Tumor Shrinkage in Response to Vitamin K2 in Hepatocellular Carcinoma with Multiple Lung Metastases: A Case Report

Introduction: Advanced or metastatic hepatocellular carcinoma (HCC) can be lethal because of the limited therapeutic approach such as sorafenib. Recently, Vitamin K2 (VK2) has been increasingly recognized to have anti-cancer effects for HCC in vitro and vivo. However, the direct anti-cancer effect of VK2 to HCC has not been established yet in human.Presentation of Case: We presented here a 88-year-HCC patient displayed a tumor shrinkage in response to VK2 in multiple lung metastases, indicating the possibility of VK2 as an anti-cancer agent in human. Menatetrenone, a VK2 analogue, was introduced for multiple lung metastases as a palliative treatment, and thereafter multiple lung metastases, except one lung lesion, displayed tumor shrinkage and disappeared within five months after VK2 intake. The residual one lesion continued to grow up during the intake of VK2, suggesting that the residual tumor was insensitive to VK2 represented by tumor heterogeneity. Consequently, after a radiation therapy for the residual lesion, the elevated tumor markers of all were finally decreased into normal levels, and he is still alive for 18 months after VK2 intake without elevated tumor marker levels and toxic adverse effects.Conclusion:VK2 may be a therapeutic option for advanced and metastatic HCCs without any toxic adverse

Irinotecan Plus S-1 Followed by Hepatectomy for a Patient with Initially Unresectable Colorectal Liver Metastases, Who Showed Severe Drug Rash with Oxaliplatin Plus 5-FU and Leucovorin (FOLFOX)

For unresectable colorectal liver metastases (CRLM), hepatic resection with or without chemotherapy is the only curative treatment that sufficiently achieves long-term survival. However, occasional severe allergic responses to anticancer drugs necessitate treatment discontinuation. A 45-year-old woman presented with metachronous unresectable colorectal liver metastases. Chemotherapy with oxaliplatin plus 5-FU and leucovorin (FOLFOX) was initiated, but severe allergic dermatitis developed after the second cycle. Although she reported no prior history of adverse reactions to tegafur-uracil, a drug lymphocyte stimulation test showed an allergic response to 5-FU. We subsequently replaced with Irinotecan plus S-1 (IRIS) chemotherapy which was well tolerated and resulted in a partial response after 3 cycles. As a result, right trisectionectomy was successfully performed and no recurrence was detected in the following 3 years. A severe allergic reaction to intravenous 5-FU-containing drug regimens can be successfully alleviated by switching to S-1-containing regimens such as IRIS or S-1 plus oxaliplatin (SOX)

Targeted expression of stepfunction opsins in transgenic rats for optogenetic studies

Abstract Rats are excellent animal models for experimental neuroscience. However, the application of optogenetics in rats has been hindered because of the limited number of established transgenic rat strains. To accomplish cell-type specific targeting of an optimized optogenetic molecular tool, we generated ROSA26/CAG-floxed STOP-ChRFR(C167A)-Venus BAC rats that conditionally express the step-function mutant channelrhodopsin ChRFR(C167A) under the control of extrinsic Cre recombinase. In primary cultured cortical neurons derived from this reporter rat, only Cre-positive cells expressing ChRFR(C167A) became bi-stable, that is, their excitability was enhanced by blue light and returned to the baseline by yellow~red light. In bigenic pups carrying the Phox2B-Cre driver, ChRFR(C167A) was specifically expressed in the rostral parafacial respiratory group (pFRG) in the medulla, where endogenous Phox2b immunoreactivity was detected. These neurons were sensitive to blue light with an increase in the firing frequency. Thus, this transgenic rat actuator/reporter system should facilitate optogenetic studies involving the effective in vivo manipulation of the activities of specific cell fractions using light of minimal intensity

Shoulder and elbow pain in elementary school baseball players : The results from a nation-wide survey in Japan

Background: Despite recommendations on how to prevent baseball injuries in youths by the Japanese Society of Clinical Sports Medicine, shoulder and elbow pain still frequently occurs in young baseball players. We conducted a questionnaire survey among baseball players at elementary schools across the country to understand the practice conditions of players, examining the risk factors of shoulder and elbow pain in baseball players. Methods: The questionnaire survey was conducted among elementary school baseball players as members of the Baseball Federation of Japan in September 2015. Results: A total of 8354 players belonging to 412 teams (average age: 8.9) responded to the survey. Among 7894 players who did not have any shoulder and/or elbow pain in September 2014, elbow pain was experienced in 12.3% of them, shoulder pain in 8.0% and shoulder and/or elbow pain in 17.4% during the previous one year. A total of 2835 (39.9% of the total) practiced four days or more per week and 97.6% practiced 3 h or more per day on Saturdays and Sundays. The risk factors associated shoulder and elbow pain included a male sex, older age, pitchers and catchers, and players throwing more than 50 balls per day. Conclusions: It has been revealed that Japanese elementary school baseball players train too much. Coaches should pay attention to older players, male players, pitchers and catchers in order to prevent shoulder and elbow pain. Furthermore, elementary school baseball players should not be allowed to throw more than 50 balls per day. Study design: Retrospective cohort study

