Dynamic changes in cell size are associated with development and pathological conditions, including aging. Although cell enlargement is a prominent morphological feature of cellular senescence, its functional implications are unknown; moreover, how senescent cells maintain their enlargement state is less understood. Here we show that an extensive remodeling of actin cytoskeleton is necessary for establishing senescence-associated cell enlargement and pro-inflammatory senescence-associated secretory phenotype (SASP). This remodeling is attributed to a balancing act between the SASP regulator GATA4 and the mechanosensor YAP on the expression of the Rho family of GTPase RHOU. Genetic or pharmacological interventions that reduce cell enlargement attenuate SASP with minimal effect on senescence growth arrest. Mechanistically, actin cytoskeleton remodeling couples cell enlargement to the nuclear localization of GATA4 and NF-κB via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. RhoU protein accumulates in mouse adipose tissue under senescence-inducing conditions. Furthermore, RHOU expression correlates with SASP expression in adipose tissue during human aging. Thus, our study highlights an unexpected instructive role of cell enlargement in modulating the SASP and reveals a mechanical branch in the senescence regulatory network. Senescent cells accumulate during aging and exhibit cell enlargement, the function of which has been unclear for decades. Here, the authors identify an antagonistic genetic circuit for hypertrophy and reveal its instructive role in modulating the SASP.

UDP-GlcNAc serves as a building block for glycosaminoglycan (GAG) chains in cartilage proteoglycans and simultaneously acts as a substrate for O-GlcNAcylation. Here, we show that transporters for UDP-GlcNAc to the endoplasmic reticulum (ER) and Golgi are significantly downregulated in osteoarthritic cartilage, leading to increased cytosolic UDP-GlcNAc and O-GlcNAcylation in chondrocytes. Mechanistically, upregulated O-GlcNAcylation governs the senescence-associated secretory phenotype (SASP) by stabilizing GATA4 via O-GlcNAcylation at S406, which compromises its degradation by p62-mediated selective autophagy. Elevated O-GlcNAcylation in the superficial layer of osteoarthritic cartilage coincides with increased GATA4 levels. The topical deletion of Gata4 in this cartilage layer ameliorates post-traumatic osteoarthritis (OA) in mice while inhibiting O-GlcNAc transferase mitigates OA by decreasing GATA4 levels. Excessive glucosamine-induced O-GlcNAcylation stabilizes GATA4 in chondrocytes and exacerbates post-traumatic OA in mice. Our findings elucidate the role of UDP-GlcNAc compartmentalization in regulating secretory pathways associated with chronic joint inflammation, providing a senostatic strategy for the treatment of OA. Here, the authors show that reduced transport of UDP-GlcNAc to the endoplasmic reticulum and Golgi leads to increased cytosolic UDP-GlcNAc and O-GlcNAcylation in chondrocytes. This, in turn, stabilizes the transcription factor GATA4, promoting the senescence-associated secretory phenotype and exacerbating osteoarthritis.

PURPOSE:Non-operative management (NOM) has emerged as a promising organ-preserving strategy for patients with rectal cancer who achieve a clinical complete response (cCR) after neoadjuvant chemoradiotherapy (CRT). However, no standardized treatment protocol has been established for watch-and-wait strategies. MATERIALS AND METHODS:This prospective study evaluated oncological outcomes of NOM combined with 4 months of adjuvant capecitabine. Patients with resectable rectal cancer (≤ 8 cm from the anal verge, cT2-4 or N+) underwent CRT (50-54 Gy in 25-27 fractions with capecitabine). Eight weeks post-CRT, a multidisciplinary team assessed cCR. Patients achieving cCR received six cycles of capecitabine (2 weeks on/1 week off) and were actively monitored. RESULTS:Among 89 patients receiving CRT (2018-2023), 17 (19.1%) achieved cCR and were included. The median age was 65 years, and 64.7% were male. Eleven (64.7%) completed all six cycles of adjuvant therapy. After a median follow-up of 31.4 months, 11 patients (64.7%) remained disease-free. Local regrowth occurred in six patients (35.3%) with 2- and 4-year rates of 34.5% and 47.6%, respectively. Five underwent radical surgery, and one received transanal excision with systemic chemotherapy. At the time of assessment, 15 patients (88.2%) showed no evidence of disease, while two (11.8%) received palliative chemotherapy. All patients were alive. CONCLUSION:NOM with adjuvant capecitabine showed promising oncological outcomes, offering an alternative to passive watch-and-wait approaches. Further refinement through multidisciplinary strategies is warranted.

