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Abstract Non-zero spin orbit coupling has been reported in several unconventional superconductors due to the absence of inversion symmetry breaking. This contrasts with cuprate superconductors, where such interaction has been neglected for a long time. The recent report of a non-trivial spin orbit coupling in overdoped Bi2212 cuprate superconductor, has re-opened an old debate on both the source and role of such interaction and its evolution throughout the superconducting dome. Using high-resolution spin- and angle-resolved photoemission spectroscopy, we reveal a momentum-dependent spin texture throughout the hole-doped side of the superconducting phase diagram for single- and double-layer bismuth-based cuprates. The universality of the reported effect among different dopings and the disappearance of spin polarization upon lead substitution, suggest a common source. We argue that local structural fluctuations of the CuO planes and the resulting charge imbalance may cause local inversion symmetry breaking and spin polarization, which might be crucial for understanding cuprates physics.

Abstract Moiré superlattices consisting of two-dimensional materials have attracted immense attention because of emergent phenomena such as flat band-induced Mott insulating states and unconventional superconductivity. However, the effects of spin-orbit coupling on these materials have not yet been fully explored. Here, we show that single- and double-bilayer antimony honeycomb lattices, referred to as antimonene, form moiré superlattices on a Bi(111) substrate due to lattice mismatch. Scanning tunnelling microscopy (STM) measurements reveal the presence of spectral peaks near the Fermi level, which are spatially modulated with the moiré period. Angle-resolved photoemission spectroscopy (ARPES) combined with density functional theory calculations clarify the surface band structure with saddle points near the Fermi level, which allows us to attribute the observed STM spectral peaks to the van Hove singularity. Moreover, spin-resolved ARPES measurements reveal that the observed surface states are Rashba-type spin-polarized. The present work has significant implications in that Fermi surface instability and symmetry breaking may emerge at low temperatures, where the spin degree of freedom and electron correlation also play important roles.

Molecular crystals are a flexible platform to induce novel electronic phases. Due to the weak forces between molecules, intermolecular distances can be varied over larger ranges than interatomic distances in atomic crystals. On the other hand, the hopping terms are generally small, which results in narrow bands, strong correlations, and heavy electrons. Here, by growing K_{x}C_{60} fullerides on hexagonal layered Bi_{2}Se_{3}, we show that upon doping the series undergoes a Mott transition from a molecular insulator to a correlated metal and an in-gap state evolves into highly dispersive Dirac-like fermions at half filling, where superconductivity occurs. This picture challenges the commonly accepted description of the low-energy quasiparticles as appearing from a gradual electron doping of the conduction states and suggests an intriguing parallel with the more famous family of the cuprate superconductors. More in general, it indicates that molecular crystals offer a viable route to engineer electron-electron interactions.

Abstract Electron-hole asymmetry is a fundamental property in solids that can determine the nature of quantum phase transitions and the regime of operation for devices. The observation of electron-hole asymmetry in graphene and recently in twisted graphene and moiré heterostructures has spurred interest into whether it stems from single-particle effects or from correlations, which are core to the emergence of intriguing phases in moiré systems. Here, we report an effective way to access electron-hole asymmetry in 2D materials by directly measuring the quasiparticle self-energy in graphene/Boron Nitride field-effect devices. As the chemical potential moves from the hole to the electron-doped side, we see an increased strength of electronic correlations manifested by an increase in the band velocity and inverse quasiparticle lifetime. These results suggest that electronic correlations intrinsically drive the electron-hole asymmetry in graphene and by leveraging this asymmetry can provide alternative avenues to generate exotic phases in twisted moiré heterostructures.

Abstract Background and Aim The mechanism underlying carcinogenesis and the genomic features of superficial non‐ampullary duodenal epithelial tumors (SNADETs) have not been elucidated in detail. In this study, we examined the genomic features of incipient SNADETs, such as small lesions resected via endoscopic treatment, using next‐generation sequencing (NGS). Methods Twenty consecutive patients who underwent endoscopic treatment for SNADETs of less than 20 mm between January and December 2017 were enrolled. Targeted genomic sequencing was performed through NGS using a panel of 160 cancer‐related genes. Furthermore, the alteration/mutation frequencies in SNADETs were examined. Results The maximum size of the SNADETs examined in this study was 12 mm in diameter. Five SNADETs were classified as low‐grade dysplasia (LGD) tumors, while 14 SNADETs were classified as high‐grade dysplasia tumors. Only one carcinoma in situ was detected. NGS data for 16 samples were obtained. APC alterations were detected in 81% of samples (13/16). KRAS, BRAF, and TP53 alterations were detected in 25% (4/16), 18.8% (3/16), and 6.3% (1/16) of cases, respectively. Conclusion We detected APC alterations in most small SNADETs resected via endoscopic treatment, from LGD to carcinoma samples. Even in SNADETs classified as small LGD exhibited KRAS and BRAF alterations.

