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The skin plays a protective role against harmful environmental stress such as ultraviolet rays. Therefore, the skin is constantly exposed to potential injuries, and wound healing is a vital process for the survival of all higher organisms. Wound healing is dependent on aging and metabolic status at a whole-body level. Because the forkhead box O (FOXO) family plays a role in aging and metabolism, we investigated the molecular functions of FOXO3a in skin wound healing using FoxO3a -/- mice. We observed that FoxO3a -/- mice showed accelerated skin wound healing. During wound healing, more fibroblasts accumulated at the wound edges and migrated into the wound bed in FoxO3a -/- mice. Moreover, cell migration of dermal fibroblasts isolated from FoxO3a -/- mice was significantly induced. During the in vitro cell migration, we observed accelerated mitochondrial fragmentation and decreased oxygen consumption in the mitochondria of FoxO3a -/- fibroblasts. These changes were caused by the upregulation of mitochondrial Rho GTPase 1 (Miro1), which is an essential mediator of microtubule-based mitochondrial motility. Miro1 inhibition significantly attenuated cell migration, mitochondrial fragmentation, and mitochondrial recruitment to the leading edge of the cells. These data indicate that FoxO3a plays a crucial role in wound healing by regulating mitochondrial dynamics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Endoscopic papillectomy (EP) is a low-invasive treatment for duodenal tumors including papilla. The limit of lesion size and local recurrence have been issues in EP. We developed endoscopic submucosal dissection (ESD) for the duodenal tumors including papilla (ESDIP: ESD including papilla) to overcome the problems. The aim of this study was to evaluate the feasibility of ESDIP., Methods: We included the patients who underwent ESDIP from August 2010 to January 2024 in this study. We evaluated the retrospective characteristics of patients and lesions, clinical results of ESDIP and of endoscopic retrograde cholangiopancreatography (ERCP) as prevention for delayed adverse events, and pathological findings. We also calculated the cumulative recurrence rate and overall survival rate at 12 months after ESDIP., Results: Fifty-four patients were included in this study. The mean lesion size was 39 mm. The third-quarter cases revealed a less than half-circumferential lesion, and the one case with a full-circumferential lesion. Resection was accomplished in 96% (n = 52), and also the en-bloc resection rate was 96%. Of the cases in accomplished resection, 98% of patients were intubated with a pancreaticobiliary drainage tube by ERCP. Intraprocedural perforation occurred in eight cases. Delayed bleeding occurred in 10 cases. Delayed perforation was seen only in one case. The incidence of post-ERCP pancreatitis was 25%. Cumulative local recurrence rate and the overall survival rate were 15% and 96%, respectively., Conclusion: ESDIP may be feasible for duodenal tumors including papilla, and is a potential alternative option to avoid pancreaticoduodenectomy., (© 2024 Japan Gastroenterological Endoscopy Society.)

Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease and highly prevalent worldwide. NASH is characterized by hepatic steatosis, inflammation, fibrosis and liver damage, which eventually results in liver dysfunction due to cirrhosis or hepatocellular carcinoma. However, the cellular and molecular mechanisms underlying NASH progression remain largely unknown. Here, we found an increase of Nr4a family of orphan nuclear receptors expression in intrahepatic T cells from mice with diet-induced NASH. Loss of Nr4a1 and Nr4a2 in T cell (dKO) ameliorated liver cell death and fibrosis, thereby mitigating liver dysfunction in NASH mice. dKO resulted in reduction of infiltrated macrophages and Th1/Th17 cells, whereas massive accumulation of T regulatory (Treg) cells in the liver of NASH mice. Combined single-cell RNA transcriptomic and TCR sequencing analysis revealed that intrahepatic dKO Tregs exhibited enhanced TIGIT and IL10 expression and were clonally expanded during NASH progression. Mechanistically, we found that dKO Tregs expressed high levels of Batf which promotes Treg cell proliferation and function upon TCR stimulation. Collectively, our findings not only provide an insight into the impact of intrahepatic Treg cells on NASH pathogenesis, but also suggest a therapeutic potential of targeting of Nr4a family to treat the disease.

Myxedema coma is a rare life-threatening form of hypothyroidism that manifests as neuropsychiatric, metabolic, respiratory, and cardiovascular dysfunction. From 2010 to 2022, our hospital managed three cases of myxedema coma. While the overall characteristics of these cases were similar to those in previous reports, we noticed that all cases were negative for thyroid autoantibodies and an autopsy in one of the cases exhibited end-stage thyroiditis. During a systematic review of cases from 1999 to 2022, we also noticed that a significant proportion of myxedema coma was caused by seronegative primary hypothyroidism especially in Japan., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Yosuke Okuno et al.)

Poly(amic ‍acid) ‍nanoparticles ‍prepared ‍by ‍‍precipitation ‍polymerization with a dispersant were evaluated by small-angle X-ray scattering (SAXS) and field-emission scanning electron microscopy (FE-SEM). The particle size evaluation of poly(amic acid) nanoparticles in the liquid phase by SAXS was performed to gain insight into the size control of poly(amic acid) nanoparticles, and showed good agreement with visual observation by FE-SEM, explaining the effect of the dispersant in obtaining polyimide nanoparticles with small particle size. This indicates that the particle size is maintained without change during the solvent evaporation process. The polyamide nanoparticles controlled by the dispersant effect maintained their size after imidization, and polyimide nanoparticles with a minimum radius of about 60 nm were prepared., Competing Interests: We declare we have no competing interests., (© 2024 The Authors.)

