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(+)-Plakevulin A (1), an oxylipin isolated from an Okinawan sponge Plakortis sp. inhibits enzymatic inhibition of DNA polymerases (pols) α and δ and exhibits cytotoxicity against murine leukemia (L1210) and human cervix carcinoma (KB) cell lines. However, the half-maximal inhibitory concentration (IC 50 ) value for cytotoxicity significantly differed from those observed for the enzymatic inhibition of pols α and β, indicating the presence of target protein(s) other than pols. This study demonstrated cytotoxicity against human promyelocytic leukemia (HL60), human cervix epithelioid carcinoma (HeLa), mouse calvaria-derived pre-osteoblast (MC3T3-E1), and human normal lung fibroblast (MRC-5) cell lines. This compound had selectivity to cancer cells over normal ones. Among these cell lines, HL60 exhibited the highest sensitivity to (+)-plakevulin A. (+)-Plakevulin A induced DNA fragmentation and caspase-3 activation in HL60 cells, indicating its role in apoptosis induction. Additionally, hydroxysteroid 17-β dehydrogenase 4 (HSD17B4) was isolated from the HL60 lysate as one of its binding proteins through pull-down experiments using its biotinylated derivative and neutravidin-coated beads. Moreover, (+)-plakevulin A suppressed the activation of interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3). Because the knockdown or inhibition of STAT3 induces apoptosis and HSD17B4 regulates STAT3 activation, (+)-plakevulin A may induce apoptosis in HL60 cell lines by suppressing STAT3 activation, potentially by binding to HSD17B4. The present findings provide valuable information for the mechanism of its action., 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.)

Purpose: We aim to clarify the precise function of Transformed growth factor-beta 1 activated kinase-1 (TAK1) in cancer-associated fibroblasts (CAFs) within human pancreatic ductal adenocarcinoma (PDAC) by investigating its role in cytokine-mediated signaling pathways., Experimental Design: The expression of TAK1 in pancreatic cancer was confirmed by TCGA data and human pancreatic cancer specimens. CAFs from freshly resected PDAC specimens were cultured and used in a three-dimensional model for direct and indirect co-culture with PDAC tumors to investigate TAK1 function. Additionally, organoids from KPC (LSL-K-RasLSLG12D/+; LSL-p53R172H/+; Pdx1-Cre) mice were mixed with CAFs and injected subcutaneously into C57BL/6 mice to explore in vivo functional interactions of TAK1., Results: TCGA data revealed significant upregulation of TAK1 in PDAC, associating with a positive correlation with the T-cell exhaustion signature. Knockdown of TAK1 in CAFs decreased the iCAF signature and increased the myCAF signature both in vitro and in vivo. The absence of TAK1 hindered CAF proliferation, blocked several inflammatory factors via multiple pathways associated with immunosuppression, and hindered EMT, outgrowth in vitro in spheroid co-cultures with PDAC cells. Additionally, TAK1 inhibitor restrained tumor growth, increased CD4+ and CD8+ T cell abundance, and reduced immunosuppressive cells present in vivo., Conclusions: Blocking the TAK1+CAF phenotype leads to the conversion of protumorigenic CAFs to antitumorigenic CAFs. This highlights TAK1 as a potential therapeutic target, particularly in CAFs, and represents a novel avenue for combined immunotherapy in PDAC.

Background: Left atrial epicardial adipose tissue (LA-EAT) is associated with the recurrence of atrial tachyarrhythmias (AF/AT) after catheter ablation for atrial fibrillation (AF). However, no previous studies have assessed the predictive value of segment-specific LA-EAT volumes for AF/AT recurrence. This study aimed to assess the relationship between segmental LA-EAT volume and AF/AT recurrence., Methods: This study included 350 consecutive patients who underwent initial AF ablation (53.7 % paroxysmal AF (PAF)). Preoperative multidetector row computed tomography assessed LA-EAT, categorized into three segments: anterior-EAT, posterior-EAT, and interatrial septal adipose tissue (IAS-AT)., Results: During a mean follow-up period of 351 ± 109 days, 56 patients (16.0 %) experienced AF/AT recurrence. The mean LA-EAT volume was 20.7 ± 11.1 ml and LA-EAT ≥26.8 ml was an independent risk factor for AF/AT recurrence (HR 2.21, 95 % confidence interval (CI): 1.24-3.93, P = 0.007). Receiver operating characteristic analyses revealed the area under the curve for IAS-AT was 0.669 (95 % CI: 0.596-0.743) with an optimal cut-off point of 1.3 ml (sensitivity 76.8 %; specificity 50.0 %), significantly outperforming the anterior- and posterior-EAT in predicting recurrent AF/AT. Multivariate analysis indicated IAS-AT was an independent predictor of AF/AT recurrence in patients with persistent AF (PeAF) (HR 3.52, 95 % CI: 1.52-8.13, P = 0.003), but not in patients with PAF., Conclusions: LA-EAT predicts AF/AT recurrence after AF ablation, with IAS-AT proving significantly more effective than other LA-EAT segments in predicting recurrence. Notably, IAS-AT emerged as an independent predictor of AF/AT recurrence in patients with PeAF but not in those with PAF., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Tumor-associated neutrophils (TANs) constitute an abundant component among tumor-infiltrating immune cells and have recently emerged as a critical player in pancreatic ductal adenocarcinoma (PDAC) progression. This study aimed to elucidate the pro-tumor mechanisms of TAN and identify a novel target for effective immunotherapy against PDAC., Methods: Microarray and cytokine array analyses were performed to identify the mechanisms underlying the function of TANs. Human and mouse TANs were obtained from differentiated HL-60 cells and orthotopically transplanted PDAC tumors, respectively. The interactions of TANs with cancer and cytotoxic T-cells were evaluated through in vitro co-culture and in vivo orthotopic or subcutaneous models. Single-cell transcriptomes from patients with PDAC were analyzed to validate the cellular findings., Results: Increased neutrophil infiltration in the tumor microenvironment was associated with poor survival in patients with PDAC. TANs secreted abundant amounts of chemokine ligand 5 (CCL5), subsequently enhancing cancer cell migration and invasion. TANs subpopulations negatively correlated with cytotoxic CD8 + T-cell infiltration in PDAC and promoted T-cell dysfunction. TANs upregulated the membranous expression of Nectin2, which contributed to CD8 + T-cell exhaustion. Blocking Nectin2 improved CD8 + T-cell function and suppressed tumor progression in the mouse model. Single-cell analysis of human PDAC revealed two immunosuppressive TANs phenotypes: Nectin2 + TANs and OLR1 + TANs. Endoplasmic reticulum stress regulated the protumor activities in TANs., Conclusions: TANs enhance PDAC progression by secreting CCL5 and upregulating Nectin2. Targeting the immune checkpoint Nectin2 could represent a novel strategy to enhance immunotherapy efficacy in PDAC., (© 2024. The Author(s).)

