This study uses “Mobile Kukan Toukei™” (Mobile Spatial Statistics) to examine the impact of COVID-19 on the transitions and characteristics of population in Nagoya City. Mobile Kukan Toukei comprises ...statistical population data created using the operational data from mobile phone networks. Comparison of the data before and after the COVID-19 outbreak showed that the impact was remarkable in many areas in April 2020. Notably, urban areas such as Nagoya Station and Sakae showed relatively more robust recovery both on weekdays and holidays. However, several tourist areas did not bounce back on holidays, despite the Japanese government’s “GoTo” campaign. More visitors are perhaps coming from closer regions than distant ones as people’s attempt to minimize the risk of being infected.
Regulation of oxidative stress and redox systems has important roles in carcinogenesis and cancer progression, and for this reason has attracted much attention as a new area of cancer therapeutic ...targets. Glutathione peroxidase 4 (GPX4), an antioxidant enzyme, has biological important functions such as signaling cell death by suppressing peroxidation of membrane phospholipids. However, few studies exist on the expression and clinical relevance of GPX4 in malignant lymphomas such as diffuse large B-cell lymphoma. In this study, we assessed the expression of GPX4 immunohistochemically. GPX4 was expressed in 35.5% (33/93) cases of diffuse large B-cell lymphoma. The GPX4-positive group had poor overall survival (P = 0.0032) and progression-free survival (P = 0.0004) compared with those of the GPX4-negative group. In a combined analysis of GPX4 and 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, there was a negative correlation between GPX4 and 8-hydroxydeoxyguanosine (P = 0.0009). The GPX4-positive and 8-hydroxydeoxyguanosine-negative groups had a significantly worse prognosis than the other groups in both overall survival (P = 0.0170) and progression-free survival (P = 0.0005). These results suggest that the overexpression of GPX4 is an independent prognostic predictor in diffuse large B-cell lymphoma. Furthermore, in vitro analysis demonstrated that GPX4-overexpressing cells were resistant to reactive oxygen species-induced cell death (P = 0.0360). Conversely, GPX4-knockdown cells were sensitive to reactive oxygen species-induced cell death (P = 0.0111). From these data, we conclude that GPX4 regulates reactive oxygen species-induced cell death. Our results suggest a novel therapeutic strategy using the mechanism of ferroptosis, as well as a novel prognostic predictor of diffuse large B-cell lymphoma.
This study uses “Mobile Kukan Toukei™” (MOBILE SPATIAL STATISTICS) to analyze the impact of the novel coronavirus (COVID-19) infection on people's movements in tourist destinations in Kansai region ...(mainly Kyoto). Mobile Kukan Toukei is statistical population data created by the operational data of mobile phone networks. Comparison of the data before and after the spread of the disease showed that the impact was remarkable in many areas in April 2020. Urban areas such as Kyoto Station and Osaka Station showed relatively more robust recovery. However, several tourist areas could not bounce back despite the “GoTo” campaign by the Japanese government.
This study uses “Mobile Kukan Toukei™” (MOBILE SPATIAL STATISTICS) to identify the number of visitors in different periods at specific tourist destinations. Mobile Kukan Toukei is statistical ...population data created by the operational data of mobile phone networks. The service makes it possible to estimate the population structure of a region by gender, age, and residential area. In addition, it attempts to demonstrate an alternative method to infer the number of visitors in specific areas more accurately. The various interests of tourists influence their keyword search before or during travel, and ultimately emerge as some kind of trend in a specific keyword’s search volume. By connecting the Mobile Kukan Toukei and keyword search volume, linear equations could be derived. These findings could lead to a model to forecast tourism demand in a destination.
In order to prevent central nervous system (CNS) involvement and improve the prognosis of primary intraocular lymphoma (PIOL), we prospectively evaluated the efficacy of combined therapy using ...intravitreal methotrexate (MTX) and systemic high‐dose MTX on treatment‐naïve PIOL. Patients with newly diagnosed PIOL whose lymphoma was limited to the eyes were enrolled. The patients were treated with weekly intravitreal MTX until the ocular lesions were resolved, followed by five cycles of systemic high‐dose MTX (3.5 g/m2) every other week. Ten patients were enrolled in this study and completed the treatment. All patients achieved complete response for their ocular lesions with rapid decrease of intravitreal interleukin‐10 concentration. Adverse events of intravitreal and systemic high‐dose MTX were mild and tolerable. With a median follow‐up of 29.5 months, four patients (40%) experienced the CNS disease development and the mean CNS lymphoma‐free survival (CLFS) time was 51.1 months. Two‐year CLFS, which was the primary end‐point of the study, was 58.3% (95% confidence interval, 23.0–82.1%). In contrast, eight patients were treated with intravitreal MTX alone in our institute, and their 2‐year CLFS was 37.5% (95% confidence interval, 8.7–67.4%). In conclusion, systemic high‐dose MTX following intravitreal MTX is feasible and might be effective in preventing CNS involvement of PIOL. Further arrangements are worth considering in order to improve the effects. This study was registered with UMIN Clinical Trials Registry (UMIN000003921).
Systemic high‐dose MTX following intravitreal MTX was effective in preventing CNS involvement of PIOL in comparison with intravitreal MTX. Adverse events of intravitreal and systemic high‐dose MTX were mild and tolerable.