Cellular metabolism is a flexible and plastic network that often dictates physiological and pathological states of the cell, including differentiation, cancer, and aging. Recent advances in cancer metabolism represent a tremendous opportunity to treat cancer by targeting its altered metabolism. Interestingly, despite their stable growth arrest, senescent cells – a critical component of the aging process – undergo metabolic changes similar to cancer metabolism. A deeper understanding of the similarities and differences between these disparate pathological conditions will help identify which metabolic reprogramming is most relevant to the therapeutic liabilities of senescence. Here, we compare and contrast cancer and senescence metabolism and discuss how metabolic therapies can be established as a new modality of senotherapy for healthy aging.

Whereas cholesterol is vital for cell growth, proliferation, and remodeling, dysregulation of cholesterol metabolism is associated with multiple age-related pathologies. Here we show that senescent cells accumulate cholesterol in lysosomes to maintain the senescence-associated secretory phenotype (SASP). We find that induction of cellular senescence by diverse triggers enhances cellular cholesterol metabolism. Senescence is associated with the upregulation of the cholesterol exporter ABCA1, which is rerouted to the lysosome, where it moonlights as a cholesterol importer. Lysosomal cholesterol accumulation results in the formation of cholesterol-rich microdomains on the lysosomal limiting membrane enriched with the mammalian target of rapamycin complex 1 (mTORC1) scaffolding complex, thereby sustaining mTORC1 activity to support the SASP. We further show that pharmacological modulation of lysosomal cholesterol partitioning alters senescence-associated inflammation and in vivo senescence during osteoarthritis progression in male mice. Our study reveals a potential unifying theme for the role of cholesterol in the aging process through the regulation of senescence-associated inflammation.

AIMS:To investigate the diagnostic performance of ultrasound-guided attenuation parameter (UGAP) for the detection of hepatic steatosis in nonalcoholic fatty liver disease (NAFLD) cohorts using histopathology as the reference standard andcomparing it with that of various imaging modalities.MATERIALS AND METHODS:A total of 87 subjects who underwent UGAP, controlled attenuation parameter (CAP), and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) between December, 2020 and January, 2022 were enrolled. Of these patients, 38 patients had NAFLD. The association between UGAP and clinical and imaging parameters was assessed using Pearson's or Spearman's correlations. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance.RESULTS:The UGAP and MRI-logPDFF demonstrated strong positive correlations (correlation coefficient= 0.704, P <0.0001). UGAP showed excellent diagnostic performance for distinguishing steatosis grade ≥1 with an AUROC of 0.821 (95% confidence interval [CI], 0.729-0.913), which was comparable to that of MRI-PDFF (0.829, 95%CI, 0.723-0.936). The AUROCs of BUSG (B-mode ultrasonography) (0.766, 95% CI, 0.767-0.856) and CAP (0.788, 95% CI, 0.684-0.891) were slightly lower than those of UGAP. The AUROCs of UGAP, MRI-PDFF, CAP, and BUSG for detecting steatosis grade ≥2 were 0.796 (95% CI, 0.616-0.975), 0.971 (95% CI, 0.936-1.000), 0.726 (95% CI, 0.561-0.891) and 0.774 (95% CI, 0.612-0.936), respectively.CONCLUSION:UGAP may be a valuable potential screening tool as a first-line assessment of liver steatosis in patients with NAFLD.

Background:The purpose of our study was to validate the oral effervescent agent improving magnetic resonance cholangiopancreatography (MRCP) in patients with suspicious pancreatobiliary disease.Methods:One hundred and eleven consecutive patients with alleged or suspected pancreatobiliary tree problems who had undergone two-dimensional (2D) MRCP imaging both before and after oral effervescent enhancement (conventional-MRCP and enhanced-MRCP) were included. Two radiologists independently scored overall image quality, visualization of ten ductal segments, and gastroduodenal fluid signal intensity score. In consensus, they assessed the presence of gastroduodenal fluids and pancreatobiliary tree overlapping. The data were analyzed using Wilcoxon's signed-rank test, McNemar test, and paired t-test.Results:The grades of overall image quality and individual biliary duct visualization for ten targeted ductal segments, and gastroduodenal fluid signal intensity scores increased significantly on enhanced-MRCP by both readers (P≤0.02), but there was no significant increase for pancreatic duct (PD) at head and tail. On enhanced-MRCP, gastroduodenal fluids except for gastric fundus were less detected rather than those on conventional-MRCP. Anatomic structures of gastroduodenal fluids overlapping extrahepatic bile duct were mainly gastric antrum, duodenal bulb, and 2nd portion on conventional-MRCP. However, these fluids were less overlapped on enhanced-MRCP (P<0.001). Gastric body and antrum were main anatomic structures of gastroduodenal fluids overlapping PD on conventional-MRCP, and fluid in these locations significantly less overlapped PD on enhanced-MRCP (P≤0.02).Conclusions:Oral administration of effervescent agent provided effective elimination of gastroduodenal fluid overlapping pancreatobiliary ductal system at MRCP and can improve the quality of the examination in the patients with known or suspected pancreatobiliary disease.