Abstract The BaAl4 prototype crystal structure is the most populous of all structure types, and is the building block for a diverse set of sub-structures including the famous ThCr2Si2 family that hosts high-temperature superconductivity and numerous magnetic and strongly correlated electron systems. The MA4 family of materials (M = Sr, Ba, Eu; A = Al, Ga, In) themselves present an intriguing set of ground states including charge and spin orders, but have largely been considered as uninteresting metals. We predict the exemplary compound BaAl4 to harbor a three-dimensional Dirac spectrum with non-trivial topology and possible nodal lines crossing the Brillouin zone, wherein one pair of semi-Dirac points with linear dispersion along the k z direction and quadratic dispersion along the k x /k y direction resides on the rotational axis with C 4v point group symmetry. An extremely large, unsaturating positive magnetoresistance in BaAl4 despite an uncompensated band structure is revealed, and quantum oscillations and angle-resolved photoemission spectroscopy measurements confirm the predicted multiband semimetal structure with pockets of Dirac holes and a Van Hove singularity (VHS) remarkably consistent with the theoretical prediction. We thus present BaAl4 as a topological semimetal, casting its prototype status into a role as a building block for a vast array of topological materials.

Background and hypothesis: It is generally considered that fragment fixation with bone pegs (FFBP) for osteochondritis dissecans (OCD) of the humeral capitellum can be indicated for stages I and II according to the International Cartilage Repair Society (ICRS) classification of OCD and it is difficult to obtain complete bone union for advanced lesions. However, the clinical and radiologic results of FFBP with cancellous bone graft for ICRS-OCD stage III with lateral wall involvement have not been described in detail. Good bone union can be achieved with the lateral wall fragment of the capitellum by FFBP in combination with refreshing the sclerotic surface at the base of the lesion and cancellous bone grafting even in ICRS-OCD stage III lesions. Methods: In total, 10 adolescent baseball players with a diagnosis of OCD, a median age of 13.5 years at the time of surgery, and 26.7 months of postoperative follow-up were included. Preoperative imaging showed that all patients had lesions in the late detached stage and of the lateral-widespread type based on the site of the focal lesion. The intraoperative ICRS-OCD classification was stage III. We aimed to preserve and fix the lateral wall fragment with cancellous bone grafting if the condition of the articular cartilage was good and the size and thickness of the segment could withstand fixation. Results: Bone union of the lateral wall fragment was achieved in all cases. The elbow extension range of motion was −3.9° ± 9.7° before surgery and was eventually −0.4° ± 6.7° at the final assessment. Flexion range of motion ranged from 138.1° ± 10.5° to 142.4° ± 6.2°. The Timmerman and Andrews score significantly improved from 165.5 ± 10.9 points before surgery to 197.0 ± 6.3 points after surgery, demonstrating excellent results in all patients. All patients were able to return to competitive baseball. Conclusion: The radiographic and clinical outcomes of FFBP for lateral wall fragments with cancellous bone graft were satisfactory, showing that the indications for this procedure could be extended to ICRS-OCD stage III.

A singularity in a material’s density of states at the Fermi energy can drive the formation of unconventional electronic phases. Here the authors show a Van Hove singularity is tunable across the Fermi energy in an oxide heterostructure, leading to enhanced electronic correlations.

Background and Aim: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare neoplasm, and its clinical features and management are still limited. We evaluated the clinicopathological factors, including CDX2 immunohistochemical expression, to predict survival in patients with LCNEC. Patients and Methods: In all, 50 patients with LCNEC who underwent surgery at 4 institutes between 2001 and 2017 were included. Clinicopathological characteristics were evaluated for prognostic factors and statistically analyzed by Kaplan-Meier curve with a log-rank test or Cox regression models. We used immunohistochemical (IHC) analysis to determine the expressions of CDX2 and compared them with clinicopathological factors and survival. Results: Sixteen of the 50 cases (32%) were CDX2 positive. No correlation was found between the CDX2 expression by IHC and clinicopathological factors. Multivariate analysis identified adjuvant chemotherapy (hazard ratio [HR] =2.86, 95% confidence interval [CI] = 1.04-8.16, P = .04) and vascular invasion (HR = 4.35, 95% CI = 1.21-15.63, P = .03) as being associated with a significantly worse rate of recurrence-free survival. Conclusion: CDX2 was expressed in 1/3 of LCNEC but not associated with prognostic factor. Adjuvant chemotherapy and vascular invasion were associated with a negative prognostic factor of LCNEC.

