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Background: Ureteral injury occurs in 0.3-1.5% of colorectal cancer surgeries. Devices to visualize the ureteral course and avoid ureteral injury are required for minimally invasive surgery (MIS). The NIRC™ fluorescent ureteral catheter (FUC) is a versatile ureteral visualization device currently available in Japan that can be used in combination with a variety of laparoscopic and robotic systems. In this study, we examined the outcomes of high-risk patients who underwent colorectal cancer surgery with FUC insertion., Methods: One hundred forty-one patients who underwent MIS for colorectal cancer and colorectal cancer recurrence at our institute between January 2021 and May 2024 underwent preoperative FUC insertion because of the high risk of ureteral injury and surgical difficulty. For these patients, patient background data and short-term outcomes were examined. The results are expressed as the median and interquartile range., Results: Age, 70 [60-78]; M:F(n), 84:57; BMI, 22.1 [19.7-24.7]; T4 (TNM classification), 52 cases (36.9%); preoperative intestinal obstruction, 45 cases (31.9%); abscess formation, 30 cases (21%); surgical history, 70 cases (50%); recurrent cancer, 14 cases (9.9%); preoperative chemo-radiotherapy, 28 cases (19.9%); time required for FUC insertion, 12 [9-19] minutes; operation time, 412 [309-552] minutes; blood loss, 10 [5-30] ml; open conversion, 0 cases; postoperative hospitalization, 12 [9-17.5]; circumferential resection margins < 1 mm (rectal surgery), 4/87 cases (4.6%); comorbidities, 0 ureteral injury, 1 urethral injury during FUC insertion (0.7%) and 16 CD Grade 3 or higher cases (11%)., Conclusions: FUC may improve the safety of MIS and reduce blood loss in addition to preventing ureteral injury and is expected to have oncological advantages for ensuring the margin of the tumor without fear of ureteral injury. However, the time required for and complications associated with FUC are challenging. New methods for less invasive and easier ureteral visualization may be needed., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Super-enhancers (SEs) play an important role in regulating tumor-specific gene expression. JQ1, a Bromodomain-containing protein 4 (BRD4) inhibitor, exerts antitumor effects by disrupting SE-mediated regulation of gene expression. We investigated the anti-adult T-cell leukemia/lymphoma (ATL) effects of JQ1. JQ1 induced apoptosis and inhibited ATL cell proliferation. JQ1 suppressed RUNX1 expression through the disruption of SE-mediated gene regulation. In the previous reports, it was shown that IC 50 s of AI-10-104 and Ro5-3335, RUNX1 inhibitors were 1-10 µM for lymphoblastic leukemia cell lines carrying RUNX1 mutations. In the present study, we demonstrated that IC 50 s of AI-10-104 and Ro5-3335 were also 1-10 µM or lower for ATL cell lines. Simultaneously, AI-10-104 suppressed MYC proto-oncogene (c-MYC) expression. RUNX1 is a potential therapeutic target for ATL that promotes c-MYC expression. We showed that RUNX1 expression is regulated via SEs in ATL and that RUNX1 may be a novel therapeutic target for ATL.

Previously, we reported the efficacy and safety of tazemetostat in Japanese patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) harboring the EZH2 mutation in a multicenter, open-label, phase II study. Here, we present a follow-up analysis of tazemetostat at a long-term median follow-up of 35.0 months. Twenty patients were enrolled: 17 in the FL cohort and three in the DLBCL cohort. In the FL cohort, the objective response rate was 70.6%, consistent with the primary analysis, and the median progression-free survival (PFS) was not reached. The 24-month and 36-month PFS rates were 72.1% (95% confidence interval [CI] 41.5%-88.6%) and 64.1% (95% CI 33.7%-83.4%), respectively. The median duration of treatment was 30.2 months. After the primary analysis at a median follow-up of 12.9 months, grade 1-2 urinary tract infection, peripheral motor neuropathy, and hypogammaglobulinemia newly emerged, but the incidence of adverse events (AEs) did not increase notably during this follow-up period. No unexpected grade ≥ 3 treatment-related AEs were reported. Long-term oral monotherapy with tazemetostat showed favorable efficacy and safety profiles, indicating that it may be a useful third-line or later treatment option for patients with relapsed/refractory FL harboring the EZH2 mutation. Trial registration: ClinicalTrials.gov: NCT03456726., (© 2024. The Author(s).)