IntroductionMegaShield® is a newly developed temperature-sensitive anti-adhesive containing micronized acellular dermal matrix. The aim of this study was to investigate the efficacy and safety of MegaShield® compared with Guardix-SG® in the prevention of adhesions in patients undergoing bilateral total thyroidectomy.MethodWe conducted a multicenter trial between October 2018 and March 2020 in patients undergoing total thyroidectomy. The patients were randomly assigned to either the MegaShield® group or the Guardix-SG® group. The primary outcome was the esophageal movement using marshmallow six weeks after the surgery and the secondary outcome was the assessed adhesion score. The safety assessment was also evaluated.ResultsThe study included 70 patients each in the MegaShield® and control (Guardix-SG®) groups. Baseline clinical characteristics, the mean score of marshmallow esophagography, and the sum of adhesion scores were not statistically different between the two groups. Inferiority test demonstrated that the efficacy of MegaShield® is not inferior to that of Guardix-SG®. There were no device-related complications in both groups.ConclusionThe efficacy and safety of MegaShield® were not inferior than those of Guardix-SG®. MegaShield® demonstrated the potential of ADM as a potential future anti-adhesive agent.Trial registrationThe name of trial registry CRIS (Clinical Research Information Service) https://cris.nih.go.kr/cris/index.jsp. (The full trial protocol can be accessed) Registration number: KCT0003204.

Cellular senescence is a complex stress response implicated in aging. Autophagy can suppress senescence but is counterintuitively necessary for full senescence. Although its anti-senescence role is well described, to what extent autophagy contributes to senescence establishment and the underlying mechanisms is poorly understood. Here, we show that selective autophagy of multiple regulatory components coordinates the homeostatic state of senescence. We combined a proteomic analysis of autophagy components with protein stability profiling, identifying autophagy substrate proteins involved in several senescence-related processes. Selective autophagy of KEAP1 promoted redox homeostasis during senescence. Furthermore, selective autophagy limited translational machinery components to ameliorate senescence-associated proteotoxic stress. Lastly, selective autophagy of TNIP1 enhanced senescence-associated inflammation. These selective autophagy networks appear to operate in vivo senescence during human osteoarthritis. Our data highlight a caretaker role of autophagy in the stress support network of senescence through regulated protein stability and unravel the intertwined relationship between two important age-related processes.

Background The relationship between the imaging parameters on postoperative ultrasound (US) other than repaired tendon integrity with clinical outcome such as postoperative residual pain has not been well defined. Purpose To investigate whether the repaired tendon thickness and subdeltoid fluid collection after rotator cuff repair are correlated with early postoperative clinical outcome. Material and Methods This retrospective study included 54 patients who underwent repair of the arthroscopic rotator cuff either by suture-bridge or single-row technique and postoperative US. We assessed the relationship between the sonographic parameters, including repaired supraspinatus tendon thickness and subdeltoid fluid collection, with the clinical outcome represented by the Korean Shoulder Scoring system (KSS) score using correlation coefficients (R). Also, the subgroup analysis was done to assess the differences by surgical technique and patients’ age. Results There was a significant inverse relationship between the amount of subdeltoid fluid collection and degree of self-assessed pain improvement of the patients ( P < 0.05), although every KSS category showed statistically insignificant tendency of inverse relationship with the fluid thickness. However, there was no statistically significant relationship between the thickness of repaired supraspinatus tendon and KSS scores. In patients aged >60 years, a statistically significant inverse relationship between thickness of subdeltoid fluid collection and difference value of the KSS scores in category of function was observed with both interpreters ( P = 0.015 and P = 0.04, respectively). Conclusion Subdeltoid fluid collection measured on US after repair of the arthroscopic rotator cuff in the early postoperative period has significant association with the patients’ subjective clinical outcome.