The sensitivity of postoperative pleural air leakage (PAL) after pulmonary resection is evaluated by a simple subjective grading method in clinical practice. A new electronic digital chest drainage evaluation system (DCS) recently became clinically available. This study was designed to evaluate the clinical application of the DCS in monitoring the airflow volume and managing postoperative PAL.We prospectively enrolled 25 patients who underwent pulmonary resection. Postoperative PAL was evaluated using both conventional PAL grading based on the physician's visual judgment (analog chest drainage evaluation system [ACS]: Level 0 = no leakage to 4 = continuous leakage) and the DCS. The DCS digital measurement was recorded as the flow volume (ml/min), which was taken once daily from postoperative day 1 to the day of chest drainage tube removal.In total, 45 measurements were performed on 25 patients during the evaluation period. Postoperative PAL was observed in five patients (20.0%) and judged as ACS Level >1. The mean DCS values corresponding to ACS Levels 0, 1, 2, and 3 were 2.42 (0.0-11.3), 48.6 (35.4-67.9), 95.6 (79.7-111.5), and 405.3 (150.3-715.6), respectively. The Spearman correlation test showed a significant positive correlation between the ACS PAL level and DCS flow volume (R = 0.8477, p < 0.001).A relationship between the visual PAL level by the ACS and the digital value by the DCS was identified in this study. The numeric volume obtained by the DCS has been successful in information-sharing with all staff. The digital PAL value evaluated by the DCS is appropriate, and the use of the DCS is promising in the treatment of postoperative PAL after pulmonary resection.

Intra-articular osteoid osteoma (OO) is uncommon, especially in the hip joint. Delayed treatment may cause early osteoarthritis; however, diagnosis and complete excision are often challenging. We describe the feasibility of the combination of T2 mapping magnetic resonance imaging evaluation and arthroscopic excision of OO in the acetabulum. A 12-year-old boy presented with a 6-month history of hip pain. An undifferentiated tumor of the medial wall of the acetabulum was suspected on radiographs and computed tomography. T2 mapping showed joint effusion, and the T2 value of the acetabular cartilage just above the tumor was significantly high. These findings suggested OO in the acetabulum. An arthroscopic excision was performed for biopsy and excision of the tumor to avoid damage to the normal cartilage and growth plate. Histologic examination confirmed the OO. At 16 months' follow-up, there was no evidence of recurrence. This is the first report to evaluate intra-articular OO by T2 mapping and to treat it arthroscopically. Arthroscopic treatment assisted by T2 mapping has excellent potential as a minimally invasive technique to enable us to approach the tumor from the area of discriminative abnormal cartilage with minimal damage to the normal cartilage and surrounding tissue.

ABSTRACT Background Cancer cachexia complicates advanced non‐small cell lung cancer (NSCLC); however, it remains unclear how often cachexia occurs and how it affects the course of chemotherapy in patients receiving first‐line systemic therapy. Methods We conducted a multicentre, prospective observational study and enrolled previously untreated NSCLC patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0–2 and cachexia between September 2020 and September 2021. The primary outcome measure was the trends in the Functional Assessment of Anorexia/Cachexia Treatment and Anorexia/Cachexia Subscale [FAACT (A/CS)] scores by cohort. Secondary outcome measures included the incidence of cachexia before the initiation of first‐line systemic therapy, quality of life (QOL) measures, body weight (BW) changes, and efficacy and safety of first‐line systemic therapy. Results A total of 887 consecutive patients with previously untreated advanced NSCLC and ECOG PS of 0–2 who were initiated on first‐line systemic therapy were evaluated. A total of 281 patients (31.7%) experienced BW loss consistent with the criteria of cachexia, and 186 were evaluated for QOL, BW and outcome measurements. Overall, 180/186 patients received first‐line systemic therapy. Cohort 1 (targeted therapy), cohort 2 [cytotoxic chemotherapy (CTx) ± immune checkpoint inhibitors (ICIs)] and cohort 3 (ICIs) included 42, 98 and 40 patients, respectively. There were significant variations in QOL trends by cohort, with chemotherapy‐associated emesis affecting early appetite‐related QOL. The change in the FAACT (A/CS) score at 1 week from baseline was worse in cohort 2 (the least square mean change ± standard error: −3.0 ± 0.9) than in cohorts 1 (1.6 ± 1.2, p = 0.003) and 3 (1.8 ± 1.0, p = 0.002); meanwhile, the change at 6 weeks was worse in cohort 1 (−1.5 ± 1.2) than in cohorts 2 (3.6 ± 0.9, p = 0.001) and 3 (3.5 ± 1.1, p = 0.004). BW reduction was observed in all cohorts within 6 weeks of therapy initiation. The targeted therapy cohort demonstrated superior progression‐free survival (PFS) and overall survival (OS) to CTx ± ICIs cohort or ICIs cohort (median PFS was 9.7 months, 6.3 months, 3.1 months, in cohort 1, 2, 3, respectively (cohort 1 vs. cohort 2: HR, 0.58, p = 0.018; cohort 1 vs. cohort 3: HR, 0.41, p = 0.001); median OS was not reached, 15.8 months, 9.9 months, respectively (cohort 1 vs. cohort 2: HR, 0.52, p = 0.033; cohort 1 vs. cohort 3: HR, 0.37, p = 0.003). Conclusions Approximately 1/3 patients with previously untreated advanced NSCLC have cachexia. Appetite‐related QOL trends vary based on the type of first‐line systemic therapy in cachectic NSCLC patients, and the PFS and OS of these patients seemed to be shorter.