Melatonin is synthesized in and secreted from the pineal glands, and regulates circadian rhythms. Although melatonin has been reported to modulate the activity of ion channels in several tissues, its effects on pineal ion channels remain unclear. In the present study, the effects of melatonin on voltage-gated K + (K V ) channels, which play a role in regulating the resting membrane potential, were examined in rat pinealocytes. The application of melatonin reduced pineal K V currents in a concentration-dependent manner (IC 50 =309 mM). An expression analysis revealed that K V 4.2 channels were highly expressed in rat pineal glands. Melatonin-sensitive currents were abolished by the small interfering RNA knockdown of K V 4.2 channels in rat pinealocytes. In human embryonic kidney 293 (HEK293) cells expressing K V 4.2 channels, melatonin decreased outward currents (IC 50 =479 mM). Inhibitory effects were mediated by a shift in voltage dependence from steady-state inactivation to a hyperpolarizing direction. This inhibition was observed even in the presence of 100 nM luzindole, an antagonist of melatonin receptors. Melatonin also blocked the activity of K V 4.3, K V 1.1, and K V 1.5 channels in reconstituted HEK293 cells. The application of 1 mM melatonin caused membrane depolarization in rat pinealocytes. Furthermore, K V 4.2 channel inhibition by 5 mM 4-aminopyridine attenuated melatonin secretion induced by 1 mM noradrenaline in rat pineal glands. These results strongly suggest that melatonin directly inhibited K V 4.2 channels and caused membrane depolarization in pinealocytes, resulting in a decrease in melatonin secretion through parasympathetic signaling pathway. This mechanism may function as a negative-feedback mechanism of melatonin secretion in pineal glands.

Adult T-cell leukaemia/lymphoma (ATLL) is an aggressive peripheral T-cell neoplasm with a poor prognosis. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an immune checkpoint receptor expressed on T and natural killer cells. Although increased TIGIT expression in the tumour microenvironment is associated with poor prognosis in various neoplasms, its relevance in ATLL remains unknown. Herein, we investigated the clinicopathological impact of TIGIT expression on ATLL using immunohistochemistry. TIGIT expression was detected in 21 of 84 patients (25%). A partial association between the clinical features and immune checkpoint molecules and the expression of TIGIT was found including sIL-2R, CD86 and GITR. TIGIT-positive patients [median survival time (MST) 8.9 months, 95% confidence interval (CI) 7.7-15.6] had inferior overall survival compared with TIGIT-negative patients (MST 18.7 months, 95% CI 12.0-36.4) (p=0.0124]. TIGIT expression maintained its prognostic value for overall survival in both univariate and multivariate analyses [hazard ratio (HR) 1.909; 95% CI 1.044-3.488; p=0.0356]. Further studies are required to clarify the clinical and biological significance of TIGIT expression in patients with ATLL., (Copyright © 2024 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background: The C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index is a novel immuno-nutritional biomarker based on the levels of CRP, serum albumin, and lymphocyte count. This study examined the prognostic value of the CALLY index in patients with colorectal cancer undergoing curative surgery., Methods: Between 2010 and 2017, 578 patients with stage II-III colorectal cancer who underwent curative resection were enrolled. The CALLY index was defined as (albumin × lymphocyte)/(CRP × 10 4 ). We investigated the association of the CALLY index with disease-free survival (DFS) and overall survival (OS)., Results: The cutoff value of the CALLY index was determined to be 2. Of the 578 patients, 175 (30%) had a preoperative CALLY index <2. In multivariate analysis, the pre-operative carcinoembryonic antigen (CEA) level (p = 0.003), cell differentiation (p = 0.045), venous invasion (p = 0.036), Tumor-Node-Metastasis stage (p < 0.001), and CALLY index score <2 (p = 0.006) were independent predictors of DFS. Meanwhile, preoperative carbohydrate antigen (CA)19-9 levels (p = 0.019), lymphatic invasion (p = 0.018), preoperative platelet (p = 0.037), and CALLY index score <2 (p = 0.007) were independent predictors of OS., Conclusion: The CALLY index may be an independent prognostic biomarker for long-term outcomes in patients with colorectal cancer., Competing Interests: Declaration of competing interest The authors declare no Conflict of Interests, and there are no funding sources for this article., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

