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Background: Although balloon enteroscopy-assisted ERCP and transgastric EUS-guided pancreatic duct drainage (EUS-PD) are treatment option for pancreaticojejunostomy anastomotic stricture (PJAS), they are often challenging with several limitations. This study aimed to examine the feasibility of transanastomotic forward-viewing EUS-PD (FVEUS-PD) via the afferent loop for PJAS after pancreaticoduodenectomy., Methods: Ten consecutive patients with symptomatic PJAS who underwent FVEUS-PD between 2015 and 2021 were retrospectively evaluated. Study outcomes included technical and clinical success, adverse events, and recurrence rates associated with FVEUS-PD. A short dumbbell-shaped, fully covered metal stent was deployed in all cases, and the stent was removed 3 month after placement, after which it became stent-free., Results: The technical success rate was 80% (8/10), and the scope could not reach the PJAS in two patients. Clinical success was achieved in all technically successful patients. No procedure-related adverse events observed. All patients were followed up for over three years after metal stent removal and becoming stent-free; the median follow-up period was 63 month. One patient developed symptomatic stricture recurrence 36 month after removal, with a stricture recurrence rate of 13% (1/8). The remaining patients did not experience any recurrence or late adverse events during the study period., Conclusions: This study is the first to investigate FVEUS-PD, demonstrating promising technical feasibility with low adverse event and recurrence rates, potentially becoming a useful treatment option for PJAS., Competing Interests: Declarations. Conflict of interests: The authors declare no competing interests. Ethical approval: The institutional review board of Aichi Medical University Hospital approved this study (approval number: 2024–083), which was conducted in accordance with the principles of the Declaration of Helsinki., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. Although AMP-activated protein kinase (AMPK), the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. By contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarization-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues in vivo, using the mito-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

RAB family proteins, which are small GTPases, are integral to the process of eukaryotic membrane trafficking. In the nematode, Caenorhabditis elegans, 31 RAB proteins have been identified through genome sequencing. Using an RNAi screen specifically targeting C. elegans rab genes, we identified multiple genes that are involved in the regulation of larval development, in particular, the rab-18 gene. Our molecular genetic studies resulted in several findings. First, RAB-18 predominantly functions in the intestine to regulate larval development by modulating steroid hormone signaling. Second, the C. elegans cholesterol transporter NCR-1 is a target of RAB-18 in the intestine. Third, the membrane trafficking of NCR-1 to the apical side in intestinal cells is particularly influenced by RAB-18. Finally, RAB-18 and NCR-1 possibly co-localize on membrane vesicles. Our study is the first to demonstrate the relationship between a RAB protein and a cholesterol transporter, in which the RAB protein probably drives the transporter to the apical membrane in the intestine to regulate cholesterol uptake. This study provides insight into the molecular mechanisms underlying human disease stemming from a transport defect of cholesterol and its derivative., Competing Interests: Declaration of competing interest All authors declare no potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We discovered novel neuroprotective compounds by phenotypic screening using SOD1-mutant amyotrophic lateral sclerosis (ALS) patient induced pluripotent stem cell (iPSC)-derived motor neurons. Mechanistic analysis showed that the protective effect of initial hit compound 1 was likely due to the inhibition of MAP4Ks, including MAP4K4, a member of the MAP4K kinase family. Structural transformation led to compound 15f, which showed improved MAP4K4 inhibitory activity and superior neuroprotective effects compared to 1 in motor neurons. The results suggest that structural optimization based on MAP4K4 inhibitory activity might improve the neuroprotective effect of this series of compounds., 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.)

Background: Cardiac malformations are a major component of heterotaxy syndrome and result in significant mortality and morbidity. This multicenter nationwide Japanese study evaluated mortality and morbidity after initial surgical palliation for patients with heterotaxy syndrome and determined predictors for mortality and morbidity among patients enrolled in the study., Methods and Results: The Japanese Congenital Cardiovascular Surgery Database (JCCVSD) collects clinical data from 119 domestic institutions specializing in congenital heart disease, covering almost all major congenital heart surgery programs in Japan. Clinical data on preoperative, operative, and postoperative characteristics and survival data within 30 and 90 days were available from the JCCVSD database. Of the 561 patients with heterotaxy syndrome who underwent any of 8 specific initial cardiovascular surgeries, 45 (8.2%) and 75 (13.4%) had died at 30 and 90 days, respectively. Preoperative emergency transport, type of heterotaxy syndrome, low hospital volume, the repair of total anomalous pulmonary vein connection, and the repair of a common atrioventricular valve were identified as significant predictive factors for operative mortality., Conclusions: Improvements in some medical circumstances, such as fetal diagnosis and the patient transport system, will be needed to improve outcomes for severely ill patients with heterotaxy syndrome. This study describes early outcomes for the largest number of main cardiovascular surgeries to date in infants with heterotaxy syndrome.

Global concerns regarding the depletion and strategic importance of phosphorus resources have increased demand for the recovery and recycling. However, waste-derived phosphorus compounds, primarily as chemically inert phosphoric acid or its salts, present a challenge to their direct conversion into high-value chemicals. We aimed to develop an innovative technology that utilizes the large quantities of sewage waste, bypasses the use of white phosphorus, and enables esterification of phosphoric acid to produce widely applicable phosphate triesters. Tetraalkyl orthosilicates emerged as highly effective reagents for the direct triple esterification of 85% phosphoric acid, as well as the esterification of organophosphinic and phosphonic acids. Furthermore, we achieved esterification of recovered phosphoric acid with tetraalkyl orthosilicate, thus pioneering a recycling pathway from sewage waste to valuable phosphorus chemicals. Experimental and theoretical investigations revealed a novel mechanism, wherein tetraalkyl orthosilicates facilitate multimolecular aggregation to achieve alkyl transfer from tetraalkylorthosilicate to phosphoric acid via multiple proton shuttling., (© 2024 Wiley‐VCH GmbH.)

In order to establish a design principle for efficient Au electrocatalysis, it is desirable to synthesize a highly loaded, robust, and atomically precise Au cluster catalyst on a conductive carbon support. In this work, heterogeneous Au 25 catalysts were prepared by calcining 5.0 wt% of mixed ligated [Au 25 (D2S) x (PET) 18- x ] 0 (D2S = second generation Fréchet-type dendron thiolate, PET = 2-phenylethanethiolate) on a carbon support. X-ray absorption fine structure analysis, powder X-ray diffraction, and aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (AC-HAADF-STEM) revealed the successful synthesis of carbon-supported partially thiolated Au 25 clusters by calcining [Au 25 (D2S) 10.7 (PET) 7.3 ] 0 at 425 °C for ≥12 h, whereas calcination of [Au 25 (PET) 18 ] 0 under the same conditions resulted in thermally induced aggregation into larger Au nanoparticles. The D2S-modified Au 25 catalyst showed better durability than PET-modified Au 25 in electrocatalytic hydrogen evolution reaction. The higher durability was attributed to the suppression of aggregation of Au 25 clusters during the reaction, as confirmed by AC-HAADF-STEM. These results indicate that the residual D2S ligands on Au 25 enhance the stability against aggregation more than the residual PET due to stronger non-covalent interactions with carbon supports and/or greater steric hindrance of dendritic structure. This work demonstrates that the stability of Au catalysts can be improved by partial decoration with designed ligands.

