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In 2020, concerns arose about the potential adverse effects of angiotensin II type 1 receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) on patients with the Coronavirus Disease 2019 (COVID-19). However, there is no national data on antihypertensive prescriptions during the COVID-19 pandemic in Japan. This study aimed to explore the trends in antihypertensive drug prescriptions in Japan throughout COVID-19 pandemic period. This study used data from the National Database (NDB) Open Data in Japan, an annual publication by the Ministry of Health, Labour and Welfare. To capture changes before and after social activity restrictions, the present study focused on extracting the number of prescribed oral medicine tablets for outpatients from the NDB Open Data from 2018 to 2021. The fiscal year 2020 exhibited the lowest for both outpatient claims and prescribed drugs. In contrast, all categories of antihypertensive drug prescription showed annual increases, and no specific changes in the prescription patterns of ARBs and ACEIs around fiscal year 2020 were observed. This study implies that antihypertensive drug prescriptions were adequately maintained throughout the COVID-19 pandemic in Japan.

Purpose This study aims to examine direct effects of qualified team gatekeepers on absorptive capacity (AC), and the mediating roles of combinative capabilities – knowledge integration capability (KIC) and interteam coordination. Design/methodology/approach A social networking analysis was used to analyze a unique data set collected from all members of 32 Japanese research and development (R&D) teams to identify key individuals who perform daily gatekeeping functions. This study analyzed the data through partial least squares structural equation modeling with higher-order latent variables. Finally, cross-validation tests were used with holdout samples to test the model’s predictive validity. Findings Qualified gatekeepers directly contribute to teams’ realized AC but not to their potential AC. Furthermore, qualified gatekeepers can improve their teams’ capability to absorb and exploit external knowledge by facilitating their capability to consolidate knowledge, that is, its KIC and interteam coordination. Originality/value Unlike prior research that asks top managers to identify team gatekeepers, this study used social network analysis to identify these vital individuals. This study provides a new framework indicating how qualified gatekeepers impact the AC of R&D teams through the examination of both the direct and indirect paths of gatekeeping abilities, two combinative capabilities as mediators and team AC.

Tumor cells generally require large amounts of nucleotides, and thus activate de novo purine synthesis ( dn PS). In the dn PS reactions, 10-formyltetrahydorofolate (10-fTHF) supplied by one-carbon metabolism is utilized as a formyl group donor. We focused on aldehyde dehydrogenase 1 family member L1 (ALDH1L1), which metabolizes 10-fTHF to tetrahydrofolate and whose expression is often attenuated in hepatocellular carcinoma (HCC). We generated ALDH1L1 -expressing HuH-7 cells to perform metabolome analysis and found that intracellular levels of serine were reduced and glycine was increased. In addition, 5-aminoimidazole-4-carboxamide ribonucleotide (ZMP), a dn PS intermediate, accumulated due to the consumption of 10-fTHF by ALDH1L1, which inhibited ZMP formylation. Importantly, ALDH1L1 -expressing cells showed reduced ZMP sensitivity and higher mitochondrial activity. The suppression of mitochondrial serine catabolism by ALDH1L1 expression was speculated to be closely related to this phenotype. Gene set enrichment analysis utilizing The Cancer Genome Atlas data revealed that genes related to oxidative phosphorylation were enriched in HCC patients with high ALDH1L1 expression. Moreover, drug sensitivity data analysis demonstrated that HCC cell lines with low expression of ALDH1L1 were sensitive to ZMP and cordycepin, a structural analog of ZMP and AMP. Our study revealed that ZMP and AMP analogs might be effective in the pharmacotherapy of HCC patients with low expression of ALDH1L1 .