Imprinted genes provide an attractive paradigm to unravel links between transcription and genome architecture. The parental allele-specific expression of these essential genes - which are clustered in chromosomal domains - is mediated by parental methylation imprints at key regulatory DNA sequences. Recent chromatin conformation capture (3C)-based studies show differential organization of topologically associating domains between the parental chromosomes at imprinted domains, in embryonic stem and differentiated cells. At several imprinted domains, differentially methylated regions show allelic binding of the insulator protein CTCF, and linked focal retention of cohesin, at the non-methylated allele only. This generates differential patterns of chromatin looping between the parental chromosomes, already in the early embryo, and thereby facilitates the allelic gene expression. Recent research evokes also the opposite scenario, in which allelic transcription contributes to the differential genome organization, similarly as reported for imprinted X chromosome inactivation. This may occur through epigenetic effects on CTCF binding, through structural effects of RNA Polymerase II, or through imprinted long non-coding RNAs that have chromatin repressive functions. The emerging picture is that epigenetically-controlled differential genome architecture precedes and facilitates imprinted gene expression during development, and that at some domains, conversely, the mono-allelic gene expression also influences genome architecture., (© 2024 The Author(s).)

Oxaliplatin, a platinum-based anticancer drug, is associated with peripheral neuropathy (oxaliplatin-induced peripheral neuropathy, OIPN), which can lead to worsening of quality of life and treatment interruption. The endothelial glycocalyx, a fragile carbohydrate-rich layer covering the luminal surface of endothelial cells, acts as an endothelial gatekeeper and has been suggested to protect nerves, astrocytes, and other cells from toxins and substances released from the capillary vessels. Mechanisms underlying OIPN and the role of the glycocalyx remain unclear. This study aimed to define changes in the three-dimensional ultrastructure of capillary endothelial glycocalyx near nerve fibers in the hind paws of mice with OIPN. The mouse model of OPIN revealed disruption of the endothelial glycocalyx in the peripheral nerve compartment, accompanied by vascular permeability, edema, and damage to the peripheral nerves. To investigate the potential treatment interventions, nafamostat mesilate, a glycocalyx protective agent was used in tumor-bearing male mice. Nafamostat mesilate suppressed mechanical allodynia associated with neuropathy. It also prevented intra-epidermal nerve fiber loss and improved vascular permeability in the peripheral paws. The disruption of endothelial glycocalyx in the capillaries that lie within peripheral nerve bundles is a novel finding in OPIN. Furthermore, these findings point toward the potential of a new treatment strategy targeting endothelial glycocalyx to prevent vascular injury as an effective treatment of neuropathy as well as of many other diseases. PERSPECTIVE: OIPN damages the endothelial glycocalyx in the peripheral capillaries, increasing vascular permeability. In order to prevent OIPN, this work offers a novel therapy approach that targets endothelial glycocalyx., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: Lung cancer is a leading cause of cancer-related mortality and remains one of the most poorly prognosed disease worldwide. Therefore, it is necessary to identify novel molecular markers with potential therapeutic effects. Recent findings have suggested that dual-specificity tyrosine-regulated kinase 2 (DYRK2) plays a tumor suppressive role in colorectal, breast, and hepatic cancers; however, its effect and mechanism in lung cancer remain poorly understood. Therefore, this study aimed to investigate the tumor-suppressive role and molecular mechanism of DYRK2 in lung adenocarcinoma (LUAD) by in vitro experiments and xenograft models., Materials and Methods: The evaluation of DYRK2 expression was carried out using lung cancer cell lines and normal bronchial epithelial