GAS41 promotes H2A.Z deposition through recognition of the N terminus of histone H3 by the YEATS domain.

Glioma amplified sequence 41 (GAS41), which has the Yaf9, ENL, AF9, Taf14, and Sas5 (YEATS) domain that recognizes lysine acetylation (Kac), regulates gene expression as a subunit of the SRCAP (SNF2-related CREBBP activator protein) complex that deposits histone H2A.Z at promoters in eukaryotes. The YEATS domains of the proteins AF9 and ENL recognize Kac by hydrogen bonding the aromatic cage to arginine situated just before K9ac or K27ac in the N-terminal tail of histone H3. Curiously, the YEATS domain of GAS41 binds most preferentially to the sequence that contains K14ac of H3 (H3K14ac) but lacks the corresponding arginine. Here, we biochemically and structurally elucidated the molecular mechanism by which GAS41 recognizes H3K14ac. First, stable binding of the GAS41 YEATS domain to H3K14ac required the N terminus of H3 (H3NT). Second, we revealed a pocket in the GAS41 YEATS domain responsible for the H3NT binding by crystallographic and NMR analyses. This pocket is away from the aromatic cage that recognizes Kac and is unique to GAS41 among the YEATS family. Finally, we showed that E109 of GAS41, a residue essential for the formation of the H3NT-binding pocket, was crucial for chromatin occupancy of H2A.Z and GAS41 at H2A.Z-enriched promoter regions. These data suggest that binding of GAS41 to H3NT via its YEATS domain is essential for its intracellular function.

CD271 promotes proliferation and migration in bladder cancer.

Bladder cancer is a urothelial cancer and effective therapeutic strategies for its advanced stages are limited. Here, we report that CD271, a neurotrophin receptor, promotes the proliferation and migration of bladder cancer cells. CD271 knockdown decreased proliferation in both adherent and spheroid cultures, and vice versa when CD271 was overexpressed in bladder cancer cell lines. CD271 depletion impaired tumorigenicity in vivo. Migration activity was reduced by CD271 knockdown and TAT-Pep5, a known CD271-Rho GDI-binding inhibitor. Apoptosis was induced by CD271 knockdown. Comprehensive gene expression analysis revealed alterations in E2F- and Myc-related pathways upon CD271 expression. In clinical cases, patients with high CD271 expression showed significantly shortened overall survival. In surgically resected specimens, pERK, a known player in proliferation signaling, colocalizes with CD271. These data indicate that CD271 is involved in bladder cancer malignancy by promoting cell proliferation and migration, resulting in poor prognosis.

Identification rate of Legionella species in non-purulent sputum culture is comparable to that in purulent sputum culture in Legionella pneumonia.

Many Legionella pneumonia patients do not produce sputum, and it is unknown whether purulent sputum is required for the identification of Legionella species. This study aimed to evaluate the identification rate of Legionella species based on sputum quality and the factors predictive of Legionella infection. This study included Legionella pneumonia patients at Kurashiki Central Hospital from November 2000 to December 2022. Sputum quality, based on gram staining, was classified as the following: Geckler 1/2, 3/6 and 4/5. Geckler 4/5 was defined as purulent sputum. The sputa of 104 of 124 Legionella pneumonia patients were cultured. Fifty-four patients (51.9%) were identified with Legionella species, most of which were Legionella pneumophila serogroup 1 (81.5%). The identification rates of Legionella species according to sputum quality were 57.1% (16/28) in Geckler 1/2 sputum, 50.0% (34/68) in Geckler 3/6 sputum, and 50.0% (4/8) in Geckler 4/5 sputum, which were not significantly different (P = 0.86). On multivariate analysis, pre-culture treatment with anti-Legionella antimicrobials (odds ratio [OR] 0.26, 95% confidence interval [CI] 0.06-0.91), Pneumonia Severity Index class ≥IV (OR 2.57 [95% CI 1.02-6.71]), and intensive care unit admission (OR 3.08, 95% CI 1.06-10.09) correlated with the ability to identify Legionella species, but sputum quality did not (OR 0.88, 95% CI 0.17-4.41). The identification rate of Legionella species in non-purulent sputum was similar to that in purulent sputum. For the diagnosis of Legionella pneumonia, sputum should be collected before administering anti-Legionella antibiotics and cultured regardless of sputum quality.