The Joint Committee for Nationwide Survey on colorectal liver metastasis (CRLM) was established to improve treatment outcomes in patients with CRLM. The aim of this study was to evaluate the transition in the characteristics and treatment strategies of patients with CRLM and to analyze the prognostic factors. The data of 5085 patients newly diagnosed between 2013 and 2017 were compared with those of 3820 patients from 2005 and 2007. In patients who underwent hepatectomy (n = 2759 and 2163), the number of CRLMs was significantly higher and in the 2013-2017 data than in the 2005-2007 data (median 2 vs. 1; p = .005). Overall survival (OS) rates after diagnosis of CRLM after hepatectomy were better in the 2013-2017 data than that in the 2005-2007 data (5-year OS, 62.4% vs. 56.7%, p < .001). Recurrence-free survival (RFS) after hepatectomy was comparable between the groups (5-year RFS, 30.5% vs. 30.7%; p = .068). Multivariate analyses identified age at diagnosis of CRLM ≥70 years, lymph node metastasis of primary lesion, preoperative carbohydrate antigen (CA) 19-9 value >100 U/mL, number of CRLM 2-4, and R2 resection as independent predictors of OS. Synchronous CRLM, concomitant extrahepatic metastasis, lymphatic invasion, lymph node metastasis of primary lesion, preoperative CA19-9 value >100 U/mL, number of CRLM 5-, and nonlaparoscopic approach were selected as that of RFS. Despite having a higher prevalence of advanced stage CRLM in the 2013-2017 patient population compared to the 2005-2007 cohort, prognostic outcomes demonstrably improved in the later period., (© 2024 The Author(s). Journal of Hepato‐Biliary‐Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Rationale: Accurate prognostic awareness (PA) and knowledge of the disease are critical for decision-making regarding treatment options, advance care planning, and end-of-life care. However, they have not been investigated in patients with interstitial lung disease (ILD)., Objectives: To determine the prevalence of patients with ILD who have accurate PA and/or knowledge of acute exacerbation. In addition, to determine whether accurate PA is associated with end-of-life medical interventions and quality of dying and death., Methods: Through a nationwide bereavement survey, we examined the prevalence of accurate PA and knowledge of acute exacerbation (AE) in patients with ILD who died in acute general hospitals between January 2018 and February 2020. Patients' PA and knowledge were assessed from the perspective of the bereaved. We also quantified the quality of dying and death from the perspective of the bereaved using three scales, the Good Death Inventory, the Quality of Dying and Death (QODD) questionnaire, and the single-item QODD overall score, and obtained information on end-of-life interventions from the electronic medical record. We examined the associations of accurate PA with end-of-life interventions and quality of dying and death., Results: A total of 296 patients whose caregivers completed questionnaires were analyzed. One hundred sixty-three patients (55.1%, 95% confidence interval [CI] = 49.2-60.8) who died of ILD had accurate PA and 138 (46.9%, 95% CI = 35.9-47.4) recognized that their disease could have AE. Multivariate regression analysis showed that accurate PA was associated with significantly fewer intensive care unit (ICU) deaths (odds ratio = 0.28, 95% CI = 0.10-0.82, P = 0.02). Patients with accurate PA had better quality of dying and death on all the three scales., Conclusions: Approximately half of the patients who died of ILD did not recognize that their disease could lead to death or AE. The lower number of ICU deaths and better quality of dying and death in patients with accurate PA suggest the potential benefits of obtaining accurate PA in patients with ILD.

Objectives: We aimed to evaluate early and late outcomes by comparing open total arch repair and endovascular arch repair using proximal landing zone analysis in a multicentre cohort., Methods: From 2008 to 2019, patients treated surgically for aortic arch disease at 6 centres were included, excluding cases with type A aortic dissection, additional aortic root replacement and extensive aortic aneurysm. In all patients and populations with proximal landing zones 0/1 (N = 144) and 2 (N = 187), early and late outcomes were compared using propensity score matching., Results: A total of 1052 patients, including 331 (31%) and 721 (69%) patients undergoing endovascular arch repair and open total arch repair, respectively, were enrolled. After propensity score match (endovascular arch repair, 295; open total arch repair, 566), no significant difference was observed in in-hospital mortality rate (endovascular arch repair, 6.8%; open total arch repair, 6.2%; P = 0.716). Open total arch repair was associated with a lower risk of all-cause death [log-rank test; P = 0.010, hazard ratio (HR) 1.41 (95% confidence interval 1.17-1.71)]. The incidence of aorta-related death was higher in endovascular arch repair [Gray's test; P = 0.030, HR; 1.44 (95% confidence interval 1.20-1.73)]. When compared to endovascular arch repair with proximal landing zone 0/1, open total arch repair was associated with lower risks of all-cause death [log-rank test; P < 0.001, HR 2.04 (95% confidence interval 1.43-2.90)] and aorta-related death [Gray's test; P = 0.002, HR 1.67 (95% confidence interval; 1.25-2.24)]. There was no difference in the risk of all-cause death [log-rank test; P = 0.961, HR 0.99 (95% confidence interval 0.67-1.46)] and aorta-related death [Gray's test; P = 0.55, HR 1.31 (95% confidence interval 1.03-1.67)] between endovascular arch repair with proximal landing zone 2 and open total arch repair., Conclusions: Open total arch repair was considered the 1st choice based on early and late results; however, endovascular arch repair may be a useful option if the proximal landing zone is limited to zone 2., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Anaplastic lymphoma kinase (ALK) is a well-known oncogene involved in various malignancies such as anaplastic large cell lymphoma, lung cancer and neuroblastoma. Several substrates for fused ALK have been identified and their biological functions have been described. However, the lack of a comprehensive identification of ALK substrates limits our understanding of the biological roles of receptor ALK. Thus, this study aimed to identify novel ALK substrates and characterize their biological functions. We screened the interactors of the kinase domain of receptor ALK using proximity-dependent biotin identification and identified 43 interactors. We narrowed down the candidates by evaluating whether these interactors were downstream of ALK in a neuroblastoma cell line, NB-1. Amongst these, we identified amyloid beta precursor protein-binding family B member 1 (APBB1) as an ALK downstream molecule involved in NB-1 cell viability. Finally, we assessed the kinase-substrate relationship between ALK and APBB1 and found that ALK phosphorylated multiple tyrosine residues in APBB1 both in-cell and in-tube assays, with tyrosine 269 as a major target. In conclusion, we successfully identified a new substrate for receptor ALK. Our results may help further elucidate the molecular mechanism of ALK downstream signalling in neuroblastoma., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Collaborative surgery by both endoscopists and surgeons is considered effective for providing less invasive local resection of gastrointestinal tumors, to offset the limitations of either pure endoscopic treatments or surgical intervention. The clinical outcomes of collaborative surgery were evaluated to investigate the feasibility and safety of this approach., Methods: In this single-center retrospective observational study, we collected data from consecutive patients who underwent collaborative surgery for lesions located from the laryngopharynx to the anus. The completeness of collaboration, technical success, procedure time, postoperative hospitalization period, and occurrence of adverse events were analyzed., Results: Collaboration surgery was performed for 134 lesions (33 laryngopharyngeal, 2 esophageal, 89 gastric, 8 duodenal and 2 recto-anal) in 131 patients. Collaboration completeness was achieved in 129 lesions (96%). En bloc resection and pathological R0 resection of lesions were achieved in 127 (95%) and 124 (93%) lesions, respectively. The mean procedure time was 188 min. The mean time of discharge was the 11 th postoperative day. Five patients (4%) developed relevant postoperative adverse events., Conclusions: These results indicate that collaborative surgery by endoscopists and surgeons was feasible and safe, and may contribute to providing less invasive treatment than conventional surgery. Collaborative surgery is worth considering as a flexible and reliable surgical option, when cooperation may outperform either treatment alone., Competing Interests: Conflict of Interest: None, (Copyright: © 2024 Hellenic Society of Gastroenterology.)