This study used “Mobile Kukan Toukei™” (mobile spatial statistics) provided by NTT DOCOMO, Inc. and DOCOMO Insight Marketing, Inc. to collect the location data of mobile phone users in order to count ...the number of visitors at specific tourist destinations and examine their characteristics. Mobile Kukan Toukei™ is statistical population data created by a mobile phone network. It is possible to estimate the population structure of a region by gender, age, and residence using this service of the company. First, I examined the data of the two hot springs, Wakura and Yamanaka. Then I compared the results of them. The opening of the Hokuriku Shinkansen brought more visitors to many areas in the prefecture. However, it also led to fewer visitors in some areas. Regarding Yamanaka hot springs, there was no significant difference in visits between different periods. Some visitors might have spent more than one night in Yamanaka hot springs. Although both Wakura and Yamanaka hot springs are a little far from Kanazawa, their results were contrary. A TV drama might have increased the number of tourists in Wakura.
The overexpression of glutathione peroxidase 4 (GPX4; an enzyme that suppresses peroxidation of membrane phospholipids) is considered a poor prognostic predictor of diffuse large B-cell lymphoma ...(DLBCL). However, the mechanisms employed in GPX4 overexpression remain unknown. GPX4 is translated as a complete protein upon the binding of SECISBP2 to the selenocysteine insertion sequence (SECIS) on the 3′UTR of GPX4 mRNA. In this study, we investigated the expression of SECISBP2 and its subsequent regulation of GPX4 and TXNRD1 in DLBCL patients. Moreover, we determined the significance of the expression of these selenoproteins in vitro using MD901 and Raji cells. SECISBP2 was positive in 45.5% (75/165 cases) of DLBCL samples. The SECISBP2-positive group was associated with low overall survival (OS) as compared to the SECISBP2-negative group (P = 0.006). Similarly, the SECISBP2 and GPX4 or TXNRD1 double-positive groups (P < 0.001), as well as the SECISBP2, GPX4, and TXNRD1 triple-positive group correlated with poor OS (P = 0.001), suggesting that SECISBP2 may serve as an independent prognostic predictor for DLBCL (hazard ratio (HR): 2.693, P = 0.008). In addition, western blotting showed a decrease in GPX4 and TXNRD1 levels in SECISBP2-knockout (KO) MD901 and Raji cells. Oxidative stress increased the accumulation of reactive oxygen species in SECISBP2-KO cells (MD901; P < 0.001, Raji; P = 0.020), and reduced cell proliferation (MD901; P = 0.001, Raji; P = 0.030), suggesting that SECISBP2-KO suppressed resistance to oxidative stress. Doxorubicin treatment increased the rate of cell death in SECISBP2-KO cells (MD901; P < 0.001, Raji; P = 0.048). Removal of oxidative stress inhibited the altered cell death rate. Taken together, our results suggest that SECISBP2 may be a novel therapeutic target in DLBCL.
SECISBP2 overexpression is an independent negative prognostic predictor in diffuse large B-cell lymphoma. Additionally, SECISBP2 positively correlates with selenoprotein expression. In vitro, SECISBP2 knockout increases intracellular reactive oxygen species accumulation via the downregulation of selenoproteins, inhibiting cell growth and promoting cell death after doxorubicin treatment. Therefore, SECISBP2 is a potential therapeutic target for malignant lymphoma.
Cancer cells, including malignant lymphoma cells, alter their metabolism, termed “metabolic reprograming,” on initiation of malignant transformation as well as upon accumulation of genetic ...abnormalities. Here, to identify a novel therapeutic target involved in the metabolic changes during malignant lymphoma, we performed global analyses combined with shotgun proteomics, in silico database analysis, and clinic-pathologic analysis of nonneoplastic lymphoid tissue and malignant lymphoma tissue and verified the molecular functions in vitro. In total, 2002 proteins were detected from both samples and proteins related to fatty acid beta-oxidation (FAO) were detected more frequently in malignant lymphoma tissue. Consequently, the most frequently detected protein, the mitochondrial trifunctional enzyme subunit-alpha (HADHA), was identified as a potential target. Immunohistochemical analyses revealed that HADHA tended to be overexpressed in a high-grade subtype of malignant lymphoma tissue. Clinicopathologic study revealed that HADHA overexpression was correlated with significantly worse overall survival (P= 0.013) and was an independent prognostic predictor in diffuse large B-cell lymphoma (P= 0.027). In vitro, downregulation of HADHA negatively regulated cell growth by causing G0/G1 arrest (P= 0.0008) similar to treatment with etomoxir, an inhibitor of FAO (P= 0.032). Moreover, downregulation of HADHA increased the susceptibility to doxorubicin (P= 0.002) and etoposide (P= 0.004). Moreover, these phenotypes were confirmed in an HADHA knockout system. Thus, we provide a basis for a novel therapeutic strategy through the regulation of HADHA and FAO in patients with refractory malignant lymphoma.
Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually ...occurs as a result of a remaining population of drug‐resistant myeloma stem cells. Side population (SP) cells show cancer stem cell‐like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non‐SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR‐S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient‐derived xenograft model. Moreover, long‐term continuous dosing of OR‐S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR‐S1, leading to significant advances in the treatment of MM.
Long‐term continuous administration of OR‐S1 completely cured all mice bearing orthotopic xenografts without eliciting any serious side‐effects. We confirmed this result by counting minimal residual cells by flow cytometric analysis. These results suggest that long‐term continuous administration of OR‐S1 impairs the self‐renewal activity of myeloma stem cells, rendering these cells unable to reconstitute disease and leading to the complete cure of MM.
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