Background: Preoperative vascular embolization is an effective strategy for managing meningiomas, neck paragangliomas, renal cell carcinomas, and bone metastasis by reducing the intraoperative bleeding volume and operation time. Although hypervascular tumors also occur in the pancreas, preoperative embolization for these tumors is not commonly practiced. We herein present a case of a giant serous cystic neoplasm (SCN) of the pancreas with significant arterial vascularity that was managed with preoperative interventional radiology and subsequently resected via pancreaticoduodenectomy., Case Presentation: A 60-year-old man presented with an 8-cm hypervascular tumor located at the head of the pancreas, identified as an SCN on pathologic examination. The tumor had increased by 13 mm over 5 years, necessitating surgical intervention. Computed tomography revealed a substantial blood supply to the tumor from the dorsal pancreatic artery and gastroduodenal artery, both branches of the superior mesenteric artery. To mitigate the risk of severe intraoperative bleeding from this giant hypervascular tumor, branches of the dorsal pancreatic artery and gastroduodenal artery were embolized using metallic coils and further secured using a gelatin sponge 1 day prior to pancreatectomy. During the laparotomy, the tumor appeared to have decreased in size, likely because of reduced distension and congestion. Despite significant adhesions to surrounding tissues secondary to prolonged compression and inflammation, the pancreaticoduodenectomy was completed successfully in 5 h and 15 min with blood loss of 763 mL. The patient was discharged on postoperative day 15 without complications., Conclusions: Preoperative arterial embolization for hypervascular pancreatic tumors might control the risk of massive intraoperative bleeding, contributing to a favorable postoperative outcome. Utilizing interventional radiology for preoperative inflow control is one of the beneficial strategies for pancreatectomy in patients with a giant SCN., (© 2024. The Author(s).)

[Purpose] This study investigated differences in the convergence mode of post-step sway between young and older adults using a step-down task to identify fall causes in older adults and assess consecutive postural adjustments. [Participants and Methods] This study included 15 young and 15 older adults (nine females and six males in each group). The participants stepped down from a standing position to a force platform 10 cm lower and maintained a one-leg standing position. The center-of-pressure total trajectory length was assessed using a force plate and regression equations for time and sway were derived from the associated time-series data for both groups. [Results] An inversely proportional aspect was observed for both groups, with significantly different coefficients and constants. The center-of-pressure total trajectory length per second from foot contact was significantly different between 2-3 s and 4-5 s in the older group but not in the younger group. [Conclusion] The results suggest a difference in the convergence mode of dynamic balance between the two groups, with young adults exhibiting a more rapid balance-sway reduction than older adults. The novel computational approach used in this study may be useful for dynamic balance measurements., Competing Interests: There are no conflicts of interest to declare., (2024©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Although the survival rate of patients with childhood cancer has greatly improved, long-term survivors face specific problems such as the late effects of cancer treatment. In this study, we estimated the number of people who had experienced childhood cancer to predict their needs for medical care and social resources. Using data from the population-based Osaka Cancer Registry, we identified children aged 0-14 years who were diagnosed with cancer between 1975 and 2019. We estimated the prevalence on December 31, 2019, and the 5- and 10-year prevalence (i.e., the number of survivors living up to 5 or 10 years after the diagnosis of cancer) over time. The prevalence proportion was age-standardized using a direct standardization method. The prevalence estimates for Osaka were applied to the national population to determine the national prevalence in Japan. Among 8186 patients diagnosed with childhood cancer in Osaka, 5252 (987 per million) survived until December 31, 2019. The 5-year prevalence per million increased from 194 in 1979 to 417 in 2019 (+116%), while the 10-year prevalence increased from 391 in 1984 to 715 in 2019 (+83%). Based on the long-term registry data, an estimated 73,182 childhood cancer survivors were living in Japan by the end of 2019. The increasing 5-year and 10-year prevalence proportions indicate the continued need for cancer survivorship support for children, adolescents, and young adults. These estimates of the prevalence of childhood cancer survivors, including long-term survivors, may be useful for policymakers and clinicians to plan and evaluate survivorship care., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: Bronchopleural fistula (BPF) is a serious complication of lung resection. To avoid BPF, the bronchial stump/anastomotic site is often covered with a flap of surrounding tissue. One risk factor for BPF is radical lung resection after induction chemoradiotherapy for lung cancer. We retrospectively reviewed our database to elucidate the characteristics of tissue flaps that prevent BPF., Methods: This retrospective study included 152 patients treated between 1999 and 2019. We examined the clinicopathological characteristics, including the type and thickness of the tissue flap used to cover the bronchial stump/anastomotic site, and postoperative complications, including BPF., Results: BPF occurred in 5 patients (3.3%). All 5 patients had complications that could have affected delayed wound healing, such as pneumonia. The covering tissue flap thickness was significantly greater in patients without BPF than in those who developed BPF (p = 0.0290). Additionally, the tissue flap thickness was significantly greater than in those with BPF (p = 0.0077), even in high-risk patients who developed pneumonia or radiation pneumonitis on the operative side within 6 months postoperatively., Conclusion: Perioperative management is crucial to avoid complications affecting the healing of the bronchial stump/anastomotic site, and the covering tissue flap thickness may be an important factor in avoiding or minimizing BPF., (© 2024. The Author(s).)

Purpose: Doublet chemotherapy with fluoropyrimidine (FP) and oxaliplatin (OX) plus bevacizumab (BEV) is a standard regimen for unresectable metastatic colorectal cancer (MCRC). However, the efficacy of adding OX to FP plus BEV (FP + BEV) remains unclear for older patients, a population for whom FP + BEV is standard. We aimed to confirm the superiority of adding OX to FP + BEV for this population., Methods: This open-label, randomized, phase III trial was conducted at 42 institutions in Japan. Patients with unresectable MCRC age 70-74 years with Eastern Cooperative Oncology Group performance status (ECOG-PS) 2 and those 75 years and older with ECOG-PS 0-2 were randomly assigned (1:1) to an FP + BEV arm or an OX addition (FP + BEV + OX) arm. Fluorouracil plus levofolinate calcium or capecitabine was declared before enrollment. The primary end point was progression-free survival (PFS). The study was registered in the Japan Registry of Clinical Trials (identifier: jRCTs031180145)., Results: Between September 2012 and March 2019, 251 patients were randomly assigned to the FP + BEV arm (n = 125) and the FP + BEV + OX arm (n = 126). The median age was 80 and 79 years in the respective arm. The median PFS was 9.4 months (95% CI, 8.3 to 10.3) in the FP + BEV arm and 10.0 months (9.0 to 11.2) in the FP + BEV + OX arm (hazard ratio [HR], 0.84 [90.5% CI, 0.67 to 1.04]; one-sided P = .086). The median overall survival was 21.3 months (18.7 to 24.3) in the FP + BEV arm and 19.7 months (15.5 to 25.5) in the FP + BEV + OX arm (HR, 1.05 [0.81 to 1.37]). The proportion of any grade ≥3 adverse events was higher in the FP + BEV + OX arm (52% v 69%). There was one treatment-related death in the FP + BEV arm and three in the FP + BEV + OX arm., Conclusion: No benefit of adding OX to FP + BEV as first-line treatment was demonstrated in older patients with MCRC. FP + BEV is recommended for this population.