Intravenously engrafted human multilineage-differentiating stress-enduring (Muse) cells rescue erectile function after rat cavernous nerve injury.

OBJECTIVE: To evaluate the effect of intravenous administration of human multilineage-differentiating stress-enduring (Muse) cells on rat postoperative erectile dysfunction (ED) with cavernous nerve (CN) injury without an immunosuppressant. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomised into three groups after CN crush injury. Either human-Muse cells, non-Muse mesenchymal stem cells (MSCs) (both 1.0 × 105 cells), or vehicle was infused intravenously at 3 h after CN injury without immunosuppressant. Erectile function was assessed by measuring intracavernous pressure (ICP) and arterial pressure (AP) during pelvic nerve electrostimulation 28 days after surgery. At 48 h and 28 days after intravenous infusion of Muse cells, the homing of Muse cells and non-Muse MSCs was evaluated in the major pelvic ganglion (MPG) after CN injury. In addition, expressions of C-X-C motif chemokine ligand (Cxcl12) and glial cell line-derived neurotrophic factor (Gdnf) in the MPG were examined by real-time polymerase chain reaction. Statistical analyses and comparisons among groups were performed using one-way analysis of variance followed by the Tukey test for parametric data and Kruskal-Wallis test followed by the Dunn-Bonferroni test for non-parametric data. RESULTS: The mean (SEM) ICP/AP values at 28 days were 0.51 (0.02) in the Muse cell group, 0.37 (0.03) in the non-Muse MSC group, and 0.36 (0.04) in the vehicle group, showing a significant positive response in the Muse cell group compared with the non-Muse and vehicle groups (P = 0.013 and P = 0.010, respectively). In the MPG, Muse cells were observed to be engrafted at 48 h and expressed Schwann cell markers S100 (~46%) and glial fibrillary acidic protein (~24%) at 28 days, while non-Muse MSCs were basically not engrafted at 48 h. Higher gene expression of Cxcl12 (P = 0.048) and Gdnf (P = 0.040) was found in the MPG of the Muse group than in the vehicle group 48 h after infusion. CONCLUSION: Intravenously engrafted human Muse cells recovered rat erectile function after CN injury in a rat model possibly by upregulating Cxcl12 and Gdnf.

Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease treatment.

The discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC50 = 0.024 µM). X-ray crystallography for the ligand-protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of γ-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner.

Statin administration ameliorates ischemia-induced overactive bladder with improvement of blood flow and anti-inflammatory effects in rats.

AIMS: Statins are widely used to treat dyslipidemia and have been shown to reduce the risk of ischemic heart disease and cerebrovascular disease. The effects of statins on ischemia-induced overactive bladder (OAB) and the associated mechanisms were investigated in a rat model of chronic pelvic ischemia. METHODS: A pelvic ischemia model was created by iliac arterial injury (AI) and a high-fat diet using male Sprague-Dawley rats. Rats were assigned to 3 groups: control group, AI group, and AI + statin group. The control group underwent sham operation and was fed a normal diet. The AI group underwent AI surgery and was fed a high-cholesterol diet. The AI + statin group was administered a statin for 4 weeks. Cystometry was performed for 8 weeks after surgery. Blood flow was evaluated by laser meter. Thickness of the iliac arteries was measured, and microvascular density in the lamina propria was evaluated by immunostaining for CD31. Expressions of inflammatory cytokines in the bladder were measured by real-time PCR. RESULTS: Cystometry showed a significantly shorter voiding interval and lower bladder capacity in the AI group than in the control group. The AI + statin group showed improvement of these findings. The AI group showed decreased bladder blood flow, increased iliac arterial wall thickening, and decreased microvascular density compared to the control group. Statin administration improved blood flow. Iliac arterial wall thickening was suppressed, and microvascular density was increased by statin administration, though not significantly. Real-time PCR showed significantly higher expressions of inflammatory cytokines (IL-6, IL-8, and TNF-α) in the AI group than in the control group, and IL-6 and IL-8 expressions were lower in the AI + statin group than in the AI group. CONCLUSIONS: The present results suggest that statins are effective in OAB caused by arteriosclerosis and ischemia. The mechanism of their effects involves improved bladder blood flow and decreased bladder inflammation.

Robotic versus open and laparoscopic pelvic exenterations for pelvic cancer: a multicenter propensity-matched analysis in Japan.