We outline a protocol to visualize all mouse lower hindlimb skeletal muscles simultaneously. We describe procedures for orientating the whole lower hindlimb in gum tragacanth prior to freezing, simplifying the proceeding experimental steps, and enhancing the comprehensiveness of characterizations. We then detail steps for quantifying muscle fiber size and fiber type characteristics in a single cryosection using histochemistry and immunofluorescence. This protocol can be applied to histological and (immuno)histochemical evaluations such as muscle regeneration, fibrosis, enzymatic activity, and glycogen content., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Demonstrating drug efficacy in slowing kidney disease progression requires large clinical trials when targeting participants with an early stage of chronic kidney disease (CKD). In this randomized, parallel-group, open-labeled trial (CANPIONE study), we assessed the effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin using the individual's change in estimated glomerular filtration rate (eGFR) slope before (pre-intervention slope) and during treatment (chronic slope). We randomly assigned (1:1) participants with type 2 diabetes, urinary albumin-to-creatinine ratio (UACR) of 50 to under 300 mg/g, and an eGFR of at least 45 ml/min/1.73m 2 to receive canagliflozin or guideline-recommended treatment except for SGLT2 inhibitors (control). The first and second primary outcomes were the geometric mean percentage change from baseline in UACR and the change in eGFR slope, respectively. Of 98 randomized participants, 96 received at least one study treatment. The least-squares mean change from baseline in log-transformed geometric mean UACR was significantly greater in the canagliflozin group than the control group (between group-difference, -30.8% (95% confidence interval -42.6 to -16.8). The between-group difference (canagliflozin group - control group) of change in eGFR slope (chronic - pre-intervention) was 4.4 (1.6 to 7.3) ml/min/1.73 m 2 per year, which was more pronounced in participants with faster eGFR decline. In summary, canagliflozin reduced albuminuria and the participant-specific natural course of eGFR decline in participants with type 2 diabetes and microalbuminuria. Thus, the CANPIONE study suggests that the within-individual change in eGFR slope may be a novel approach to determine the kidney protective potential of new therapies in early stages of CKD., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Endoscopic trisectoral metal stent (MS) placement for malignant hilar biliary obstruction (MHBO) poses technical challenges, although it may prolong survival and stent patency. Combined stent-by-stent and stent-in-stent (SBSIS) methods can reduce technical difficulty. This study aimed to examine the use of the SBSIS in patients with Bismuth type III or IV MHBO., Methods: This prospective pilot study enrolled 30 eligible patients between January 2020 and October 2022. The study outcomes included technical and clinical success, recurrent biliary obstruction (RBO), and adverse events (AE) besides RBO associated with SBSIS for MHBO., Results: The technical success rate was 93.3% (28/30 patients). Clinical success was achieved in all patients with technical success. The early and late AEs rates were 6.7% (2/30) and 7.1% (2/28), respectively. The incidence of RBO was 35.7% (10/28). RBO was treated with an endoscopic transpapillary approach in eight patients and an endoscopic ultrasound-guided transmural approach in two patients. The median time to RBO was 162 days, and the median overall survival was 148 days., Conclusions: This first prospective study investigating the SBSIS method demonstrated good technical feasibility with a low AE rate. Therefore, it can be considered a better option when contemplating trisectoral MS placement for high-grade MHBO., Competing Interests: Declarations Conflict of interest The authors declare no conflict of interests for this study. Ethical approval The institutional review board of Aichi Medical University Hospital approved this study (approval number: 2019-143), which was conducted in accordance with the principles of the Declaration of Helsinki., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study explored the relationship between the morphological characteristics of the first tarsometatarsal ligaments and fibularis longus (FL) and the severity of articular cartilage degeneration in the first tarsometatarsal joint. Sixty legs from 30 cadavers were examined. The plantar, dorsal, and medial first tarsometatarsal ligaments were classified by fiber bundle number, and their morphological characteristics (fiber bundle length, width, thickness) were measured. The FL was categorized by its continuity with the plantar first tarsometatarsal ligament (PTML): Type A, connection with the PTML only on the first metatarsal; Type B, connection along the entire PTML; and Type C, no connection with the PTML. The severity of articular cartilage degeneration was assessed in four stages. No significant differences in cartilage degeneration among ligament types were found. Negative correlations were observed between the fiber bundle width and thickness of the PTML and the severity of cartilage degeneration. FL was classified as Type A in 68%, Type B in 27%, and Type C in 5% of feet. The fiber bundle thickness of the PTML in Type B was greater than in other types. Our findings suggest that smaller fiber bundle width and thickness in the PTML may be associated with severe cartilage degeneration. The FL had continuity with the PTML in 95% of feet and could enhance the mechanical strength of the PTML in Type B feet., (© 2024 American Association of Clinical Anatomists and British Association of Clinical Anatomists.)