The objective of this study was to establish an evaluation technique for the feline pelvic cavity using computed tomography (CT). Client-owned cats with a normal pelvis (n = 50) or pelvic stenosis (n = 3) were included. We categorized pelvic CT images in the normal pelvis group into two types according to pelvic cavity shape, then calculated the sacral index (SI), pelvic canal area (PCA), and PCA/sacral width index (PSI). The reference intervals of these variables were determined based on the results in the normal pelvis group. In the normal pelvis group, the PSI, unlike the SI and PCA, was not affected by body weight. In addition to high intraobserver and interobserver reproducibilities, the PSI showed no significant differences according to pelvic cavity shape. However, the SI exhibited significant differences among pelvic cavity shapes. In the stenosis group, the postoperative PSI in all cats was within the reference interval. However, the postoperative SI in one case was lower than the reference interval. The PSI may become a new method for evaluation of the pelvic cavity, including the pelvic floor., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: The transmission of carbapenemase-producing Enterobacterales (CPE) in the external environment, especially through food, presents a significant public health risk., Objectives: To investigate the prevalence and genetic characteristics of CPE in food markets of Dhaka, Bangladesh, using WGS., Methods: CPE isolates were obtained from different food and water samples collected from food markets in the southern part of Dhaka, Bangladesh. The isolates subsequently underwent molecular typing, WGS employing both short- and long-read sequencers, and plasmid analysis., Results: This study unveiled an extensive spread of CPE, with no significant difference in contamination rates observed in samples ( N  = 136), including meat ( n  = 8), fish ( n  = 5), vegetables ( n  = 36) or various food-washed water ( n  = 65) from markets near hospitals or residential areas. Thirty-eight Enterobacterales from 33 samples carried carbapenemase genes ( bla NDM-1, -4, -7 , bla KPC-2 , bla OXA-181 or bla IMI-1 ). Among these, the high-risk Escherichia coli ST410 clone was the most prevalent and distributed across various locations. Furthermore, the identification of IncHI2 plasmids co-harbouring resistance genes like bla NDM-5 and mcr-1.1 , without discernible epidemiological connections, is a unique finding, suggesting their widespread dissemination., Conclusions: The analysis unveils a dynamic landscape of CPE dissemination in food markets, underscored by the proliferation of novel IncHI2 hybrid plasmids carrying both colistin- and carbapenem-resistance genes. This illuminates the ever-evolving landscape of antimicrobial resistance in Dhaka, urging us to confront its emergent challenges., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Aims: The new nomenclature of steatotic liver disease (SLD) including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) has recently been proposed. We aimed to elucidate the relationship between each category of SLD and chronic kidney disease (CKD)., Methods: We investigated the effects of various SLDs on the development of CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 or positive for urinary protein, during a 10-year period in 12 138 Japanese subjects (men / women, 7984/4154; mean age, 48 years) who received annual health examinations including abdominal ultrasonography., Results: The prevalences of SLD without metabolic dysfunction (SLD-MD[-]), MASLD, MetALD, and ALD were 1.7%, 26.3%, 4.9%, and 1.9%, respectively. During the follow-up period, 1963 subjects (16.2%) (men / women, 1374 [17.2%]/589 [14.2%]) had new onset of CKD. Multivariable Cox proportional hazard model analyses after adjustment of age, sex, eGFR, current smoking habit, diabetes mellitus, hypertension, and dyslipidemia showed that the hazard ratios (HR [95% confidence interval]) for the development of CKD in subjects with MASLD (1.20 [1.08-1.33], p = 0.001) and those with ALD (1.41 [1.05-1.88], p = 0.022), but not those with MetALD (1.11 [0.90-1.36], p = 0.332), were significantly higher than the HR in subjects with non-SLD. Interestingly, subjects with SLD-MD[-] had a significantly lower HR (0.61 [0.39-0.96], p = 0.034) than that in subjects with non-SLD. The addition of the novel classification of SLDs into traditional risk factors for the development of CKD significantly improved the discriminatory capacity., Conclusions: MASLD and ALD, but not SLD-MD[-], are independently associated with the development of CKD., (© 2024 The Japan Society of Hepatology.)

Pancreatic acinar cell carcinoma (PACC) is a very rare subtype of pancreatic cancer. Due to small number of patients, no standard chemotherapy protocol has been established. We experienced an extremely rare case of PACC with liver metastasis that showed a pathological complete response after modified FOLFIRINOX (mFFX) therapy. A 42-year-old man who underwent distal pancreatectomy for an 80 mm tumor at the pancreatic tail 3 years ago was referred to our hospital in September 2017 for the treatment of a recurrent liver tumor. Percutaneous biopsy revealed an acinar-neuroendocrine carcinoma, similar to the surgical specimen. He received eight cycles of irinotecan plus cisplatin chemotherapy. However, the tumor increased in size, and treatment was switched to mFFX therapy. The tumor in the liver shrank remarkably after nine cycles of mFFX therapy. Conversion surgery was selected, and the patient underwent hepatic left and caudate lobectomy 8 months after administration of mFFX. The resected specimen showed no viable tumor cells, indicating a pathological complete response. The histological diagnosis was reconsidered, and PACC was finally diagnosed via an additional immunohistological review. The patient has remained well with no recurrence for 6 years after surgery. This study is the first to report a case of pathological complete response with mFFX therapy for the recurrence of PACC., (© 2024. Japanese Society of Gastroenterology.)