Abstract Background Postoperative neurogenic bladder (PONB) frequently occurs as a complication after rectal cancer surgery. This study aimed to analyze risk factors for developing PONB after rectal cancer surgery, particularly the association between pelvic anatomy and visceral fat mass. Methods We included 138 patients who underwent rectal resection for lower rectal cancer in our department between 2017 and 2021. PONB was defined as the need for urethral catheter reinsertion or oral medication administration for urinary retention after catheter removal with severe NB that required treatment for ≥ 60 days. We obtained visceral fat area (VFA) at the umbilical level based on a CT scan and measured five pelvic dimensions. Results Of the 138 patients, 19 developed PONB, with 16 being severe cases. PONB more frequently occurs in patients with a height of

Abstract The number of dengue cases has increased dramatically in recent years. In Latin America, the number of cases and deaths in 2023 was the highest ever recorded. We report on a patient who had been infected with dengue virus during his stay in Costa Rica in September 2023, and developed the disease after returning to Japan. Plasma obtained from the patient was used for diagnosis and dengue virus serotyping by real-time PCR. The nucleotide sequence of the envelope region of dengue virus was then determined by the direct sequencing method, and this sequence was used for phylogenetic analyses. The patient was found to be infected with dengue virus type 3 genotype III. The sequence from the present case was more homologous with sequences registered in Florida, USA, associated with travel to Cuba in 2022 than with sequences registered in Costa Rica 10 years ago. The Pan American Health Organization reported that only dengue virus type 1 and 2 cases were reported in Costa Rica in 2019–2021, whereas dengue virus type 3 and 4 cases started being reported in 2022. In 2023, the reported numbers of cases with dengue virus types 3 and 4 exceeded those of dengue virus types 1 and 2. In addition, regional differences in endemic strains have been observed in Costa Rica. Our findings suggest that the dengue virus type 3 that infected the patient was more likely an influx of a strain that had been circulating in Caribbean countries such as Cuba in recent years, rather than a re-emergence of an indigenous virus in Costa Rica. The serotypes of dengue virus prevalent in Costa Rica have been changing since 2022. All four serotypes were prevalent in 2023, with a particularly sharp increase in the number of cases of dengue virus types 3 and 4. Future monitoring and surveillance are essential because changes in endemic serotypes can cause antibody-dependent enhancement, which can lead to severe dengue disease presentations.

Introduction: This study aimed to evaluate the association of obesity and diabetes mellitus (DM) comorbidity with hepatocellular carcinoma (HCC) recurrence and survival. Methods: We investigated 1,644 patients who underwent hepatic resection for solitary HCC without vascular invasion using computed tomography. Patients were categorized into four groups according to the combination of obesity and DM comorbidities: OB (+) or (−) and DM (+) or (−). Postoperative cumulative recurrence rates within and beyond 2 years and beyond 5 years were assessed. Results: Multivariate Cox proportional hazard regression analysis revealed that the adjusted hazard ratios (HRs) of reduced recurrence-free survival was 1.10 (95% confidence interval [CI]: 0.91–1.33; p = 0.31), 0.94 (95% CI: 0.78–1.12; p = 0.48), and 1.24 (95% CI: 1.01–1.54; p = 0.045) in the OB(+)DM(−), OB(−)DM(+), and OB(+)DM(+) groups compared with the OB(−)DM(−) group, respectively. Additionally, the corresponding adjusted HRs of reduced overall survival were 0.93 (p = 0.57), 0.97 (p = 0.76), and 1.38 (p = 0.013) for OB(+)DM(−), OB(−)DM(+), and OB(+)DM(+) groups, respectively. No significant difference in the early recurrence rate was determined among the four groups. The OB(+)DM(+) group demonstrated an increased risk for late recurrence beyond 2 years and 5 years postoperatively compared with the OB(−)DM(−) group (HR: 1.51; p = 0.024 and HR: 2.53; p = 0.046, respectively). The OB(+)DM(−) and OB(−)DM(+) groups demonstrated an increased risk for late recurrence beyond 5 years postoperatively (HR: 3.83; p < 0.001 and HR: 1.95; p = 0.037, respectively). Conclusions: Obesity and DM coexistence increased late recurrence and worsened prognosis in patients with HCC undergoing hepatic resection. The results help surgeons develop possible different surveillance protocol and need to focus on diabetes/obesity control during life-long surveillance for patients with HCC.