Aim: No pharmacotherapeutic treatment has been established for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). This trial compared the effects of pemafibrate and omega-3-acid ethyl ester on hepatic function in patients with hypertriglyceridemia complicated by MASLD., Methods: Patients with hypertriglyceridemia complicated by MASLD were enrolled, randomly assigned to the pemafibrate or omega-3-acid ethyl ester group, and followed for 24 weeks. The primary endpoint was the change in alanine aminotransferase (ALT) from baseline to week 24. The secondary endpoints included other hepatic enzymes, lipid profiles, and hepatic fibrosis biomarkers., Results: A total of 80 patients were enrolled and randomized. The adjusted mean change in ALT from baseline to week 24 was significantly lower in the pemafibrate group (-19.7±5.9 U/L) than in the omega-3-acid ethyl ester group (6.8±5.5 U/L) (intergroup difference, -26.5 U/L; 95% confidence interval, -42.3 to -10.7 U/L; p=0.001). Pemafibrate significantly improved the levels of other hepatic enzymes (aspartate aminotransferase and gamma-glutamyl transpeptidase), lipid profiles (triglycerides, total cholesterol, high-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol), and hepatic fibrosis biomarkers (Mac-2 binding protein glycan isomer and Fibrosis-4 index). No cases of discontinuation due to adverse drug reactions were identified in either group, and there were no safety concerns., Conclusions: Pemafibrate is recommended over omega-3-acid ethyl ester for lipid management and MASLD treatment in patients with hypertriglyceridemia complicated by MASLD. The study results may contribute to the development of future treatment strategies for patients with MASLD/MASH.

Measurement of thyroglobulin in fine-needle aspirates (FNA-Tg) is useful for the diagnosis of lymph node metastasis in thyroid carcinoma; however, the cutoff value remains unclear, particularly for the differential diagnosis of neck masses. To evaluate the cutoff value of FNA-Tg, we conducted a retrospective study of patients with neck masses outside the thyroid who pre-operatively underwent both FNAC and FNA-Tg, followed by pathological examination at our hospital from October 2015 to September 2020. The cutoff value of FNA-Tg was calculated using the receiver operating characteristic curve. Among 210 lesions, 57 were of thyroid origin and 153 lesions were not of thyroid origin. A high FNA-Tg value was observed in the lesions of thyroid origin (P: 0.001), and the cutoff value at the minimum point of 100% specificity was 32.2 ng/mL with a sensitivity of 87.7%. Regarding the effect of serum anti-Tg antibodies, FNA-Tg values were significantly lower or not significantly different depending on the grouping, warranting further studies. Among the cases with papillary thyroid carcinoma, the sensitivity of FNAC and FNA-Tg was 71.4% and 87.5%, respectively. The cutoff value of FNA-Tg for the differential diagnosis of neck masses was higher compared to previous reports because some metastatic lymph nodes of carcinomas and lesions, other than lymph nodes, exhibited higher FNA-Tg values. Therefore, if FNA-Tg is to be used as a screening test for the differential diagnosis of neck masses in patients without proven thyroid carcinoma, it is necessary to establish a higher cutoff value.

Objectives: The prognosis of patients with colorectal diverticular perforations requiring surgery is poor, and the efficacy of polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) in these patients has not yet been established. In the present study, we evaluated the prognostic factors and the efficacy of PMX-DHP in surgically treated patients with perforated colorectal diverticula., Methods: Of the 116 patients with colorectal perforations who underwent emergency surgery at our hospital between April 2018 and May 2023, we retrospectively reviewed 46 patients with perforated colorectal diverticula. Preoperative, surgical, and postoperative factors were compared between the survival and mortality groups. Subgroup analysis was performed to evaluate the efficacy of PMX-DHP in severe cases., Results: The postoperative mortality group included 7 patients (15.2%), and PMX-DHP was performed in 14 (30.4%). PMX-DHP was performed significantly more often in the mortality group (P<0.01). In multivariate analysis, antithrombotic drug administration (hazard ratio, 16.600; 95% confidence interval, 1.32-209; P<0.05) and higher lactate levels (≥ 3.0 mmol/L) (hazard ratio, 42.300; 95% confidence interval, 2.69-667, P<0.01) were independent risk factors for postoperative mortality. PMX-DHP was performed in severe cases (patients with higher lactate levels, APACHE II scores, ventilator management frequencies, and noradrenalin use). PMX-DHP was not effective in improving prognosis in severe cases., Conclusions: Administration of antithrombotic drugs and higher lactate levels (≥ 3.0 mmol/L) are independent prognostic factors in colorectal diverticular perforations. PMX-DHP may not be effective in patients with severe preoperative conditions., Competing Interests: Conflicts of Interest There are no conflicts of interest., (Copyright © 2024 The Japan Society of Coloproctology.)

Background: Supravalvular aortic stenosis (SVAS) is a relatively rare form of left ventricular outflow tract obstruction, often accompanied by other cardiac conditions. However, a standard surgical reparative technique has not been established and repairing SVAS remains challenging., Case Presentation: We repaired SVAS of a 3-year-old boy accompanied by a bicuspid aortic valve and malpositioned coronary orifices by partial Brom's technique with two glutaraldehyde-treated autologous pericardial patches, using recent advanced preoperative information, including geometric and effective heights. Echocardiography after the surgery revealed release of SVAS without aortic regurgitation., Conclusions: In repair for SVAS, it is important not only to release stenosis but also to make a functional aortic valve, using recent advanced preoperative information. In the case of children, repairing the aortic valve by only using autologous tissue having growth potential, is also important., (© 2024. The Author(s).)

The mechanisms underlying obesity-induced insulin resistance remain incompletely understood, as impaired cellular insulin signaling, traditionally considered the primary driver of insulin resistance, does not always accompany impaired insulin action. Overnutrition rapidly increases plasma norepinephrine (NE), suggesting overactivation of the sympathetic nervous system (SNS). However, the role of the SNS in obesity is controversial, as both increased and decreased SNS activity (SNA) have been reported. Here, we show that reducing catecholamine (CA) release from the SNS protects against overnutrition-induced insulin resistance as well as hyperglucagonemia, adipose tissue dysfunction, and fatty liver disease, as we demonstrate utilizing a mouse model of inducible and peripherally restricted deletion of tyrosine hydroxylase (th; THΔper). A key mechanism through which heightened SNA induces insulin resistance is by triggering adipose tissue lipolysis. Increased SNA emerges as a critical driver in the pathogenesis of overnutrition-induced insulin resistance and metabolic disease independent of cellular insulin signaling., Competing Interests: Declaration of interests C.B. received research support from Pfizer and consulted for Boehringer and Novo Nordisk, all of which were unrelated to the work described in this manuscript. G.M. is part of the editorial team at Elsevier., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bioassay-guided isolation of a dihydroxy flavone from the cell extract of Penicillium EU0013 was carried out using preparative LCMS and the structure was interpreted using 1D and 2D NMR spectra. The fungus was fermented in three different nutrient media i.e. Glucose Nutrient Broth, Glucose Peptone Yeast Broth, and Yeast Extract Broth and the cell extract was obtained using organics. Comparative LCMS profiles of the fungus confirmed the enhanced production of dihydroxy flavone in GPYB media. In this study, the pathogenicity of the dihydroxy flavone is reported for the first time against Fusarium oxysporum f.sp. lycopersici , wilt causing pathogen of a tomato plant. In MIC experiments, the compound inhibited the pathogen at 80 µg mL -1 . Molecular docking studies of the compound with Fol tomatinase showed five binding interactions. These docking studies may help explore dihydroxy flavones as a lead for developing new fungicides to prevent wilt disease in tomatoes.

