Chemoradiotherapy with 3-weekly CDDP 80 mg/m2 for head and neck squamous cell carcinoma: 5-year survival data from a phase 2 study

ObjectiveThe global standard for chemoradiation therapy (CCRT) for head and neck squamous cell carcinoma is cisplatin 100 mg/m2 administered once every three weeks, although cisplatin 80 mg/m2 is also widely used as an alternative treatment to reduce adverse events in Japan. We aimed to assess the long-term survival outcomes and late adverse events associated with CCRT with a 3-weekly cisplatin dose of 80 mg/m2.MethodsA phase 2 study on CCRT with a 3-weekly cisplatin dose of 80 mg/m2 was performed in 47 patients between April 2015 and December 2016 at four centers in Japan. Survival outcomes and late adverse events at 5 years after this phase 2 trial were investigated.ResultsThe median follow-up period was 61 months. The 5-year progression-free survival/overall survival of all 47 patients was 66.0%/76.6%, while that of patients with stage III, IV disease (UICC) was 65.6%/71.9%. Seventeen patients (36%) experienced dysphagia as a late adverse event. Univariate and multivariate analyses revealed a significant association between acute mucositis/low body mass index (BMI) during CCRT and late dysphagia.ConclusionThe survival outcomes of CCRT with a 3-weekly cisplatin dose of 80 mg/m2 may be comparable to the previously reported dose of 100 mg/m2. Acute mucositis and low BMI at CCRT were risk factors for late dysphagia, indicating the importance of managing these conditions during CCRT to prevent late adverse events. Caution and care for acute mucositis and swallowing training in patients with low BMI may be important for preventing late-stage dysphagia

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

Ultrastructural localization of Cu, Zn-SOD in hepatocytes of patients with various liver diseases

The ultrastructural localization of copper, zinc-superoxide dismutase (Cu, Zn-SOD) in the liver of patients with acute hepatitis, chronic hepatitis, liver cirrhosis and alcoholic fatty liver was studied by means of the indirect immunoperoxidase technique. In hepatocytes Cu, Zn-SOD was found to be localized in perinuclear cisternae, rough endoplasmic reticulum (rER), vesicles and Golgi apparatus. The Cu, Zn-SOD was also detected around the lipid droplets in hepatocytes as well as on the cytoplasmic membrane in cases of liver cirrhosis. These findings suggest that Cu, Zn-SOD is produced in the rER in hepatocytes and protects the cells from cellular injury caused by superoxide anion radical in various disorders of the liver

A Case of Adult Type 1 Gaucher Disease Complicated by Temporal Intestinal Hemorrhage

A 21-year-old man with a history of sudden rectal hemorrhage was referred to our hospital. Examination disclosed thrombocytopenia and hepatosplenomegaly. A liver biopsy specimen demonstrated Gaucher cells in Glisson's capsule. Additional investigations revealed a low level of leukocyte β-glucosidase activity and common mutations of the glucocerebrosidase gene, L444P/D409H. We diagnosed the patient with Gaucher disease type 1. He underwent enzyme replacement therapy. Thrombocytopenia and hepatosplenomegaly improved at a rate of approximately 50 and 20%, respectively, within 6 months. This case suggests that we must pay attention to adult Gaucher disease as a differential diagnosis for cryptogenic thrombocytopenia

An AsCas12f-based compact genome-editing tool derived by deep mutational scanning and structural analysis

SpCas9 and AsCas12a are widely utilized as genome-editing tools in human cells. However, their relatively large size poses a limitation for delivery by cargo-size-limited adeno-associated virus (AAV) vectors. The type V-F Cas12f from Acidibacillus sulfuroxidans is exceptionally compact (422 amino acids) and has been harnessed as a compact genome-editing tool. Here, we developed an approach, combining deep mutational scanning and structure-informed design, to successfully generate two AsCas12f activity-enhanced (enAsCas12f) variants. Remarkably, the enAsCas12f variants exhibited genome-editing activities in human cells comparable with those of SpCas9 and AsCas12a. The cryoelectron microscopy (cryo-EM) structures revealed that the mutations stabilize the dimer formation and reinforce interactions with nucleic acids to enhance their DNA cleavage activities. Moreover, enAsCas12f packaged with partner genes in an all-in-one AAV vector exhibited efficient knock-in/knock-out activities and transcriptional activation in mice. Taken together, enAsCas12f variants could offer a minimal genome-editing platform for in vivo gene therapy