BACKGROUND: Pelvic exenteration (PE) is the last resort for achieving a complete cure for pelvic cancer; however, it is burdensome for patients. Minimally invasive surgeries, including robot-assisted surgery, have been widely used to treat malignant tumors and have also recently been used in PE. This study aimed to evaluate the safety and efficacy of robot-assisted PE (RPE) by comparing the outcomes of open PE (OPE) with those of conventional laparoscopic PE (LPE) for treating pelvic tumors. METHODS: Following the ethics committee approval, a multicenter retrospective analysis of patients who underwent pelvic exenteration between January 2012 and October 2022 was conducted. Data on patient demographics, tumor characteristics, and perioperative outcomes were collected. A 1:1 propensity score-matched analysis was performed to minimize group selection bias. RESULTS: In total, 261 patients met the study criteria, of whom 61 underwent RPE, 90 underwent OPE, and 110 underwent LPE. After propensity score matching, 50 pairs were created for RPE and OPE and 59 for RPE and LPE. RPE was associated with significantly less blood loss (RPE vs. OPE: 408 mL vs. 2385 ml, p < 0.001), lower transfusion rate (RPE vs. OPE: 32% vs. 82%, p < 0.001), and lower rate of complications over Clavien-Dindo grade II (RPE vs. OPE: 48% vs. 74%, p = 0.013; RPE vs. LPE: 48% vs. 76%, p = 0.002). CONCLUSION: This multicenter study suggests that RPE reduces blood loss and transfusion compared with OPE and has a lower rate of complications compared with OPE and LPE in patients with locally advanced and recurrent pelvic tumors.

Three cases of hospitalized Legionella pneumonia patients successfully treated with lascufloxacin.

Legionella pneumonia is one of the major causes of severe pneumonia, in which treatment delay might lead to a poor prognosis. Therefore, as far as possible, early diagnosis and treatment of Legionella pneumonia is essential. Regarding the antimicrobials for Legionella pneumonia, fluoroquinolones, such as levofloxacin, or macrolides, such as azithromycin (AZM), are recommended in Japan and other countries. Lascufloxacin (LSFX), the newest fluoroquinolone developed in Japan, has been in use in daily clinical practice since January 2020. However, there are only few reports of Legionella pneumonia cases treated with LSFX. Here, we report three cases of hospitalized Legionella pneumonia patients that were successfully treated using LSFX. All three patients were admitted to the medical ward on admission, although one patient was subsequently transferred to the ICU for mechanical ventilatory management due to worsening of the pneumonia on day 3. All patients improved and were discharged following LSFX treatment (the patient admitted to the ICU was treated using LSFX + AZM combination therapy) without any severe adverse events. LSFX might be considered to be the first antibiotic choice for Legionella pneumonia, similar to levofloxacin. However, further data regarding the treatment of Legionella pneumonia cases using LSFX are needed to evaluate its efficacy and safety.

Development of an Artificial Nucleic Acid Skeleton Allowing for Unnatural-Type Triplex DNA Formation with Duplex DNA Having a TA Inversion Site.

Triplex DNA formation has generated much interest as a genomic targeting tool that directly targets duplex DNA. However, fundamental limitations in the base pairs of target duplex DNA sequences that can form stable triplex DNA have limited the application. Recently, we have reported on the recognition of CG and 5mCG base pairs by artificial nucleic acid derivatives with a 2'-deoxynebularine skeleton. Therefore, we attempted to explore the basic skeleton that is important for the development of new artificial nucleic acids allowing for the recognition of TA base pairs. In this study, we focused on a benzimidazole skeleton and introduced a hydroxyl group to enable one-point hydrogen bonding. We have synthesized artificial nucleoside analogues with hydroxyl group on the benzimidazole and incorporated their amidite derivatives into triplex forming oligonucleotides (TFOs). The gel shift assay was performed to evaluate the triplex DNA formation ability of synthesized TFOs, and TFOs containing hydroxybenzimidazole were successfully recognized TA base pairs for all four different sequences. Moreover, compared to the results for the TFOs containing benzimidazole, which suggested hydrogen bonding formation at the hydroxyl group. Therefore, hydroxybenzimidazole would be an important artificial nucleic acid skeleton for TA base pair recognition.

