Conclusion</p> <p>In cases of recurrent Budd-Chiari syndrome, the blocked hepatic venous outflow is not always relieved, even with invasive therapies. We have to take into account the possibility of adopting alternative salvage therapies if the first therapeutic modalities fail. When invasive therapy such as percutaneous transluminal angioplasty fails, liver transplantation should be considered as an alternative option.</p

Breast cancer incidence highest in the range of one species of house mouse, Mus domesticus

Incidence of human breast cancer (HBC) varies geographically, but to date no environmental factor has explained this variation. Previously, we reported a 44% reduction in the incidence of breast cancer in women fully immunosuppressed following organ transplantation (Stewart et al (1995) Lancet346: 796–798). In mice infected with the mouse mammary tumour virus (MMTV), immunosuppression also reduces the incidence of mammary tumours. DNA with 95% identity to MMTV is detected in 40% of human breast tumours (Wang et al (1995) Cancer Res55: 5173–5179). These findings led us to ask whether the incidence of HBC could be correlated with the natural ranges of different species of wild mice. We found that the highest incidence of HBC worldwide occurs in lands where Mus domesticus is thse resident native or introduced species of house mouse. Given the similar responses of humans and mice to immunosuppression, the near identity between human and mouse MTV DNA sequences, and the close association between HBC incidence and mouse ranges, we propose that humans acquire MMTV from mice. This zoonotic theory for a mouse-viral cause of HBC allows testable predictions and has potential importance in prevention. © 2000 Cancer Research Campaig

Translation, reliability, and validity of Japanese version of the Respiratory Distress Observation Scale

Dyspnea is a common, distressing symptom of cardiopulmonary and neuromuscular diseases and is defined as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity.” However, Japanese intensive care units (ICUs) do not routinely screen for dyspnea, as no validated Japanese version of the Respiratory Distress Observation Scale (RDOS) is available. Therefore, we aimed to translate the English version of this questionnaire into Japanese and assess its validity and reliability. To translate the RDOS, we conducted a prospective observational study in a 12-bed ICU of a universal hospital that included 42 healthcare professionals, 10 expert panels, and 128 ventilated patients. The English version was translated into Japanese, and several cross-sectional web-based questionnaires were administered to the healthcare professionals. After completing the translation process, a validity and reliability evaluation was performed in the ventilated patients. Inter-rater reliability was evaluated using Cohen’s weighted kappa coefficient. Criterion validity was ascertained based on the correlation between RDOS and the dyspnea visual analog scale. The area under the receiver operating characteristic curve analysis was used to evaluate the ability of the RDOS to identify patients with self-reported dyspnea. The average content validity index at the scale level was 0.95. Data from the 128 patients were collected and analyzed. Cohen’s weighted kappa coefficient and the correlation coefficient between the two scales were 0.76 and 0.443 (95% confidence intervals 0.70–0.82 and 0.23–0.62), respectively. For predicting self-reported dyspnea, the area under the receiver operating characteristic curve was 0.81 (95% confidence interval 0.67–0.97). The optimal cutoff used was 1, with a sensitivity and specificity of 0.89 and 0.61, respectively. Our findings indicated that the Japanese version of the RDOS is acceptable for face validity, understandability, criterion validity, and inter-rater reliability in lightly sedated mechanically ventilated patients, indicating its clinical utility

大腸Cold Snare Polypectomyにおける手技の工夫とその切除検体の臨床病理学的検討

京都府立医科大学附属北部医療センター　消化器内科京都府立医科大学附属北部医療センター　病理診断科市立福知山市民病院消化器内科京都府立医科大学消化器内科学Department of Gastroentarology and Hepatology, North Medical Center, Kyoto Prefectural University of MedicineDepartment of Pathology, North Medical Center, Kyoto Prefectural University of MedicineDepartment of Gastroentarology and Hepatology, Fukuchiyama City HospitalDepartment of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science近年、Cold Snare Polypectomy(CSP) は、その簡便性、安全性から急速に普及しており、当院でも2014年よりCSPを導入している。CSP導入当初の臨床病理学的解析では、病変の完全一括切除率は67％であった。一方、本検討では、3本編細径スネアの導入を含めた手技の工夫により完全一括切除率は94％まで向上を認めた。本研究は少数例の検討であり、今後前向き試験による検討が必要である

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