Objective: To determine the interobserver variability for complications of pancreatoduodenectomy as defined by the International Study Group for Pancreatic Surgery (ISGPS) and others., Summary Background Data: Good interobserver variability for the definitions of surgical complications is of major importance in comparing surgical outcomes between and within centers. However, data on interobserver variability for pancreatoduodenectomy-specific complications are lacking., Methods: International cross-sectional multicenter study including 52 raters from 13 high-volume pancreatic centers in 8 countries on 3 continents. Per center, 4 experienced raters scored 30 randomly selected patients after pancreatoduodenectomy. In addition, all raters scored six standardized case vignettes. This variability and the 'within centers' variability were calculated for twofold scoring (no complication/grade A vs grade B/C) and threefold scoring (no complication/grade A vs grade B vs grade C) of postoperative pancreatic fistula (POPF), post-pancreatoduodenectomy hemorrhage (PPH), chyle leak (CL), bile leak (BL), and delayed gastric emptying (DGE). Interobserver variability is presented with Gwet's AC-1 measure for agreement., Results: Overall, 390 patients after pancreatoduodenectomy were included. The overall agreement rate for the standardized cases vignettes for twofold scoring was 68% (95%-CI: 55%-81%, AC1 score: moderate agreement) and for threefold scoring 55% (49%-62%, AC1 score: fair agreement). The mean 'within centers' agreement for twofold scoring was 84% (80%-87%, AC1 score; substantial agreement)., Conclusion: The interobserver variability for the ISGPS defined complications of pancreatoduodenectomy was too high even though the 'within centers' agreement was acceptable. Since these findings will decrease the quality and validity of clinical studies, ISGPS has started efforts aimed at reducing the interobserver variability., Competing Interests: Conflicts of Interest and Source of Funding: No conflicts of interest declared or source of funding, (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Recent advances in treating colorectal cancer (CRC) have increased the importance of multidisciplinary treatment. This study aimed to clarify trends in the treatment and survival of CRC using population-based cancer registry data in Japan. We analyzed the survival of CRC cases diagnosed from 1995 through 2015 from a population-based cancer registry of six prefectures. The year of diagnosis was classified into five periods, and the trends in the detailed categorization of treatments and survival were identified. We calculated net survival and excess hazard of death from cancer using data on 256,590 CRC patients. The use of laparoscopic surgery has been increasing since 2005 and accounts for the largest proportion of treatment types in the most recent period. Net survival of CRC patients diagnosed after 2005 remained high for laparoscopic surgery and endoscopic surgery (endoscopic mucosal resection or endoscopic submucosal dissection). There was an upward trend in treatment with chemotherapy in addition to open and laparoscopic surgery. Using the excess hazard ratio at the regional stage since 2005, there has been a significant improvement in survival in the younger age group and the rectum cancer group. By type of treatment, there was a tendency toward significant improvement in the open surgery + chemotherapy group. We clarified the trends in treating CRC and the associated trends in survival. Continuous survey based on population-based data helps monitor the impact of developments in treatment., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

In 2023, the Japan Pancreas Society (JPS) published the new eighth edition of the Japanese classification of pancreatic carcinoma. We present here an excerpted version in English, based on the latest edition. The major changes in this revision are as follows: In the eighth edition of the Union for International Cancer Control (UICC), the T category was changed to be based on tumor size; however, the eighth edition of the Japanese classification retains the previous T category based on local invasion factors. Lymph nodes have been renamed, and regional lymph nodes have been defined by location. Peritoneal cytology, which was not previously included in distant metastasis (M), has now been included in the M category. Moreover, significant additions have been made regarding the pathological diagnosis of endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) and criteria for histological assessment of the effects after chemotherapy and radiation therapy. Although this classification is aimed at carcinoma originating in the pancreas, not in the bile duct or duodenum, if the differentiation of the primary organ is difficult, this classification should be applied. It is also desirable to describe tumors other than carcinoma and metastatic tumors to the pancreas in accordance with this classification., (© 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.)

Purpose: The purpose of this study was to reveal the changes in the shape of the posterior femoral condyle and the morphology of the ACL, both before and after epiphyseal closure. The hypothesis of this study is that the morphological change of the posterior femoral condyle and that of the ACL may be correlated to some extent., Methods: Eighty-one patients who underwent surgery for the knee joint (meniscal repair, arthroscopic synovectomy, medial patellofemoral ligament reconstruction) between 2016 and 2021 were included in this study, 48 patients aged 13 years or under (before epiphysis closure; mean age: 10.9 (range: 7-13) and 33 patients aged over 18 years or over (after epiphysis closure; mean age: 21.7 (range: 18-30). The shape of the posterior femoral condyle was evaluated via lateral view radiographs, and the morphology of the ACL was measured via sagittal and coronal magnetic resonance imaging (MRI) images., Results: The morphology of the posterior condyle in the lateral view radiograph in patients aged 13 and under was larger in the direction of the short axis of the femur compared with that in those aged 18 and over (p < 0.001). The mean value of the inclination angle of the anterior cruciate ligament (ACL) in the sagittal plane was significantly smaller in patients aged 13 and under (41.7° ± 3.7) than in those aged 18 and over (48.5° ± 4.2) (p < 0.001). The mean values of the inclination angle of the ACL in the coronal plane were significantly smaller in patients aged 13 and under (55.7° ± 6.4) than in those aged 18 and over (63.4° ± 4.4) (p < 0.001)., Conclusion: This study evaluates and compares the shape of the posterior femoral condyle and the morphology of the ACL fiber before and after epiphyseal closure. The posterior femoral condyle grew posteriorly rather than longitudinally, and the inclination of the ACL fibers was thought to change accordingly., Level of Evidence: Level Ⅲ., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Although oral tolerance is a critical system in regulating allergic disorders, the mechanisms by which dietary factors regulate the induction and maintenance of oral tolerance remain unclear. To address this, we explored the differentiation and function of various immune cells in the intestinal immune system under fasting and ad libitum-fed conditions before oral ovalbumin (OVA) administration. Fasting mitigated OVA-specific Treg expansion, which is essential for oral tolerance induction. This abnormality mainly resulted from functional defects in the CX3CR1 + cells responsible for the uptake of luminal OVA and reduction of tolerogenic CD103 + dendritic cells. Eventually, fasting impaired the preventive effect of oral OVA administration on asthma and allergic rhinitis development. Specific food ingredients, namely carbohydrates and arginine, were indispensable for oral tolerance induction by activating glycolysis and mTOR signaling. Overall, prior food intake and nutritional signals are critical for maintaining immune homeostasis by inducing tolerance to ingested food antigens., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hand washing instructions for children have been implemented in school education to establish good lifestyle habits. However, repeated hand washing through education from early childhood was common for both teachers and children. If this continues, children might assume they already know how to wash their hands, stop taking handwashing instructions seriously, and become increasingly lax about washing their hands., Purpose: This study aimed to develop a new handwashing education method for children., Methods: We applied the adenosine triphosphate (ATP) test to health education on hand washing in elementary schools. This study was conducted as part of a class for elementary school students in October 2023, in Hokkaido, Japan. The subjects were 157 third-grade (9-10 years old) elementary school students. After excluding absent pupils, 147 were included in the analysis., Results: Both pre- and post-education, ATP values after handwashing were lower than those before handwashing. Following the education, children's handwashing behavior improved, with an increase in the number of point washed and appropriate timing of handwashing., Conclusion: The new handwashing education program utilizing the ATP-test succeeded in promoting handwashing behavior among many children. Visualizing handwashing using ATP values was effective in motivating children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Oura, Naito, Yako-Suketomo, Nakata, Koyama and Ohnishi.)