Objectives: This study was conducted to verify the effectiveness of Anterior Support Screw (AS2) for unstable femoral trochanteric fractures., Design: A multicenter, prospective, randomized controlled trial SETTING: This study was conducted across 15 academic medical centers in Japan PATIENTS/PARTICIPANTS: We enrolled 240 cases of femoral trochanteric fractures with posterior crushing and intramedullary displacement of proximal bone fragments across 15 institutions in Japan., Intervention: All patients were subjected to a reduction in which the anterior cortex was brought into contact. The patients were randomly assigned to the anterior support screw group (AS2 group) and the non-screw group (control group)., Main Outcome Measurements: Two computed-tomography (CT) scans were taken immediately after surgery and early postoperative period (day 14-21) to investigate the reduction loss rate of the anterior cortex and sliding distances in the early postoperative period., Results: The reduction loss rate was 4.5 % in the AS2 group and 16.8 % in the control group, indicating a significantly lower reduction loss rate in the AS2 group (p = 0.003). The average sliding distance was 1.8 mm in the AS2 group and 2.8 mm in the control group, indicating a significantly shorter sliding distance in the AS2 group (p < 0.0001)., Conclusion: Adding a screw in front of the intramedullary nail significantly reduces reduction loss, and maintains anterior bony contact. This study also showed that these screws suppress the sliding distance during the postoperative period., Level of Evidence: Therapeutic Level I., Competing Interests: Declaration of competing interest In this study, Zimmer Biomet and its affiliates were involved in preparing research implementation plans, research management, and statistical analysis. Each research institution receives research funds from Zimmer Biomet in return for the data provided., (Copyright © 2024. Published by Elsevier Ltd.)

Magnetic resonance (MR) imaging is a powerful imaging modality for obtaining anatomical information with high spatial and temporal resolution. In the drug delivery system (DDS) framework, nanoparticles such as liposomes are potential candidates for MR imaging. We validated that RGD peptides are possible targeting molecules for pancreatic cancer with αvβ3 integrin expression. This study aimed to evaluate RGD-modified liposomes loaded with ferrioxamine B for pancreatic cancer imaging. We synthesized four types of RGD-modified liposomes encapsulated with ferrioxamine B (SH-, H-, M-, and L-RGD-liposomes). The binding affinity of RGD-modified liposomes was evaluated in a competitive inhibition study using 125I-echistatin. To investigate the pharmacokinetics of RGD-modified liposomes, a biodistribution study using RGD-liposomes labeled with 111In was carried out in a human pancreatic cancer PANC-1 xenograft mouse model. Finally, MR was performed using ferrioxamine-B-loaded liposomes. RGD-liposomes inhibited the binding of 125I-echistatin to RGD. The biodistribution study revealed that 111In-RGD-liposomes accumulated significantly in the liver and spleen. Among the 111In-RGD-liposomes, 111In-H-RGD-liposomes showed the highest tumor-to-normal tissue ratio. In the MR study, H-RGD-liposomes loaded with ferrioxamine B showed higher tumor-to-muscle signal ratios than RKG-liposomes loaded with ferrioxamine B (control). We successfully synthesized RGD-liposomes that can target αvβ3 integrin., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yoshimoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Although the treatment of nonsmall cell lung cancer (NSCLC) has rapidly progressed recently, there is little evidence of treatment for patients with symptomatic brain metastases (BM) and poor performance status (PS). However, in symptomatic BM patients, appropriate upfront intracranial treatment can often lead to rapid improvement in PS and effective systemic therapy. Thus, this study investigated the prognostic factors for the survival of poor PS NSCLC patients with synchronous BM., Methods: Data of patients with BM and Karnofsky PS (KPS) ≤70 at the first diagnosis of NSCLC who were treated in our hospital between January 2017 and December 2021 were reviewed. Patient survival was compared among patients stratified by type of first-line regimen of systemic treatment. Correlations between patient characteristics and survival were examined., Results: Fifty patients receiving aggressive treatment were enrolled. The median survival times for tyrosine kinase inhibitor (TKI), immune checkpoint inhibitor (ICI), and chemotherapy alone groups were 19 (95 % confidence interval [CI], 2.8-68.5), 19 (3.0-62.0), and 13 (1.2-24.8) months, respectively. Survival in the TKI and ICI groups was significantly longer than in the chemotherapy alone group (p = 0.046, TKI vs. chemo; p = 0.022, ICI vs. chemo; p = 0.023). Both sex and type of systemic treatment correlated to survival time on univariate analysis. Chemotherapy alone for systemic treatment [p = 0.034; hazard ratio (HR), 0.44 (0.20-0.94)] remained significant for predicting overall survival in the multivariate analysis., Conclusion: Even in patients with poor PS and BM at the initial diagnosis of NSCLC, the ICI group had a survival time comparable to that of the TKI group when combined with tailor-made intracranial treatment. There is a subgroup in the patient population that was previously considered unsuitable for ICI, whose PS improves with individualized intracranial treatment, and who may benefit from immunotherapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Laser-driven neutron sources (LDNSs) can generate strong short-pulse neutron beams, which are valuable for scientific studies and engineering applications. Neutron resonance transmission analysis (NRTA) is a nondestructive technique used for determining the areal density of each nuclide in a material sample using pulsed thermal and epithermal neutrons. Herein, we report the first successful NRTA performed using an LDNS driven by the Laser for Fast Ignition Experiment at the Institute of Laser Engineering, Osaka University. The key challenge was achieving a well-resolved resonance transmission spectrum for material analysis using an LDNS with a limited number of laser shots in the presence of strong background noise. We addressed this by employing a time-gated 6 Li -glass scintillation neutron detector to measure the transmission spectra, reducing the impact of electromagnetic noise and neutron and gamma-ray flashes. Output waveforms were recorded for each laser shot and analyzed offline using a counting method. This approach yielded a spectrum with distinct resonances, which were attributed to 115 In and 109 Ag , as confirmed through neutron transmission simulation. The spectrum was analyzed using the least-square nuclear-resonance fitting program, REFIT, demonstrating the possibility of using an LDNS for nondestructive areal-density material characterization., (© 2024. The Author(s).)