Zinc finger E-box binding homeobox 1 (ZEB1) has been identified as a key factor in cancer cell differentiation and metastasis, and has been well studied in the field of cancer cell biology. ZEB2 has a highly similar conformation to ZEB1, but its role in head and neck squamous cell carcinoma (HNSCC) cells is not fully understood. Here, we separately overexpressed ZEB1 and ZEB2 in C57BL/6 mouse oral cancer (MOC) cells and investigated their cellular characteristics, including E-cadherin levels, motile properties, chemoresistance, and metastatic ability in immunocompetent mice. Both ZEB1 and ZEB2 overexpression reduced epithelial traits and converted cells to an aggressive phenotype. Surprisingly, ZEB1 overexpression increased the endogenous level of ZEB2 in MOC cells, and vice versa. The molecular mechanisms underlying these findings remain unclear. However, the in vitro anchorage-independent growth of MOC cells overexpressing ZEB2 was considerably greater than that of MOC cells overexpressing ZEB1. These findings suggest that ZEB2, like ZEB1, has the ability to induce the differentiation of cancer cells into those with highly aggressive traits., (© 2024 The Author(s). Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Background and Aim: Delayed endoscopic sphincterotomy-related bleeding (ES bleeding) is an unavoidable adverse event (AE) that can have serious ramifications. Intraoperative ES bleeding, which stops spontaneously in most cases, is a known risk factor for delayed bleeding. This study aimed to examine the preventive effect of a novel self-assembling peptide (SAP) for delayed ES bleeding in patients who attained spontaneous hemostasis after intraoperative ES bleeding., Methods: A total of 1507 patients met the eligibility criteria for inclusion in this study. The rates of delayed ES bleeding and AE besides bleeding were compared between patients administered the SAP (SAP group) and those who were simply observed after spontaneous hemostasis of intraoperative ES bleeding (control group). Propensity score matching was performed to adjust for differences between the groups., Results: The rate of delayed ES bleeding was significantly lower in the SAP group than that in the control group (0.9% vs 3.8%, P = 0.044). The rates of AEs other than bleeding were 2.4% and 3.8% in the SAP and control groups, respectively, and the difference lacked statistical significance (P = 0.481). Multivariate analysis revealed that the use of SAP was significantly associated with a lower frequency of delayed ES bleeding (odds ratio, 0.35; 95% confidence interval, 0.13-0.98; P = 0.047)., Conclusions: Self-assembling peptide may be a simple, safe, and useful way to reduce the risk of delayed ES bleeding in patients who experienced intraoperative ES bleeding and obtained subsequent spontaneous hemostasis., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Preoperative chemotherapy with 5-fluorouracil and cisplatin (FP) followed by surgery has been considered a standard treatment for patients with stage II/III esophageal squamous cell carcinoma (ESCC) based on the results of a phase III trial (JCOG9907) in Japan. Subsequently, the phase III NExT trial (JCOG1109) revealed the survival benefit of the neoadjuvant DCF regimen, which adds docetaxel to FP, and it became a standard treatment. However, the long-term results and prognostic factors of neoadjuvant DCF therapy in the real world are unknown., Methods: We retrospectively investigated 50 patients with ESCC treated with neoadjuvant DCF therapy from July 2012 to December 2017 at The University of Tokyo Hospital., Results: Median overall survival (OS) and progression-free survival (PFS) were 32.3 [95% confidence interval (CI) 21.0-NA] and 10.0 months (95% CI 6.3-15.6), respectively. Median OS [not reached (95% CI 31.5-NA) vs. 21.4 months (95% CI 13.5-33.0); p = 0.028] and PFS [83.3 months (95% CI 6.4-NA) vs. 7.4 months (95% CI 6.0-12.8] were significantly longer in patients with an objective response than in non-responders. Of 44 surgical cases, median PFS tended to be longer in pathological lymph node metastasis-negative patients. Conversely, survival did not differ according to cStage (II/III vs. IV) or the average relative dose intensity (ARDI, ≥ 85% vs. < 85%)., Discussion: The response to neoadjuvant DCF therapy could predict patient prognosis. Additionally, pN+ tended to increase the recurrence risk, whereas cStage and ARDI did not influence survival., (© 2024. The Author(s).)

Purpose: Post-transplant biliary stricture (PBS) is a common and important complication following orthotopic liver transplantation (LT). This study clarified the incidence of PBS and identified its risk factors., Methods: We retrospectively reviewed the medical records of 67 patients who underwent living-donor LT (LDLT) at our institute between June 2010 and July 2022 and analyzed their clinical characteristics, prognosis, and risk factors for PBS., Results: Of the 67 patients, 26 (38.8%) developed PBS during the observation period. Multivariate analyses revealed the following independent risk factors for PBS formation: increased red cell transfusion volume per body weight (> 0.2 U/kg; hazard ratio [HR], 3.8; P = 0.002), increased portal vein pressure (PVP) at the end of LT (> 16 mmHg; HR, 2.88; P = 0.032), postoperative biliary leakage (HR, 4.58; P = 0.014), and prolonged warm ischemia time (WIT) (> 48 min; HR, 4.53; P = 0.008). In patients with PBS, the cumulative incidence of becoming stent free was significantly higher in patients with a WIT ≤ 48 min than in those with a WIT > 48 min (P = 0.038)., Conclusion: Prolonged WIT is associated with intractable PBS following LDLT., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

To our best knowledge, the formation of a pancreatico-renal fistula and the presence of pancreatic fluid collection in the renal subcapsular space have not been reported as autoimmune pancreatitis (AIP) complications. We describe a case of a pancreatico-renal fistula associated with type 1 AIP. The patient presented with abdominal and back pain accompanied by pancreatic cystic lesions during an untreated course of AIP. The diagnosis of pancreatico-renal fistula was based on the presence of a left renal subcapsular fluid collection containing pancreatic amylase, disappearance of pancreatic cysts, and a defect in the partial anterior renal fascia observed on imaging studies. Treatment with steroids and percutaneous drainage resulted in improvement. Pancreatic pseudocysts can affect other organs owing to their digestive action. Similar symptoms may occur in patients with AIP., (© 2024. Japanese Society of Gastroenterology.)