Prostate-specific antigen follow-up and management for patients undergoing holmium laser enucleation of the prostate.

OBJECTIVES: To investigate who needs a careful postoperative monitoring for prostate cancer (PCa) after holmium laser enucleation of the prostate (HoLEP). We examined characteristics and oncological outcomes of HoLEP-related PCa. METHODS: Patients who underwent HoLEP during 2002-2017 in a Japanese tertiary center were retrospectively analyzed. Patients were divided into non-PCa, PCa with HoLEP specimen (PCa-Ope), and PCa diagnosed during follow-up (PCa-Post). Outcomes of all HoLEP-related PCa were monitored. RESULTS: Of the total 758, 60 (7.9%) were diagnosed with PCa from resected specimen of HoLEP and 9 (1.2%) were diagnosed postoperatively. Preoperative prostate-specific antigen (iPSA), postoperative PSA (pPSA), and PSA density were significantly higher in both PCa groups than those in non-PCa group. While iPSA significantly correlated to prostate volume (PV), pPSA was not associated with PV. A receiver-operating-characteristics curve demonstrated that pPSA 1.2 ng/mL achieved the optimal cut-off (AUC 0.95) for the incidence of PCa-Post. In addition to the incidence of PCa and iPSA, lower enucleation efficiency (enucleated volume /PV) was significantly associated with pPSA >1.2 ng/mL. Among PCa-Ope, 51 were Grade Group (GG) ≤2 and 42 were followed-up with active surveillance, whereas 8 of 9 PCa-Post were GG ≥3 and 2 progressed to death. CONCLUSIONS: Patients undergoing HoLEP are associated with some risk of potential PCa. While oncological outcomes were favorable among PCa-Ope, postoperative PSA should be carefully monitored even if not diagnosed with PCa with HoLEP specimen. Enucleation efficiency should be also considered not to misread pPSA value.

Wide-Targeted Semi-Quantitative Analysis of Acidic Glycosphingolipids in Cell Lines and Urine to Develop Potential Screening Biomarkers for Renal Cell Carcinoma.

Glycosphingolipids (GSLs), mainly located in the cell membrane, play various roles in cancer cell function. GSLs have potential as renal cell carcinoma (RCC) biomarkers; however, their analysis in body fluids is challenging because of the complexity of numerous glycans and ceramides. Therefore, we applied wide-targeted lipidomics using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with selected reaction monitoring (SRM) based on theoretical mass to perform a comprehensive measurement of GSLs and evaluate their potency as urinary biomarkers. In semi-quantitative lipidomics, 240 SRM transitions were set based on the reported/speculated structures. We verified the feasibility of measuring GSLs in cells and medium and found that disialosyl globopentaosylceramide (DSGb5 (d18:1/16:0)) increased GSL in the ACHN medium. LC-MS/MS analysis of urine samples from clear cell RCC (ccRCC) patients and healthy controls showed a significant increase in the peak intensity of urinary DSGb5 (d18:1/16:0) in the ccRCC group compared with that in the control group. Receiver operating characteristic analysis indicated that urinary DSGb5 could serve as a sensitive and specific marker for RCC screening, with an AUC of 0.89. This study demonstrated the possibility of urinary screening using DSGb5 (d18:1/16:0). In conclusion, urinary DSGb5 (d18:1/16:0) was a potential biomarker for cancer screening, which could contribute to the treatment of RCC patients.

Comparison of body composition and muscle mass by age in amateur soccer players.

[Purpose] This study aimed to elucidate the changes in body composition components associated with aging in amateur male soccer players. Specifically, we investigated the alterations in the phase angle and regional muscle mass distribution. [Participants and Methods] The study included a cohort of 163 male participants categorized into three age groups: U15 (12-15 years), U18 (16-18 years), and O19 (≥19 years). Precise body composition assessments were performed, employing the InBodyS10 body composition scale. [Results] The findings revealed substantial age-related disparities in various body composition parameters. Data revealed a consistent trend of increasing basic body composition metrics with age. Notably, the body fat percentage progressively increased with age. Muscle mass and phase angle exhibited age-related increases with nuanced variations in different anatomical regions. [Conclusion] In the general Japanese population, muscle mass tends to decrease with age after 18 years. However, in this study on amateur soccer players, we observed a plateau in the height and lower limb phase angle around the age of 18 years, whereas muscle mass exhibited an increasing trend.

