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1.
The clinical practice guideline for the management of amyotrophic lateral sclerosis in Japan-update 2023.
Urushitani, M, Warita, H, Atsuta, N, Izumi, Y, Kano, O, Shimizu, T, Nakayama, Y, Narita, Y, Nodera, H, Fujita, T, et al
Rinsho shinkeigaku = Clinical neurology. 2024;(4):252-271
Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.
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Circular RNAs hsa_circ_0001438 and hsa_circ_0000417 are downregulated and upregulated, respectively, in hepatocellular carcinoma.
Imanishi, S, Nagata, S, Fujita, T, Fujii, H
International journal of experimental pathology. 2022;(6):245-251
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Abstract
Hepatocellular carcinoma (HCC) is the most predominant type of liver cancer and is frequently fatal. Alpha-fetoprotein, alpha-fetoprotein-L3, and protein induced by vitamin K absence or antagonist-II are used as biomarkers to diagnose HCC. However, these biomarkers are not highly specific, especially for early-stage HCC diagnosis; therefore, more specific biomarkers are needed. Recently, circular RNA (circRNA) biomarkers have been used to diagnose several intractable diseases. In this study, we sought to identify circRNA biomarkers for the specific diagnosis of HCC. To this end, we compared the expression levels of circRNAs in primary HCC and normal tissues using publicly available RNA-seq data. Our analysis revealed that the expression levels of eight circRNAs were altered in primary HCC tissues compared with normal tissues. To confirm our findings, we examined the expression levels of selected circRNAs in HCC cell lines and normal hepatocytes. The expression level of hsa_circ_0001438, a circRNA that was downregulated in primary HCC, was lower in poorly and well-differentiated HCC cell lines than in normal hepatocytes. By contrast, the expression level of hsa_circ_0000417, which was increased in primary HCC, was strongly upregulated in a well-differentiated HCC cell line compared with normal hepatocytes. Thus, hsa_circ_0001438 and hsa_circ_0000417 might be potential biomarkers for the specific diagnosis of HCC. The experimental strategy described here, using publicly available RNA-seq data, is a useful and cost-effective method of identifying circRNA biomarkers.
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Co-expression effect of LLGL2 and SLC7A5 to predict prognosis in ERα-positive breast cancer.
Hisada, T, Kondo, N, Wanifuchi-Endo, Y, Osaga, S, Fujita, T, Asano, T, Uemoto, Y, Nishikawa, S, Katagiri, Y, Terada, M, et al
Scientific reports. 2022;(1):16515
Abstract
Lethal giant larvae homolog 2 (LLGL2) and solute carrier family 7 member 5 (SLC7A5) have been reported to be involved in resistance to endocrine therapy. This study aimed to assess the effects of LLGL2/SLC7A5 co-expression in predicting prognosis and response to tamoxifen therapy in ERα-positive breast cancer patients according to LLGL2/SLC7A5 mRNA and protein expression in long-term follow-up invasive breast cancer tissues. We identified that low LLGL2/SLC7A5 mRNA co-expression (LLGL2low/SLC7A5low) was associated with disease-free survival (DFS) compared with other combination groups in all breast cancer patients. In ERα-positive breast cancer patients, LLGL2low/SLC7A5low showed longer DFS and overall survival (OS) compared with LLGL2high/SLC7A5high and a positive trend of longer survival compared with the other combination groups. We also observed that LLGL2low/SLC7A5low showed longer survival compared with LLGL2high/SLC7A5high in ERα-positive breast cancer patients receiving adjuvant tamoxifen therapy. Multivariate analysis demonstrated that LLGL2low/SLC7A5low was an independent favorable prognostic factor of both DFS and OS, not only in all breast cancer patients, but also in ERα-positive breast cancer patients. High co-expression of LLGL2 and SLC7A5 protein showed a positive trend of shorter survival. Our study showed that co-expression of LLGL2 and SLC7A5 mRNA is a promising candidate biomarker in early breast cancer patients.
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Glucose-dependent diuresis in relation to improvements in renal-tubular markers of sodium-glucose cotransporter-2 inhibitors in hospitalized heart failure patients with diabetes.
