Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment.

Isocitrate dehydrogenase-mutant low-grade gliomas (IDHmut-LGG) grow slowly but frequently undergo malignant transformation, which eventually leads to premature death. Chemotherapy and radiotherapy treatments prolong survival, but can also induce genetic (or epigenetic) alterations involved in transformation. Here, we developed a mathematical model of tumor progression based on serial tumor volume data and treatment history of 276 IDHmut-LGGs classified by chromosome 1p/19q codeletion (IDHmut/1p19qcodel and IDHmut/1p19qnoncodel) and performed genome-wide mutational analyses, including targeted sequencing and longitudinal whole-exome sequencing data. These analyses showed that tumor mutational burden correlated positively with malignant transformation rate, and chemotherapy and radiotherapy significantly suppressed tumor growth but increased malignant transformation rate per cell by 1.8 to 2.8 times compared with before treatment. This model revealed that prompt adjuvant chemoradiotherapy prolonged malignant transformation-free survival in small IDHmut-LGGs (≤ 50 cm3). Furthermore, optimal treatment differed according to genetic alterations for large IDHmut-LGGs (> 50 cm3); adjuvant therapies delayed malignant transformation in IDHmut/1p19qnoncodel but often accelerated it in IDHmut/1p19qcodel. Notably, PI3K mutation was not associated with malignant transformation but increased net postoperative proliferation rate and decreased malignant transformation-free survival, prompting the need for adjuvant therapy in IDHmut/1p19qcodel. Overall, this model uncovered therapeutic strategies that could prevent malignant transformation and, consequently, improve overall survival in patients with IDHmut-LGGs.Significance: A mathematical model successfully estimates malignant transformation-free survival and reveals a link between genetic alterations and progression, identifying precision medicine approaches for optimal treatment of IDH-mutant low-grade gliomas.

Genetic analysis in glioma has been developed recently. Spinal cord glioma is less common than intracranial glioma. Thus, the clinical significance of genetic mutations in spinal cord gliomas remains unclear. Furthermore, because the spinal cord is an important communication channel between the brain and the rest of the body, increased attention should be paid to its functional prognosis. In this study, we investigated the functional prognosis and driver genetic mutations in eight patients with spinal cord gliomas (World Health Organization grade I, three cases; grade II, two cases; grade III/IV, three cases). IDH mutations were detected in all grade II cases and H3F3A mutations were detected in all grade III/IV cases. The functional status of grade I and II gliomas remained unchanged or improved 1 year after surgery, whereas grade III/IV gliomas remained unchanged or deteriorated. Spinal glioma progenitor cells with H3F3A mutations were associated with accelerated tumor-associated spinal cord injury, which led to functional impairment. Conversely, the presence of IDH mutations, which are rarely reported in spinal gliomas, indicated a relatively favorable functional prognosis.

Subarachnoid hemorrhage (SAH) due to ruptured cerebral aneurysms is the most severe form of stroke, and treatment outcomes remain poor. Brain damage after SAH can be broadly divided into early brain injury (EBI) and delayed cerebral ischemia (DCI). Although the causes of these events are multifactorial, free hemoglobin generated after hemolysis in the subarachnoid space is believed to be one of the most important causative factors. Recently, cerebral lymphatic vessels, previously thought to be non-existent, have been identified, suggesting their involvement not only in maintaining homeostasis but also in brain injury. Furthermore, new findings have been reported regarding cerebrospinal fluid (CSF) circulation. Because intracranial CSF circulation and lymphatic drainage to the extracranial blood and lymphatic vessels affect free hemoglobin metabolism in the CSF, these factors are likely to affect EBI and DCI. In addition, matricellular protein tenascin-C, which we have reported to be involved in the pathogenesis of EBI and DCI, has been reported to inhibit lymphatic vessel proliferation in non-central nervous system pathologies. However, the relationship between post-SAH brain injury and intracranial lymphatics remains unknown. This review aimed to summarize recent findings regarding intracranial lymphatics and CSF circulation and to discuss how they may affect post-SAH pathology.

症例は82歳男性. 頭痛, 意識障害で救急搬送となり, 頭部CTで右後頭葉の脳出血と急性硬膜下血腫を認めた. 脳血管撮影で出血部に一致してpiral AVFとnon-sinus type dural AVFの併存を疑う所見を認めた. 直達手術で確認したところ, 両者が併存しており, 異なるシャントポイントから同一単独の脳皮質静脈に流出しており, 根治には位置関係を見極めて処置する必要があった. このような症例においては, 複数のシャントポイントを直視下に確認して確実に処置できる直達手術の優位性が高い.

Purpose: To evaluate the amide proton transfer (APT), tumor blood flow (TBF), and apparent diffusion coefficient (ADC) combined diagnostic value for differentiating intracranial malignant tumors (MTs) from benign tumors (BTs) in young patients, as defined by the 2021 World Health Organization classification of central nervous system tumors. Methods: Fifteen patients with intracranial MTs and 10 patients with BTs aged 0–30 years underwent MRI with APT, pseudocontinuous arterial spin labeling (pCASL), and diffusion-weighted imaging. All tumors were evaluated through the use of histogram analysis and the Mann–Whitney U test to compare 10 parameters for each sequence between the groups. The diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. Results: The APT maximum, mean, 10th, 25th, 50th, 75th, and 90th percentiles were significantly higher in MTs than in BTs; the TBF minimum (min) was significantly lower in MTs than in BTs; TBF kurtosis was significantly higher in MTs than in BTs; the ADC min, 10th, and 25th percentiles were significantly lower in MTs than in BTs (all p < 0.05). The APT 50th percentile (0.900), TBF min (0.813), and ADC min (0.900) had the highest area under the curve (AUC) values of the parameters in each sequence. The AUC for the combination of these three parameters was 0.933. Conclusions: The combination of APT, TBF, and ADC evaluated through histogram analysis may be useful for differentiating intracranial MTs from BTs in young patients.