The Efficacy of Mirabegron for the Relief of Ureteral Stent-Related Symptoms

To investigate the efficacy of mirabegron for lower urinary tract symptoms in patients with an indwelling ureteral stent after ureterorenoscopic lithotripsy. This was a prospective follow-up study of 76 patients with stent-related symptoms (SRSs). Patients with upper urinary calculi who were pre-stented for > 2 weeks before lithotripsy were examined for the presence of SRSs by tests including the International Prostate Symptom Score (IPSS), OAB Symptom Score (OABSS), and urinary bother and pain measured by a Visual Analogue Scale (VAS) before lithotripsy. Mirabegron (50 mg/day) was prescribed post-lithotripsy for 2 weeks. SRSs were assessed at the time of stent removal. The IPSS scores improved significantly from 16.2 to 14.3 (p<0.001) and the IPSS-QoL scores decreased significantly from 5.0 to 4.6 (p=0.012). The OABSS scores improved significantly from 7.7 to 6.8 (p=0.006), and the urinary urgency scores (OABSS-Q3) decreased significantly from 3.24 to 2.68 (p<0.001). The number of nocturia episodes decreased significantly from 2.5 to 2.2 (p=0.045). Urinary bother and pain assessed by the VAS declined from 4.2 and 3.1 to 3.8 (p=0.15) and 2.5 (p=0.075), respectively. Mirabegron significantly improved SRSs and the number of nocturia episodes due to a ureteral stent

p53-armed oncolytic adenovirus induces autophagy and apoptosis in KRAS and BRAF-mutant colorectal cancer cells

Colorectal cancer (CRC) cells harboring KRAS or BRAF mutations show a more-malignant phenotype than cells with wild-type KRAS and BRAF. KRAS/BRAF-wild-type CRCs are sensitive to epidermal growth factor receptor (EGFR)-targeting agents, whereas KRAS/BRAF-mutant CRCs are resistant due to constitutive activation of the EGFR-downstream KRAS/BRAF signaling pathway. Novel therapeutic strategies to treat KRAS/BRAF mutant CRC cells are thus needed. We recently demonstrated that the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 exhibit therapeutic potential against KRAS-mutant human pancreatic cancer cells. In this study, we evaluated the therapeutic potential of OBP-301 and OBP-702 against human CRC cells with differing KRAS/BRAF status. Human CRC cells with wild-type KRAS/BRAF (SW48, Colo320DM, CACO-2), mutant KRAS (DLD-1, SW620, HCT116), and mutant BRAF (RKO, HT29, COLO205) were used in this study. The antitumor effect of OBP-301 and OBP-702 against CRC cells was analyzed using the XTT assay. Virus-mediated modulation of apoptosis, autophagy, and the EGFR-MEK-ERK and AKT-mTOR signaling pathways was analyzed by Western blotting. Wild-type and KRAS-mutant CRC cells were sensitive to OBP-301 and OBP-702, whereas BRAF-mutant CRC cells were sensitive to OBP-702 but resistant to OBP-301. Western blot analysis demonstrated that OBP-301 induced autophagy and that OBP-702 induced autophagy and apoptosis in human CRC cells. In BRAF-mutant CRC cells, OBP-301 and OBP-702 suppressed the expression of EGFR, MEK, ERK, and AKT proteins, whereas mTOR expression was suppressed only by OBP-702. Our results suggest that p53-armed oncolytic virotherapy is a viable therapeutic option for treating KRAS/BRAF-mutant CRC cells via induction of autophagy and apoptosis