[Purpose] To examine the influence of exercise using the Valsalva maneuver on vital signs. [Participants and Methods] Twenty-five healthy university students participated in the study. All participants were instructed to perform the squat under two loading intensities, that is, with barbell weights of 40% and 80% of body weight, under two conditions: no breath-holding (Control group) and breath-holding (Valsalva group). Blood pressure, pulse pressure, lactic acid level, and Borg scale scores were measured before and after each exercise session. [Results] Systolic blood pressure, mean blood pressure, and pulse pressure increased in the 80% Control, 40% Valsalva, and 80% Valsalva groups. [Conclusion] The use of the Valsalva maneuver could influence the vital signs of young, healthy participants., Competing Interests: The authors have no conflicts of interests to disclose., (2024©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Faithful DNA replication is essential for genome integrity 1-4 . Under-replicated DNA leads to defects in chromosome segregation, which are common during embryogenesis 5-8 . However, the regulation of DNA replication remains poorly understood in early mammalian embryos. Here we constructed a single-cell genome-wide DNA replication atlas of pre-implantation mouse embryos and identified an abrupt replication program switch accompanied by a transient period of genomic instability. In 1- and 2-cell embryos, we observed the complete absence of a replication timing program, and the entire genome replicated gradually and uniformly using extremely slow-moving replication forks. In 4-cell embryos, a somatic-cell-like replication timing program commenced abruptly. However, the fork speed was still slow, S phase was extended, and markers of replication stress, DNA damage and repair increased. This was followed by an increase in break-type chromosome segregation errors specifically during the 4-to-8-cell division with breakpoints enriched in late-replicating regions. These errors were rescued by nucleoside supplementation, which accelerated fork speed and reduced the replication stress. By the 8-cell stage, forks gained speed, S phase was no longer extended and chromosome aberrations decreased. Thus, a transient period of genomic instability exists during normal mouse development, preceded by an S phase lacking coordination between replisome-level regulation and megabase-scale replication timing regulation, implicating a link between their coordination and genome stability., (© 2024. The Author(s).)

In cone-beam computed tomography (CBCT) for image-guided radiation therapy (IGRT) of the head, we evaluated the exposure dose reduction effect to the crystalline lens and position-matching accuracy by narrowing one side (X2) of the X-ray aperture (blade) in the X-direction. We defined the ocular surface dose of the head phantom as the crystalline lens exposure dose and measured using a radiophotoluminescence dosimeter (RPLD, GD-352 M) in the preset field (13.6 cm) and in each of the fields when blade X2 aperture was reduced in 0.5 cm increments from 10.0 to 5.0 cm. Auto-bone matching was performed on CBCT images acquired five times with blade X2 aperture set to 13.6 cm and 5.0 cm at each position when the head phantom was moved from - 5.0 to + 5.0 mm in 1.0 mm increment. The maximum reduction rate in the crystalline lens exposure dose was - 38.7% for the right lens and - 13.2% for the left lens when blade X2 aperture was 5.0 cm. The maximum difference in the amount of position correction between blade X2 aperture of 13.6 cm and 5.0 cm was 1 mm, and the accuracy of auto-bone matching was similar. In CBCT of the head, reduced blade X2 aperture is a useful technique for reducing the crystalline lens exposure dose while ensuring the accuracy of position matching., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Background: Prevention of heart failure (HF) is a public health issue. Using the National Vital Statistics, we explored risk factors for HF and coronary artery disease (CAD) mortality., Methods and Results: Altogether, 7,556 Japanese individuals aged ≥30 years in 1990 were followed over 25 years; of these, 139 and 154 died from HF and CAD, respectively. In multivariable Cox proportional hazard analysis, common risk factors for CAD and HF mortality were hypertension (hazard ratio [HR] 1.48 [95% confidence interval {CI} 1.00-2.20] and 2.31 [95% CI 1.48-3.61], respectively), diabetes (HR 2.52 [95% CI 1.63-3.90] and 2.07 [95% CI 1.23-3.50], respectively), and current smoking (HR 2.05 [95% CI 1.27-3.31) and 1.86 [95% CI 1.10-3.15], respectively). Specific risk factors for CAD were male sex, chronic kidney disease, history of cardiovascular disease, and both abnormal T and Q waves, with HRs (95% CIs) of 1.75 (1.05-2.92), 1.78 (1.19-2.66), 2.50 (1.62-3.88), and 11.4 (3.64-36.0), respectively. Specific factors for HF were current drinking (HR 0.43; 95% CI 0.24-0.78) and non-high-density lipoprotein cholesterol (non-HDL-C; HR 0.81; 95% CI 0.67-0.98). There was an inverse association between non-HDL-C and HF in those aged ≥65 years (HR 0.71; 95% CI 0.56-0.90), but not in those aged <65 years., Conclusions: We identified common risk factors for HF and CAD deaths; a history of cardiovascular disease was a specific risk for CAD.

Rationale: Despite variants in the Dlgap1 gene having the two lowest p-value in a genome-wide association study of obsessive compulsive disorder (OCD), previous studies reported the absence of OCD-like phenotypes in Dlgap1 knockout (KO) mice. Since these studies observed behavioral phenotypes only for a short period, development of OCD-like phenotypes in these mice at older ages was still plausible., Objective: To examine the presence or absence of development of OCD-like phenotypes in Dlgap1 KO mice and their responsiveness to fluvoxamine., Methods and Results: Newly produced Dlgap1 KO mice were observed for a year. Modified SHIRPA primary screen in 2-month-old homozygous mutant mice showed only weak signs of anxiety, stress conditions and aggression. At older ages, however, these mutant mice exhibited excessive self-grooming characterized by increased scratching which led to skin lesions. A significant sex difference was observed in this scratching behavior. The penetrance of skin lesions reached 50% at 6-7 months of age and 90% at 12 months of age. In the open-field test performed just after the appearance of these lesions, homozygous mutant mice spent significantly less time in the center, an anxiety-like behavior, than did their wild-type and heterozygous littermates, none and less than 10% of which showed skin lesions at 1 year, respectively. The skin lesions and excessive self-grooming were significantly alleviated by two-week treatment with fluvoxamine., Conclusion: Usefulness of Dlgap1 KO mice as a tool for investigating the pathogenesis of OCD-like phenotypes and its translational relevance was suggested., (© 2024. The Author(s).)