Abstract We report the first synthesis of a water‐soluble [9]cycloparaphenylene derivative containing three hydrindacene (1,2,3,5,6,7‐hexahydro‐s‐indacene) units with four carboxylates at the 2,6‐positions via a macrocyclic gold complex. This crown‐shaped macrocyclic compound exhibits remarkable water solubility, of up to 16 mmol L−1 (2.6 g/100 mL), as well as strong visible fluorescence in water (λem=447 nm, ϕF=0.64, brightness (ϵ×ϕF)=5.1×104). This molecule effectively encapsulates cationic guest compounds, such as methyl viologen dichloride, as indicated by a change in visible fluorescence.

Abstract Background This study aims to explore novel microRNAs in urine for screening and predicting clinical characteristics in pancreatic cancer (PC) patients using a microRNA array-based approach. Methods We used the Toray® 3D-Gene microRNA array-based approach to compare urinary levels between PC patients and healthy volunteers. Results (1) Four oncogenic microRNAs (miR-744-5p, miR-572, miR-210-3p, and miR-575) that were highly upregulated in the urine of PC patients compared to healthy individuals were identified by comprehensive microRNA array analysis. (2) Test-scale analysis by quantitative RT-PCR for each group of 20 cases showed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P = 0.009). (3) Validation analysis (58 PC patients and 35 healthy individuals) confirmed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P

In the routine maintenance of piping systems in power plants, maintenance management priorities are determined based on quantitative indicators, such as safety classification guidelines and probabilistic risk assessments, as well as qualitative metrics, such as supply reliability, operating experience, and work safety. In power plants, quantifying the level of maintenance criticality for areas that pose little risk to safety is difficult. Assuming damage to the piping system due to deterioration, the internal fluid flowing to the surrounding area may affect the functions of the peripheral equipment and work safety at the site. If the fluid temperature is high, the risk of burning increases. This study was aimed at quantifying the indicators of human burns that may pose a risk to work safety. Based on indicators related to the severity of human burns, we constructed an evaluation model using the results of fluid experiments and analysis of heat conduction in the skin to estimate the PBI, which in turn can be used to estimate the prognosis of burns. It was found that, especially under the condition for the evaluation of flashing, when a phase change occurs before and after a leak, the fluid diffusion range is large, and the fluid temperature is also high near the leak source. Such flow conditions can induce serious burns over a wide area. Based on the trends of the indicators related to human burns obtained in this study, we will construct a model to evaluate work safety risks in power plants using design information like temperature, pressure, and piping layout of the system.

Abstract Postoperative hepatobiliary enzyme abnormalities often present as postoperative liver dysfunction in patients with gastric cancer (GC). This study aimed to identify the risk factors for postoperative liver dysfunction and their clinical impact after GC surgery. We retrospectively analyzed the data of 124 patients with GC who underwent laparoscopic or robotic surgery at Kyoto Prefectural University of Medicine between 2017 and 2019. Twenty (16.1%) patients with GC developed postoperative liver dysfunction (Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 ≥ Grade 3). Univariate analyses identified robotic surgery as a risk factor for postoperative liver dysfunction (P = 0.005). There was no correlation between the postoperative liver dysfunction status and postoperative complications or postoperative hospital stays. Patients with postoperative liver dysfunction did not have significantly worse overall survival (P = 0.296) or recurrence-free survival (P = 0.565) than those without postoperative liver dysfunction. Robotic surgery is a risk factor for postoperative liver dysfunction; however, postoperative liver dysfunction does not affect short or long-term outcomes.

Abstract Background Lymphovascular invasion (LVI) is a poor prognostic factor in various malignancies. However, its prognostic effect in remnant gastric cancer (RGC) remains unclear. We examined the correlation between LVI and disease prognosis in patients with T1N0-3 or T2-3N0 RGC in whom adjuvant chemotherapy was not indicated and a treatment strategy was not established. Methods We retrospectively analyzed patients with T1N0-3 and T2-3N0 RGC who underwent curative surgery at the Kyoto Prefectural University of Medicine between 1997 and 2019 and at the Kyoto Chubu Medical Center between 2009 and 2019. Results Fifteen of 38 patients (39.5%) with RGC were positive for LVI. Patients with LVI had a significantly poorer prognosis for both overall survival ([OS]: P = 0.006) and recurrence-free survival ([RFS]: P = 0.001) than those without LVI. Multivariate analyses using the Cox proportional hazards model revealed LVI as an independent prognostic factor affecting OS (P = 0.024; hazard ratio 8.27, 95% confidence interval:1.285–161.6) and RFS (P = 0.013; hazard ratio 8.98, 95% confidence interval:1.513–171.2). Conclusions LVI is a prognostic factor for patients with T1N0-3 or T2-3N0 RGC. Evaluating LVI may be useful for determining treatment strategies for RGC.