Real-time monitoring of enzyme-catalyzed phosphoribosylation of anti-influenza prodrug favipiravir by time-lapse nuclear magnetic resonance spectroscopy.

Favipiravir (brand name Avigan), a widely known anti-influenza prodrug, is metabolized by endogenous enzymes of host cells to generate the active form, which exerts inhibition of viral RNA-dependent RNA polymerase activity; first, favipiravir is converted to its phosphoribosylated form, favipiravir-ribofuranosyl-5'-monophosphate (favipiravir-RMP), by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Because this phosphoribosylation reaction is the rate-determining step in the generation of the active metabolite, quantitative and real-time monitoring of the HGPRT-catalyzed reaction is essential to understanding the pharmacokinetics of favipiravir. However, assay methods enabling such monitoring have not been established. 19 F- or 31 P-based nuclear magnetic resonance (NMR) are powerful techniques for observation of intermolecular interactions, chemical reactions, and metabolism of molecules of interest, given that NMR signals of the heteronuclei sensitively reflect changes in the chemical environment of these moieties. Here, we demonstrated direct, sensitive, target-selective, nondestructive, and real-time observation of HGPRT-catalyzed conversion of favipiravir to favipiravir-RMP by performing time-lapse 19 F-NMR monitoring of the fluorine atom of favipiravir. In addition, we showed that 31 P-NMR can be used for real-time observation of the identical reaction by monitoring phosphorus atoms of the phosphoribosyl group of favipiravir-RMP and of the pyrophosphate product of that reaction. Furthermore, we demonstrated that NMR approaches permit the determination of general parameters of enzymatic activity such as Vmax and Km . This method not only can be widely employed in enzyme assays, but also may be of use in the screening and development of new favipiravir-analog antiviral prodrugs that can be phosphoribosylated more efficiently by HGPRT, which would increase the intracellular concentration of the drug's active form. The techniques demonstrated in this study would allow more detailed investigation of the pharmacokinetics of fluorinated drugs, and might significantly contribute to opening new avenues for widespread pharmaceutical studies.

Improving reactivity of naphthalimide-based GST probe by imparting TPP cation: Development and application for live cell imaging.

Glutathione S-transferases (GSTs) are a superfamily of multifunctional enzymes comprising multiple classes and subtypes. This paper describes the synthesis and characterization of TPPBN-1, a naphthalimide derivative conjugated with a triphenylphosphonium (TPP) cation. When 4-bromonaphthalimide (BrNaph), a previously characterized GST substrate, was conjugated to a TPP cation, the conjugate showed increased reactivity towards most alpha- and mu-class GSTs, particularly the GSTA2 subtype, compared to the parent compound, but hardly towards Pi-class GSTs. Using this probe with enhanced reactivity, the enzymatic activity of endogenous GSTA1/2 in HepG2 cells was visualized by confocal fluorescence microscopy. The results demonstrated that modification with TPP cations, which are often used as tags for targeting mitochondria, can be used to enhance the reactivity of probes for specific GST subtypes.

An algorithm for PCT-guided antimicrobial therapy: a consensus statement by Japanese experts.

In Japan, a national antimicrobial resistance (AMR) action plan was adopted in 2016, advocating a 20% reduction in antibiotic consumption by 2020. However, there is still room for improvement to accomplish this goal. Many randomized controlled trials have reported that procalcitonin (PCT)-guided antimicrobial therapy could help to reduce antibiotic consumption without negative health effects, specifically in acute respiratory infections. In September 2018, some experts in Europe and the USA proposed algorithms for PCT-guided antimicrobial therapy in mild to moderate infection cases outside the ICU and severe cases in the ICU (the international experts consensus). Thereafter, a group of Japanese experts, including specialists in intensive care medicine, emergency medicine, respiratory medicine and infectious diseases, created a modified version of a PCT-guided algorithm (Japanese experts consensus). This modified algorithm was adapted to better fit Japanese medical circumstances, since PCT-guided therapy is not widely used in daily clinical practice in Japan. The Japanese algorithm has three specific characteristics. First, the target patients are limited to only hospitalized ICU or non-ICU patients. Second, pneumonia due to Pseudomonas aeruginosa, Staphylococcus aureus and Legionella species are excluded. Finally, a different timing of PCT follow-up measurement was proposed to meet restrictions of the Japanese medical insurance system. The adapted algorithms has high potential to further improve the safe reduction in antibiotic consumption in Japan, while reducing the spread of AMR pathogens.