cells. Overexpression of DYRK2 was induced by an adenovirus vector, and cell proliferation was assessed through MTS assay and Colony Formation Assay. Cell cycle analysis was performed using flow cytometry. Additionally, proliferative capacity was evaluated in a xenograft model by subcutaneously implanting A549 cells into SCID mice (C·B17/Icr-scidjcl-scid/scid)., Results: Immunoblotting assays showed that DYRK2 was downregulated in most LUAD cell lines. DYRK2 overexpression using adenovirus vectors significantly suppressed cell proliferation compared with that in the control group. Additionally, DYRK2 overexpression suppressed tumor growth in a murine subcutaneous xenograft model. Mechanistically, DYRK2 overexpression inhibited the proliferation of LUAD cells via p21-mediated G1 arrest, which was contingent on p53., Conclusion: Taken together, these findings suggest that DYRK2 may serve as potential prognostic biomarker and therapeutic target for LUAD., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Stoma construction and closure are common surgical strategies in patients with colorectal cancer. The present study evaluated the influence of multiple incisional sites resulting from stoma closure on incisional hernia after colorectal cancer surgery., Methods: The study included 1681 patients who underwent colorectal cancer surgery. Multiple incisional sites were defined as the coexistence of incisions at the midline and stoma closure sites. We retrospectively investigated the relationship between the presence of multiple incisional sites and incisional hernia development in patients with colorectal cancer., Results: Among the 1681 patients, 420 (25%) underwent stoma construction, with a stoma closure-to-construction ratio of 33% (139/420), and 155 (9.2%) developed incisional hernias after colorectal cancer surgery. In the multivariate analysis, female sex (p < 0.001), body mass index (p < 0.001), multiple incisional sites (p = 0.001), wound infection (p = 0.003), and postoperative chemotherapy (p = 0.030) were independent predictors of incisional hernia. In the multiple incisional sites group, the age (p < 0.001), surgical approach (laparoscopic) (p = 0.013), wound infection rate (p = 0.046), small bowel obstruction rate (p < 0.001), and anastomotic leakage rate (p = 0.008) were higher in those in the single incisional site group., Conclusions: Multiple incisional sites resulting from stoma closure are associated with the development of incisional hernia following colorectal cancer surgery., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: In digestive tract surgery, dissection of an avascular space consisting of loose connective tissue (LCT) appearing by countertraction improves oncological outcomes and reduces complications. 1-3 Kumazu et al. 4 described a deep learning approach that automatically segments LCT to help surgeons. 4 During left colorectal surgery, lumbar splanchnic, hypogastric, and pelvic visceral nerve injuries cause sexual dysfunction and/or urinary issues. 5 As nerve preservation is critical for functional preservation, the AI model Kumazu reported is named Eureka (Anaut Inc., Tokyo, Japan) and was developed to separate nerves automatically. The educative efficacy of intraoperative nerve visualization has been described. 6 Artificial intelligence (AI) assisted navigation is expected to aid in the anatomical recognition of nerves and the safe dissection layers surrounding nerves in the future., Methods: We used Eureka as an educational tool for surgeons' training during laparoscopic colorectal surgery. The laparoscopic system used was Olympus VISERA ELITE3 (Tokyo, Japan)., Results: Total mesorectal excision (TME) was safely performed with nerve preservation. No postoperative complications occurred. Automatic segmentation and highlighting of LCT in the dissected layers, lumbar splanchnic, hypogastric, and pelvic visceral nerves (S3, S4), were performed in real time., Conclusions: In colorectal cancer surgery, the nerves are vital anatomical structures serving as landmarks for dissection. Lumbar splanchnic, hypogastric, and pelvic visceral nerve injuries (S3, S4) cause sexual dysfunction or urinary disorders. 5 Nerve preservation is important for functional preservation. AI-assisted navigation methods are noninvasive, user-friendly, and expected to improve in accuracy in the future. They have the potential to develop nerve-guided TME., (© 2023. The Author(s).)

