Management of aortic valve insufficiency in patients with continuous-flow left ventricular assist device: a republication of the review published in Japanese Journal of Artificial Organs.

Since 2011, implantable ventricular assist devices have been a standard treatment for severe heart failure alongside heart transplantation in Japan. However, the limited availability of donors has led to a prolonged wait for transplants, now averaging 1719 days, intensifying the issue of aortic insufficiency in patients with continuous flow ventricular assist devices. These devices limit the opening of the aortic valve, leading to sustained closure and increased shear stress, which accelerates valve degradation. Risk factors for aortic insufficiency include having a smaller body surface area, being of advanced age, and the presence of mild aortic insufficiency prior to device implantation. In patients presenting with mild or moderate aortic regurgitation at the time of ventricular assist device implantation, interventions such as aortic valve repair or bioprosthetic valve replacement are performed with the aim of halting its progression. The choice of surgical procedure should be tailored to each patient's individual condition. The management of de novo aortic insufficiency in patients with continuous flow ventricular assist devices remains challenging, with no clear consensus on when to intervene. Interventions for significant aortic insufficiency typically consider the patient's symptoms and aortic insufficiency severity. De novo aortic insufficiency progression in continuous flow ventricular assist devices patients necessitates careful monitoring and intervention based on individual patient assessments and valve condition. This review was created based on a translation of the Japanese review written in the Japanese Journal of Artificial Organs in 2023 (Vol. 52, No. 1, pp. 77-80), with some modifications.

Growth Transformation of B Cells by Epstein-Barr Virus Requires IMPDH2 Induction and Nucleolar Hypertrophy.

The in vitro growth transformation of primary B cells by Epstein-Barr virus (EBV) is the initial step in the development of posttransplant lymphoproliferative disorder (PTLD). We performed electron microscopic analysis and immunostaining of primary B cells infected with wild-type EBV. Interestingly, the nucleolar size was increased by two days after infection. A recent study found that nucleolar hypertrophy, which is caused by the induction of the IMPDH2 gene, is required for the efficient promotion of growth in cancers. In the present study, RNA-seq revealed that the IMPDH2 gene was significantly induced by EBV and that its level peaked at day 2. Even without EBV infection, the activation of primary B cells by the CD40 ligand and interleukin-4 increased IMPDH2 expression and nucleolar hypertrophy. Using EBNA2 or LMP1 knockout viruses, we found that EBNA2 and MYC, but not LMP1, induced the IMPDH2 gene during primary infections. IMPDH2 inhibition by mycophenolic acid (MPA) blocked the growth transformation of primary B cells by EBV, leading to smaller nucleoli, nuclei, and cells. Mycophenolate mofetil (MMF), which is a prodrug of MPA that is approved for use as an immunosuppressant, was tested in a mouse xenograft model. Oral MMF significantly improved the survival of mice and reduced splenomegaly. Taken together, these results indicate that EBV induces IMPDH2 expression through EBNA2-dependent and MYC-dependent mechanisms, leading to the hypertrophy of the nucleoli, nuclei, and cells as well as efficient cell proliferation. Our results provide basic evidence that IMPDH2 induction and nucleolar enlargement are crucial for B cell transformation by EBV. In addition, the use of MMF suppresses PTLD. IMPORTANCE EBV infections cause nucleolar enlargement via the induction of IMPDH2, which are essential for B cell growth transformation by EBV. Although the significance of IMPDH2 induction and nuclear hypertrophy in the tumorigenesis of glioblastoma has been reported, EBV infection brings about the change quickly by using its transcriptional cofactor, EBNA2, and MYC. Moreover, we present here, for the novel, basic evidence that an IMPDH2 inhibitor, namely, MPA or MMF, can be used for EBV-positive posttransplant lymphoproliferative disorder (PTLD).

Morphologic Analysis of M2 Macrophage in Glioblastoma: Involvement of Macrophage Extracellular Traps (METs).

Macrophages are classified into two phenotypes, M1 and M2, based on their roles. M2 macrophages suppress inflammation and increase in proportion to the malignancy of brain tumors. Recently, macrophage extracellular traps (METs), which change into a network, have been reported as a unique form of macrophage cell death. In this study, immunohistochemical analysis of macrophages in METs in human glioblastoma was performed. To distinguish between M1 and M2 macrophages, multiple immunostainings with Iba1 combined with CD163 or CD204 were performed. M2 macrophages were present in small amounts in normal and borderline areas but showed an increasing trend as they shifted to tumor areas, and most of them were the activated- or phagocytic-type. We also successfully detected METs coexisting with fibrin and lactoferrin near the border between the tumor and necrotic area. M2 macrophages not only suppressed inflammation but also were involved in the formation of METs. This study found that M2 macrophages play various roles in unstable situations.

D­allose enhances the efficacy of hydroxychloroquine against Lewis lung carcinoma cell growth by inducing autophagy.