Ectopic endometriosis in the pelvic cavity evokes bladder hypersensitivity via transient receptor potential ankyrin 1 hyperexpression in rats.

INTRODUCTION AND HYPOTHESIS: In women with chronic pelvic pain (CPP), interstitial cystitis/bladder pain syndrome (IC/BPS) and endometriosis frequently coexist. The mechanism of these diseases coexisting is explained by cross-sensitization between endometriosis and IC/BPS. The overlapped symptoms may be related to cross-sensitization with transient receptor potential vanilloid 1 (TRPV1) and/or transient receptor potential ankyrin 1 (TRPA1) hyperexpression. This study was aimed at exploring whether bladder hypersensitivity is evoked in the surgically induced ectopic endometriosis rat and whether TRPV1 and/or TRPA1 play a vital role. METHODS: A total of 63 Sprague-Dawley female rats were divided into two groups, 39 for physiological examination and 24 for molecular analysis. Surgical induction of ectopic endometriosis (ENDO, n=27), surgical sham treatment (n=18), and treatment for endometriosis by GnRH analog (ENDO-G) (n=18) were performed. Bladder function was investigated by cystometry (for TRPV1 in the sham [n=6] and ENDO [n=9] groups and for TRPA1 in the sham [n=6], ENDO [n=9], and ENDO+G [n=9] groups), and TRPV1 and TRPA1 mRNA expressions were measured using real-time qPCR in the bladder and dorsal root ganglia (DRGs). RESULTS: On cystometry, the relative intercontraction interval (ICI) after/before resiniferatoxin (RTx; TRPV1 activator) infusion to the bladder showed no significant difference between the two groups, whereas relative ICI after/before allyl isothiocyanate (AITC; TRPA1 activator) infusion was significantly lower in the ENDO group than in the sham group. TRPA1 mRNA expression in the bladder and L5 DRG was considerably higher in the ENDO group than in the sham group on real-time qPCR. TRPA1 mRNA hyperexpression and bladder hypersensitivity after AITC infusion were reduced in the ENDO-G group. CONCLUSIONS: Bladder cross-sensitization in ENDO rats occurs in association with hyperexpression of TRPA1 at both the DRG and the bladder mucosa. This can be understood by the "cross-sensitization of endometriosis to bladder" theory explaining overlapping symptoms among BPS/IC and ectopic endometriosis.

Relationship between Total Kihon Checklist Score and Age-Specific Deaths among Late-Stage Older Adults in Otawara City (Aged 75 and Older) over a 15-Year Period.

INTRODUCTION: While the Japanese long-term care insurance system supports an ageing society, there are concerns about the shortage of financial resources and labour force. Further, extending healthy life expectancy and narrowing the gap with the average life expectancy are important issues. In this study, we aimed to examine, over a 15-year period, the relationship between the total Kihon Checklist (t-KCL) score and age-specific deaths among late-stage older adults aged 75 and older who were not certified for long-term care insurance. METHODS: The participants were older adults residing in Otawara City, Tochigi Prefecture, who were aged 75 years or older as of 2006. The participants, who were not certified by the long-term care insurance system, were asked to complete the KCL by a community welfare committee member. Based on their t-KCL scores, the participants were classified as robust (0-3 points), pre-frail (4-7 points), and frail (≥8 points). The deaths of those aged 75-89 years who had completed the KCL were investigated. Information on deaths was obtained from local authorities. Statistics were examined for the risk of robust, pre-frail, and frail mortality using a Cox proportional hazards model with age and gender as covariates for the 75-79, 80-84, and 85-89 age groups. RESULTS: Of the 7,924 participants, 3,423 (75-79 years: 1,990, 80-84 years: 1,059, 85-89 years: 374) were ultimately eligible for the study. Of these, 2,450 (75-79 years: 1,238, 80-84 years: 861, 85-89 years: 351) died over the 15-year study period. Hazard ratios for death in frailty as determined by the t-KCL score were 1.337 (95% confidence interval [CI], 1.162-1.540) for the pre-frail group and 2.012 (95% CI, 1.7756-2.305) for the frail group at 75-79 years, respectively, compared with the robust group; 1.511 (95% CI, 1.271-1.797) at 80-84 years only in the frail group; and 1.567 (95% CI, 1.140-2.154) at 85-89 years, also in the frail group. DISCUSSION: The relationship between frailty and mortality weakens after age 80. The results suggest that factors other than frailty may have a stronger influence on mortality risk after the age of 80.