Influence of Gas Flow Rate and Reactor Length on NO Removal Using Pulsed Power

A short duration of 100-ns pulsed power has been used to remove nitric oxide (NO) in a mixture of nitrogen, oxygen, water vapor, and NO, simulating flue gases from a power station. The effects of the gas flow rate, the reactor length, and the pulse repetition rate on the percentage of NO removal and its energy efficiency are reported. The percentage of NO removal at a fixed gas flow rate increased with increasing pulse repetition rate due to the increased energy into the discharge. At a fixed pulse rate, the removal of NO increased with decreasing gas flow rate due to the increased residence time of the gas in the discharge reactor, thus facilitating the creation of increased radicals of O and N which then decreased NO. The energy removal efficiency of NO (in mol/kWh) decreased with increasing gas flow rate and increasing removal ratio of NO. The removal of NO increased with increasing energy density (J/I) input into the discharge at different reactor length

Combination of C-reactive protein/albumin ratio and time to castration resistance enhances prediction of prognosis for patients with metastatic castration-resistant prostate cancer

ObjectiveThis study aimed to identify the prediction accuracy of the combination of C-reactive protein (CRP) albumin ratio (CAR) and time to castration resistance (TTCR) for overall survival (OS) following development of metastatic castration-resistant prostate cancer (mCRPC).MethodsClinical data from 98 mCRPC patients treated at our institution from 2009 to 2021 were retrospectively evaluated. Optimal cutoff values for CAR and TTCR to predict lethality were generated by use of a receiver operating curve and Youden’s index. The Kaplan–Meier method and Cox proportional hazard regression models for OS were used to analyze the prognostic capabilities of CAR and TTCR. Multiple multivariate Cox models were then constructed based on univariate analysis and their accuracy was validated using the concordance index.ResultsThe optimal cutoff values for CAR at the time of mCRPC diagnosis and TTCR were 0.48 and 12 months, respectively. Kaplan–Meier curves indicated that patients with CAR &gt;0.48 or TTCR &lt;12 months had a significantly worse OS (both p &lt; 0.005). Univariate analysis also identified age, hemoglobin, CRP, and performance status as candidate prognostic factors. Furthermore, a multivariate analysis model incorporating those factors and excluding CRP showed CAR and TTCR to be independent prognostic factors. This model had better prognostic accuracy as compared with that containing CRP instead of CAR. The results showed effective stratification of mCRPC patients in terms of OS based on CAR and TTCR (p &lt; 0.0001).ConclusionAlthough further investigation is required, CAR and TTCR used in combination may more accurately predict mCRPC patient prognosis

The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b−/− mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b−/− neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b−/− and Calr+/− mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis

The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b−/− mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b−/− neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b−/− and Calr+/− mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis

Detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDG-PET/CT)

The purpose of this study was to analyze the detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT). Data for a total of 492 patients who had undergone both PET/CT and colonoscopy were analyzed. After the findings of PET/CT and colonoscopy were determined independently, the results were compared in each of the six colonic sites examined in all patients. The efficacy of PET/CT was determined using colonoscopic examination as the gold standard. In all, 270 colorectal lesions 5 mm or more in size, including 70 pathologically confirmed malignant lesions, were found in 172 patients by colonoscopy. The sensitivity and specificity of PET/CT for detecting any of the colorectal lesions were 36 and 98%, respectively. For detecting lesions 11 mm or larger, the sensitivity was increased to 85%, with the specificity remaining consistent (97%). Moreover, the sensitivity for tumors 21 mm or larger was 96% (48/50). Tumors with malignant or high-grade pathology were likely to be positive with PET/CT. A size of 10 mm or smaller [odds ratio (OR) 44.14, 95% confidence interval (95% CI) 11.44-221.67] and flat morphology (OR 7.78, 95% CI 1.79-36.25) were significant factors that were associated with false-negative cases on PET/CT. The sensitivity of PET/CT for detecting colorectal lesions is acceptable, showing size- and pathology-dependence, suggesting, for the most part, that clinically relevant lesions are detectable with PET/CT. However, when considering PET/CT for screening purposes caution must be exercised because there are cases of false-negative results