Objectives: A total mesenteric excision (TME) with lateral pelvic lymph node dissection (LLND) is the standard treatment for advanced low rectal cancer in Japan. Recently, neoadjuvant (chemo)radiotherapy (n(C)RT) has been used with LLND to improve outcomes at multiple Japanese institutes. This study evaluates the benefits of adding nCRT to TME with LLND. Methods: Seventy-two consecutive patients who underwent TME and LLND with or without nCRT between 2006-2019 to treat advanced low rectal cancer were retrospectively reviewed. The clinicopathological data were compared and the risk factors for local recurrence were evaluated. Results: Fifty-seven patients (79.1%) underwent TME and LLND with nCRT, and 15 patients (20.9%) without nCRT. There was no significant difference in the clinicopathological characteristics except the clinical T stage. The occurrence of postoperative complications was statistically insignificant. The 5-year local recurrence rate of patients with nCRT was significantly lower than those without (4.0% versus 26.6%, in all patients, p=0.002). Multivariate analysis revealed that the absence of nCRT was an independent risk factor for local recurrences in patients who underwent TME with LLND (hazard ratio: 6.04, p=0.04). Conclusions: The administration of nCRT prevented local recurrences more effectively in patients with advanced low rectal cancer who underwent TME with LLND.

Abstract A chemical proteomics approach using Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) inhibitor–immobilized sepharose (TIM-063-Kinobeads) identified main targets such as CaMKKα/1 and β/2, and potential off-target kinases, including AP2-associated protein kinase 1 (AAK1), as TIM-063 interactants. Because TIM-063 interacted with the AAK1 catalytic domain and inhibited its enzymatic activity moderately (IC50 = 8.51 µM), we attempted to identify potential AAK1 inhibitors from TIM-063-derivatives and found a novel AAK1 inhibitor, TIM-098a (11-amino-2-hydroxy-7H-benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one) which is more potent (IC50 = 0.24 µM) than TIM-063 without any inhibitory activity against CaMKK isoforms and a relative AAK1-selectivity among the Numb-associated kinases family. TIM-098a could inhibit AAK1 activity in transfected cultured cells (IC50 = 0.87 µM), indicating cell-membrane permeability of the compound. Overexpression of AAK1 in HeLa cells significantly reduced the number of early endosomes, which was blocked by treatment with 10 µM TIM-098a. These results indicate TIM-063-Kinobeads-based chemical proteomics is efficient for identifying off-target kinases and re-evaluating the kinase inhibitor (TIM-063), leading to the successful development of a novel inhibitory compound (TIM-098a) for AAK1, which could be a molecular probe for AAK1. TIM-098a may be a promising lead compound for a more potent, selective and therapeutically useful AAK1 inhibitor.

Abstract Background Selecting pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum‐based chemotherapy (COMB) for patients with nonsmall cell lung cancer (NSCLC) and high programmed death‐ligand 1 (PD‐L1) expression is an important issue in clinical practice. We previously conducted a retrospective multicenter observational study of patients with NSCLC and high PD‐L1 expression who received MONO or COMB as a first‐line treatment. Here, we report updated data and evaluate the long‐term outcomes. Methods We performed a retrospective multicenter study of 298 patients with NSCLC and high PD‐L1 expression who received MONO or COMB as first‐line treatment between December 2018 and January 2020. We reviewed the medical records and assessed the clinical efficacy and toxicity using a prolonged data cutoff. Results In total, 164 (median age: 74 years) and 134 (median age: 68 years) patients received MONO and COMB, respectively; patients who received COMB were younger and had better performance statuses (0–1). At the prolonged data cutoff, the median follow‐up was 20.2 (range: 0.1–41.4) months. The median progression‐free survivals were 7.5 and 13.1 months, and overall survivals (OSs) were 17.2 and 33.7 months for MONO and COMB, respectively. Treatment discontinuation rates were 21.9% and 20.1% for the MONO and COMB, respectively. With prolonged follow‐up, although COMB demonstrated an OS benefit and higher objective response rate than MONO, in the propensity score matching analysis COMB didn't demonstrate a significant benefit compared to the MONO. Conclusions COMB may be effective as a first‐line treatment for NSCLC with high PD‐L1 expression in a selected subset of patients.