Identification of a derivative of the alkaloid emetine as an inhibitor of the YAP-TEAD interaction and its potential as an anticancer agent.

TEAD is a transcription factor responsible for the output of the tumor suppressor Hippo pathway. The transcriptional activity of TEAD requires molecular interaction with its transcriptional coactivator, YAP. Aberrant activation of TEAD is deeply involved in tumorigenesis and is associated with poor prognosis, suggesting that inhibitors targeting the YAP-TEAD system are promising as antitumor agents. In this study, we identified NPD689, an analog of the natural product alkaloid emetine, as an inhibitor of the YAP-TEAD interaction. NPD689 suppressed the transcriptional activity of TEAD and reduced the viability of human malignant pleural mesothelioma and non-small cell lung cancer cells but not the viability of normal human mesothelial cells. Our results suggest that NPD689 is not only a new useful chemical tool for elucidating the biological role of the YAP-TEAD system but also has potential as a starting compound for developing a cancer therapeutic agent that targets the YAP-TEAD interaction.

Short-course remdesivir for healthcare-associated COVID-19: Case series from a non-acute care hospital.

Healthcare-associated COVID-19 among vulnerable patients leads to disproportionate morbidity and mortality. Early pharmacologic intervention may reduce negative sequelae and improve survival in such settings. This study aimed to describe outcome of patients with healthcare-associated COVID-19 who received early short-course remdesivir therapy. We reviewed the characteristics and outcome of hospitalized patients who developed COVID-19 during an outbreak that involved two wards at a non-acute care hospital in Japan and received short-course remdesivir. Forty-nine patients were diagnosed with COVID-19, 34 on a comprehensive inpatient rehabilitation ward and 15 on a combined palliative care and internal medicine ward. Forty-seven were symptomatic and 46 of them received remdesivir. The median age was 75, and the median Charlson comorbidity index was 6 among those who received it. Forty-one patients had received one or two doses of mRNA vaccines, while none had received a third dose. Most patients received 3 days of remdesivir. Of the patients followed up to 14 and 28 days from onset, 41/44 (95.3%) and 35/41(85.4%) were alive, respectively. Six deaths occurred by 28 days in the palliative care/internal medicine ward and two of them were possibly related to COVID-19. Among those who survived, the performance status was unchanged between the time of onset and at 28 days.

Preoperative prognostic model for localized and locally advanced renal cell carcinoma: Michinoku Japan Urological Cancer Study Group.

BACKGROUND: The Modified International Metastatic Renal Cell Carcinoma Dataset Consortium model (mIMDC) is a preoperative prognostic model for pT3cN0M0 renal cell carcinoma (RCC). This study aimed to validate the mIMDC and to construct a new model in a localized and locally advanced RCC (LLRCC). METHODS: A database was established (the Michinoku Japan Urological Cancer Study Group database) consisting of 79 patients who were clinically diagnosed with LLRCC (cT3b/c/4NanyM0) and underwent radical nephrectomy from December 2007 to May 2018. Using univariable and multivariable analyses, we retrospectively analyzed disease-free survival (DFS) and overall survival (OS) in this database, constructed a new prognostic model according to these results, and estimated the model fit using c-index on the new and mIMDC models. RESULTS: Independent poorer prognostic factors for both DFS and OS include the following: ≥ 1 Eastern Cooperative Oncology Group performance status, 2.0 mg/dL C-reactive protein, and > upper normal limit of white blood cell count. The median DFS in the favorable (no factor), intermediate (one factor), and poor-risk group (two or three factors) was 76.1, 14.3, and 4.0 months, respectively (P < 0.001). The 3-year OS in the favorable, intermediate, and poor-risk group were 92%, 44%, and 0%, respectively (P < 0.001). The c-indices of the new and mIMDC models were 0.67 and 0.60 for DFS (P = 0.060) and 0.74 and 0.63 for OS (P = 0.012), respectively. CONCLUSION: The new preoperative prognostic model in LLRCC can be used in patient care and clinical trials.