Background and aims The aim of this study was to evaluate structural and functional alterations of human serum albumin (HSA), with a special focus on the oxidized and reduced forms, in patients with chronic liver disease. We also investigated whether oral branched-chain amino acid (BCAA) supplementation could induce structural changes and improve the functions of HSA. Methods The proportion of reduced and oxidized HSA was determined in 16 healthy controls and in 20 chronic hepatitis and 100 cirrhotic patients with stable conditions. To evaluate the functional properties of HSA, this study focused on the antioxidant and binding functions. The radical scavenging activity and binding ability of purified HSA were measured in 68 participants. After BCAA administration for 6 months, 29 patients were evaluated for HSA structural changes, with 19 out of the 29 patients also analyzed for HSA functional changes. Results There was a significant decrease in the amounts of reduced HSA in conjunction with liver disease progression. Receiver operating characteristic curve analysis demonstrated that the levels of reduced HSA had high accuracy in determining disease progression. Functional alterations were strongly correlated to the levels of reduced HSA. BCAA supplementation led to substantial increases in the amount of reduced HSA. The altered HSA was able to scavenge significantly more radicals and restore the binding ability. Conclusion This study describes structural alterations and functional disturbances of HSA in patients with chronic liver disease, and indicates that the levels of reduced HSA might reflect disease progression and the functional properties of HSA. Moreover, oral BCAA supplementation increases the amount of reduced HSA, thereby leading to the restoration of HSA function in cirrhotic patients.

Mutations in isocitrate dehydrogenases IDH1 and IDH2 are common in human gliomas and acute myeloid leukaemias; here, mice that carry the IDH1(R132H) mutation are described, in a new model that should help in investigating the links between mutant IDH1 and leukaemia. An IDH1 –mutant-mouse leukaemia model Mutations in the IDH1 and IDH2 genes, which encode isocitrate dehydrogenases, are frequently found in human glioblastomas and acute myeloid leukaemias. These mutations drive the synthesis of the metabolite R-2-hydroxyglutarate (2HG), which inhibits enzymes that regulate levels of DNA and histone methylation. Here, Tak Mak and colleagues characterize conditional knock-in mice of the most common IDH1 mutation, IDH1–R132H , expressed in haematopoietic cells. The mutant mice have increased numbers of early haematopoietic progenitors and develop splenomegaly, anaemia and extramedullary haematopoiesis. Furthermore, cells exhibit changes in patterns of DNA and histone methylation that are similar to those observed in human IDH1/2 -mutant acute myeloid leukaemias. This mouse model should be useful for the study of mechanistic links between mutant IDH1 and leukaemia. Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas 1 and cytogenetically normal acute myeloid leukaemias (AML) 2 . These alterations are gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG) 3 . It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2 -mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.

Mps one binder 1a (MOB1A) and MOB1B are key components of the Hippo signaling pathway and are mutated or inactivated in many human cancers. Here we show that intact Mob1a or Mob1b is essential for murine embryogenesis and that loss of the remaining WT Mob1 allele in Mob1a(Δ/Δ)1b(tr/+) or Mob1a(Δ/+)1b(tr/tr) mice results in tumor development. Because most of these cancers resembled trichilemmal carcinomas, we generated double-mutant mice bearing tamoxifen-inducible, keratinocyte-specific homozygous-null mutations of Mob1a and Mob1b (kDKO mice). kDKO mice showed hyperplastic keratinocyte progenitors and defective keratinocyte terminal differentiation and soon died of malnutrition. kDKO keratinocytes exhibited hyperproliferation, apoptotic resistance, impaired contact inhibition, enhanced progenitor self renewal, and increased centrosomes. Examination of Hippo pathway signaling in kDKO keratinocytes revealed that loss of Mob1a/b altered the activities of the downstream Hippo mediators LATS and YAP1. Similarly, YAP1 was activated in some human trichilemmal carcinomas, and some of these also exhibited MOB1A/1B inactivation. Our results clearly demonstrate that MOB1A and MOB1B have overlapping functions in skin homeostasis, and exert their roles as tumor suppressors by regulating downstream elements of the Hippo pathway.

Background Lenvatinib is a novel tyrosine kinase inhibitor that exhibits an antitumor effect on hepatocellular carcinoma (HCC). An established strategy that involves surgery and usage of lenvatinib for advanced HCC remains elusive. Case presentation A 58-year-old male patient with advanced HCC and untreated hepatitis B was referred to our hospital. The tumor at the right lobe was 10 cm in diameter with right portal vein thrombus. Because of the possible lung metastasis and concern about the remaining hepatic function after extended right hepatectomy, lenvatinib was initiated before surgery. After the confirmation of a sharp decrease of tumor markers during the 3-week lenvatinib therapy, only a right portal vein transection was done leaving the enlargement of the left lobe for improved post-hepatectomy liver function while lenvatinib therapy was continued. The laparotomy revealed that the tumor was invading the right diaphragm. After 7 weeks of lenvatinib administration after right portal vein transection, an extended right hepatectomy with resection of the tumor-invaded diaphragm was successfully done. The lung nodules that were suspected as metastases had disappeared. The patient has been doing well without any sign of recurrence for 1 year. Conclusion The strategy involving the induction of lenvatinib to conversion hepatectomy including the portal vein transection was effective for advanced HCC.

MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) are protein-serine/threonine kinases that are activated by ERK or p38 and phosphorylate eIF4E, which is involved in cap-dependent translation initiation. However, Mnk1/2 double knockout (Mnk-DKO) mice show normal cell growth and development despite an absence of eIF4E phosphorylation. Here we show that the tumorigenesis occurring in the Lck-Pten mouse model (referred to here as tPten⁻ / ⁻ mice) can be suppressed by the loss of Mnk1/2. Phosphorylation of eIF4E was greatly enhanced in lymphomas of parental tPten⁻ / ⁻ mice compared with lymphoid tissues of wild-type mice, but was totally absent in lymphomas of tPten⁻ / ⁻; Mnk-DKO mice. Notably, stable knockdown of Mnk1 in the human glioma cell line U87MG resulted in dramatically decreased tumor formation when these cells were injected into athymic nude mice. Our data demonstrate an oncogenic role for Mnk1/2 in tumor development, and highlight these molecules as potential anticancer drug targets that could be inactivated with minimal side effects.

Sodium‐glucose co‐transporter 2 (SGLT2) inhibitors have demonstrated blood pressure (BP)‐lowering effects; however, most studies included patients taking antihypertensive medications. Using real‐world Japanese data, we assessed factors associated with SGLT2 inhibitor‐mediated BP reduction in patients not taking antihypertensive therapy. After excluding those taking antihypertensive medications, we retrospectively analyzed 6,988 patients newly prescribed SGLT2 inhibitors (2014‒2023). BP was evaluated using health check‐up data before and after SGLT2 inhibitor prescription. The mean patient age was 61.6 years, and 66.8% were male. Systolic/diastolic BP were reduced by 2.3±7.6/2.3±8.4%, respectively, following SGLT2 inhibitor initiation. Multiple regression analysis identified baseline systolic BP as the strongest predictor (R 2 = 8.83%), while BMI change was substantially associated with SBP reduction (R 2 = 2.76%). Compared with a propensity score‐matched cohort of DPP‐4 inhibitor new users, greater BP reduction was observed in the SGLT2 inhibitor group, with differences of 2.3%/2.1% for systolic/diastolic BP. An ≈2% BP reduction may occur following SGLT2 inhibitor initiation.

Cell growth demands new protein synthesis, which requires nucleolar ribosomal functions. Ribosome biogenesis consumes a large proportion of the cell's resources and energy, and so is tightly regulated through an intricate signaling network to guarantee fidelity. Thus, events that impair ribosome biogenesis cause nucleolar stress. In response to this stress, several nucleolar ribosomal proteins (RPs) translocate to the nucleoplasm and bind to MDM2. MDM2‐mediated ubiquitination and degradation of the tumor suppressor p53 is then blocked, resulting in p53 accumulation and the induction of p53‐dependent cell cycle arrest and apoptosis. Nucleolar stress is therefore a quality control surveillance mechanism that monitors the synthesis and assembly of the rRNA and protein components of ribosomes. Although nucleolar stress signaling pathways have been extensively analyzed, critical questions remain about their regulatory mechanisms. For example, how do RPs translocate from the nucleolus to the nucleoplasm to exert their functions, and do these p53‐regulating RPs influence the prognosis of human cancer patients? Our laboratory recently identified the nucleolar protein PICT1 as a novel regulator of nucleolar stress. PICT1 sequesters the ribosomal protein RPL11 in the nucleolus, preventing it from binding to MDM2. MDM2 is then free to degrade p53, favoring tumor cell growth. Accordingly, the level of PICT1 in a tumor is becoming a useful prognostic marker for human cancers. This review summarizes the evidence that links nucleolar stress to tumorigenesis, and casts PICT1 as an oncogenic player in human cancer biology. (Cancer Sci 2012; 103: 632–637)