Ikeda, Y, Ishii, S, Maemura, K, Oki, T, Yazaki, M, Fujita, T, Nabeta, T, Maekawa, E, Koitabashi, T, Ako, J
Heart and vessels. 2021;(7):978-985
Abstract
Clinical parameters with correlation to diuretic effects after initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors are unclear. We aimed to identify the factors associated with the diuretic effect observed following the initiation of SGLT2 inhibitors in patients with diabetes having an acute heart failure (HF). Fifty-six patients included were hospitalized for acute HF with diabetes and started on SGLT2 inhibitors. Changes in urine volume (ΔUV) and blood/urine laboratory parameters before and during the first 4 days of therapy were evaluated. Data were prospectively obtained under clinically stable conditions after initial HF treatment. UV increased following the initiation of SGLT2 inhibitors [UV at baseline (BL): 1383 ± 479 mL/day; ΔUV over 4 days: + 189 ± 358 mL/day]. Multivariate analysis revealed no association between BL-hemoglobin A1c or BL-estimated glomerular filtration rate and ΔUV. Conversely, higher BL-fasting plasma glucose (FPG) and higher BL-urine N-acetyl-β-D-glucosaminidase (NAG) were associated with a higher ΔUV. ΔUV was inversely associated with ΔFPG and ΔNAG, and positively associated with Δurinary sodium excretion. Elevated FPG and NAG both improved over 4 days of treatment. In conclusion, the diuretic effect of SGLT2 inhibitors was glycemia-dependent, and was associated with a reduction in elevated renal-tubular markers in hospitalized HF complicated with diabetes.
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Role of Rho in Salt-Sensitive Hypertension.
Kawarazaki, W, Fujita, T
International journal of molecular sciences. 2021;(6)
Abstract
A high amount of salt in the diet increases blood pressure (BP) and leads to salt-sensitive hypertension in individuals with impaired renal sodium excretion. Small guanosine triphosphatase (GTP)ase Rho and Rac, activated by salt intake, play important roles in the pathogenesis of salt-sensitive hypertension as key switches of intracellular signaling. Focusing on Rho, high salt intake in the central nervous system increases sodium concentrations of cerebrospinal fluid in salt-sensitive subjects via Rho/Rho kinase and renin-angiotensin system activation and causes increased brain salt sensitivity and sympathetic nerve outflow in BP control centers. In vascular smooth muscle cells, Rho-guanine nucleotide exchange factors and Rho determine sensitivity to vasoconstrictors such as angiotensin II (Ang II), and facilitate vasoconstriction via G-protein and Wnt pathways, leading to increased vascular resistance, including in the renal arteries, in salt-sensitive subjects with high salt intake. In the vascular endothelium, Rho/Rho kinase inhibits nitric oxide (NO) production and function, and high salt amounts further augment Rho activity via asymmetric dimethylarginine, an endogenous inhibitor of NO synthetase, causing aberrant relaxation and increased vascular tone. Rho-associated mechanisms are deeply involved in the development of salt-sensitive hypertension, and their further elucidation can help in developing effective protection and new therapies.
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Prostacyclin analog beraprost sodium efficacy in primary glomerular disease or nephrosclerosis: Analysis of the Japanese subgroup in CASSIOPEIR study.