Purpose: A consensus has been reached regarding diverting stoma (DS) construction in rectal cancer surgery to avoid reoperation related to anastomotic leakage. However, the incidence of stoma-related complications (SRCs) remains high. In this study, we examined the perioperative outcomes of DS construction in patients who underwent sphincter-preserving surgery for rectal cancer., Methods: We included 400 participants who underwent radical sphincter-preserving surgery for rectal cancer between 2005 and 2017. These participants were divided into the DS (+) and DS (-) groups, and the outcomes, including postoperative complications, were compared., Results: The incidence of ileus was higher in the DS (+) group than in the DS (-) group (P<0.01); however, no patients in the DS (+) group showed grade 3 anastomotic leakage. Furthermore, early SRCs were observed in 33 patients (21.6%) and bowel obstruction-related stoma outlet syndrome occurred in 19 patients (12.4%). There was no significant intergroup difference in the incidence of grade 3b postoperative complications. However, the most common reason for reoperation was different in the 2 groups: anastomotic leakage in 91.7% of patients with grade 3b postoperative complications in the DS (-) group, and SRCs in 85.7% of patients with grade 3b postoperative complications in the DS (+) group., Conclusion: Patients with DS showed higher incidence rates of overall postoperative complications, severe postoperative complications (grade 3), and bowel obstruction, including stoma outlet syndrome, than patients without DS. Therefore, it is important to construct an appropriate DS to avoid SRCs and to be more selective in assigning patients for DS construction.

Introduction: To verify the value of the pathological criteria for additional treatment in locally resected pT1 colorectal carcinoma (CRC) which have been used in the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines since 2009., Methods: We enrolled 4,667 patients with pT1 CRC treated at 27 institutions between July 2009 and December 2016 (1,257 patients with local resection alone [group A], 1,512 patients with additional surgery after local resection [group B], and 1,898 patients with surgery alone [group C]). All 5 factors of the JSCCR guidelines (submucosal resection margin, tumor histologic grade, submucosal invasion depth, lymphovascular invasion, and tumor budding) for lymph node metastasis (LNM) had been diagnosed prospectively., Results: Any of the risk factors were present in 3,751 patients. The LNM incidence was 10.4% (95% confidence interval 9.4-11.5) in group B/C patients with risk factors, whereas it was 1.8% (95% confidence interval 0.4-5.3) in those without risk factors ( P < 0.01). In group A, the incidence of recurrence was 3.6% in patients with risk factors, but it was only 0.4% in patients without risk factors ( P < 0.01). The disease-free survival rate of group A patients classified as risk positive was significantly worse than those of groups B and C patients. However, the 5-year disease-free survival rate in group A patients with no risk was 99.6%., Discussion: Our large-scale real-world multicenter study demonstrated the validity of the JSCCR criteria for pT1 CRC after local resection, especially regarding favorable outcomes in patients with low risk of LNM., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

The isotopic compositions of samples returned from Cb-type asteroid Ryugu and Ivuna-type (CI) chondrites are distinct from other carbonaceous chondrites, which has led to the suggestion that Ryugu/CI chondrites formed in a different region of the accretion disk, possibly around the orbits of Uranus and Neptune. We show that, like for Fe, Ryugu and CI chondrites also have indistinguishable Ni isotope anomalies, which differ from those of other carbonaceous chondrites. We propose that this unique Fe and Ni isotopic composition reflects different accretion efficiencies of small FeNi metal grains among the carbonaceous chondrite parent bodies. The CI chondrites incorporated these grains more efficiently, possibly because they formed at the end of the disk's lifetime, when planetesimal formation was also triggered by photoevaporation of the disk. Isotopic variations among carbonaceous chondrites may thus reflect fractionation of distinct dust components from a common reservoir, implying CI chondrites/Ryugu may have formed in the same region of the accretion disk as other carbonaceous chondrites.

Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer's signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.

The carbon spheres synthesized by pyrolysis of resorcinol-formaldehyde (RF) semiconducting resins exhibit enhanced activity for electrocatalytic oxygen reduction. The spheres consist of narrow reticulated carbon layers, which are derived from the donor-acceptor π-stacking interaction of the resins, and show high electron conductivity.

Recently, targeted protein degradation has attracted increasing interest as a new drug discovery approach. This method aims to control the function of drug targets by inducing their degradation through protein degradation systems such as the proteasome. Concurrently, compounds that enhance proteasome activity have also garnered attention. In 2023, we reported that anthricin (also known as 4-deoxypodophyllotoxin), a natural product that belongs to the lignan family, enhances proteasome activity. However, whether this enhancement was because of increased proteasome expression or improved proteasome function remains unclear. In this study, we investigated the structure-activity relationship of anthricin and its analogs in enhancing proteasome activity, the effects of anthricin on proteasome-related gene expression, and the direct binding between anthricin and the proteasome using pull-down assay. Moreover, we assessed the interaction between anthricin and the proteasome using molecular dynamics (MD) simulations. The results showed that anthricin does not induce proteasome-related gene expression, but instead binds to the β-subunit of the proteasome, bringing the side chains of three amino acid residues (Thr 1 , Asp 17 , and Lys 33 ) at the catalytic site closer together, thereby inducing a hyperactive state. To the best of our knowledge, this study is the first to suggest the mechanism of proteasome activity enhancement by anthricin at the molecular level. The findings could contribute to the development of new chemotypes to enhance the effects of targeted protein degraders by regulating proteasome activity., Competing Interests: KS, RF and EKA is a full-time employees of Ichimaru Pharcos Co. Ltd. TH declare that there are no competing interests associated with this manuscript., (© 2024 The Authors.)

Background: Schizophrenia often involves persecutory delusions, which cause psychological distress. Some patients use online gaming as a coping tool. However, excessive online gaming has raised concerns about internet gaming disorders (IGD), while any soothing effects of online gaming on psychological distress remain unclear. Herein, we report changes in anxiety and IGD severity, measured using rating scales, in a patient with schizophrenia who used online gaming as a coping strategy for psychological distress., Case Presentation: A 43-year-old woman diagnosed with schizophrenia had worsening persecutory delusions, including that of being targeted by snipers, and had difficulty going out because of anxiety. She coped with her psychological distress using online shooting games. We assessed her state and trait anxiety, social anxiety, avoidance behavior when alone, and IGD severity. There was a notable reduction in the state anxiety score after the introduction of online gaming. The scores for trait anxiety, social anxiety, and avoidance behavior when alone decreased noticeably after the acquisition of coping strategies. This case demonstrates the presence of IGD only during the acquisition of coping strategies., Conclusion: This case highlights the potential of online gaming as a coping strategy for schizophrenia-related anxiety. However, excessive gaming can lead to IGD and thus necessitates caution. Further research should explore the applicability and potential risks of using online gaming to cope with psychological distress among patients with schizophrenia., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Hydrogen sulfide (H2S) played a pivotal role in the early evolution of life on Earth before the predominance of atmospheric oxygen. The legacy of a persistent role for H2S in life's processes recently emerged through its discovery in modern biochemistry as an endogenous cellular signalling modulator involved in numerous biological processes. One major mechanism through which H2S signals is protein cysteine persulfidation, an oxidative post-translational modification. In recent years, chemoproteomic technologies have been developed to allow the global scanning of protein persulfidation targets in mammalian cells and tissues, providing a powerful tool to elucidate the broader impact of altered H2S in organismal physiological health and human disease states. While hundreds of proteins were confirmed to be persulfidated by global persulfidome methodologies, the targeting of specific proteins of interest and the investigation of further mechanistic studies are still underdeveloped due to a lack of stringent specificity of the methods and the inherent instability of persulfides. This review provides an overview of the processes of endogenous H2S production, oxidation, and signalling and highlights the application and limitations of current persulfidation labelling approaches for investigation of this important evolutionarily conserved biological switch for protein function., (© 2024 The Author(s).)

