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Clinical features associated with NeoRAS wild-type metastatic colorectal cancer A SCRUM-Japan GOZILA substudy

Abstract“NeoRAS WT” refers to the loss of RAS mutations (MTs) following first-line treatment in metastatic colorectal cancer (mCRC). We evaluate the incidence and clinicopathological characteristics of NeoRAS WT mCRC using next-generation sequencing of plasma circulating tumor DNA. Patients with mCRC enrolled in the GOZILA study initially diagnosed with tissue RAS MT mCRC and received subsequent systemic therapy are eligible. NeoRAS WT is defined as the absence of detectable RAS MT in plasma and assessed in all eligible patients (Group A) and in a subgroup with at least one somatic alteration detected in plasma (Group B). Overall, 478 patients are included. NeoRAS WT prevalence is 19.0% (91/478) in Group A and 9.8% (42/429) in Group B. Absence of liver or lymph node metastasis and tissue RAS MTs other than KRAS exon 2 MTs are significantly associated with NeoRAS WT emergence. Overall, 1/6 and 2/6 patients with NeoRAS WT treated with anti-EGFR monoclonal antibodies (mAbs) show partial response and stable disease for ≥6 months, respectively. NeoRAS WT mCRC is observed at a meaningful prevalence, and anti-EGFR mAb-based therapy may be effective

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

Use of intercostal nerves for neurotization of the musculocutaneous nerve in infants with birth-related brachial plexus palsy

Object. The use of intercostal nerves (ICNs) for the neurotization of the musculocutaneous nerve (MCN) in adult patients with traumatic brachial plexus palsy has been well described. However, its use for brachial plexus palsy in infants has rarely been reported. The authors surgically created 31 ICN—MCN communications for birth-related brachial plexus palsy and present the surgical results. Methods. Thirty-one neurotizations of the MCN, performed using ICNs, were conducted in 30 patients with birth-related brachial plexus palsy. In most cases other procedures were combined to reconstruct all upper-extremity function. The mean patient age at surgery was 5.8 months and the mean follow-up period was 5.2 years. Intercostal nerves were transected 1 cm distal to the mammary line and their stumps were transferred to the axilla, where they were coapted directly to the MCN. Two ICNs were used in 26 cases and three ICNs in five cases. The power of the biceps muscle of the arm was rated Grade M4 in 26 (84%) of 31 patients. In the 12 patients who underwent surgery when they were younger than 5 months of age, all exhibited a grade of M4 (100%) in their biceps muscle power. These results are better than those previously reported in adults. Conclusions. Neurotization of the MCN by surgically connecting ICNs is a safe, reliable, and effective procedure for reconstruction of the brachial plexus in patients suffering from birth-related palsy.</jats:p

Abstract 3525: SOX2 promotes tumor growth via activation of the PI3K/Akt/mTORC1 signaling pathway in esophageal squamous cell carcinoma

Abstract Our previous study revealed that SOX2, a master regulator during embryogenesis, is an amplification target of 3q26.3 in esophageal squamous cell carcinoma (ESCC) and that SOX2 promotes ESCC cell proliferation. To identify the mechanisms by which SOX2 promotes proliferation of ESCC cells, we assayed multiple signaling pathways activated by SOX2 using a phosphoprotein array. We determined that SOX2 activated the AKT/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Immunoblotting confirmed that SOX2 elevated levels of p-AKT and levels of p-p70S6K and p-4E-BP1 which are direct targets of mTORC1. Effects of SOX2 knockdown, including reduced levels of p-AKT and decreased ESCC cell viability, were reversed with constitutive activation of AKT with PTEN knockdown. SOX2 also promoted in vivo tumor growth of ESCC with AKT/mTORC1 activation in mouse xenografts. LY294002, a PI3K inhibitor, suppressed the ability of SOX2 to enhance tumor growth of ESCC by reducing cell proliferation. Furthermore, tissue microarray analysis showed a positive correlation between expression levels of SOX2 and p-AKT in 61 primary ESCC tumors. Our results suggest that SOX2 promotes ESCC tumor growth via activation of the PI3K/AKT / mTORC1 signaling pathway, which enhances cell proliferation. Citation Format: Yasuyuki Gen, Kohichiroh Yasui, Tomoko Kitaichi, Akira Tomie, Yoshito Ito. SOX2 promotes tumor growth via activation of the PI3K/Akt/mTORC1 signaling pathway in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3525. doi:10.1158/1538-7445.AM2014-3525</jats:p