Background: Antitumor effect of chimeric antigen receptor (CAR)-T cells against solid tumors is limited due to various factors, such as low infiltration rate, poor expansion capacity, and exhaustion of T cells within the tumor. NR4A transcription factors have been shown to play important roles in T-cell exhaustion in mice. However, the precise contribution of each NR4a factor to human T-cell differentiation remains to be clarified., Methods: In this study, we deleted NR4A family factors, NR4A1 , NR4A2, and NR4A3, in human CAR-T cells recognizing human epidermal growth factor receptor type 2 (HER2) by using the CRISPR/Cas9 system. We induced T-cell exhaustion in these cells in vitro through repeated co-culturing of CAR-T cells with Her2 + A549 lung adenocarcinoma cells and evaluated cell surface markers such as memory and exhaustion phenotypes, proliferative capacity, cytokine production and metabolic activity. We validated the antitumor toxicity of NR4A1/2/3 triple knockout (TKO) CAR-T cells in vivo by transferring CAR-T cells into A549 tumor-bearing immunodeficient mice., Results: Human NR4A-TKO CAR-T cells were resistant against exhaustion induced by repeated antigen stimulation in vitro, and maintained higher tumor-killing activity both in vitro and in vivo compared with control CAR-T cells. A comparison of the effectiveness of NR4A single, double, and TKOs demonstrated that triple KO was the most effective in avoiding exhaustion. Furthermore, a strong enhancement of antitumor effects by NR4A TKO was also observed in T cells from various donors including aged persons. Mechanistically, NR4A TKO CAR-T cells showed enhanced mitochondrial oxidative phosphorylation, therefore could persist for longer periods within the tumors., Conclusions: NR4A factors regulate CAR-T cell persistence and stemness through mitochondrial gene expression, therefore NR4A is a highly promising target for the generation of superior CAR-T cells against solid tumors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mammalian odorant receptors (ORs) are crucial for detecting a broad spectrum of odorants, yet their functional expression poses a significant challenge, often requiring Receptor-transporting proteins (RTPs). This study examines mouse Olfr733 and Olfr732, which, despite high homology, show different functional expression profiles in heterologous cell systems. Our research aimed to identify key amino acids impacting Olfr733's functional expression. We discovered that G112FBW3.40 and L148PBW4.49 (Ballesteros-Weinstein numbering in superscript) substitutions in Olfr732 markedly enhance its RTP-independent expression and ligand responsiveness, mirroring Olfr733. These substitutions, particularly Phe112 and Leu148, are crucial for aldehyde recognition and membrane localization in Olfr733, respectively. While Olfr732-type ORs are conserved across species, Olfr733-types, unique to specific rodents, appear to have evolved from Olfr732, with Pro148 enhancing membrane expression and aldehyde sensitivity. Mouse ORs with ProBW4.49 tend to exhibit improved membrane expression compared to their paralogs, especially when co-expressed with RTP1S. This study concludes that the Pro residue in the fourth transmembrane domain significantly contributes to the structural stability of certain olfactory receptors, highlighting the intricate molecular mechanisms underlying OR functionality and evolution., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

The temperature measurement of material inside of an object is one of the key technologies for control of dynamical processes. For this purpose, various techniques such as laser-based thermography and phase-contrast imaging thermography have been studied. However, it is, in principle, impossible to measure the temperature of an element inside of an object using these techniques. One of the possible solutions is measurements of Doppler brooding effect in neutron resonance absorption (NRA). Here we present a method to measure the temperature of an element or an isotope inside of an object using NRA with a single neutron pulse of approximately 100 ns width provided from a high-power laser. We demonstrate temperature measurements of a tantalum (Ta) metallic foil heated from the room temperature up to 617 K. Although the neutron energy resolution is fluctuated from shot to shot, we obtain the temperature dependence of resonance Doppler broadening using a reference of a silver (Ag) foil kept to the room temperature. A free gas model well reproduces the results. This method enables element(isotope)-sensitive thermometry to detect the instantaneous temperature rise in dynamical processes., (© 2024. The Author(s).)

While block copolymer (BCP) lithography is theoretically capable of printing features smaller than 10 nm, developing practical BCPs for this purpose remains challenging. Herein, we report the creation of a chemically tailored, highly reliable, and practically applicable block copolymer and sub-10-nm line patterns by directed self-assembly. Polystyrene-block-[poly(glycidyl methacrylate)-random-poly(methyl methacrylate)] (PS-b-(PGMA-r-PMMA) or PS-b-PGM), which is based on PS-b-PMMA with an appropriate amount of introduced PGMA (10-33 mol%) is quantitatively post-functionalized with thiols. The use of 2,2,2-trifluoroethanethiol leads to polymers (PS-b-PG F Ms) with Flory-Huggins interaction parameters (χ) that are 3.5-4.6-times higher than that of PS-b-PMMA and well-defined higher-order structures with domain spacings of less than 20 nm. This study leads to the smallest perpendicular lamellar domain size of 12.3 nm. Furthermore, thin-film lamellar domain alignment and vertical orientation are highly reliably and reproducibly obtained by directed self-assembly to yield line patterns that correspond to a 7.6 nm half-pitch size., (© 2024. The Author(s).)

Objectives: Smokers comprise the majority of surgical patients with primary lung cancer. Epidermal growth factor receptor (EGFR) mutation-negative status impacts the treatment of recurrence. However, the prognostic impact of cigarette smoking stratified by EGFR mutation status has not been reported. Therefore, we assessed its impact on patients with resected lung cancer., Methods: We retrospectively analysed 362 consecutive patients who underwent complete resection for stage 1 primary lung cancer at our institution between 2012 and 2021. The EGFR mutation status was evaluated using the real-time polymerase chain reaction. We compared the overall survival (OS) and disease-free survival (DFS) between patients with and without a history of smoking., Results: The EGFR mutation-negative group included 194 patients, of whom 160 (83%) had a history of smoking. Male sex (P < 0.01), forced expiratory volume in 1 s (P < 0.01) and adenocarcinoma (P < 0.01) showed significant differences between the groups. In the EGFR mutation-positive group, the 5-year OS and DFS were similar regardless of smoking status (OS: 86% vs 75%; DFS: 73% vs 73%). In the EGFR mutation-negative group, the 5-year OS and DFS were significantly poorer in the smoking group (OS: 87% vs 65%, P = 0.05; DFS: 84% vs 54%, P = 0.01). Deaths from other diseases were relatively high (n = 19, 53%)., Conclusions: Cigarette smoking may be associated with a poor prognosis in EGFR mutation-negative lung cancer but had no impact on the prognosis of the EGFR mutation-positive group. This finding underscores the potential influence of smoking on the treatment of lung cancer recurrence but also highlights its significance in contributing to death from other diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