Introduction: Pelvic arteriovenous malformation is often a source of intraoperative bleeding. Here, we report our experience with a case of ureteral cancer with pelvic arteriovenous malformation treated using laparoscopic nephroureterectomy with temporary intraoperative occlusion of the internal iliac artery., Case Presentation: A 75-year-old man presented to our hospital with asymptomatic macro-hematuria. Contrast-enhanced computed tomography revealed right ureteral tumor with no apparent metastases, and right pelvic arteriovenous malformation. Three months later, multiple bladder cancers were identified and the patient underwent trans-urethral resection of bladder tumor. The pathological diagnosis was urothelial carcinoma, pTa. We performed right laparoscopic nephroureterectomy with temporary intraoperative occlusion of the internal iliac artery. There was little intraoperative bleeding, and the surgery was safely completed. The pathological diagnosis was urothelial carcinoma, pT2 + Tis., Conclusion: A patient showing ureteral cancer with pelvic arteriovenous malformation was safely treated using laparoscopic nephroureterectomy with temporary occlusion of the internal iliac artery., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

Returned samples from the carbonaceous asteroid (162173) Ryugu provide pristine information on the original aqueous alteration history of the Solar System. Secondary precipitates, such as carbonates and phyllosilicates, reveal elemental partitioning of the major component ions linked to the primordial brine composition of the asteroid. Here, we report on the elemental partitioning and Mg isotopic composition ( 25 Mg/ 24 Mg) of breunnerite [(Mg, Fe, Mn)CO 3 ] from the Ryugu C0002 sample and the A0106 and C0107 aggregates by sequential leaching extraction of salts, exchangeable ions, carbonates, and silicates. Breunnerite was the sample most enriched in light Mg isotopes, and the 25 Mg/ 24 Mg value of the fluid had shifted lower by ~0.38‰ than the initial value (set to 0‰) before dolomite precipitation. As a simple model, the Mg 2+ first precipitated in phyllosilicates, followed by dolomite precipitation, at which time ~76-87% of Mg 2+ had been removed from the primordial brine. A minor amount of phyllosilicate precipitation continued after dolomite precipitation. The element composition profiles of the latest solution that interacted with the cation exchange pool of Ryugu were predominantly Na-rich. Na + acts as a bulk electrolyte and contributes to the stabilization of the negative surface charge of phyllosilicates and organic matter on Ryugu., (© 2024. The Author(s).)

Purpose: This study aimed to compare the deviation of hypermobile teeth in partially edentulous dental arches during impression taking using digital and conventional techniques., Methods: A partially edentulous mandibular model with three target hypermobile teeth (including the left first premolar, #34; left second molar, #37; and right first premolar, #44), was used as the simulation model. After reference data were acquired using a desktop scanner, impressions of the simulation model were obtained using a digital intraoral scanner (IOS) and two conventional techniques (hydrocolloid material with a stock tray and silicone material with a custom tray as impression data (n=12/group). The three-dimensional accuracy (root mean square value) and two-dimensional accuracy (mesiodistal and buccolingual displacements) of the target teeth in each impression dataset were calculated based on the reference data. The comparison among three impression techniques was statistically performed using the Kruskal-Wallis test (α=0.05)., Results: For #34 and #44, the three- and two-dimensional accuracies of the impressions fabricated through data acquired through digital scanning (digital impression) were significantly superior to those of the hydrocolloid impression (P < 0.05), whereas no significant difference was found between the digital and silicone impressions. For #37, no significant difference in the accuracy of the impression data for the target teeth was observed among the three impression techniques., Conclusions: Digital impression acquiring using an IOS is recommended over using a conventional hydrocolloid impression to prevent the deviation of hypermobile teeth in partially edentulous dental arches. Hypermobile tooth deviation in digital impression data depends on the tooth location.

The increased risk of adverse drug reactions due to the concomitant use of antipsychotics is problematic in the treatment of schizophrenia. Therefore, the simultaneous analysis of their plasma concentrations is required. In this study, we developed a simultaneous liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for analyzing plasma antipsychotics approved in Japan for therapeutic drug monitoring (TDM) applications. First, we counted the prescriptions for 16 antipsychotics and concomitant drugs used at the Tohoku University Hospital. LC-MS/MS was used for the simultaneous analysis of 16 antipsychotics and four drug metabolites. This analysis was conducted using a combination of selected reaction monitoring mode and reversed-phase chromatography. Following the examination of the MS/MS and LC conditions, an analytical method validation test was conducted. The developed method was used to analyze plasma antipsychotic levels in patients with schizophrenia. One-third of the patients received treatment with multiple antipsychotics. Under LC-MS/MS conditions, LC separation was performed using a combination of a C18 column and ammonium formate-based mobile phases with a gradient flow. The calibration curves were optimized by adjusting the ion abundance, and 11 compounds met the criteria for intra- and inter-day reproducibility tests. Some stability test results did not meet these criteria; therefore, further investigation is required. The developed method permitted the measurement of all the plasma parameters, including concentrations above the therapeutic range. Therefore, this method may be useful in the daily TDM practice of antipsychotics., (© 2024. The Author(s).)