Galectin-3 is a beta-galactoside-binding lectin that plays important roles in diverse physiological functions, such as cell proliferation, apoptosis, and mRNA splicing. This protein is expressed on inflammatory cells and acts as a local inflammatory mediator. Recently, galectin-3 has been detected in several diseases, such as chronic liver, heart, and kidney diseases, diabetes, viral infection, autoimmune and neurodegenerative diseases, and tumors, and its role as a biomarker has attracted attention. Alpha-galactosylceramide is an artificially synthesized sphingolipid that can induce acute liver injury via the natural killer T pathway. However, the pathophysiological roles and kinetics of galectin-3 in acute liver injury are not fully understood. This study aimed to elucidate the expression and time course of galectin-3 in liver tissues during acute liver injury following alpha-galactosylceramide injection. Animals were histologically examined on days 1, 2, 4, and 7 after intraperitoneal injection of alpha-galactosylceramide, and the expressions of galectin-3 and ionized calcium-binding adaptor molecule 1 were analyzed. Notably, galectin-3 formed characteristic cluster foci, particularly on day 2 after injection. Cluster formation was not observed in chronic liver disease. Simultaneously, ionized calcium-binding adaptor molecule 1-positive cells were observed in the cluster foci. Serum galectin-3 levels increased on day 2 of treatment and correlated well with the number of galectin-3-positive cell clusters in the liver. Moreover, galectin-3 expression was an important mediator of the early phase of liver injury after alpha-galactosylceramide injection. These results suggest that serum galectin-3 may be a biomarker for the early diagnosis of acute liver injury and that clusters of galectin-3-positive cells may be a specific finding in acute liver injury., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Matsuo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Defunctioning loop ileostomy has been reported to reduce symptomatic anastomotic leakage after rectal cancer surgery; however, stoma outlet obstruction (SOO) is a serious postileostomy complication. We, therefore, explored novel risk factors for SOO in defunctioning loop ileostomy after rectal cancer surgery., Methods: This is a retrospective study that included 92 patients who underwent defunctioning loop ileostomy with rectal cancer surgery at our institution. Among them, 77 and 15 ileostomies were created at the right lower abdominal and umbilical sites, respectively. We defined the output volume MAX as the maximum output volume the day before the onset of SOO or-for those without SOO-that was observed during hospitalization. Univariate and multivariate analyses were performed to evaluate risk factors for SOO., Results: SOO was observed in 24 cases, and the median onset was 6 days postoperatively. The stoma output volume in the SOO group was consistently higher than that in the non-SOO group. In the multivariate analysis, the rectus abdominis thickness (p < 0.01) and output volume MAX (p < 0.01) were independent risk factors for SOO., Conclusion: A high-output stoma may predict SOO in patients with defunctioning loop ileostomy for rectal cancer. Considering that SOO occurs even at umbilical sites with no rectus abdominis, a high-output stoma may trigger SOO primarily., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Aim: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous disease that can be classified into the PTCL-TBX21 and PTCL-GATA3 subtypes., Methods: In this study, we compared the clinicopathological features of PTCL-NOS in a Japanese cohort, classified using an IHC algorithm., Results: One hundred patients with PTCL-NOS were categorized as having PTCL-TBX21 (n = 55), PTCL-GATA3 (n = 24), or PTCL-unclassified (n = 21). When comparing PTCL-TBX21 and PTCL-GATA3, PTCL-TBX21 showed significantly lower CD4 positivity (p = 0.047), lower counts of high endothelial venules (p = 0.032), and a tendency for a better response to initial treatment (p = 0.088). Gene expression analysis using the nCounter system showed higher expression of tumor immunity-related genes, such as PD-L1, LAG3, and IDO1, in PTCL-TBX21 than in PTCL-GATA3. PTCL-GATA3 had significantly worse overall survival (OS) than those with PTCL-TBX21 (p = 0.047), although a similar tendency was observed for progression-free survival (PFS) (p = 0.064). PTCL-GATA3 was a prognostic factor for OS in univariate analysis (HR 2.02; 95% CI, 1.09-3.77; p = 0.027), although multivariate analysis did not show significance (HR 2.07; 95% CI, 0.93-4.61; p = 0.074). In the PFS analysis, PTCL-GATA3 was an independent prognostic factor by univariate analysis (HR 1.96; 95% CI, 1.08-3.56; p = 0.027) and multivariate analysis (HR 2.34; 95% CI, 1.07-5.11; p = 0.032)., Conclusion: The classification of PTCL-NOS into PTCL-TBX21 and PTCL-GATA3 is useful for predicting the prognosis of Japanese patients and stratifying the administration of tumor immune checkpoint inhibitors in clinical practice., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia-lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4 + T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3 + T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4 + T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL.