The formation of ABC triblock terpolymers through solution casting is still challenging. In this study, core-shell double gyroid network structures are fabricated via solution casting using poly(2,2,2-trifluoroethyl methacrylate) (PTFEMA) (F)-b-[poly(4-vinylpyridine) (P4VP) (P)]-b-[polystyrene (PS) (S)] (FPS) triblock terpolymers in N,N-dimethylformamide (DMF). Upon heat treatment, the polymer tends to form a sphere-in-lamellar structure at the F/S interface. Given the solubility properties of each component in DMF, it is anticipated that the effective volume fraction of F relative to P would increase in concentrated solutions and the effective volume fraction of S would decrease. The microphase-separated structure derived from the DMF solution consistently results in the formation of a network structure composed of a core-shell double gyroid, with F as the matrix, P as the shell, and S as the core, and their periodic lengths gradually increase to 110.8, 131.8, and 162.7 nm as increase molecular weights of PS blocks to 13.8, 20.7, and 28.8 kg mol -1 . Based on the solubility properties of the polymer components highlighted in this study, the solvent selection strategy is broadly applicable to ABC triblock terpolymers featuring various polymer components, offering a more efficient avenue for fabricating core-shell double gyroid structures., (© 2024 The Authors. Macromolecular Rapid Communications published by Wiley‐VCH GmbH.)

Lymphocytes such as CD4 + T cells and B cells mainly infiltrate the salivary glands; however, the precise roles and targets of autoreactive T cells and autoantibodies in the pathogenesis of Sjögren's Syndrome (SS) remain unclear. This study was designed to clarify the role of autoreactive T cells and autoantibodies at the single-cell level involved in the development of sialadenitis. Infiltrated CD4 + T and B cells in the salivary glands of a mouse model resembling SS were single-cell-sorted, and their T cell receptor (TCR) and B cell receptor (BCR) sequences were analyzed. The predominant TCR and BCR clonotypes were reconstituted in vitro, and their pathogenicity was evaluated by transferring reconstituted TCR-expressing CD4 + T cells into Rag2 -/- mice and administering recombinant IgG in vivo. The reconstitution of Th17 cells expressing TCR (#G) in Rag2 -/- mice resulted in the infiltration of T cells into the salivary glands and development of sialadenitis, while an autoantibody (IgGr22) was observed to promote the proliferation of pathogenic T cells. IgGr22 specifically recognizes double-stranded RNA (dsRNA) and induces the activation of dendritic cells, thereby enhancing the expression of IFN signature and inflammatory genes. TCR#G recognizes antigens related to the gut microbiota. Antibiotic treatment severely reduces the activation of TCR#G-expressing Th17 cells and suppresses sialadenitis development. These data suggest that the anti-dsRNA antibodies and, TCR recognizing the gut microbiota involved in the development of sialadenitis like SS. Thus, our model provides a novel strategy for defining the roles of autoreactive TCR and autoantibodies in the development and pathogenesis of SS., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

Bitter taste perception is important in preventing animals from ingesting potentially toxic compounds. Whole-genome assembly (WGA) data have revealed that bitter taste receptor genes (TAS2Rs) comprise a multigene family with dozens of intact and disrupted genes in primates. However, publicly available WGA data are often incomplete, especially for multigene families. In this study, we employed a targeted capture (TC) approach specifically probing TAS2Rs for ten species of cercopithecid primates with diverse diets, including eight omnivorous cercopithecine species and two folivorous colobine species. We designed RNA probes for all TAS2Rs that we modeled to be intact in the common ancestor of cercopithecids ("ancestral-cercopithecid TAS2R gene set"). The TC was followed by short-read and high-depth massive-parallel sequencing. TC retrieved more intact TAS2R genes than found in WGA databases. We confirmed a large number of gene "births" at the common ancestor of cercopithecids and found that the colobine common ancestor and the cercopithecine common ancestor had contrasting trajectories: four gene "deaths" and three gene births, respectively. The number of intact TAS2R genes was markedly reduced in colobines (25-28 detected via TC and 20-26 detected via WGA analysis) as compared with cercopithecines (27-36 via TC and 19-30 via WGA). Birth or death events occurred at almost every phylogenetic-tree branch, making the composition of intact genes variable among species. These results show that evolutionary change in intact TAS2R genes is a complex process, refute a simple general prediction that herbivory favors more TAS2R genes, and have implications for understanding dietary adaptations and the evolution of detoxification abilities., (© 2024. The Author(s).)

Small antibody fragments have recently been used as alternatives to full-length monoclonal antibodies in therapeutic applications. One of the most popular fragment antibodies is single-chain fragment variables (scFvs), consisting of variable heavy (V H ) and variable light (V L ) domains linked by a flexible peptide linker. scFvs have small molecular sizes, which enables good tissue penetration and low immunogenicity. Despite these advantages, the use of scFvs, especially for therapeutic purpose, is still limited because of the difficulty to regulate the binding activity and conformational stability. In this study, we constructed and analyzed 10 scFv fragments derived from 10 representatives of FDA-approved mAbs to evaluate their physicochemical properties. Differential scanning calorimetry analysis showed that scFvs exhibited relatively high but varied thermostability, from 50 to 70°C of melting temperatures, and different unfolding cooperativity. Surface plasmon resonance analysis revealed that scFvs fragments that exhibit high stability and cooperative unfolding likely tend to maintain antigen binding. This study demonstrated the comprehensive physicochemical properties of scFvs derived from FDA-approved antibodies, providing insights into antibody design and development., (© 2024 The Protein Society.)

The alignment of each cell in human myocardium is considered critical for the efficient movement of cardiac tissue. We investigated 96-well microstripe-patterned plates to align human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), which resemble fetal myocardium. The aligned CMs (ACMs) cultured on the microstripe-patterned plates exhibited pathology, motor function, gene expression, and drug response that more closely resembled those of adult cells than did unaligned CMs cultured on a flat plate (FCMs). We used these ACMs to evaluate drug side effects and efficacy, and to determine whether these were similar to adult-like responses. When CMs from patients with hypertrophic cardiomyopathy (HCMs) were seeded and cultured on the microstripe-patterned plates or layered on top of the ACMs, both sets of HCMs showed increased heart rate and synchronized contractions, indicating improved cardiac function. It is suggested that the ACMs could be used for drug screening as cells representative of adult-like CMs and be transplanted in the form of a cell sheet for regenerative treatment of heart failure., (Creative Commons Attribution license.)