In the management of osteoporosis, anti-resorptive agents serve as a primary therapeutic approach. However, in cases where individuals exhibit an increased susceptibility to fractures, such as those characterized by severe low bone mass or a history of vertebral or hip fractures that markedly diminish life expectancy, the immediate reduction of fracture risk through the administration of osteoanabolic agents could be beneficial. Teriparatide, available in daily, once-weekly, or twice-weekly dosages, along with abaloparatide and romosozumab, constitutes a trio of such agents. Each of these medications is defined by unique characteristics, distinct efficacy profiles, and specific adverse effects. There is growing evidence to suggest that these agents have a superior effect on enhancing bone mineral density and reducing fracture incidence when compared to traditional bisphosphonate therapies. Nonetheless, their employment demands thorough consideration of clinical indications, which includes evaluating economic factors, the frequency of injections required, and the potential for adverse effects. The objective of this review is to consolidate the current evidence focusing primarily on the efficacy of these agents, with the goal of enhancing understanding and aiding in making more informed treatment decisions, particularly for those individuals who are at an elevated risk of fractures., (© 2024. The Author(s).)

Background: The clinical success of liver transplantation has led to increased demand, requiring further expansion of the donor pool. Therapeutic interventions to optimize organs from donation after circulatory death (DCD) have significant potential to mitigate the organ shortage. Dysfunction in DCD liver grafts is mediated by microvascular thrombosis during the warm ischemic period, and strategies that reduce this thrombotic burden may improve graft function. We hypothesized that the administration of the fibrinolytic enzyme plasmin to the donor organ during the cold storage period would reduce the thrombotic burden and improve DCD liver graft function., Methods: In 2 separate cohorts, 32 syngeneic orthotopic rat liver transplants were performed in Lewis rats. Livers were procured from donors with 45 min of warm ischemic injury. Liver grafts were flushed with histidine-tryptophan-ketoglutarate preservation solution mixed with either plasmin (experimental group) or albumin (control group). All investigators were blinded to treatment group. After preparing the liver for implant using a modified cuff technique, the liver was stored for 1 h by static cold storage at 4 °C. Immediately before implantation, the liver graft was flushed, and this effluent was analyzed for fibrin degradation products to determine graft clot burden. Twenty-four hours following transplantation, animals were euthanized, and samples were collected., Results: Recipient survival was significantly higher for DCD liver grafts treated with plasmin compared with control. Moreover, histology of liver graft tissue immediately before implant reflected significantly reduced congestion in plasmin-treated livers (score, mean ± SD: 0.73 ± 0.59 versus 1.12 ± 0.48; P  = 0.0456). The concentration of fibrin degradation products in the final flush before implantation was significantly reduced in plasmin-treated livers (743 ± 136 versus 10 919 ± 4642 pg/mL; P  = 0.0001), reflecting decreased clot burden in the graft., Conclusions: The present study demonstrates that plasmin improves survival and may reduce thrombotic burden in DCD liver grafts with prolonged warm ischemic injury, meriting further study., Competing Interests: M.G.H. and A.S.B. are members of the Medical Advisory Board of BMI OrganBank. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Pseudocirrhosis, which is radiologically and clinically similar to liver cirrhosis, may develop following chemotherapy for breast cancer with liver metastasis. There are few reports of eribulin treatment. We report 5 patients with metastatic or recurrent breast cancer who developed pseudocirrhosis during eribulin treatment. All patients had diffuse liver metastasis, and the liver metastases significantly reduced in size during the early phase of eribulin treatment, when they developed pseudocirrhosis. Subsequently, the patients had poor prognoses.

Background: Recently, two molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) have been proposed: the "Classical" and "Basal-like" subtypes, with the former showing better clinical outcomes than the latter. However, the "molecular" classification has not been applied in real-world clinical practice. This study aimed to establish patient-derived organoids (PDOs) for PDAC and evaluate their application in subtype classification and clinical outcome prediction., Methods: We utilized tumor samples acquired through endoscopic ultrasound-guided fine-needle biopsy and established a PDO library for subsequent use in morphological assessments, RNA-seq analyses, and in vitro drug response assays. We also conducted a prospective clinical study to evaluate whether analysis using PDOs can predict treatment response and prognosis., Results: PDOs of PDAC were established at a high efficiency (> 70%) with at least 100,000 live cells. Morphologically, PDOs were classified as gland-like structures (GL type) and densely proliferating inside (DP type) less than 2 weeks after tissue sampling. RNA-seq analysis revealed that the "morphological" subtype (GL vs. DP) corresponded to the "molecular" subtype ("Classical" vs. "Basal-like"). The "morphological" classification predicted the clinical treatment response and prognosis; the median overall survival of patients with GL type was significantly longer than that with DP type (P < 0.005). The GL type showed a better response to gemcitabine than the DP type in vitro, whereas the drug response of the DP type was improved by the combination of ERK inhibitor and chloroquine., Conclusions: PDAC PDOs help in subtype determination and clinical outcome prediction, thereby facilitating the bench-to-bedside precision medicine for PDAC., (© 2024. The Author(s).)

