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BACKGROUND: Previous studies reported that vitamin B12 deficiency is associated with an increased risk of stroke. However, studies examining the association between excessive vitamin B12 and stroke risk are limited. Our study aimed to investigate the relationship between excessive vitamin B12 levels and the risk of stroke and explore whether this association varies according to sex. METHODS: Utilizing the Korean Genome Epidemiology Study (KoGES) prospective cohort data, our primary exposure variables were vitamin B12 plasma concentration and sex. The occurrence of stroke served as the main outcome of interest. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression analysis. An interaction analysis was conducted to assess the interaction effect of vitamin B12 and sex on stroke incidence. RESULTS: Cox proportional logistic regression analysis, adjusting for confounders, showed that excessive vitamin B12 did not significantly alter stroke risk (HR 1.22, 95% CI: 0.82-1.71) and revealed no significant sex-based differences in stroke risk (HR 0.90, 95% CI: 0.75-1.04). However, interaction analysis indicated that excessive vitamin B12 was linked to a significant increase in stroke risk in males (HR 1.81, 95% CI: 1.10-2.99), but not in females (HR 1.04, 95% CI: 0.66-1.60), with statistically significant interaction effect (p<0.01). CONCLUSION: Our study demonstrated that while excessive vitamin B12 alone does not significantly increase stroke risk, it increases the risk in males when considering the interaction with sex.
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OBJECTIVES: Our study aimed to investigate the association between shift work and stroke and determine whether this association varies depending on the presence of insomnia. METHODS: Utilizing the KoGES prospective cohort data, our primary exposure variables were shift work and insomnia. The occurrence of stroke was the main outcome of interest. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression analysis. An interaction analysis was conducted to assess the interaction of shift work and insomnia on stroke incidence. RESULTS: In the interaction analysis, shift work was significantly associated with stroke incidence only in groups with insomnia and an HR of 2.49 (1.02-6.11). CONCLUSIONS: Our study demonstrated that shift work was associated with a higher risk of stroke among the population with insomnia.
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Heart failure is a leading cause of death and is often accompanied by activation of quiescent cardiac myofibroblasts, which results in cardiac fibrosis. In this study, we aimed to identify novel circular RNAs that regulate cardiac fibrosis. We applied transverse aortic constriction (TAC) for 1, 4, and 8 weeks in mice. RNA sequencing datasets were obtained from cardiac fibroblasts isolated by use of a Langendorff apparatus and then further processed by use of selection criteria such as differential expression and conservation in species. CircSMAD4 was upregulated by TAC in mice or by transforming growth factor (TGF)-ß1 in primarily cultured human cardiac fibroblasts. Delivery of si-circSMAD4 attenuated myofibroblast activation and cardiac fibrosis in mice treated with isoproterenol (ISP). si-circSmad4 significantly reduced cardiac fibrosis and remodeling at 8 weeks. Mechanistically, circSMAD4 acted as a sponge against the microRNA miR-671-5p in a sequence-specific manner. miR-671-5p was downregulated during myofibroblast activation and its mimic form attenuated cardiac fibrosis. miR-671-5p mimic destabilized fibroblast growth factor receptor 2 (FGFR2) mRNA in a sequence-specific manner and interfered with the fibrotic action of FGFR2. The circSMAD4-miR-671-5p-FGFR2 pathway is involved in the differentiation of cardiac myofibroblasts and thereby the development of cardiac fibrosis.
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Macrophages are the major primary immune cells that mediate the inflammatory response. In this process, long non-coding RNAs (lncRNAs) play an important, yet largely unknown role. Therefore, utilizing several publicly available RNA sequencing datasets, we predicted and selected lncRNAs that are differentially expressed in M1 or M2 macrophages and involved in the inflammatory response. We identified SUGCT-AS1, which is a human macrophage-specific lncRNA whose expression is increased upon M1 macrophage stimulation. Conditioned media of SUGCT-AS1-depleted M1 macrophages induced an inflammatory phenotype of vascular smooth muscle cells, which included increased expression of inflammatory genes (IL1B and IL6), decreased contractile marker proteins (ACTA2 and SM22α), and increased cell migration. Depletion of SUGCT-AS1 promoted the expression and secretion of proinflammatory cytokines, such as TNF, IL1B, and IL6, in M1 macrophages, and transcriptomic analysis showed that SUGCT-AS1 has functions related to inflammatory responses and cytokines. Furthermore, we found that SUGCT-AS1 directly binds to hnRNPU and regulates its nuclear-cytoplasmic translocation. This translocation of hnRNPU altered the proportion of the MALT1 isoforms by regulating the alternative splicing of MALT1, a mediator of NF-κB signaling. Overall, our findings suggest that lncRNAs can be used for future studies on macrophage regulation. Moreover, they establish the SUGCT-AS1/hnRNPU/MALT1 axis, which is a novel inflammatory regulatory mechanism in macrophages.