Abstract Aims This study investigated fatigue in individuals with 22q11.2 deletion syndrome (22q11.2DS), identifying both physical and psychosocial factors. Methods We conducted a cross‐sectional web‐based survey of 125 parents of individuals with 22q11.2DS. Significant factors of fatigue were identified using bivariate analysis and forward stepwise binary logistic regression. Results Overall, 34% (42 of 125) of the participants reported fatigue. Bivariate analysis identified 37 variables linked with fatigue, of which 11 were significant in multivariable analysis: older age (odds ratio [OR] = 1.28, 95% confidence interval [CI] [1.07, 1.53], P = 0.008), history of auditory hypersensitivity (OR = 36.4, 95% CI [4.08, 323.8], P = 0.001), delayed motor development (OR = 10.4, 95% CI [1.78, 61.0], P = 0.009), difficulty participating in events (OR = 33.5, 95% CI [1.1, 1068.2], P = 0.047), inability to join groups (OR = 47.9, 95% CI [4.8, 481.7], P = 0.001), concerns about marriage (OR = 17.0, 95% CI [2.6, 112.7], P = 0.003), inability to attend facilities (OR = 20.4, 95% CI [1.4, 308.0], P = 0.029), poor coordination when changing medical facilities (OR =

Abstract Histone variants play a central role in shaping the chromatin landscape in plants, yet, how their distinct combinations affect nucleosome properties and dynamics is still largely elusive. To address this, we developed a novel chromatin assembly platform for Arabidopsis thaliana, using wheat germ cell-free protein expression. Four canonical histones and five reported histone variants were used to assemble twelve A. thaliana nucleosome combinations. Seven combinations were successfully reconstituted and confirmed by supercoiling and micrococcal nuclease (MNase) assays. The effect of the remodeling function of the CHR11-DDR4 complex on these seven combinations was evaluated based on the nucleosome repeat length and nucleosome spacing index obtained from the MNase ladders. Overall, the current study provides a novel method to elucidate the formation and function of a diverse range of nucleosomes in plants.

Abstract Adrenal venous sampling (AVS) is crucial for subtyping primary aldosteronism (PA) to explore the possibility of curing hypertension. Because AVS availability is limited, efforts have been made to develop strategies to bypass it. However, it has so far proven unsuccessful in applying clinical practice, partly due to heterogeneity and missing values of the cohorts. For this purpose, we retrospectively assessed 210 PA cases from three institutions where segment-selective AVS, which is more accurate and sensitive for detecting PA cases with surgical indications, was available. A machine learning-based classification model featuring a new cross-center domain adaptation capability was developed. The model identified 102 patients with PA who benefited from surgery in the present cohort. A new data imputation technique was used to address cross-center heterogeneity, making a common prediction model applicable across multiple cohorts. Logistic regression demonstrated higher accuracy than Random Forest and Deep Learning [(0.89, 0.86) vs. (0.84, 0.84), (0.82, 0.84) for surgical or medical indications in terms of f-score]. A derived integrated flowchart revealed that 35.2% of PA cases required AVS with 94.1% accuracy. The present model enabled us to reduce the burden of AVS on patients who would benefit the most.

Abstract Background Pleomorphic liposarcoma is the rarest subtype of liposarcoma. Pleomorphic liposarcomas are generally unresponsive to chemotherapy and radiotherapy. Moreover, metastasis in the liver, as the first and sole site, from a primary extremity soft tissue sarcoma, including pleomorphic liposarcoma, is extremely rare. Information regarding the appropriate management of these lesions is limited. Case presentation A 50-year-old Japanese woman presented with a mass in the left thigh. Imaging examination revealed a soft tissue sarcoma on the left posterior thigh. The tumor was histologically diagnosed as pleomorphic liposarcoma. Computed tomography examination for assessment of metastases incidentally detected a huge liver mass. Wide excision of sarcoma was performed prior to chemotherapy. Right trisectionectomy was necessary to achieve hepatic clearance; however, the future liver remnant volume was insufficient. Therefore, we decided to administer anthracycline-based chemotheraphy to shrink the tumor. After seven courses of adriamycin-based chemotherapy, the liver tumor size was reduced from 211 mm × 106 mm × 180 mm to 105 mm × 66 mm × 90 mm. Finally, a right hemihepatectomy was performed. The patient was continuously monitored and was metastasis or local recurrence free within 5 months after liver surgery. Conclusion Chemotherapy is effective in some cases for the treatment of unresectable liver metastases of pleomorphic liposarcoma, and complete resection is possible with conversion surgery. If the patient’s general condition permits, anthracycline-based chemotherapy can be used for the treatment of stage 4 pleomorphic liposarcoma.