Natural capitals for nature’s contributions to people: the case of Japan

Recently, natural capital has gained the attention of researchers and policymakers to promote sustainability. Previous studies have investigated the value of ecosystem services with respect to specific areas or species. Other studies have investigated the value of various types of ecosystem services and natural capital by integrating a number of findings using meta-analyses at the global level. Although these studies have provided information on either the global value of natural capital or the local value of specific subjects, there is little evidence on the country-specific values of natural capital in Japan, which will provide useful information for national environmental policies. We investigated the perceived values of terrestrial and marine natural capital in Japan using internet surveys and payment card methods. Data on various natural forms of capital were collected in a unified format and comparable manner. We found that some explanatory variables, such as perceived importance and visit frequency, as well as sociodemographic characteristics, are significant drivers of the willingness to pay (WTP), which maintains each aspect of natural capital. In addition, we conducted future predictions of terrestrial and marine natural capital using a scenario developed in a previous study. Our results indicate that Japan should follow a population dispersed scenario for the sustainable management of natural capital up to 2050

IMiD/CELMoD-induced growth suppression of adult T-cell leukemia/lymphoma cells via cereblon through downregulation of target proteins and their downstream effectors

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Our purpose in this study was to elucidate the IMiD-mediated anti-ATL mechanisms. Thirteen ATL-related cell lines were divided into LEN-sensitive or LEN-resistant groups. CRBN knockdown (KD) led to a loss of LEN efficacy and IKZF2-KD-induced LEN efficacy in resistant cells. DNA microarray analysis demonstrated distinct transcriptional alteration after LEN treatment between LEN-sensitive and LEN-resistant ATL cell lines. Oral treatment of LEN for ATL cell-transplanted severe combined immunodeficiency (SCID) mice also indicated clear suppressive effects on tumor growth. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL

Essays on Macroeconomics

This thesis examines the dynamics of macroeconomy and investigates the implicationsof changing environments from three different perspectives. Comprising three papers, the thesis contributes to the understanding of macroeconomic dynamics and provides insights on macroeconomic policy. Chapter 1 focuses on the dynamics of labor market. Average hours worked per adult in Japan fell by around one third over the last half-century. The leading explanation focuses on government policies that distort labor supply decisions. This paper provides a new interpretation that stresses the role of income effects in preferences. Through the lens of a model of the market and home sectors and using non-homothetic preferences, I show that the main driver of Japan’s decline in hours worked is income effects, rather than labor-market distortions or population aging. The model predicts that average hours of leisure will rise and home-production hours will remain roughly constant over the period, which is consistent with evidence from time-use surveys. An alternative calibration based on only labor market distortions counterfactually predicts that home production hours will rise. Chapter 2 answers the following questions related to population aging. How does a grayer society affect the political decision making regarding inflation rates? Is deflation preferred as a society ages? In order to answer these questions, the co-authors and I, referred to as “we” throughout this chapter, compute the optimal rates of inflation that maximize the lifetime utility of the young and the old households respectively, and explore how they change with demographic factors, using a New Keynesian model with overlapping generations. The long-run inflation target has a redistribution effect on households’ earnings and thus results in their heterogeneous preferences toward inflation. The rates that maximizes the steady state welfare is nagative for the representative old household but is close to zero for the representative young household. When the transition dynamics are taken into account, their preferred inflation rates both decrease and become negative. Because the old household’s preferred rate is lower, population aging generates a negative composition effect on the population-weighted average of these rates. We find, however, that both rates increase when population aging is made severer, and that the population-weighted average also increases. Chapter 3 turns to an analyses of industrial policy. A key recipe advocated to poorer nations to leapfrog in their socio-economic development is to quickly absorb expertise from countries at the technological frontier. This chapter examines the role of education policies enabling technology diffusion across countries. The co-author and I, referred to as “we” throughout this chapter, use the difference-in-difference framework to assess the role of educational reforms, changes in the length of compulsory schooling, implemented to different degrees and at different timings across countries. Our estimation results suggest that the marginal impact of extending compulsory schooling by one year has a positive effect on a country’s ability to receive products that embodies more advanced technology, while it is not statistically significant