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ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Interleucina-6/genética , Empalme Alternativo , Proteínas Contráctiles , Citocinas/genética , MacrófagosRESUMEN
BACKGROUND: There have been no previous studies that directly compared outcomes between cap-fitted forward-viewing and side viewing endoscopes (SE). This study aimed to compare the technical success rate and occurrence of adverse events between the side viewing and cap-fitted forward-viewing endoscope (CE) groups among patients with Billroth II anatomy who underwent ERCP. METHODS: The medical records of patients with a previous history of subtotal gastrectomy using Billroth II reconstruction who underwent ERCP at Yeungnam University Hospital between January 2004 and December 2020 were reviewed retrospectively. The patients were divided into CE and SE group. Propensity score matching analysis was performed to minimize selection bias. RESULTS: Propensity score matching resulted in 55 matched pairs for further analysis. Patients' characteristics were comparable in the matched cohorts. Final success rate of selective bile duct cannulation was not significantly different between the SE and CE groups (98.2% vs. 94.5%, p = 0.308). The complete CBD stone removal rate in CBD stone and successful biliary drainage rate in malignant biliary obstruction were not significantly different between the two groups. The rate of total ERCP-related adverse events was higher in the CE group than in the SE group, but the difference was not statistically significant (10.9% vs. 7.3%, p = 0.507). Among adverse events, the rate of post-ERCP pancreatitis showed higher tendency in the CE group than in the SE group (10.9% vs. 5.5%, p = 0.297). CONCLUSION: In conclusion, CE seems to be equally effective as SE for ERCP in patients with Billroth II anatomy. However, attention should be paid to development of post ERCP complications, especially pancreatitis, when performed by CE.
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Colangiopancreatografia Retrógrada Endoscópica , Pancreatitis , Humanos , Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Colangiopancreatografia Retrógrada Endoscópica/métodos , Estudios Retrospectivos , Endoscopios , Anastomosis Quirúrgica , Gastroenterostomía/efectos adversos , Gastroenterostomía/métodos , Pancreatitis/etiología , GastrectomíaRESUMEN
Background and Objectives: Acute peripancreatic fluid collection (APFC) is an acute local complication of acute pancreatitis (AP) according to the revised Atlanta classification. Sometimes APFC resolves completely, sometimes it changes into a pseudocyst or walled-off necrosis (WON), so called late complications. The aim of this study is to investigate the natural course of APFC detected on early computed tomography (CT) in moderately severe (MSAP) or severe AP (SAP). Materials and Methods: From October 2014 to September 2015, patients with MSAP or SAP were enrolled if there was APFC within 48 h of onset on imaging studies at six medical centers. The status of fluid collection was followed 4-8 weeks after onset. Initial laboratory findings, CT findings and clinical scoring systems were analyzed. Results: A total of 68 patients were enrolled and APFC was completely resolved in 32 (66.7%) patients in the MSAP group and 9 (34.6%) in the SAP group. Patients with a high bedside index for severity in acute pancreatitis (BISAP) score (≥3 points) were common in the SAP group. C-reactive protein (CRP) after 48 h from admission and BUN level were also high in the SAP group. In multivariate analysis, BISAP score (≥3 points), elevation of CRP after 48 h (≥150 mg/L) and nasojejunal feeding after 48 h were risk factors for the development of late complications. Conclusions: Spontaneous resolution of APFC was more common in MSAP group and APFC can be changed to pseudocyst or WON in patients with elevated BISAP score, CRP level after 48 h, and non-improved abdominal pain.
