Author Correction: Longitudinal assessment of tumor development using cancer avatars derived from genetically engineered pluripotent stem cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Diffusely Infiltrating Cerebellar Anaplastic Astrocytoma Effectively Controlled with Bevacizumab: Case Report and Literature Review

BackgroundGliomas that show extensive diffuse infiltration from the cerebellum to the brainstem without masslike expansion are extremely rare. The efficacy of bevacizumab treatment for diffusely infiltrating gliomas remains uncertain.Case DescriptionA 75-year-old man presented with a cerebellar anaplastic astrocytoma showing diffuse infiltration to the brainstem without a definite mass. He had experienced rapidly progressive nausea and dysarthria, as well as vertigo and headache for 2 months. Magnetic resonance imaging (MRI) revealed a poorly demarcated T2 high-intensity area in the right cerebellum and brainstem. The tumor in the right cerebellum showed sparse enhancement with gadolinium (Gd). Suboccipital decompressive craniotomy and partial removal of the tumor was emergently performed because of the rapid progression of symptoms and severe tonsillar herniation demonstrated on MRI. The pathologic diagnosis was anaplastic astrocytoma, and genomic analyses revealed no mutation in IDH1, H3F3A, or BRAF. During concomitant chemoradiotherapy with temozolomide, rapid worsening of the neurologic symptoms developed and significant enlargement of the T2 high-intensity area extending to the cerebral peduncle was seen, as well as a new Gd-enhancing lesion in the midbrain. After administration of bevacizumab, the neurologic symptoms gradually improved, the T2 high-intensity area decreased, and the Gd-enhancing lesion disappeared. At follow-up 2 years after the operation, no worsening of neurologic symptoms was seen and the residual T2 high-intensity area remained unchanged on MRI.ConclusionsBevacizumab treatment may be a salvage treatment option for patients with diffusely infiltrating cerebellar gliomas that exhibits rapid progression during standard treatment

Concomitant administration of radiation with eribulin improves the survival of mice harboring intracerebral glioblastoma

Glioblastoma is the most common and devastating type of malignant brain tumor. We recently found that eribulin suppresses glioma growth in vitro and in vivo and that eribulin is efficiently transferred into mouse brain tumors at a high concentration. Eribulin is a non‐taxane microtubule inhibitor approved for breast cancer and liposarcoma. Cells arrested in M‐phase by chemotherapeutic agents such as microtubule inhibitors are highly sensitive to radiation‐induced DNA damage. Several recent case reports have demonstrated the clinical benefits of eribulin combined with radiation therapy for metastatic brain tumors. In this study, we investigated the efficacy of a combined eribulin and radiation treatment on human glioblastoma cells. The glioblastoma cell lines U87MG, U251MG and U118MG, and SJ28 cells, a patient‐derived sphere culture cell line, were used to determine the radiosensitizing effect of eribulin using western blotting, flow cytometry and clonogenic assay. Subcutaneous and intracerebral glioma xenografts were generated in mice to assess the efficacy of the combined treatment. The combination of eribulin and radiation enhanced DNA damage in vitro. The clonogenic assay of U87MG demonstrated the radiosensitizing effect of eribulin. The concomitant eribulin and radiation treatment significantly prolonged the survival of mice harboring intracerebral glioma xenografts compared with eribulin or radiation alone (P < .0001). In addition, maintenance administration of eribulin after the concomitant treatment further controlled brain tumor growth. Aberrant microvasculature was decreased in these tumors. Concomitant treatment with eribulin and radiation followed by maintenance administration of eribulin may serve as a novel therapeutic strategy for glioblastomas

Photodynamic Diagnosis Using 5-Aminolevulinic Acid in 41 Biopsies for Primary Central Nervous System Lymphoma

We evaluated the feasibility of 5-aminolevulinic acid (5-ALA)-mediated photodynamic diagnosis (PDD) in the biopsy for primary central nervous system lymphoma (PCNSL). 5-ALA (20 mg kg−1) was administered orally 4 hours preoperatively. Forty-one biopsies obtained under PDD in 47 consecutive biopsies (46 patients) that were finally pathologically diagnosed as PCNSL were evaluated. Positive fluorescence was observed in 34 of those 41 biopsies (82.9%). An intraoperative pathological diagnosis (IOD) of suspected PCNSL was made in 21 of the biopsies with positive fluorescence (61.8%). However, the eight IODs in the remaining 13 biopsies (23.5%) were not correct (atypical cell, 4; high-grade glioma, 1; gliosis, 1; unremarkable, 2). In those 8 biopsies, PCNSL was confirmed by the final pathological diagnosis. There was no difference in the mean Mib-1 labeling index between the biopsies with positive fluorescence (86.5%) and those without positive fluorescence (90.0%). IOD was not performed in 6 biopsies; however, 5 of those biopsies (83.3%) showed positive fluorescence and were finally pathologically diagnosed as PCNSL. Use of PDD in biopsies for patients with suspected PCNSL is a reliable way of obtaining specimens of adequate quality for the final pathological diagnosis and may lead to improved diagnostic yield in the biopsy of PCNSL

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

Predictive factors of metamorphopsia after reduced-fluence photodynamic therapy in patients with central serous chorioretinopathy with good baseline visual acuity.

This retrospective study was conducted to investigate the predictive factors associated with metamorphopsia after reduced-fluence photodynamic therapy (RFPDT) in patients with central serous chorioretinopathy (CSC) with good baseline visual acuity. A total of 36 eyes of 36 consecutive patients with resolved CSC after RFPDT and best-corrected visual acuity (BCVA) better than 1.0 (logarithm of the minimal angle of resolution (logMAR) 0) at baseline were examined. Metamorphopsia was measured using M-CHARTS at 12 months after RFPDT. An average of the horizontal and vertical M-CHARTS scores was applied for defining the extent of metamorphopsia. The association between M-CHARTS score at 12 months after RFPDT and clinical parameters (age, sex, duration of symptoms, BCVA, and findings of optical coherence tomography (OCT)) was investigated at baseline or 12 months after RFPDT. The M-CHARTS score at 12 months correlated significantly with duration of symptoms (P = 0.005), baseline outer nuclear layer (ONL) thickness (P = 0.009), central foveal thickness (CFT) (P = 0.001) at 12 months, and ONL thickness (P = 0.001) at 12 months after RFPDT. In the multivariate analysis of baseline-related factors, thinner ONL thickness before RFPDT (P = 0.010) was significantly associated with large metamorphopsia at 12 months after RFPDT in CSC patients with good baseline BCVA. Baseline ONL thickness may be a useful predictive factor of metamorphopsia after RFPDT in CSC patients with good baseline BCVA

SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability.

Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SMARCB1 loss and the process of neural development, we introduced an inducible SMARCB1 loss-of-function system into human induced pluripotent stem cells (iPSCs) that were subjected to either directed neuronal differentiation or differentiation into cerebral organoids. Using this system, we identified substantial differences in the downstream effects of SMARCB1 loss depending on differentiation state and identified an interaction between SMARCB1 loss and neural differentiation pressure that causes a resistance to terminal differentiation and a defect in maintenance of a normal cell state. Our results provide insight into how SMARCB1 loss might interact with neural development in the process of ATRT tumorigenesis