Impact of Anatomical Resection for Hepatocellular Carcinoma With Microportal Invasion (vp1): A Multi-institutional Study by the Kyushu Study Group of Liver Surgery

Objective: The aim of the present study was to evaluate the value of anatomical resectionfor HCC with micro-portal vascular invasion (vp1) between 2000 and 2010. Summaryof Background: Vascular invasion has been reported as a prognostic factor of liverresection for hepatocellular carcinoma (HCC). Anatomical resection for HCC has resulted in optimum outcomes of eradicating intrahepatic micrometastases through the portal vein, but opposite results have also been reported. Methods: A clinical chart review was performed for 546 HCC patients with vp1. We retrospectively evaluated the recurrence-free survival (RFS) between anatomical (AR)and non-anatomical resection (NAR). The site of recurrence was also compared between these groups. The influence of AR on the overall survival (OS) and RFS rates was analyzed in patients selected by propensity score matching, and the prognostic factors were identified.Results: A total of 546 patients were enrolled, including 422 in the AR group and 124 in the NAR group. There was no difference in the 5-year OS and RFS rates between the two groups. Local recurrence was significantly more frequent in the NAR group than in the AR group. In a multivariate analysis, hepatitis C (HCV), PIVKAII ?380 mAU/ml, tumor diameter ?5 cm and ?70 years of age were significant predictors of a poor RFS after liverresection. There were no significant differences in the OS or RFS between the AR and NAR groups by a propensity score-matched analysis. Conclusion: Although local recurrence around the resection site was suppressed by AR, AR for HCC with vp1 did not influence the RFS or OS rates after hepatectomy in the modern era

Role of leukocyte cell-derived chemotaxin 2 as a biomarker in hepatocellular carcinoma

We sought to identify a secreted biomarker for β-catenin activation commonly seen in hepatocellular carcinoma (HCC). By examination of our previously published genearray of hepatocyte-specific β-catenin knockout (KO) livers, we identified secreted factors whose expression may be β-catenin-dependent. We verified expression and secretion of the leading factor in HCC cells transfected with mutated (Hep3BS33Y)-β- catenin. Serum levels of biomarker were next investigated in a mouse model of HCC with β-catenin gene (Ctnnb1) mutations and eventually in HCC patients. Leukocyte cell-derived chemotaxin-2 (LECT2) expression was decreased in KO livers. Hep3BS33Y expressed and secreted more LECT2 in media as compared to Hep3BWT. Mice developing HCC with Ctnnb1 mutations showed significantly higher serum LECT2 levels. However patients with CTNNB1 mutations showed LECT2 levels of 54.28±22.32 ng/mL (Mean ± SD; n = 8) that were insignificantly different from patients with non-neoplastic chronic liver disease (32.8±21.1 ng/mL; n = 15) or healthy volunteers (33.2±7.2 ng/mL; n = 11). Intriguingly, patients without β-catenin mutations showed significantly higher serum LECT2 levels (54.26 ± 22.25 ng/mL; n = 46). While β-catenin activation was evident in a subset of non-mutant β-catenin HCC group with high LECT2 expression, serum LECT2 was unequivocally similar between β-catenin-active and -normal group. Further analysis showed that LECT2 levels greater than 50 ng/ml diagnosed HCC in patients irrespective of β-catenin mutations with specificity of 96.1% and positive predictive value of 97.0%. Thus, LECT2 is regulated by β-catenin in HCC in both mice and men, but serum LECT2 reflects β-catenin activity only in mice. Serum LECT2 could be a potential biomarker of HCC in patients. © 2014 Okabe et al

Molecular liver cancer prevention in cirrhosis by organ transcriptome analysis and lysophosphatidic acid pathway inhibition

Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention

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

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

Successful treatment of ruptured duodenal varices with dual balloon-occluded embolotherapy

Duodenal varices are ectopic portosystemic shunts that do not tend to result in gastrointestinal bleeding. Balloon-occluded retrograde transvenous obliteration is an established treatment for gastric varices. We report a 60-year-old man with melena due to ruptured duodenal varices originating at an inferior pancreaticoduodenal vein; drainage was into a gonadal vein. His ruptured duodenal varices were successfully treated by dual balloon-occluded embolotherapy