Autophagy and cellular senescence are two potent tumor suppressive mechanisms activated by various cellular stresses, including the expression of activated oncogenes. However, emerging evidence has also indicated their pro-tumorigenic activities, strengthening the case for the complexity of tumorigenesis. More specifically, tumorigenesis is a systemic process emanating from the combined accumulation of changes in the tumor support pathways, many of which cannot cause cancer on their own but might still provide excellent therapeutic targets for cancer treatment. In this review, we discuss the dual roles of autophagy and senescence during tumorigenesis, with a specific focus on the stress support networks in cancer cells modulated by these processes. A deeper understanding of such context-dependent roles may help to enhance the effectiveness of cancer therapies targeting autophagy and senescence, while limiting their potential side effects. This will steer and accelerate the pace of research and drug development for cancer treatment.

Macroautophagy/autophagy is a sophisticated quality control program that limits cellular damage and maintains homeostasis, being an essential part of several lifespan-promoting interventions. However, autophagy is also necessary for full establishment of cellular senescence, a causal factor for many age-related diseases and aging. What lies ahead of us to unravel such a paradoxical role of autophagy in senescence is to identify specific targets degraded by autophagy during senescence and determine their importance in the senescence regulatory network. Recently, we developed the "Selective autophagy substrates Identification Platform (SIP)" to advance these goals, providing a rich set of autophagy substrate proteins involved in senescence. Our study demonstrated that selective autophagy coordinates the stress support networks in senescent cells by degrading multiple regulatory components, echoing its homeostatic roles in normal cells. Targeting this type of selective autophagy might provide a unique opportunity to develop non-senescence addiction-based therapeutic strategies for senotherapy by disturbing the homeostatic state of senescent cells.

Senescent cells constantly experience stressful conditions and restrain their protein translation to cope with it. Here, we present a detailed protocol to measure the rate of global protein synthesis using L-azidohomoalanine (L-AHA)-based click chemistry in human senescent fibroblasts. We optimized several aspects of the procedure, including senescence induction, a flow cytometry analysis of senescent cells, and the duration of L-AHA incorporation. This protocol uses senescent human fibroblasts but can be applied to other types of cells or circumstances. For complete details on the use and execution of this protocol, please refer to Lee et al. (2021).

The metabolic syndrome (MetS), defined as the co-occurrence of disorders including obesity, dyslipidemia, insulin resistance, and hepatic steatosis, has become increasingly prevalent in the world over recent decades. Dietary and other environmental factors interacting with genetic predisposition are likely contributors to this epidemic. Among the involved dietary factors, excessive fructose consumption may be a key contributor. When fructose is consumed in large amounts, it can quickly produce many of the features of MetS both in humans and mice. The mechanisms by which fructose contributes to metabolic disease and its potential interactions with genetic factors in these processes remain uncertain. Here, we generated a small F2 genetic cohort of male mice derived from crossing fructose-sensitive and -resistant mouse strains to investigate the interrelationships between fructose-induced metabolic phenotypes and to identify hepatic transcriptional pathways that associate with these phenotypes. Our analysis indicates that the hepatic transcriptional pathways associated with fructose-induced hypertriglyceridemia and hyperinsulinemia are distinct from those that associate with fructose-mediated changes in body weight and liver triglyceride. These results suggest that multiple independent mechanisms and pathways may contribute to different aspects of fructose-induced metabolic disease.