Background: Whether smoking is associated with worse quality of life (QoL) or not is relatively controversial. The current study is to investigate the relationship between smoking and subjective QoL in a long cohort study., Methods: The NIPPON DATA 90 project collected 8,383 community residents in 300 randomly selected areas as baseline data in 1990, administered four follow-up QoL surveys, and evaluated mortality statistics. We conducted multinomial logistic regression analysis to compare past smokers and current smokers to never smokers, with impaired QoL and mortality as outcomes., Results: In four follow-ups, QoL data was collected from 2,035, 2,252, 2,522, and 3,280 participants in 1995, 2000, 2005, and 2012, respectively. In the 1995 follow-up, current smoking at baseline was not associated with worse QoL. In 2000 and 2005 follow-ups, smoking was significantly associated with worse QoL (odds ratio [OR] 2.1; 95% confidence interval [CI], 1.33-3.36 and OR 2.29; 95% CI, 1.38-3.80, respectively). In the 2012 follow-up, smoking was not associated with QoL. Sensitivity analysis did not change the result significantly., Conclusion: In this study we found that baseline smoking was associated with worse QoL in long-follow-up.

This study investigated residual stresses in glass crowns cemented with resin cements. Glass caps were cemented to cylindrical cores using a conventional resin composite cement, a self-adhesive resin cement, or a methyl methacrylate (MMA)-based cement in dual-cure or self-cure mode. The cemented caps were stored in 37°C water for 28 days, and stresses on the cap surface were repeatedly measured. The water sorption, water solubility, and elastic modulus of the cements were also measured. Polymerization of the cements initially generated compressive stresses on the surfaces. Dual-curing or a greater modulus yielded greater initial stress. The stresses gradually decreased over time and lingered on the surfaces at 28 days with all the cements. Greater sorption tended to lead to greater stress reduction; however, the MMA-based cement exhibited less stress reduction despite exhibiting the greatest sorption. The use of a resin composite cement or dual-curing is recommended to reinforce crown restorations.

Background: Bexarotene, which has been approved for use in Japan since 2016, is an effective drug for cutaneous T-cell lymphoma; however, careful management is imperative because of its adverse events. We previously demonstrated the severity of bexarotene-associated hypertriglyceridemia and the need for bexarotene dose reduction for patients with cutaneous T-cell lymphoma and high body mass index (BMI); however, high BMI does not affect the efficacy of combined bexarotene and phototherapy treatment., Objective: This study aimed to verify the effects of BMI on hypertriglyceridemia associated with oral bexarotene therapy., Methods: We conducted a post hoc analysis of data from a previous randomized, open-label clinical study that compared combined bexarotene-phototherapy treatment with bexarotene monotherapy for cutaneous T-cell lymphoma by dividing patients into two groups based on BMI (<23 kg/m 2 and ≥23 kg/m 2 )., Results: No statistically significant association was observed between patients with BMI ≥23 kg/m 2 and severe hypertriglyceridemia; however, there was a significant association between BMI ≥23 kg/m 2 and severe hypertriglyceridemia for patients who received bexarotene monotherapy, but not for those who received combined bexarotene-phototherapy treatment. The exact reasons for the discrepancies between the results of this thorough analysis and those of our past research are unclear. However, high BMI may be a risk factor for hypertriglyceridemia. Additional unidentified risk factors could also affect treatment outcomes., Conclusion: High BMI is the primary reason for hypertriglyceridemia-associated bexarotene dose reduction; however, unexplored risk factors other than high BMI could exist., (© 2024. The Author(s).)

The bright red color of Parma ham is mainly derived from zinc protoporphyrin IX (ZnPP), which exists in both water-soluble and insoluble states. Water-soluble ZnPP mainly binds to hemoglobin, however, the presence of water-insoluble ZnPP remains unexplained. Therefore, we aimed to elucidate how ZnPP exists in a water-insoluble state by focusing on its binding substance. Depending on the skeletal muscle, water-insoluble ZnPP comprised 30-50% of total ZnPP. The ZnPP water extractability was positively correlated with muscle pH. Water-insoluble ZnPP was extractable with a high-pH solution and existed as a complex with myoglobin or hemoglobin; nevertheless, myoglobin-binding ZnPP was more abundant. Furthermore, the water solubility of the myoglobin globin moiety at pH 5.5-6.0 was reduced by ZnPP binding. These results suggest that water-insoluble ZnPP mainly exists as a ZnPP-Mb complex, with low solubility attributed to the low pH of the ham., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Species of the family Felidae are thought to be obligate carnivores. However, detection of plants in their faeces raises questions about the role of plants in their diet. This is particularly true for the snow leopard ( Panthera uncia ). Our study aimed to comprehensively identify the prey and plants consumed by snow leopards. We applied DNA metabarcoding methods on 90 faecal samples of snow leopards collected in Kyrgyzstan, employing one vertebrate and four plant markers. We found that argali ( Ovis ammon ) was detected only from male snow leopards. Myricaraia sp. was the most consumed among 77 plant operational taxonomic units found in snow leopard samples. It frequently appeared in samples lacking any prey animal DNA, indicating that snow leopards might have consumed this plant especially when their digestive tracts were empty. We also observed differences in the patterns of plant consumption between male and female snow leopards. Our comprehensive overview of prey and plants detected in the faeces of snow leopards and other sympatric mammals will help in formulating hypotheses and guiding future research to understand the adaptive significance of plant-eating behaviour in felids. This knowledge supports the enhancement of their captive environments and the conservation planning of their natural habitats., Competing Interests: We declare we have no competing interests., (© 2024 The Authors.)

