Dokkyo Medical University Repository / 獨協医科大学リポジトリ
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Mechanisms of CAR-T Cell Exhaustion and its Application for Next-generation CAR-T Cells to Overcome Solid Tumors
Full text linkChimeric antigen receptor (CAR) is a chimeric molecule consisting of an extracellular antigen recognition domain and an intracellular signal transduction domain. Although the idea about CAR-T cells has been considered for quite some time, it has not been easy to show its efficacy. However, recently developed immunotherapy using CAR-T cells targeting CD19 is rapidly attracting attention because of its remarkable response rate against B-cell malignancies. CAR-T cell therapy has been approved in several countries, and used as standard treatment for relapsed or refractory cases. Under these circumstances, along with immune checkpoint inhibitors, CAR-T cell therapy is now recognized as the fourth treatment option for cancer. On the other hand, it has become clear that CAR-T cell therapy targeting CD19 also has a high relapse rate after complete remission. In addition, the response rate for solid tumors has still been low. One of the reasons for this is known to be exhaustion of CAR-T cells. It is essential to improve the function and characteristics of CAR-T cells in order to improve the response rate of CAR-T therapy and to expand its application to solid tumors. In this paper, the mechanisms of CAR-T cell exhaustion and its contributing factors are summarized. Also, the recent strategies to overcome CAR-T cell exhaustion will be reviewed for developing the nextgeneration CAR-T cells against solid tumors.journal articl
Correlation between Serum Vitamin D Binding Protein and Serum Calcium in Bronchial Asthma and the Effects of Single Nucleotide Polymorphisms
Full text linkBronchial asthma (BA) is characterized by airway stenosis due to chronic airway inflammation. CYP2R1 is an enzyme primarily responsible for vitamin D metabolism, and some of its single nucleotide polymorphisms (SNPs) have been implicated in BA. Vitamin D binding protein (VDBP) is primarily responsible for vitamin D transport, and some of its SNPs have also been implicated in asthma. Here, we investigated the relationship between serum VDBP, serum 25(OH)D, and serum calcium, as well as correlations between serum VDBP and laboratory data, in Japanese patients with BA and healthy donors (HDs). We also compared results between genotypes at SNPs of CYP2R1 (rs12794714 and rs10741657) and an SNP of VDBP (rs7041). Serum VDBP levels were significantly higher in the BA group compared with the HD group. Laboratory data did not differ between SNP genotypes in either group. The only parameter significantly correlated with VDBP was serum calcium in both groups. In addition, serum VDBP was correlated with serum calcium in all genotypes in the HD group, but was correlated with only the AA/AG genotype at rs12794714 and rs10741657 and TT/TG genotype at rs7041 in the BA group. Thus, SNP genotypes with an A allele (AA and AG) at rs12794714 and rs10741657 and a T allele (TT and TG) at rs7041, but not the GG genotype, may be involved in the serum VDBP-mediated regulation of serum calcium in BA.journal articl
COVID-19 Cluster in a Psychiatric Institution in Tochigi Prefecture: Experience Report as a DMAT Commander
Full text linkA cluster of COVID-19 outbreaks occurred at a psychiatric institution. The prefectural government ordered Disaster Medical Assistance Team to be dispatched. Patients with moderate disease cannot be transferred to other hospitals, which forces them to support themselves. Although the outside-of-hospital command supporters had zoned from the initial stage, private rooms were limited, and the ward was a mixture of those who had developed the disease and asymptomatic polymerase chain reaction-positive and -negative patients. Only two part-time internists were available to treat the patients, and treating the wards required much work. Unfortunately, no concrete support has been provided by the prefecture’s medical association. Measures to support the hospital include adjustments to zoning on a case-by-case basis, reassignment of existing nurses, educational activities on how to wear personal protective equipment, and improving the environment. Additionally, several issues regarding slander existed. To address these various issues, prefectural health and medical coordination headquarters for emerging infectious diseases should be established. Furthermore, guidelines should be provided for ward management strategies, treatment protocols, and staff education in the event of an outbreak of emerging infectious diseases in psychiatric institutions.journal articl
Capitals and their young inhabitants in the novels of 20th century
Full text linkOne of my favorite novels I read as a student in Tokyo in the early 1980's is Hotta YOSHIE's "Portraits of Young Poets" (1969). We can think of a genre of novels about a young man who comes to the capital from a rural district and gets various experiences there. In Japan, in the 20th century, not a few famous authors wrote such novels. Valerian Pidmohylny's "The City" (1928) also can be classified in this category in the Ukrainian reality of its period.departmental bulletin pape
Significance of Adding the Mucosal Fibrosing Method to Endoscopic Injection Sclerotherapy to Suppress the Recurrence of Esophageal Varices
Full text linkntroduction: Esophageal varices are usually asymptomatic but can cause major bleeding if they rupture. Treatment with endoscopic procedures like variceal ligation and injection sclerotherapy is common. This study focuses on the efficacy of secondary sclerotherapy and mucosal cauterization following injection sclerotherapy, aiming to prevent variceal recurrence.
Methods: We performed a retrospective statistical review of the cases. 98 patients were included in this study and divided into three groups; ethanolamine oleate (EO) method with/without ligation (EO+/-L) (group A; n = 51), EO+/-L and aethoxysclerol (AS) method (group B; n = 11), and EO+/-L plus AS and the mucosal fibrosing method (MFM) (group C; n = 36).