Kurumatani, H, Okada, K, Origasa, H, Fujita, T, Isono, M, Nakamoto, H
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2021;(5):551-564
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Abstract
We conducted a multicenter, randomized, double-blind, placebo-controlled, phase IIb/III study (CASSIOPEIR) using a renal composite endpoint (i.e., doubling of SCr or end-stage renal disease) in seven Asian countries/region. CASSIOPEIR compared TRK-100STP (120 μg and 240 μg) with placebo in patients with non-diabetic CKD patients with primary glomerular disease or nephrosclerosis (n = 892). However, the superiority of TRK-100STP over placebo was not observed. A prior phase II study on which the Phase IIb/III study design was based included only Japanese patients. We therefore evaluated TRK-100STP efficacy and safety in a subgroup of Japanese patients using the CASSIOPEIR dataset. As the timing of treatment initiation is important in CKD, we conducted additional subgroup analyses based on the baseline serum creatinine (SCr) and eGFR. ITT analysis was performed in a Japanese subgroup (n = 339) in which the primary endpoint was the first occurrence of renal composite endpoint. Significant differences were observed for TRK-100STP 240 μg vs. placebo (P = 0.0493; HR 0.69 [95% CI: 0.47, 1.00]), but no significant difference was observed between TRK-100 120 μg and placebo (P = 0.3523; HR 0.85). More prominent improvement was observed with TRK-100STP 240 μg vs. placebo for baseline SCr < 3.0 mg/dL (P = 0.0031; HR 0.43); SCr < 3.5 mg/dL (P = 0.0237, HR 0.59); and eGFR ≥ 10 mL/min/1.73 m2 (P = 0.0339, HR0.67), respectively. No significant changes in urinary albumin/creatinine ratio and blood pressure were observed. TRK-100STP was generally well tolerated and most adverse drug reactions were mild or moderate in severity. In conclusion, in the Japanese subgroup of CASSIOPEIR, TRK-100STP 240 μg/day significantly improved the renal composite endpoint compared with placebo, with greater efficacy in subjects with SCr < 3.5 or eGFR ≥ 10 mL/min/1.73 m2 .
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The Mineralocorticoid Receptor in Salt-Sensitive Hypertension and Renal Injury.
Ayuzawa, N, Fujita, T
Journal of the American Society of Nephrology : JASN. 2021;(2):279-289
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Abstract
Hypertension and its comorbidities pose a major public health problem associated with disease-associated factors related to a modern lifestyle, such high salt intake or obesity. Accumulating evidence has demonstrated that aldosterone and its receptor, the mineralocorticoid receptor (MR), have crucial roles in the development of salt-sensitive hypertension and coexisting cardiovascular and renal injuries. Accordingly, clinical trials have repetitively shown the promising effects of MR blockers in these diseases. We and other researchers have identified novel mechanisms of MR activation involved in salt-sensitive hypertension and renal injury, including the obesity-derived overproduction of aldosterone and ligand-independent signaling. Moreover, recent advances in the analysis of cell-specific and context-dependent mechanisms of MR activation in various tissues-including a classic target of aldosterone, aldosterone-sensitive distal nephrons-are now providing new insights. In this review, we summarize recent updates to our understanding of aldosterone-MR signaling, focusing on its role in salt-sensitive hypertension and renal injury.
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Low RAI2 expression is a marker of poor prognosis in breast cancer.
Nishikawa, S, Uemoto, Y, Kim, TS, Hisada, T, Kondo, N, Wanifuchi-Endo, Y, Fujita, T, Asano, T, Katagiri, Y, Terada, M, et al
Breast cancer research and treatment. 2021;(1):81-93
Abstract
PURPOSE Retinoic acid-induced 2 (RAI2) has been shown to be a putative suppressor of the early hematogenous dissemination of tumor cells to the bone marrow in breast cancer. Here, we investigated the associations of RAI2 mRNA and protein expression with clinicopathological factors and prognosis in breast cancer patients with long-term follow-up. METHODS Invasive breast cancer tissues (n = 604) were analyzed for RAI2 mRNA expression. We examined the associations of clinicopathological factors with the expression levels of RAI2 mRNA in these samples. We also analyzed RAI2 protein expression by immunohistochemistry in invasive breast cancer tissues (n = 422). RESULTS We identified significant positive associations between low expression of RAI2 mRNA and shorter disease-free survival (DFS), breast-cancer-specific survival (BCSS), and overall survival (OS) in breast cancer patients. We also identified significant positive associations between negative for RAI2 protein expression and shorter DFS, BCSS, and OS in breast cancer patients. Low RAI2 mRNA and negative for RAI2 protein expression were positively associated with larger tumor size, higher tumor grade, and ERα-negativity. Multivariate analyses indicated that not only RAI2 mRNA but also RAI2 protein expression were independent risk factors for both DFS and BCSS in breast cancer patients. The median follow-up periods were 10.3 and 9.3 years for the RAI2 mRNA and protein expression analyses, respectively. CONCLUSIONS Our findings suggest that RAI2 has a role in the metastasis of breast cancer, and that RAI2 expression could be a promising candidate biomarker of prognosis in breast cancer patients.