Systemic chemotherapy is the standard treatment for non-small cell lung cancer with distant metastases. However, additional local treatment for brain and thoracic lesions is recommended for patients with synchronous solitary brain metastases (SSBM). We report the case of a 71-year-old male diagnosed with pulmonary adenocarcinoma and SSBM. Pathological examination of the brain metastasis showed positive immunostaining for programmed cell death ligand 1 expression. After four cycles of chemotherapy with immune checkpoint inhibitors, right upper lobectomy with ND2a-1 was performed. Pathological examination revealed complete pathological response, and this patient is expected to experience long-term survival., Competing Interests: None., (© 2024 Published by Elsevier Ltd.)

Background: Koalas, an Australian arboreal marsupial, depend on eucalypt tree leaves for their diet. They selectively consume only a few of the hundreds of available eucalypt species. Since the koala gut microbiome is essential for the digestion and detoxification of eucalypts, their individual differences in the gut microbiome may lead to variations in their eucalypt selection and eucalypt metabolic capacity. However, research focusing on the relationship between the gut microbiome and differences in food preferences is very limited. We aimed to determine whether individual and regional differences exist in the gut microbiome of koalas as well as the mechanism by which these differences influence eucalypt selection., Methods: Foraging data were collected from six koalas and a total of 62 feces were collected from 15 koalas of two zoos in Japan. The mitochondrial phylogenetic analysis was conducted to estimate the mitochondrial maternal origin of each koala. In addition, the 16S-based gut microbiome of 15 koalas was analyzed to determine the composition and diversity of each koala's gut microbiome. We used these data to investigate the relationship among mitochondrial maternal origin, gut microbiome and eucalypt diet selection., Results and Discussion: This research revealed that diversity and composition of the gut microbiome and that eucalypt diet selection of koalas differs among regions. We also revealed that the gut microbiome alpha diversity was correlated with foraging diversity in koalas. These individual and regional differences would result from vertical (maternal) transmission of the gut microbiome and represent an intraspecific variation in koala foraging strategies. Further, we demonstrated that certain gut bacteria were strongly correlated with both mitochondrial maternal origin and eucalypt foraging patterns. Bacteria found to be associated with mitochondrial maternal origin included bacteria involved in fiber digestion and degradation of secondary metabolites, such as the families Rikenellaceae and Synergistaceae. These bacteria may cause differences in metabolic capacity between individual and regional koalas and influence their eucalypt selection., Conclusion: We showed that the characteristics (composition and diversity) of the gut microbiome and eucalypt diet selection of koalas differ by individuals and regional origins as we expected. In addition, some gut bacteria that could influence eucalypt foraging of koalas showed the relationships with both mitochondrial maternal origin and eucalypt foraging pattern. These differences in the gut microbiome between regional origins may make a difference in eucalypt selection. Given the importance of the gut microbiome to koalas foraging on eucalypts and their strong symbiotic relationship, future studies should focus on the symbiotic relationship and coevolution between koalas and the gut microbiome to understand individual and regional differences in eucalypt diet selection by koalas., Competing Interests: The authors declare there are no competing interests., (©2024 Kondo et al.)

We report the preparation of chiral silica using a linear polysiloxane main chain with a preferred-handed helical structure as the template. Poly(methylvinyl siloxane) (PMVS) with a cysteine derivative side chain designated as PMVS-Cys was prepared using anionic polymerization and an ene-thiol reaction. PMVS-Cys forms a helical conformation in both solution and film via hydrogen bonding between amide groups at side chains. The helical structure remains during the calcination process, resulting in silica with helical structure. The silica with a helical structure shows optical activity.

In this study, the photoluminescence (PL) behavior of two aluminosilicate glass series containing alkali-niobates ranging from 0.4 to 20 mol% was investigated. The glasses exhibit an intense visible emission centered at ~18,400 cm -1 for the peralkaline series and at higher energies (~19,300 cm -1 ) for the metaluminous glasses. However, the photoluminescence emission intensity varies significantly with the niobate content and the bulk chemistry. PL and fluorescence lifetime measurements indicate that the broad emission bands result from the overlap of different niobate populations, whose distribution changes with niobate content. The distinct PL behavior in the two glass series was related to the structural evolution of the niobate units upon niobium addition. An enhancement of the visible emission was observed for a higher fraction of distorted [NbO 6 ] units. Eu-doping was carried out as a structural probe of the glass network, and also to determine if these glasses could be used as potential rare earth element (REE) activators. The crystal field strength around Eu ions is strongly dependent on the bulk chemistry and the niobate content. Furthermore, the peralkaline series showed energy transfer from the host [NbO 6 ] to Eu 3+ , confirming the feasibility of exploring niobate glasses and glass-ceramics as lanthanide ion-activated luminescent materials. In addition, glass-ceramics (GCs) containing alkali-niobate phases with a perovskite-like structure were developed and studied to verify the optical performance of these materials. It was verified that the bulk chemistry influences crystallization behavior, and also the photoluminescence response. The transparent GC from the metaluminous series exhibits a quenching of the Eu 3+ emission, whereas an enhanced emission intensity is observed for the peralkaline GC. The latter shows a strong excitation-dependent PL emission, suggesting energy transfer and migration of electronic excitation from one Eu population to another. Additionally, Eu 3+ emissions arising from the D15 and D25 excited states were observed, highlighting the low phonon energy achievable in niobo-aluminosilicate hosts.