Various cancer cells require massive amounts of glucose as an energy source for their dysregulated growth. Although D­allose, a rare sugar, inhibits tumor cell growth via inhibition of glucose uptake, a few cells can survive after treatment. However, the mechanism by which D­allose­resistant cells are generated remains unclear. Here, we investigated the properties of D­allose­resistant cells and evaluated the efficacy of combined treatment with this rare sugar and antitumor drugs. To this end, we established a D­allose­resistant tumor cell line and prepared a C57BL/6J mouse tumor xenograft model using Lewis lung carcinoma (LLC) cells. Xenograft­bearing mice were treated with D­allose (9 g/kg) and/or hydroxychloroquine (HCQ, 60 mg/kg), an autophagy inhibitor, for two weeks. Although D­allose inhibited LLC cell growth in a dose­dependent manner, a few cells survived. The upregulation of LC3­II, a classical autophagy marker, and the downregulation of mTOR and its downstream molecule Beclin1 were observed in established D­allose­resistant LLC cells, which were more sensitive to cell death induced by HCQ. Similarly, in the tumor xenograft model, the tumor volume in mice co­treated with D­allose and HCQ was considerably smaller than that in untreated or HCQ­treated mice. Importantly, the administration of D­allose induced autophagy selectively at the tumor site of the xenograft­bearing mice. These results provide a new therapeutic strategy targeting autophagy which is induced in tumor cells by D­allose administration, and may be used to improve therapies for lung cancer.

Expression status of p53 and organic cation transporter 1 is correlated with poor response to preoperative chemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly malignant neoplasm. DNA-damaging drugs, such as cisplatin (CDDP) and 5-fluorouracil (5-FU), are most frequently used in preoperative chemotherapy for ESCC. However, the response to preoperative chemotherapy varies among patients. p53, encoded by TP53, participates in apoptotic pathways following chemotherapy with DNA-damaging drugs, and mutation of TP53 contributes to chemoresistance. Organic cation transporter 1 (OCT1) participates in the uptake of CDDP, and its reduced expression is associated with CDDP resistance. The aim of this study was to evaluate the predictive impact of the expression status of p53 and OCT1 in response to preoperative chemotherapy in ESCC. METHODS: We retrospectively assessed 66 ESCC patients who received preoperative chemotherapy with CDDP/5-FU (CF) or docetaxel/CDDP/5-FU (DCF). p53 and OCT1 expression in pretreatment biopsy specimens was immunohistochemically determined and correlated with histological response to preoperative chemotherapy. RESULTS: p53 with wild-type (p53WT-ex) and mutant-type (p53MT-ex) expression patterns was identified in 40.9% and 59.1% of patients, respectively. High expression of OCT1 (OCT1High) was detected in 45.5%, and the remaining 54.5% showed low expression (OCT1Low). In a univariate analysis of the entire cohort, p53MT-ex was significantly correlated with poor response (P = 0.026), whereas OCT1Low showed marginal significance (P = 0.091). In a combined analysis, tumors with either p53MT-ex or OCT1Low showed a significant correlation with poor response compared with tumors with both p53WT-ex and OCT1High (P < 0.001). The sensitivity, specificity, and accuracy of combined p53/OCT1 were 93.9%, 47.1%, and 81.8%, respectively. Multivariate analysis identified p53 (P = 0.017), OCT1 (P = 0.032), and combined p53/OCT1 (P < 0.001) as independent predictors of histological response. When samples were stratified according to chemotherapy regimen in the univariate analysis, combined p53/OCT1 was the only significant factor for poor response in the CF (P = 0.011) and DCF (P = 0.021) groups, whereas p53 showed no statistical significance. CONCLUSIONS: Our results suggest that either p53MT-ex or OCT1Low expression in pretreatment biopsy specimens may be a potential predictor of poor response to preoperative chemotherapy with the CF-based regimens in ESCC, although the specificity needs to be improved.

Visualization of three-dimensional stigmoid body in FFPE and ultrathin sections of mouse.

Huntingtin-associated protein 1 (HAP1) is abundantly expressed in the neurons of the central nervous system and forms unique intracytoplasmic inclusions of unknown function called 'stigmoid bodies' (STBs). Transmission electron microscopy has revealed that the STBs are aggregates of granules containing cavities with a diameter of 0.5-3 µm. Small STBs fuse to form larger STBs, the size of which is said to vary depending on the developmental growth stage and brain region. Light microscopy can only reveal that these STBs have similar circular shapes due to its limited resolution. Therefore, light microscopy is only fit for the study of the STB distribution and quantitative changes. We, herein, suggest the adoption of correlative light and electron microscopy, which combines confocal laser scanning microscopy and scanning electron microscopy as the method allowing us to identify the huntingtin-associated protein 1-positive STBs in formalin-fixed paraffin-embedded (FFPE) sections. This approach allows us to study the three-dimensional morphology of immunolabeled objects in histopathological specimens. The STBs in FFPE sections of murine hypothalami reflected the transmission electron microscopic images of Epon-embedded STBs, although we were not able to observe any organelle covering the STBs of the FFPE sections. Furthermore, we were able to reconstruct the three-dimensional structure of the STB, and we identified it to be of spherical form, covered with mitochondria and rough endoplasmic reticulum, and bearing a cluster of cavities in the centre. In the future, we might gain new insights by comparing the three-dimensional structure of the STB between different neurons and under a variety of conditions.