Results: As there were only 11 cases in group B, it was difficult to conduct a statistical analysis of the three groups. Therefore, a comparative study was conducted between groups A and B (hereinafter referred to as group AB) and group C. There was a clear difference in the rate of recurrent esophageal varices bleeding, 12.2% in group AB and 0% in group C (Exp(B) = 0.022). There was a significant difference in the morphological recurrence rate of esophageal varices, which was 29.0% in the AB group and 11.1% in the C group (p = 0.025). Although further observation is needed due to the different observation periods, a clear difference in survival rate was also observed, 22.7% in the AB group and 5.6% in the C group (p = 0.036).
Conclusions: MFM is useful in preventing recurrence of esophageal varices.journal articl
Fumarate Hydratase-deficient Renal Cell Carcinoma Successfully Treated with Cabozantinib: A Case Report
Full text linkFumarate hydratase-deficient renal cell carcinoma arises from mutations in the fumarate hydratase (FH) gene, representing a rare subset of renal cell carcinoma (RCC). Approximately 19% of patients formerly diagnosed with type 2 papillary RCCs are FH deficient. FH-deficient RCC typically exhibits an aggressive course and is associated with hereditary leiomyomatosis and RCC syndrome in cases with germline mutations. Herein, we report the case involving a 34-year-old Japanese man who experienced a 20-kg weight loss. Computed tomography identified a left renal tumor, leading to a subsequent left nephrectomy. Pathological analysis confirmed FH-deficient RCC. Following diagnosis, the patient underwent treatment with ipilimumab and nivolumab for liver metastasis. Due to disease progression, cabozantinib was administered as second-line therapy, achieving a partial response. Currently, no established standard therapy exists for FH-deficient RCC.
Nevertheless, in this case, the multi-kinase inhibitor cabozantinib was effective in combating resistance to immune checkpoint inhibitors.journal articl
Successful Treatment for Anti-melanoma Differentiationassociated Protein 5 Antibody-positive Dermatomyositis/ Interstitial Lung Disease Associated with Lung Adenocarcinoma
Full text linkWe encountered a rare case of early-stage lung adenocarcinoma and dermatomyositis with anti-melanoma differentiation-associated protein 5 antibody (MDA5-DM). The patient was a 57-year-old man with rapidly progressive interstitial lung disease (RP-ILD). Based on prognosis predicted by detailed evaluation of the patient’s MDA5-DM/RP-ILD and lung adenocarcinoma, combined immunosuppressive therapy was started before surgical treatment of his lung adenocarcinoma. After 9 months of immunosuppressive therapy, the patient underwent radical thoracoscopic lobectomy. Cancer-associated dermatomyositis, especially MDA5-DM, should be prioritized for treatment based on the prognostic prediction for each disease.journal articl
A Case Report of a Giant Thrombosed Aneurysm Requiring Differentiation from a Cavernous Hemangioma. A Case Report
Full text linkThis report describes a challenging case of a completely thrombosed giant cerebral aneurysm in which the differentiation of the lesion from a cavernous hemangioma was complicated by the lack of continuity with normal vessels. A 66-year-old man presented with nausea, vomiting, and left-sided neurologic symptoms. Head Magnetic Response imating (MRI) revealed a 37 mm mass with mixed intensity and concentric pattern on T2-weighted images (T2WI) lateral to the right parietal lobe and thalamus. T2* showed multiple hypointense lesions. Cerebral angiography showed normal middle cerebral artery (MCA) branches and no contrast inflow into the mass, posing a challenge in differentiating a thrombosed aneurysm from a cavernous hemangioma. Intraoperatively, direct visualization demonstrated continuity of the mass with the right MCA M4 segment through a narrow neck, confirming the diagnosis of a thrombosed aneurysm. While most thrombosed aneurysms show inflow of contrast material into the lumen on angiography, MRI signal patterns similar to hematomas can complicate differentiation from cavernous hemangiomas. In cases where preoperative imaging reveals mass lesions with characteristics similar to those of thrombosed aneurysms, it is critical to consider the possibility of a completely thrombosed giant aneurysm, even in the absence of apparent continuity with normal vessels on neuroimaging, to allow for optimal surgical planning.journal articl
Analysis of Nonlinear Dynamics in Epilepsy using a Koopman Operator Framework
Full text linkEpilepsy is a disorder characterized by recurrent seizures, and seizure prediction using electroencephalogram (EEG) and electrocorticogram (ECoG) signals is challenging. Conventional signal processing methods, which assume stationarity and linearity for the system considered, are inefficient at capturing the complex temporal structures of these signals; therefore, this study focused on dynamic mode decomposition (DMD), which has recently been used in fluid dynamics to extract the spatiotemporal dynamic features of non-stationary and nonlinear signals. This study applied an advanced data-driven nonlinear time series analysis method that combines time-delay embedding, diffusion mapping, and Koopman operator analysis, to the nonlinear dynamics of epileptic ECoG data. We analyzed 5 min of ECoG data from an 11-year-old boy with refractory Rolandic epilepsy. The collected data were embedded into a high-dimensional time-delayed coordinate space, and then its dimensions were reduced by diffusion mapping. The Koopman operator was estimated using extended DMD (eDMD), yielding its eigenvalues, modes, and eigenfunctions that represent the underlying dynamics of brain activity. We identified 11 of 32 Koopman eigenfunctions as significantly correlated with the occurrence of epileptic spikes, representing the temporal features of the ECoG data. We also found six Koopman modes that were significantly correlated with the spatial pattern of epileptic spike propagation, capturing the spatial features of the ECoG data. Understanding the spatiotemporal brain dynamics underlying epileptic EEG and ECoG signals may provide new clues to seizure prediction in epilepsy.journal articl