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Pancreatitis , Enfermedad Aguda , Proteína C-Reactiva/metabolismo , Hospitalización , Humanos , Necrosis , Pancreatitis/complicaciones , Pancreatitis/diagnóstico , Índice de Severidad de la EnfermedadRESUMEN
We previously showed that the matricellular protein CCN5 reverses established cardiac fibrosis (CF) through inducing apoptosis in myofibroblasts (MyoFBs) but not in cardiomyocytes or fibroblasts (FBs). In this study, we set out to elucidate the molecular mechanisms underlying CCN5-mediated selective apoptosis of MyoFBs. We first observed that the apoptotic protein p53 and the anti-apoptotic protein NFκB are simultaneously induced in MyoFBs. When the expression level of p53 was suppressed using a siRNA, CCN5 did not induce apoptosis in MyoFBs. By contrast, when NFκB signaling was inhibited using IKK VII, an IκB inhibitor, MyoFBs underwent apoptosis even in the absence of CCN5. SMAD7 is one of the downstream targets of CCN5 and it was previously shown to potentiate apoptosis in epithelial cells through inhibition of NFκB. In accordance with these reports, when the expression of SMAD7 was suppressed using a siRNA, NFκB signaling was enhanced, and CCN5 did not induce apoptosis. Lastly, we used a luciferase reporter construct to show that CCN5 positively regulated SMAD7 expression at the transcriptional level. Collectively, our data suggest that a delicate balance between the two mutually antagonistic proteins p53 and NFκB is maintained for MyoFBs to survive, and CCN5 tips the balance in favor of the apoptotic protein p53. This study provides insight into the anti-fibrotic activity of CCN5 during the regression of CF.
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Proteínas CCN de Señalización Intercelular/metabolismo , Miofibroblastos , Proteínas Represoras/metabolismo , Proteína p53 Supresora de Tumor , Apoptosis , Fibrosis , Humanos , FN-kappa B , ARN Interferente Pequeño , Proteína smad7/genéticaRESUMEN
Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration due to dystrophin gene mutations. Patients with DMD initially experience muscle weakness in their limbs during adolescence. With age, patients develop fatal respiratory and cardiac dysfunctions. During the later stages of the disease, severe cardiac fibrosis occurs, compromising cardiac function. Previously, our research showed that the matricellular protein CCN5 has antifibrotic properties. Therefore, we hypothesized that CCN5 gene transfer would ameliorate cardiac fibrosis and thus improve cardiac function in DMD-induced cardiomyopathy. We utilized mdx/utrn (±) haploinsufficient mice that recapitulated the DMD-disease phenotypes and used an adeno-associated virus serotype-9 viral vector for CCN5 gene transfer. We evaluated the onset of cardiac dysfunction using echocardiography and determined the experimental starting point in 13-month-old mice. Two months after CCN5 gene transfer, cardiac function was significantly enhanced, and cardiac fibrosis was ameliorated. Additionally, running performance was improved in CCN5 gene-transfected mice. Furthermore, in silico gene profiling analysis identified utrophin as a novel transcriptional target of CCN5. This was supplemented by a utrophin promoter assay and RNA-seq analysis, which confirmed that CCN5 was directly associated with utrophin expression. Our results showed that CCN5 may be a promising therapeutic molecule for DMD-induced cardiac and skeletal dysfunction.
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The matricellular protein CCN5 exerts anti-fibrotic activity in hearts partly by inducing reverse trans-differentiation of myofibroblasts (MyoFBs) to fibroblasts (FBs). CCN5 consists of three structural domains: an insulin-like growth factor binding protein (IGFBP), a von Willebrand factor type C (VWC), and a thrombospondin type 1 (TSP-1). In this study, we set out to elucidate the roles of these domains in the context of the reverse trans-differentiation of MyoFBs to FBs. First, human cardiac FBs were trans-differentiated to MyoFBs by treatment with TGF-ß; this was then reversed by treatment with recombinant human CCN5 protein or various recombinant proteins comprising individual or paired CCN5 domains. Subcellular localization of these recombinant proteins was analyzed by immunocytochemistry, cellular fractionation, and western blotting. Anti-fibrotic activity was also evaluated by examining expression of MyoFB-specific markers, α-SMA and fibronectin. Our data show that CCN5 is taken up by FBs and MyoFBs mainly via clathrin-mediated endocytosis, which is essential for the function of CCN5 during the reverse trans-differentiation of MyoFBs. Furthermore, we showed that the TSP-1 domain is essential and sufficient for endocytosis and nuclear localization of CCN5. However, the TSP-1 domain alone is not sufficient for the anti-fibrotic function of CCN5; either the IGFBP or VWC domain is needed in addition to the TSP-1 domain.