Nutritional disorders in patients with chronic obstructive pulmonary disease (COPD) are associated with cachexia, sarcopenia, and weight loss. In particular, weight loss is a prognostic factor in COPD independent of pulmonary function, and energy malnutrition is a contributing factor. Frequent exacerbation hospitalization is also a prognostic factor for COPD patients. The impact of energy malnutrition on adverse events such as exacerbation hospitalization is unknown, and this study aimed to investigate that. We included 163 male subjects with COPD. Respiratory quotient (RQ), an index of energy malnutrition, was calculated by expiratory gas analysis using an indirect calorimeter. RQ <0.85 was categorized as the energy malnutrition group. Kaplan-Meier analysis was used to compare the hospitalization avoidance rate between the with and without energy malnutrition groups. Independent factors associated with exacerbation hospitalization were evaluated by Cox regression analysis. We finally analyzed data from 56 selected subjects (median age: 74 y). The exacerbation hospitalization rate was significantly higher in the energy malnutrition group. Fifty percent of the energy malnutrition group was hospitalized for an exacerbation, and the median hospitalization avoidance time was 701 d. In Cox regression analysis (adjusted for age, BMI, mMRC dyspnea scale score, %FEV 1 , and 6-min walk test), energy malnutrition was an independent factor associated with exacerbation hospitalization (HR 4.14, 95% CI 1.13-15.1, p=0.03). Energy malnutrition may be the risk factor for exacerbation hospitalization. Energy malnutrition may be an early nutritional disorder and early detection and intervention may reduce exacerbation hospitalizations.

The ionotropic purinergic P2X7 receptor responds to extracellular ATP and can trigger proinflammatory immune signaling in macrophages. Caveolin-1 (Cav-1) is known to modulate functions of macrophages and innate immunity. However, it is unknown how Cav-1 modulates P2X7 receptor activity in macrophages. We herein examined P2X7 receptor activity and macrophage functions using bone marrow-derived macrophages (BMDMs) from wild-type (WT) and Cav-1 knockout (KO) mice. ATP (1 mM) application caused biphasic increase in cytosolic [Ca 2+ ] and sustained decrease in cytosolic [K + ]. A specific P2X7 receptor blocker, A-740003, inhibited the maintained cytosolic [Ca 2+ ] increase and cytosolic [K + ] decrease. Total internal reflection fluorescent imaging and proximity ligation assays revealed a novel molecular complex formation between P2X7 receptors and Cav-1 in WT BMDMs that were stimulated with lipopolysaccharides. This molecular coupling was increased by ATP application. Specifically, the ATP-induced Ca 2+ influx and K + efflux through P2X7 receptors were increased in Cav-1 KO BMDMs, even though the total and surface protein levels of P2X7 receptors in WT and Cav-1 KO BMDMs were unchanged. Cell-impermeable dye (TO-PRO3) uptake analysis revealed that macropore formation of P2X7 receptors was enhanced in Cav-1 KO BMDMs. Cav-1 KO BMDMs increased ATP-induced IL-1β secretion, reactive oxygen species production, Gasdermin D (GSDMD) cleavage, and lactate dehydrogenase release indicating pyroptosis. A-740003 completely prevented ATP-induced pyroptosis. In combination, these datasets show that Cav-1 has a negative effect on P2X7 receptor activity in BMDMs and that Cav-1 in macrophages may contribute to finely tuned immune responses by preventing excessive IL-1β secretion and pyroptosis. NEW & NOTEWORTHY In bone marrow-derived macrophages, Cav-1 suppresses the macropore formation of P2X7 receptors through their direct or indirect interactions, resulting in reduced membrane permeability of cations (Ca 2+ and K + ) and large cell-impermeable dye (TO-PRO3) induced by ATP. Cav-1 also inhibits ATP-induced IL-1β secretion, ROS production, GSDMD cleavage, and pyroptosis. Cav-1 contributes to the maintenance of proper immune responses by finely tuning IL-1β secretion and cell death in macrophages.