Aims: To investigate effects of tirzepatide, a dual receptor agonist for glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), on eating behaviors., Methods: Eating behaviors were evaluated by using a validated questionnaire survey in 33 Japanese patients with type 2 diabetes mellitus (T2DM) (mean age: 51.8 years) who were treated with tirzepatide (2.5 mg/week for 4 weeks and then 5.0 mg/week) for 6 months (M)., Results: Treatment with tirzepatide significantly decreased median hemoglobin A1c (HbA1c) (baseline/3 M/6 M: 7.3 %/6.0 %/5.8 %), mean body weight (BW) (baseline/3 M/6 M: 87.7 kg/82.0 kg/79.6 kg) and mean relative score of eating behaviors (baseline/3 M/6 M: 57.0/50.7/45.9). In the GLP-1 receptor agonist (GLP-1RA) naïve group (n = 20, men/women: 13/7), HbA1c and BW were continuously decreased up to 6 M. Changes in eating behaviors were mainly observed in the first 3 M. In the GLP-1RA non-naïve group (n = 13, men/women: 8/5), reductions in HbA1c and BW were predominant in the first 3 M, and changes in eating behaviors were observed up to 6 M. There were no significant correlations of changes in scores of eating behaviors with changes in glycemic control or those in BW., Conclusions: Tirzepatide ameliorates eating behaviors as well as glycemic management and obesity in Japanese patients with T2DM, and the patterns of improvement are partially dependent on prior exposure to GLP-1RAs., Competing Interests: Declaration of competing interest Tor.S., Tat.S. and M.F. received honoraria from Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Corporation., MSD K.K., Novo Nordisk Pharma Ltd., Sanofi K.K., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aimed to evaluate the mechanical properties of bone plug fixation to the tibia with a novel device, the Bone plug Tensioning and Fixation (BTF) system.Forty bone-tendon-bone grafts consisting of the whole patella-patellar tendon-tibial bone plug of 10-mm width and tibiae from the porcine were prepared. After creating a 10-mm tibial tunnel, the tibial bone plug was fixed to the tibia with the BTF system or the interference screw (IFS) to prepare a test specimen of the patella-patellar tendon-tibial bone plug fixed to the tibia. For the graft tension controllability study, a predetermined initial tension of 9.8 or 19.6 N was applied and maintained for 5 minutes. Then the bone plug was fixed to the tibia with the BTF system or IFS in 10 specimens, monitoring the residual tension for an additional 5 minutes. Then, a cyclic loading test and a tension-to-failure test were performed.The mean difference between the residual tension and the predetermined tension was significantly smaller in BTF fixation (9.8 N → 10.6 ± 2.2 N; 19.6 N → 18.9 ± 2.1 N) than in IFS fixation (9.8 N → 23.4 ± 7.4 N; 19.6 N → 28.9 ± 11.5 N). The mean displacement of the bone plug after cyclic loading was significantly less in the BTF group (1.2 ± 0.6 mm) than in the IFS group (2.2 ± 1.0 mm; p  < 0.01). Stiffness was significantly greater in the BTF group (504.6 ± 148.8 N/mm) than in the IFS group (294.7 ± 96.7 N/mm; p  < 0.01), whereas the maximum failure loads in the two groups did not differ significantly (724.2 ± 180.3 N in the BTF and 634.8 ± 159.4 N in the IFS groups).BTF system better performed in graft tension controllability than IFS did. BTF fixation was superior to IFS fixation in the displacement of the bone plug during the cyclic loading test and in stiffness in the tension-to-failure test., Competing Interests: None declared., (Thieme. All rights reserved.)

This study aimed to confirm urinary protein fragments in relation to the presence of pancreatic ductal adenocarcinoma (PDAC) via a C-terminal proteomics strategy using exploratory and validation cohorts. Urinary fragments were examined by iTRAQ-labelling of tryptic peptides and concentrations of C-terminal fragments were evaluated. Only the urinary CD276 fragment showed a fold change (FC) of > 1.5 with a significant difference of P < 0.01 between healthy (H) and PDAC participants in both the exploratory (H, n = 42; PDAC, n = 39) and validation cohorts (H, n = 36; resectable PDAC, n = 28). The sensitivity and specificity of the CD276 fragment for diagnosing resectable PDAC were 75% and 89%, respectively, in the validation cohort. Postoperative urinary levels of the CD276 fragment were low as compared to those before surgery (n = 18, P < 0.01). Comprehensive C-terminus proteomics identified an increase in the urinary CD276 fragment level as a feature of patients with PDAC. The urinary CD276 fragment is a potential biomarker for detecting resectable PDAC., (© 2024. The Author(s).)

Purpose: To establish if osteosarcopenia is related to postoperative complications, prognosis, and recurrence of colorectal cancer (CRC) after curative surgery., Methods: The clinical data of 594 patients who underwent curative resection for CRC between January, 2013 and December, 2018 were analyzed retrospectively to examine the relationship between clinicopathological data and osteosarcopenia. The following definitions were used: sarcopenia, low skeletal muscle mass index; osteopenia, low bone mineral density on computed tomography at the level of the 11th thoracic vertebra; and osteosarcopenia, sarcopenia with osteopenia., Results: Osteosarcopenia was identified in 98 patients (16.5%) and found to be a significant risk factor for postoperative complications (odds ratio 2.53; p = 0.011). The 5-year overall survival (OS) and recurrence-free survival (RFS) rates of the patients with osteosarcopenia were significantly lower than those of the patients without osteosarcopenia (OS: 72.5% and 93.9%, respectively, p < 0.0001; RFS: 70.8% and 92.4%, respectively, p < 0.0001). Multivariate analysis identified osteosarcopenia as an independent prognostic factor associated with OS (hazard ratio 3.31; p < 0.0001) and RFS (hazard ratio 3.67; p < 0.0001)., Conclusion: Osteosarcopenia may serve as a predictor of postoperative complications and prognosis after curative surgery for CRC., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Skeletal muscle injury (SMI) is often treated conservatively, although it can lead to scar tissue formation, which impedes muscle function and increases muscle re-injury risk. However, effective interventions for SMIs are yet to be established., Hypothesis: The administration of Silk Elastin® (SE), a novel artificial protein, to the SMI site can suppress scar formation and promote tissue repair., Study Design: A controlled laboratory study., Methods: In vitro : Fibroblast migration ability was assessed using a scratch assay. SE solution was added to the culture medium, and the fibroblast migration ability was compared across different concentrations. In vivo : An SMI model was established with Sprague-Dawley rats, which were assigned to three groups based on the material injected to the SMI site: SE gel (SE group; n = 8), atelocollagen gel (Atelo group; n = 8), and phosphate buffer saline (PBS group; n = 8). Histological evaluations were performed at weeks 1 and 4 following the SMI induction. In the 1-week model, we detected the expression of transforming growth factor (TGF)-β1 in the stroma using immunohistological evaluation and real-time polymerase chain reaction analysis. In the 4-week model, we measured tibialis anterior muscle strength upon peroneal nerve stimulation as a functional assessment., Results: In vitro : The fibroblast migration ability was suppressed by SE added at a concentration of 10⁴ μg/mL in the culture medium. In vivo : In the 1-week model, the SE group exhibited significantly lower TGFβ -1 expression than the PBS group. In the 4-week model, the SE group had a significantly larger regenerated muscle fiber diameter and smaller scar formation area ratio than the other two groups. Moreover, the SE group was superior to the other two groups in terms of regenerative muscle strength., Conclusion: Injection of SE gel to the SMI site may inhibit tissue scarring by reducing excessive fibroblast migration, thereby enhancing tissue repair., Clinical Relevance: The findings of this study may contribute to the development of an early intervention method for SMIs., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kyohei Nakata reports equipment, drugs, or supplies was provided by Hiroshima University Hospital. Silk elastin is provided by Sanyo Chemical Industries, Ltd. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

An association between periodontal disease and the development of pancreatic cancer has been pointed out since before. Advances in genome analysis technology have revealed that a pancreatic cancer-specific microbiome is formed in the intestines and tumors of pancreatic cancer patients and modifies the progression of pancreatic cancer. Disturbance of microbiome( dysbiosis)suppresses anti-tumor immunity against pancreatic cancer, promoting cancer progression. Therefore, attempts are being made to correct dysbiosis by administration of probiotics or transplantation of microbiome, which is especially activating immune checkpoint inhibitors against cancer. In addition, specific intratumor bacteria has been identified that create an immunosuppressive microenvironment through crosstalk with pancreatic cancer cells. In the future, analysis of the microbiome distribution in pancreatic cancers may determine the following treatment strategy as an individualized treatment. We hope that innovations in omics technology will reveal more detailed functions of microbiome and lead to the development of effective treatments for pancreatic cancer.