Skeletal muscle MRI studies in limb-girdle muscular dystrophy (LGMD) have increased over the past decades, improving the utility of MRI as a differential diagnostic tool. Nevertheless, the relative rarity of individual genotypes limits the scope of what each study can address, making it challenging to obtain a comprehensive overview of the MRI image of this splintered group. Furthermore, MRI studies have varied in their methods for assessing fat infiltration, which is essential in skeletal muscle MRI evaluation. It stayed problematic and impeded attempts to integrate multiple studies to cover the core MRI features of a distinct LGMD. In this study, we conducted a systematic review of LGMD in adults published until April 2023; 935 references were screened in PubMed and EMBASE, searches of the gray literature, and additional records were added during the screening process. Finally, 39 studies were included in our final analysis. We attempted to quantitatively synthesize the MRI data sets from the 39 individual studies. Finally, we illustrated ideal and simple MRI muscle involvement patterns of six representative LGMD genotypes. Our summary synthesis reveals a distinct distribution pattern of affected muscles by LGMD genotypes, which may be helpful for a quick first-tier differential diagnosis guiding genetic diagnostics.

This study analyzes the perezhivanie of one second-language learner (Chinese L1) who studied Japanese as a second language and engaged in her learning experience in a Japanese cultural setting through yearlong language advisory sessions. Perezhivanie, a Russian term, and a Vygotskian concept, is employed in the study to observe L2 learner development and to capture the bidirectional influences of the characteristics of agency and the environment. The data analyzed come from two sources: (a) our written correspondence, including email exchanges, from before the study was conducted and (b) audio-recorded data of six face-to-face/ online advisory sessions on a bimonthly basis with a particular focus on her perezhivanie. By applying perezhivanie as a unit of analysis that avoids the cognition-or-emotion and person-or-context dichotomies, the findings revealed the developmental processes of one L2 learner and focused on how both advisor and advisee mutually transform the specific social situation into a social situation of collectividual development through yearlong advisory sessions. Notably, the participant evaluated her original experience negatively at first, but eventually, she learned to value the failure and reinterpreted the initial experience. The significance of the study is to contribute to describing the detailed case of learner perezhivanie with a particular focus on entrance exams in East Asian sociocultural settings.

Abstract Purpose Immune‐checkpoint inhibitors (ICIs) are effective against advanced non‐small cell lung cancer (NSCLC). However, whether the efficacy and safety of ICI treatment in elderly patients are similar to those in younger patients is unclear. This study was designed to address this question. Methods We enrolled patients who received ICI monotherapy in Japan between December 2015 and December 2017; those ≥75 years of age comprised the elderly group. We compared the efficacy and safety of ICI monotherapy in elderly patients with those in younger patients and explored prognostic factors in elderly patients. Results We enrolled 676 patients; 137 (20.3%) were assigned to the elderly group. The median age of the elderly and younger groups was 78 (range, 75–85) and 66 (range, 34–74) years. The median progression‐free survival (4.8 months vs. 3.3 months, p = 0.1589) and median overall survival (12.3 months vs. 13.0 months, p = 0.5587) were similar between the elderly and younger groups. Multivariate analysis revealed that a significantly better OS in the elderly group was associated with better responses to first‐ or second‐line ICI treatment (p = 0.011) and more immune‐related adverse events (irAEs) (p = 0.02). IrAEs that led to ICI discontinuation occurred in 34 of 137 patients (24.8%) in the elderly group, and their survival was significantly higher than that in those who did not have irAEs. Conclusion ICI is also effective in elderly NSCLC patients, and treatment discontinuation due to irAEs may be a good prognostic marker.

Prolyl 4-hydroxylase (P4H) generates hydroxyproline residues in proteins. Two classes of P4H have been found in plants. Type 1 P4H has a signal anchor at the N-terminus, while type 2 P4H has both an N-terminal signal peptide and a C-terminal toxin homology domain (Tox1 domain) with six conserved cysteine residues. We analyzed the localization of tobacco type 2 P4H (NtP4H2.2) in tobacco BY-2 cells. Cell fractionation studies, immunostaining of cells, and GFP fusion study indicated that NtP4H2.2 localizes predominantly to the Golgi apparatus and is a peripheral membrane protein associated with the luminal side of organelles. Expression of the GFP-Tox1 domains of NtP4H2.2 and another tobacco type 2 P4H NtP4H2.1 in BY-2 cells and Arabidopsis epidermal cells indicated that these proteins were targeted to the Golgi. The Tox1 domains from Arabidopsis and rice type 2 P4Hs also directed GFP to the Golgi in tobacco BY-2 cells. The Tox1 domain of NtP4H2.2 increased the membrane association of GFP, and mutation of the cysteine residues in this domain abolished Golgi localization. Furthermore, the catalytic domain of NtP4H2.2 also directed GFP to the Golgi. Thus, the Tox1 domains of plant P4Hs are the Golgi localization domains, and tobacco P4H2.2 localizes to the Golgi by the action of both this domain and the catalytic domain.