Summary Background Significant hepatic fibrosis is associated with higher mortality. However, data on the estimated prevalence of liver fibrosis in the general population are scarce. Aim To use magnetic resonance elastography (MRE) to investigate the prevalence of hepatic fibrosis in a Korean health check‐up clinic cohort. Methods We enrolled 2170 participants at our health check‐up clinic between January 2015 and May 2018, all of whom had MR with chemical shift technique and MRE. The primary objective was to estimate the prevalence of liver fibrosis. For generalisation, sex‐ and age‐standardised prevalence was calculated based on the Korean Statistical Information Service (KOSIS) during the period 2015‐2018. Results The prevalence of F2 (≥3.0 kPa) and F3 (≥3.6 kPa) in the overall cohort was 5.1% and 1.3% respectively (sex‐ and age‐adjusted prevalence of 3.8% and 1.3%). Non‐alcoholic fatty liver disease (NAFLD) prevalence (>5% fat fraction) was 27.7% in the average risk population (after excluding alcohol use and viral hepatitis), and the prevalence of significant and advanced fibrosis in NAFLD participants was 8.0% and 1.5% respectively. In participants with diabetes, 12.5% had ≥F2 and 4.3% ≥F3. In participants with NAFLD plus diabetes, 24.1% had ≥F2 and 6.0% ≥F3. On multivariate analysis, only age, insulin, diabetes and fatty liver on MR were independently associated with significant fibrosis. Conclusions In a Korean health check‐up clinic setting, the prevalence of significant and advanced liver fibrosis was 5.1% and 1.3% (sex‐ and age‐adjusted prevalence of 3.8% and 1.3%). The prevalence of advanced liver fibrosis was five times higher for diabetic participants with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease driven by genetic and environmental factors. MicroRNAs (miRNAs) serve as pleiotropic post‐transcriptional regulators of cellular pathways. Although several miRNAs have been associated with NAFLD and fibrosis, there are limited studies in humans examining their differential association with pathogenic factors or histological features of NAFLD. We examined the differential relationships of five of the best‐described circulating microRNAs (miR‐34a, miR‐122, miR‐191, miR‐192, and miR‐200a) with histological features and pathogenic factors of NAFLD. A cross‐sectional study was conducted to examine the relationship between relative levels of circulating microRNAs standardized by z‐scores and histological features of NAFLD, common NAFLD genetic polymorphisms, and insulin resistance measured by the enhanced lipoprotein insulin resistance index in 132 subjects with biopsy‐proven NAFLD. We found that miR‐34a, miR‐122, miR‐192, miR‐200a, but not miR‐191, strongly correlate with fibrosis in NAFLD by increases of 0.20 to 0.40 SD (P < 0.005) with each stage of fibrosis. In multivariate analysis, miR‐34a, miR‐122, and miR‐192 levels are independently associated with hepatic steatosis and fibrosis, but not lobular inflammation or ballooning degeneration, whereas miR‐200a is only associated with fibrosis. Among the four miRNAs, miR‐34a, miR‐122, and miR‐192 are associated with pathogenic factors of NAFLD, including insulin resistance measured by eLP‐IR, patatin‐like phospholipase domain containing 3 I148M, and transmembrane 6 superfamily 2 (TM6SF2) E167K polymorphisms. In contrast, miR‐200a is only associated with the TM6SF2 E167K variant. Finally, miR‐34a has the strongest predictive value for various stages of fibrosis, with C‐statistic approximates–combined predictive score for miRNAs. Conclusion: miR‐34a, miR‐122, miR‐192, and miR‐200a demonstrate strong associations with NAFLD severity by histology, but differential associations with pathogenic factors.

PURPOSE:We evaluated the impact of preoperative magnetic resonance cholangiopancreatography (MRCP) on patient outcomes, and found which patients should be considered for MRCP before cholecystectomy.METHODS:We performed retrospective analysis of 2,072 patients that underwent cholecystectomy for benign gallbladder disease from January 2014 to June 2017. Patients were grouped as CT only group (n = 737) and MRCP group (n = 1,335), including both CT and MRCP (n = 1,292) or MRCP only (n = 43). The main outcome measure was associated with complications after cholecystectomy, and the secondary outcomes were hospital stay, readmission, and events that could impact patient management due to addition of MRCP.RESULTS:There were no statistical differences in occurrence of intraoperative or postoperative complications or readmission rate between the 2 groups. Hospital stay was about 0.6 days longer in the MRCP group. However, MRCP group was more susceptible to complications due to underlying patient demographics (older age, higher frequency of diabetes, and higher level of the inflammatory markers). MRCP diagnosed common bile duct (CBD) stones in 6.5% of patients (84/1,292) without CBD stones in CT, and bile duct anomalies were identified in 41 patients (3.2%). Elevated γ-GT was the only independent factor for additional detection of CBD stones (adjusted odds ratio [OR], 2.89; P = 0.029) and subsequent biliary procedures (adjusted OR, 3.34; P = 0.018) when additional MRCP was performed.CONCLUSION:MRCP is valuable for identification of bile duct variation and CBD stones. Preoperative MRCP can be considered, particularly in patients with elevated γ-GT, for proper preoperative management and avoidance of complications.

Fibromuscular dysplasia is a nonatheromatous, noninflammatory arterial disorder that results in stenosis and/or aneurysm formation and rarely involves the mesenteric arteries. Herein, we report a case of fibromuscular dysplasia limited to the inferior mesenteric artery, which manifested with arterial aneurysms and ischemic colitis.

Serous cystic neoplasms of the pancreas are usually benign, with a low malignant potential. Herein, we report a case of malignant serous cystic neoplasm of the pancreas treated with subtotal pancreatectomy, which progressed to local recurrence and metachronous hepatic metastasis during the regular follow-up period.