Background: Anterior cruciate ligament injury frequently occurs in the deceleration with the knee-extended position. In addition, a rapid hip internal rotation is concomitantly observed. However, how the extended knee position induces the hip internal rotation is unclear., Methods: Sixteen healthy participants performed the simulated foot impact task on the experimental chair. To vary the knee flexion angle, the following four-foot placement positions relative to the pelvis segment, i.e.: 1) near; 2) middle; 3) far; and 4) far + heel strike, were tested. The reflective marker positions and the ground reaction force (GRF) data were collected. The moment of inertia of the entire lower limb around its long axis as well as the peak hip internal rotation angular velocity were calculated and compared among four conditions (Wilcoxon Signed-Rank Test with Bonferroni correction, P<0.0083)., Results: As the knee extended from the near to far + heel strike condition, the moment of inertia of the entire lower limb significantly decreased and hip internal rotation angular velocity significantly increased (P<0.001)., Conclusions: The extended knee position with far foot placement from torso reduces the inertial resistance of the entire lower limb around its long axis and is vulnerable to the hip internal rotation.

Background: Left ventricular ejection fraction (LVEF) is the most commonly clinically used imaging parameter for assessing cancer therapy-related cardiac dysfunction (CTRCD). However, LVEF declines may occur late, after substantial injury. This study sought to investigate cardiovascular magnetic resonance (CMR) imaging markers of subclinical cardiac injury in a miniature swine model., Methods: Female Yucatan miniature swine (n = 14) received doxorubicin (2 mg/kg) every 3 weeks for 4 cycles. CMR, including cine, tissue characterization via T 1 and T 2 mapping, and late gadolinium enhancement (LGE) were performed on the same day as doxorubicin administration and 3 weeks after the final chemotherapy cycle. In addition, magnetic resonance spectroscopy (MRS) was performed during the 3 weeks after the final chemotherapy in 7 pigs. A single CMR and MRS exam were also performed in 3 Yucatan miniature swine that were age- and weight-matched to the final imaging exam of the doxorubicin-treated swine to serve as controls. CTRCD was defined as histological early morphologic changes, including cytoplasmic vacuolization and myofibrillar loss of myocytes, based on post-mortem analysis of humanely euthanized pigs after the final CMR exam., Results: Of 13 swine completing 5 serial CMR scans, 10 (77%) had histological evidence of CTRCD. Three animals had neither histological evidence nor changes in LVEF from baseline. No absolute LVEF <40% or LGE was observed. Native T 1 , extracellular volume (ECV), and T 2 at 12 weeks were significantly higher in swine with CTRCD than those without CTRCD (1178 ms vs. 1134 ms, p = 0.002, 27.4% vs. 24.5%, p = 0.03, and 38.1 ms vs. 36.4 ms, p = 0.02, respectively). There were no significant changes in strain parameters. The temporal trajectories in native T 1 , ECV, and T 2 in swine with CTRCD showed similar and statistically significant increases. At the same time, there were no differences in their temporal changes between those with and without CTRCD. MRS myocardial triglyceride content substantially differed among controls, swine with and without CTRCD (0.89%, 0.30%, 0.54%, respectively, analysis of variance, p = 0.01), and associated with the severity of histological findings and incidence of vacuolated cardiomyocytes., Conclusion: Serial CMR imaging alone has a limited ability to detect histologic CTRCD beyond LVEF. Integrating MRS myocardial triglyceride content may be useful for detection of early potential CTRCD., Competing Interests: Declaration of competing interests Reza Nezafat, PhD, receives grant support from NIH5R01HL129185, 5R01HL127015, 1R01HL129157. The remaining authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Catheter ablation is the curative treatment for paroxysmal supraventricular tachycardia (SVT). However, atrial tachycardia (AT) diagnosis is often challenging, especially when SVT is terminated by pacing., Objectives: This study sought to develop a novel method for AT diagnosis., Methods: A total of 147 SVTs including 28 ATs, 87 atrioventricular nodal re-entrant tachycardias, and 32 orthodromic reciprocating tachycardias were prospectively studied. Single atrial extrastimulation was performed at the proximal coronary sinus from a coupling interval 20 milliseconds shorter than the tachycardia cycle length and gradually decreased until the His bundle (HB) was first reset and further until the SVT was terminated. The response of the SVT during the first HB resetting and the termination pattern were examined., Results: In 27 of 28 ATs, tachycardia was unaffected when HB resetting whereas, in atrioventricular nodal re-entrant tachycardias or orthodromic reciprocating tachycardias (non-AT), tachycardia was simultaneously reset when HB resetting or was terminated with an atrio-Hisian block. When the coupling interval was further shortened for cases in which tachycardia persisted, all 33 SVTs with tachycardia termination with atrio-Hisian block were non-ATs, whereas 5 ATs and 7 non-ATs were terminated with Hisian-atrial block. The sensitivity, specificity, and positive and negative predictive values of the pattern of tachycardia that was unaffected when HB resetting for AT diagnosis were 96%, 100%, 100%, and 99%, respectively. Those of the pattern of tachycardia termination with atrio-Hisian block for non-AT diagnosis were 92%, 100%, 100%, and 42%, respectively., Conclusions: Single atrial extrastimulation from the proximal coronary sinus during tachycardia was useful and effective for AT diagnosis., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aim: A high level of directly measured small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for atherosclerotic cardiovascular disease. A method for estimating sdLDL-C by using Sampson's equation that includes levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C and triglycerides (TG) has recently been proposed. We investigated the validation and exploration of estimated sdLDL-C level., Methods: The associations between measured and estimated sdLDL-C levels were investigated in 605 Japanese subjects (men/women: 280/325; mean age: 65±15 years) who received annual health check-ups in the Tanno-Sobetsu Study, a population-based cohort., Results: Estimated sdLDL-C level was highly correlated with measured sdLDL-C level in all subjects (R 2 =0.701), nondiabetic subjects without any medication (n=254, R 2 =0.686) and subjects with diabetes mellitus (n=128, R 2 =0.721). Multivariable regression analysis showed that levels of non-HDL-C, TG and γ-glutamyl transpeptidase (γGTP) were independent predictors of measured sdLDL-C level. In a stratification of the LDL window, all of the subjects with a combination of high non-HDL-C (≥ 170 mg/dL) and high TG (≥ 150 mg/dL) had high levels of measured and estimated sdLDL-C (≥ 35 mg/dL). Furthermore, machine learning-based estimation of sdLDL-C level by artificial intelligence software, Prediction One, was substantially improved by using components of Sampson's equation (R 2 =0.803) and by using those components with the addition of γGTP and deletion of TC (R 2 =0.929)., Conclusions: sdLDL-C level estimated by Sampson's equation can be used instead of measured sdLDL-C level in general practice. By building multiple machine learning models of artificial intelligence, a more accurate and practical estimation of sdLDL-C level might be possible.