Background: Maintenance avelumab is currently recommended for patients with unresectable and/or metastatic (mUC) achieving at least stable disease (SD) on first-line platinum-based chemotherapy (1L-CT). Pembrolizumab is an alternative therapeutic avenue for this patient cohort in clinical practice. We investigated real-world data, focusing on the correlation between response to 1L-CT and oncological efficacy of subsequent immune checkpoint inhibitor (ICI) therapy with avelumab or pembrolizumab., Methods: A multicenter database registered 626 patients with mUC diagnosed from 2008-2023; among these, 175 receiving 2-6 cycles of 1L-CT followed by ICI therapy. Patients were categorized based on response to 1L-CT using the Response Evaluation Criteria in Solid Tumors (v1.1). Objective response rate on ICI, progression to ICI-free survival (ICI-PFS), and overall survival from start of 1L-CT were compared between avelumab-treated and pembrolizumab-treated patients in each response subgroup., Results: ICI-PFS was significantly longer in patients achieving partial response on 1L-CT and subsequently receiving pembrolizumab compared to those receiving avelumab. Notably, patients achieving SD on 1L-CT and subsequently receiving pembrolizumab manifested significantly higher objective response rate (14% and 41%, respectively) and prolonged ICI-PFS relative to those receiving avelumab. In contrast, overall survival did not delineate difference between patients treated with avelumab versus pembrolizumab. Similar findings were discerned in the subanalysis of patients having favorable SD (tumor shrinkage, from - 29 to 0%) and unfavorable SD (tumor enlargement, from + 1 to + 19%) on 1L-CT., Conclusions: Our study provides real-world evidence regarding difference of oncological efficacy between maintenance avelumab and subsequent pembrolizumab in patients with mUC who achieved partial response or SD on 1L-CT., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. Using propensity score matching, we previously reported that the 3-year disease-free survival (DFS) rate was significantly higher in patients treated with uracil and tegafur plus leucovorin (UFT/LV) against surgery alone. We report the final results, including updated 5-year overall survival (OS) rates and risk factor analysis outcomes., Methods: In total, 1902 high-risk stage II CC patients with T4, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, and/or < 12 dissected lymph nodes were enrolled in this prospective, non-randomized controlled study based on their self-selected treatment. Oral UFT/LV therapy was administered for six months after surgery., Results: Of the 1880 eligible patients, 402 in Group A (surgery alone) and 804 in Group B (UFT/LV) were propensity score-matched. The 5-year DFS rate was significantly higher in Group B than in Group A (P = 0.0008). The 5-year OS rates were not significantly different between groups. The inverse probability of treatment weighting revealed significantly higher 5-year DFS (P = 0.0006) and 5-year OS (P = 0.0122) rates in group B than in group A. Multivariate analyses revealed that male sex, age ≥ 70 years, T4, < 12 dissected lymph nodes, and no adjuvant chemotherapy were significant risk factors for DFS and/or OS., Conclusion: The follow-up data from our prospective non-randomized controlled study revealed a considerable survival advantage in DFS offered by adjuvant chemotherapy with UFT/LV administered for six months over surgery alone in individuals with high-risk stage II CC., Trial Registration: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019), UMIN Clinical Trials Registry: UMIN000007783 (date of registration: 18/04/2012)., (© 2024. The Author(s).)

Purpose: The suprapatellar bursa is located in the proximal deep layer of the patella and is thought to reduce tissue friction by changing from a single-membrane structure to a double-membrane structure during knee joint motion. However, the dynamics of the suprapatellar bursa have only been inferred from positional relationships, and the actual dynamics have not been confirmed., Methods: Dynamics of the suprapatellar bursa during knee joint motion were observed in eight knees of four Thiel-fixed cadavers and the angle at which the bursa begins to show a double membrane was revealed. The flexion angles of knee joints were measured when the double-membrane structure of the suprapatellar bursa began to appear during knee joint extension., Results: The suprapatellar bursa changes from a single membrane to a double-membrane structure at 91 ± 4° of flexion, when the knee joint is moved from a flexed position to an extended position., Conclusion: The suprapatellar bursa may be involved in limitations to knee joint range of motion and pain at an angle of approximately 90°. Further studies are needed to verify whether the same dynamics are observed in living subjects., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Sex differences in the development and progression of cardiovascular disease manifest across multiple life stages. These differences are associated with variations in cardiovascular morphology and function between the sexes. Although estrogens and sex hormones are associated with sex differences in cardiovascular diseases in reproductive adults, the molecular mechanisms of cardiovascular sex differences during development are largely unknown. Thus, we investigated sex differences in cardiovascular development. We used a newly developed coronary arteriogram system to visualize the morphology of the coronary arteries in murine anterior surface ventricles at embryonic day 17.5 by injecting nanoparticle ink at a constant pressure. No sex difference was found in the length of ventricle. Based on the boundary value of the distribution of that length, the hearts were divided into "long" and "short" groups and the diameters of the left coronary arteries were analyzed. The mean diameter of the coronary arteries was significantly smaller in females than in males only in the group with the longer length of ventricle. This ventricular size-specific sex difference was observed in the presence of vasodilators such as NOC7 (1-Hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene). When NOC7 was perfused into the left coronary arteries of embryonic day 17.5 mice, females with longer ventricles showed larger left coronary arteries than males. These sex differences in vasodilation capacity suggest that factors related to drug reactivity such as signaling pathways are present at a late embryonic stage. These results indicate that sex differences in the functional morphology of the left coronary arteries exist at a late embryonic stage in mice. NEW & NOTEWORTHY This study introduces a novel coronary angiography method for analyzing murine embryonic hearts, revealing sex differences in coronary artery morphology and contractile function in the late stage of the fetal period. By categorizing heart components based on size, we unveil nuanced insights into sexual dimorphism during this critical fetal period. This work contributes insights into the early origins of sexual dimorphism in coronary vessels, laying the foundation for further understanding of cardiovascular development.

Competing Interests: The authors declare that they have no conflict of interest.

Objectives: To achieve a more beautiful and younger appearance, reducing wrinkles is a key concern. The process of wrinkle formation is complex and the development of truly effective cosmetic ingredients to reduce wrinkles remains a challenge. Recent studies have revealed a close relationship between wrinkles and skin thinning, suggesting that preventing skin thinning could also prevent wrinkle formation. In this study, we examined the role of extracellular adenosine triphosphate (eATP) in the progression of thinning, as eATP reportedly increases skin ageing factors, such as senescence-associated secreted phenotype (SASP) factors in epidermal cells. We determined the effects of Mentha piperita leaf extract on suppressing eATP to reduce thinning and wrinkles., Methods: Adenosine triphosphate (ATP) levels were measured in normal human epidermal keratinocytes (NHEK) in the presence of M. piperita leaf extract. Dryness, high pH, and UVB radiation were used as extrinsic ageing factors. Intrinsic skin ageing was evaluated by comparing cells from adults (AD-NHEK) and newborns (NB-NHEK). A placebo-controlled in vivo study was carried out with a formulation containing 1% M. piperita leaf extract., Results: The eATP levels were significantly higher in AD-NHEK compared with that in NB-NHEK cells. M. piperita leaf extract significantly decreased eATP levels in adult cells. Extrinsic ageing factors increased eATP levels in NHEK, whereas M. piperita leaf extract significantly suppressed eATP under all conditions. The active components of M. piperita leaf extract, luteolin glucuronide and rosmarinic acid, also decreased eATP. Moreover, compared with placebo lotion, M. piperita leaf extract-formulated lotion markedly increased dermal thickness and reduced wrinkles associated with crow's feet and the neck area., Conclusion: We demonstrated for the first time that M. piperita leaf extract containing rosmarinic acid and luteolin-7-O-glucuronide has the potential to reduce eATP release from epidermal keratinocytes. An increase in eATP was observed not only during inflammation but also during natural ageing. Furthermore, the in vivo experiment revealing that 1% M. piperita leaf extract-containing lotion improved dermal thinning and wrinkles across multiple areas is attributed to the amelioration of dermal thinning. Thus, our data suggest the possibility of a novel cosmetic approach for reducing skin ageing by reducing eATP-mediated dermal thinning., (© 2024 Society of Cosmetic Scientists and Societe Francaise de Cosmetologie.)