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U-Shaped Association Between Intraoperative Net Fluid Balance and Risk of Postoperative Recurrent Atrial Tachyarrhythmia Among Patients Undergoing the Cryo-Maze Procedure: An Observational Study.
Minami, K, Kabata, D, Kakuta, T, Fukushima, S, Fujita, T, Shintani, A, Yoshitani, K, Ohnishi, Y
Journal of cardiothoracic and vascular anesthesia. 2021;(8):2392-2396
Abstract
OBJECTIVE The ability of perioperative fluid management to prevent postoperative recurrence of atrial tachyarrhythmia remains controversial. The aim of the present study was to assess if intraoperative net fluid balance was associated with atrial tachyarrhythmia recurrence after the Cryo-Maze procedure. DESIGN An observational cohort study. SETTING A tertiary care hospital from April 2007 to May 2019. PARTICIPANTS Four hundred forty-four patients undergoing the Cryo-Maze procedure in conjunction with other cardiac surgeries. INTERVENTIONS The Cryo-Maze procedure in conjunction with other cardiac surgeries. MEASUREMENTS AND MAIN RESULTS The main outcome was early atrial tachyarrhythmia recurrence, consisting of atrial fibrillation, atrial flutter, or atrial tachycardia, within the first three months after surgery. Complete follow-up was achieved in 443 patients (99.8%), of them 127 (28.6%) developed early atrial tachyarrhythmia recurrence. The median intraoperative net fluid balance was 1,627 mL (interquartile range, -215 to 3,557 mL). Multivariate logistic regression showed that intraoperative net fluid balance (p = 0.001), preoperative AF duration (adjusted odds ratio, 1.40; 95% CI, 1.17-1.68; p < 0.001) and left atrial volume index (aOR, 1.61; 95% CI, 1.06-2.45; p = 0.025) were independent predictors of early atrial tachyarrhythmia recurrence. The adjusted log odds were lowest (-1.52) when net fluid balance was 1,557 mL. CONCLUSIONS There is a significant U-shaped association between intraoperative net fluid balance and early atrial tachyarrhythmia recurrence among patients undergoing the Cryo-Maze procedure.
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Impact of adjunctive tolvaptan on sympathetic activity in acute heart failure with preserved ejection fraction.
Tamaki, S, Yamada, T, Morita, T, Furukawa, Y, Kawasaki, M, Kikuchi, A, Kawai, T, Seo, M, Abe, M, Nakamura, J, et al
ESC heart failure. 2020;(3):933-937
Abstract
AIMS: Acute decompensated heart failure (ADHF) is generally treated by decongestion using diuretic therapy. However, the use of loop diuretics is associated with increased cardiac sympathetic nerve activity (CSNA). We aimed to evaluate the effect of adjunctive tolvaptan therapy on CSNA in ADHF patients with preserved left ventricular ejection fraction (LVEF). METHODS AND RESULTS We enrolled 51 consecutive ADHF patients with LVEF ≥45%. Patients were randomly assigned to receive either tolvaptan add-on (n = 25) or conventional diuretic therapy (n = 26). Cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging was performed after stabilisation of heart failure symptoms, and the cardiac MIBG heart-to-mediastinum ratio (HMR) and washout rate (WR) were calculated. There were no significant differences in the body weight change and total urine volume during 2 days after randomisation or in the HMR on delayed image (HMR(d)) and WR between the tolvaptan and conventional groups. After stratification based on the median change in body weight, the patients with higher weight reduction had a significantly lower HMR(d) (P = 0.0128) and tended to have a higher WR (P = 0.0786) in the conventional group, whereas the cardiac MIBG imaging results were not influenced by body weight reduction in the tolvaptan group. CONCLUSIONS Adjunctive tolvaptan therapy may provide rapid decongestion without a harmful effect on CSNA in ADHF patients with preserved LVEF.