Background: Ex vivo kidney perfusion is an evolving platform that demonstrates promise in preserving and rehabilitating the kidney grafts. Despite this, there is little consensus on the optimal perfusion conditions. Hypothermic perfusion offers limited functional assessment, whereas normothermic perfusion requires a more complex mechanical system and perfusate. Subnormothermic machine perfusion (SNMP) has the potential to combine the advantages of both approaches but has undergone limited investigation. Therefore, the present study sought to determine the suitability of SNMP for extended kidney preservation., Methods: SNMP at 22-25 °C was performed on a portable device for 24 h with porcine kidneys. Graft assessment included measurement of mechanical parameters and biochemical analysis of the perfusate using point-of-care tests. To investigate the viability of kidneys preserved by SNMP, porcine kidney autotransplants were performed in a donation after circulatory death (DCD) model. SNMP was also compared with static cold storage (SCS). Finally, follow-up experiments were conducted in a subset of human kidneys to test the translational significance of findings in porcine kidneys., Results: In the perfusion-only cohort, porcine kidneys all displayed successful perfusion for 24 h by SNMP, evidenced by stable mechanical parameters and biological markers of graft function. Furthermore, in the transplant cohort, DCD grafts with 30 min of warm ischemic injury demonstrated superior posttransplant graft function when preserved by SNMP in comparison with SCS. Finally, human kidneys that underwent 24-h perfusion exhibited stable functional and biological parameters consistent with observations in porcine organs., Conclusions: These observations demonstrate the suitability and cross-species generalizability of subnormothermic machine perfusion to maintain stable kidney perfusion and provide foundational evidence for improved posttransplant graft function of DCD kidneys after SNMP compared with SCS., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Postoperative radiotherapy for breast cancer reportedly increases the risk of thoracic soft tissue sarcomas, particularly angiosarcomas; however, the risk in the Japanese population remains unknown. Therefore, this study aimed to investigate the incidence of thoracic soft tissue sarcoma among patients with breast cancer in Japan and determine its association with radiotherapy. This retrospective cohort study used data from the population-based cancer registry of the Osaka Prefecture. The inclusion criteria were female sex, age 20-84 years, diagnosis of breast cancer between 1990 and 2010, no supraclavicular lymph node or distant metastasis, underwent surgery and survived for at least 1 year. The primary outcome was the occurrence of thoracic soft tissue sarcomas 1 year or later after breast cancer diagnosis. Among the 13 762 patients who received radiotherapy, 15 developed thoracic soft tissue sarcomas (nine angiosarcomas and six other sarcomas), with a median time of 7.7 years (interquartile range, 4.0-8.6 years) after breast cancer diagnosis. Among the 27 658 patients who did not receive radiotherapy, four developed thoracic soft tissue sarcomas (three angiosarcomas and one other sarcoma), with a median time of 11.6 years after diagnosis. The 10-year cumulative incidence was higher in the radiotherapy cohort than in the non-radiotherapy cohort (0.087 vs. 0.0036%, P < 0.001). Poisson regression analysis revealed that radiotherapy increased the risk of thoracic soft tissue sarcoma (relative risk, 6.8; 95% confidence interval, 2.4-24.4). Thus, although rare, breast cancer radiotherapy is associated with an increased risk of thoracic soft tissue sarcoma in the Japanese population., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

The rhizomes of Acorus tatarinowii Schott and Acorus gramineus Solander are widely used for treating amnesia in traditional Chinese medicine. In contrast, their leaves are usually discarded without their medicinal properties being known. Here, we found that the hot water extract of leaves improved cognition and tau pathology in model mice of frontotemporal dementia, similar to or even better than that of rhizomes. To explore the optimal method of processing, we made three preparations from dried leaves: hot water extract, extraction residue, and non-extracted simple crush powder. Among them, the simple crush powder had the strongest effect on tauopathy in mice. The crush powder also ameliorated Aβ and α-synuclein pathologies and restored cognition in mouse models of Alzheimer's disease and dementia with Lewy bodies. These findings suggest the potential of Acorus tatarinowii / gramineus leaves as a dietary source for dementia prevention and reveal that simple crushing is a better way to maximize their efficacy.

Introduction: Biomechanical stimulation is reportedly pivotal in meniscal regeneration, although its effect on mesenchymal stem cell (MSC) meniscal differentiation remains elusive. In this study, we investigated how cyclic compressive loading (CCL) could impact MSCs using three-dimensional cultures in atelocollagen-based meniscal substitute (ACMS). Methods: We extracted MSCs from the meniscus, synovium, and articular cartilage, cultured them in three-dimensional cultures, and exposed them to CCL for 7 days. We then compared the transcriptomes of MSCs treated with and without CCL. Results: Our RNA-seq analysis revealed that CCL induced significant transcriptome changes, significantly affecting chondrocyte-related genes, including SOX9, TGFB1, and PRG4 upregulation. CCL induced transcriptional differentiation of meniscus progenitors toward mature meniscal cells. Conclusion: This study unveils the potential of mechanical stress in promoting MSC meniscal differentiation within ACMS. Our investigations provide new insights for mechanisms underlying meniscal regeneration with ACMS., Competing Interests: Authors SOy and SI were employed by Taisho Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Taisho Pharmaceutical Co., Ltd. The funder had the following involvement in the study: study design, interpretation of data, analysis, and the writing of this article., (Copyright © 2024 Oyama, Kanamoto, Ebina, Etani, Hirao, Goshima, Otani, Hikida, Yamakawa, Ito, Okada and Nakata.)

Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Shinichi Toyooka received research funding from Eli Lilly Japan, Taiho (Japan) and Chugai (Japan), and lecture fees from Chugai. All other authors have declared that no competing interests exist., (Copyright: © 2024 Thu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC., Methods: We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment., Results: HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8 + T cells, and cytotoxic CD8 + T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8 + T cell penetration and efficacy, overcoming resistance to ICB therapy., Conclusions: HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy., (© 2024. The Author(s).)