山陰地方における天然スギの直径分布

This paper discribes an exprssions of diameter distribution that was reserched for the natural regenerated "SUGI" in uneven-aged stands on the Sanbe and Hikimi forest, Shimane Prefecture. In an uneven-aged stand, the curve of numbers of trees plotted over dbh approaches an inverse J-shaped form, and this is a essential characteristic of an uneven-aged distribution. To determine whether a given diameter distribution was balanced or not, H. A. Meyer suggested plotting numbers of trees over dbh on semi-logarithmic paper. But the actual data shown that uncomform to this relationship as Fig. 1 and 2. Hence, we fitted Pearson's frequency distribution function for the these distribution, and decided that 1 type of the distribution curve. The results of calculated was as follows. Sanbe y = 5.14x^ ^ Hikimi y = 4.83x^ ^ The both equations confimed that well-iftting at statistic test

Abstract 5186: Reduced expression of BRM in hepatocellular carcinoma

Abstract Background: Hepatocellular carcinoma (HCC) is the fifth most common malignancy in men and the eighth most common in women worldwide. The eukaryotic genome is organized into highly ordered chromatin structures in the nucleus. Chromatin creates a barrier to nuclear processes, such as transcription, by obstructing the access of the transcriptional machinery and gene-specific regulators to recognition sequences within target promoters. The SWI/SNF protein complex, an ATPase-dependent chromatin remodeling enzyme, mobilizes nucleosomes and functions as a master regulator of gene expression and chromatin dynamics. SWI/SNF is a large multiprotein complex that contains either BRG1 or brahma (BRM) as the catalytic ATPase. Each SWI/SNF complex thus incorporates one of two possible ATPases, BRG1 or BRM. Aims: To examine alterations of BRG1 and BRM in HCC. Methods: We investigated DNA copy number aberrations in human HCC cell lines using a high-density oligonucleotide microarray. We determined DNA copy numbers and expression levels of BRG1 and BRM genes in primary HCC tumors, and conducted further searches for mutations in BRG1 and BRM genes. Results: Homozygous deletion of the BRG1 gene was found in HCC cell line SNU398. Copy number losses of BRG1 and BRM genes were observed in 14 (26%) and 7 (13%) of 54 primary HCC tumors respectively. We found four somatic missense mutations in the BRG1 gene in two of 36 primary HCC tumors, but no mutations in BRM gene. Expression of BRM mRNA, but not BRG1 mRNA, was significantly reduced in primary HCC tumors, compared to non-tumor tissue counterparts. Immunohistochemical analyses of non-tumour liver tissues showed that BRM protein was expressed in hepatocytes and bile-duct epithelial cells, whereas BRG1 protein was expressed in bile-duct epithelial cells, but not in hepatocytes. BRM protein expression was lost in nine (22.5%) of 40 HCC tumours. Loss of BRM protein expression was significantly associated with poor overall survival. Conclusion: Reduced expression of BRM may contribute to the carcinogenesis of HCC. Although deletions and mutations in BRG1 gene were identified, the role of BRG1 in HCC tumourigenesis remains unclear. Citation Format: Kohichiroh Yasui, Yasuyuki Gen, Akira Tomie, Tomoko Kitaichi, Yoshito Itoh. Reduced expression of BRM in hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5186. doi:10.1158/1538-7445.AM2014-5186</jats:p