Pedunculated pulmonary artery intimal sarcoma with poor uptake in 18F-FDG PET/CT: A case report.

Pulmonary artery intimal sarcoma (PAIS) is a rare tumor with an incidence of 0.001%-0.03% that usually grows along artery walls and absorbs fluorodeoxyglucose. It is difficult to distinguish PAIS from pulmonary thromboembolism due to the similarities of their symptoms. Therefore, contrast-enhanced computed tomography and positron emission tomography-computed tomography (PET-CT) should be used to establish a correct diagnosis. Here we report a case of an extremely rare type of PAIS, pedunculated PAIS, which could not be visualized on PET-CT. Histological features of a tumor with a low accumulation of fluorodeoxyglucose revealed low-cellularity and necrotizing background. Multimodal imaging was useful to diagnose PET-CT negative PAIS accurately. .

Morphological and functional abnormalities of hippocampus in APC1638T/1638T mice.

In the present study, we examined morphology and function of hippocampus in the APC1638T/1638T mouse. Expression levels of the APC mRNA and protein were both identical in the hippocampus of the APC+/+ and APC1638T/1638T mice. The dentate gyrus of the APC1638T/1638T hippocampus was thicker, and has more densely-populated granule cells in the APC1638T/1638T mouse hippocampus. Immunoelectron microscopy revealed co-localization of APC with alpha-amino-3- hydroxy-5-methyl- isoxazole-4-propionate receptor (AMPA-R) and with PSD-95 at post-synapse in the APC+/+ hippocampus, while APC1638T was co-localized with neither AMPA-R nor PSD-95 in the APC1638T/1638T hippocampus. By immunoprecipitation assay, full-length APC expressed in the APC +/+ mouse was co-immunoprecipitated with AMPA-R and PSD-95. In contrast, APC1638T expressed in the APC1638T/1638T mouse was not co-immunoprecipitated with AMPA-R and PSD-95. In the hippocampal CA1 region of the APC1638T/1638T mouse, c-Fos expression after electric foot shock was decreased compared with the APC+/+ mouse. The present study showed some abnormalities on morphology of the hippocampus caused by a truncated APC (APC1638T). Also, our findings suggest that failure in APC binding to AMPA-R and PSD-95 may bring about less activities of hippocampal neurons in the APC1638T/1638T mouse.

[Surgical Treatment for Primary Pulmonary Artery Sarcoma;Report of a Case].

Primary pulmonary artery sarcoma is a very rare tumor. The prognosis of primary pulmonary artery sarcoma is extremely poor and it is reported as 1.5 months without treatment. Here we report our experience of surgical treatment of primary pulmonary artery sarcoma. A 66-year-old woman with a diagnosis of pulmonary sarcoma by chest computed tomography( CT) scan was referred to our hospital because of a loss of consciousness. An emergecy surgery was planned to eliminate the risk of sudden death. To avoid circulatory collapse, we placed her on extracorporeal bypass before anesthesia induction. The tumor extending from right ventricle outflow tract to bilateral pulmonary artery was removed and resected without leaving residual mass, but the surgical margin was positive, and adjuvant chemoradiotherapy was performed after discharge. In conclusion, surgical resection was succesfully conducted to avoid sudden death.

An analysis of monocytes and dendritic cells differentiated from human peripheral blood monocyte-derived induced pluripotent stem cells.

Dendritic cell-based immunotherapy, which uses a patient's own immune cells, can be used for cancer treatment and allergy control, such as autoimmune disease and rejection associated with transplantation. However, these treatments create a burden on patients due to repeated blood collection. We used cell biological analysis of monocytes with few mutations obtained from minimal blood collection for genome recombination. Next, we established human peripheral blood monocyte-derived induced pluripotent stem cells (iPSCs) using a commercial vector and standard culture method. We found that when established iPSCs were induced to differentiate, monocytes showed phagocytic properties and expressed CD14 and CX3CR1. Further, the generated dendritic cells (DCs) expressed CCL17 and highly expressed HLA-DR following the addition of the mite antigen. Taken together, these data show that monocyte-derived iPS cells can be used to differentiate into monocytes and DCs. In addition, the use of these cells can be applied to the pathological analysis of dendritic cell therapy and monocyte diseases.