The adjunct product with enzymatic activity from Aspergillus oryzae is beneficial for flavor enrichment in the ripened cheese. However, an excessive lipolytic reaction leads to the release of volatile free fatty acids. Accordingly, a strong off-flavor (i.e., rancidity) has been detected when A. oryzae AHU 7139 is used. To identify the rancidity-related lipase from this strain, we evaluated the substrate specificity and lipase distribution using five mutants cultured on a whey-based solid medium under different initial pH conditions. The results showed a higher diacylglycerol lipase activity than triacylglycerol lipase activity. Moreover, an initial pH of 6.5 for the culture resulted in higher lipolytic activity than a pH of 4.0, and most of the activity was found in the extracellular fraction. Based on the gene expression analysis by real-time polymerase chain reaction and location and substrate specificity, five genes (No. 1, No. 19, mdlB, tglA, and cutL) were selected among 25 annotated lipase genes to identify the respective knockout strains. Because ΔtglA and ΔmdlB showed an outstanding involvement in the release of free fatty acids, these strains were applied to in vitro cheese curd experiments. In conclusion, we posit that triacylglycerol lipase (TglA) plays a key role as the trigger of rancidity and the resulting diglycerides have to be exposed to diacylglycerol lipase (MdlB) to stimulate rancidity in cheese made with A. oryzae AHU 7139. This finding could help screen suitable A.oryzae strains as cheese adjuncts to prevent the generation of the rancid-off flavor., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Background: Deviations of hemoglobin from normal levels may be a factor in cardiovascular disease (CVD) risk; however, conclusive evidence is lacking. In addition, preclinical conditions may influence hemoglobin concentrations, but studies focusing on reverse causation are limited. Thus, we examined the relationship between hemoglobin concentrations and CVD mortality risk, considering reverse causation., Methods and results: In a prospective cohort representative of the general Japanese population (1990-2015), we studied 7,217 individuals (mean age 52.3 years; 4,219 women) without clinical CVD at baseline. Participants were categorized into sex-specific hemoglobin quintiles (Q1-Q5) and data were analyzed using the Cox proportional hazards model adjusted for possible confounders. During a 25-year follow-up, 272 men and 334 women died from CVD. Adjusted hazard ratios for CVD mortality across sex-specific quintiles, using Q3 as the reference, were significantly higher for Q1 (1.40; 95% confidence interval [CI] 1.08-1.82) and Q5 (1.49; 95% CI 1.14-1.96), and remained significant after excluding deaths within the first 5 years of follow-up to consider reverse causation (1.35 [95% CI 1.02-1.79] and 1.45 [95% CI 1.09-1.94], respectively). A similar U-shaped association was seen between transferrin saturation levels and CVD mortality, but after excluding deaths within the first 5 years the association was significant only for Q1., Conclusions: Low and high hemoglobin concentrations were associated with an increased risk of CVD mortality.

Toothed whales have developed specialized echolocation abilities that are crucial for underwater activities. Acoustic fat bodies, including the melon, extramandibular fat body, and intramandibular fat body, are vital for echolocation. This study explores the transcriptome of acoustic fat bodies in toothed whales, revealing some insight into their evolutionary origins and ecological significance. Comparative transcriptome analysis of acoustic fat bodies and related tissues in a harbor porpoise and a Pacific white-sided dolphin reveals that acoustic fat bodies possess characteristics of both muscle and adipose tissue, occupying an intermediate position. The melon and extramandibular fat body exhibit specific muscle-related functions, implying an evolutionary connection between acoustic fat bodies and muscle tissue. Furthermore, we suggested that the melon and extramandibular fat body originate from intramuscular adipose tissue, a component of white adipose tissue. The extramandibular fat body has been identified as an evolutionary homolog of the masseter muscle, supported by the specific expression of MYH16, a pivotal protein in masticatory muscles. The intramandibular fat body, located within the mandibular foramen, shows possibilities of the presence of several immune-related functions, likely due to its proximity to bone marrow. Furthermore, this study sheds light on leucine modification in the catabolic pathway, which leads to the accumulation of isovaleric acid in acoustic fat bodies. Swallowing without chewing, a major toothed whale feeding ecology adaptation, makes the masticatory muscle redundant and leads to the formation of the extramandibular fat body. We propose that the intramuscular fat enlargement in facial muscles, which influences acoustic fat body development, is potentially related to the substantial reorganization of head morphology in toothed whales during aquatic adaptation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Postoperative complications following liver resection remain high, ranging from 20% to 50%. Patients are hospitalized for a certain period of time following liver resection because of the risk of postoperative complications. We hypothesized that the risk of complications decreases with each complication-free postoperative day after open and minimally invasive liver resections and can be stratified using a recently reported three-level complexity classification., Methods: Patients undergoing first liver resection without concomitant other organ resections between 2006 and 2019 were included. The three-level complexity classification was used to categorize liver resection procedures into grades I-III. We assessed the rate of cumulative postoperative complications from the time of liver resection to the time of post-hepatectomy complications (≥ Clavien-Dindo grade II)., Results: Of the 911 patients included, 200 underwent resection of grade I procedures, 185 underwent resection of grade II procedures, and 526 underwent resection of grade III procedures. The risks of post-hepatectomy complications changed over time and were stratified by surgical complexity. For patients at the time of liver resection, the estimated 30-day complication rate was 21.8% for open grade I resection, 26.7% for open grade II resection, 38.4% for open grade III resection, 8.6% for laparoscopic grade I resection, and 12.5% for laparoscopic grade II resection. For patients without complications at 7 days, the estimated 30-day complication rate decreased to 2.1% for open grade I, 9.2% for open grade II, 17.6% for open grade III, 1.3% for laparoscopic grade I, and 4.5% for laparascopic grade II., Conclusions: The post-hepatectomy complication risks were stratified by surgical complexity, liver resection approach, and the period without complication after liver resection., (© 2023 The Authors. Journal of Hepato‐Biliary‐Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Objectives: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation., Methods: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center., Results: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis., Conclusion: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

T cell exhaustion impairs tumor immunity and contributes to resistance against immune checkpoint inhibitors. The nuclear receptor subfamily 4 group A (NR4a) family of nuclear receptors plays a crucial role in driving T cell exhaustion. In this study, we observe that NR4a1 and NR4a2 deficiency in CD8 + tumor-infiltrating lymphocytes (TILs) results in potent tumor eradication and exhibits not only reduced exhaustion characteristics but also an increase in the precursors/progenitors of exhausted T (Pre-Tex) cell fraction. Serial transfers of NR4a1 -/- NR4a2 -/- CD8 + TILs into tumor-bearing mice result in the expansion of TCF1 + (Tcf7 + ) stem-like Pre-Tex cells, whereas wild-type TILs are depleted upon secondary transfer. NR4a1/2-deficient CD8 + T cells express higher levels of stemness/memory-related genes and illustrate potent mitochondrial oxidative phosphorylation. Collectively, these findings suggest that inhibiting NR4a in tumors represents a potent immuno-oncotherapy strategy by increasing stem-like Pre-Tex cells and reducing exhaustion of CD8 + T cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)