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Trombospondina 1 , Trombospondinas , Fibrosis , Humanos , Miofibroblastos , Proteínas Recombinantes/farmacología , Trombospondina 1/genéticaRESUMEN
Vascular calcification (VC), or calcium deposition inside the blood vessels, is common in patients with atherosclerosis, cardiovascular disease, and chronic kidney disease. Although several treatments are available to reduce calcification, the incidence of VC continues to rise. Recently, there have been several reports describing the regulation of circular RNAs (circRNAs) in various diseases. However, the role of circRNAs in VC has not yet been fully explored. Here, we investigated the function of circSmoc1-2, one of the circRNAs generated from the Smoc1 gene, which is downregulated in response to VC. CircSmoc1-2 is localized primarily to the cytoplasm and is resistant to exonuclease digestion. Inhibition of circSmoc1-2 worsens VC, while overexpression of circSmoc1-2 reduces VC, suggesting that circSmoc1-2 can prevent calcification. We went on to investigate the mechanism of circSmoc1-2 as a microRNA sponge and noted that miR-874-3p, the predicted target of circSmoc1-2, promotes VC, while overexpression of circSmoc1-2 reduces VC by suppressing miR-874-3p. Additionally, we identified the potential mRNA target of miR-874-3p as Adam19. In conclusion, we revealed that the circSmoc1-2/miR-874-3p/Adam19 axis regulates VC, suggesting that circSmoc1-2 may be a novel therapeutic target in the treatment of VC.
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BACKGROUND/AIMS: While switching strategies of P2Y12 receptor inhibitors (RIs) have sometimes been used in acute myocardial infarction (AMI) patients, the current status of in-hospital P2Y12RI switching remains unknown. METHODS: Overall, 8,476 AMI patients who underwent successful revascularization from Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH) were divided according to in-hospital P2Y12RI strategies, and net adverse cardiovascular events (NACEs), defined as a composite of cardiac death, non-fatal myocardial infarction (MI), stroke, or thrombolysis in myocardial infarction (TIMI) major bleeding during hospitalization were compared. RESULTS: Patients with in-hospital P2Y12RI switching accounted for 16.5%, of which 867 patients were switched from clopidogrel to potent P2Y12RI (C-P) and 532 patients from potent P2Y12RI to clopidogrel (P-C). There were no differences in NACEs among the unchanged clopidogrel, the unchanged potent P2Y12RIs, and the P2Y12RI switching groups. However, compared to the unchanged clopidogrel group, the C-P group had a higher incidence of non-fatal MI, and the P-C group had a higher incidence of TIMI major bleeding. In clinical events of in-hospital P2Y12RI switching, 90.9% of non-fatal MI occurred during pre-switching clopidogrel administration, 60.7% of TIMI major bleeding was related to pre-switching P2Y12RIs, and 71.4% of TIMI major bleeding was related to potent P2Y12RIs. Only 21.6% of the P2Y12RI switching group switched to P2Y12RIs after a loading dose (LD); however, there were no differences in clinical events between patients with and without LD. CONCLUSION: In-hospital P2Y12RI switching occurred occasionally, but had relatively similar clinical outcomes compared to unchanged P2Y12RIs in Korean AMI patients. Non-fatal MI and bleeding appeared to be mainly related to pre-switching P2Y12RIs.
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Infarto del Miocardio , Intervención Coronaria Percutánea , Clopidogrel/efectos adversos , Hemorragia/inducido químicamente , Hospitales , Humanos , Infarto del Miocardio/tratamiento farmacológico , Intervención Coronaria Percutánea/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Clorhidrato de Prasugrel/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Resultado del TratamientoRESUMEN
Acute cholecystitis (AC), defined as inflammation of the gallbladder, is mainly caused by gallstones. Over 90% of AC results from obstruction of the cystic duct by stones or sludge, which subsequently increases the intraluminal pressure within the gallbladder and, in conjunction with the presence of bile supersaturated with cholesterol, activates an acute inflammatory cascade. Clinical features play an important role in the diagnosis of AC. The Tokyo Guidelines 2018 for acute cholecystitis designates the presence of local inflammatory signs and systemic inflammatory signs for a suspected diagnosis. It requires confirmation by radiological imaging along with these two factors for a definitive diagnosis. Thanks to less invasiveness, easy availability, ease of use, and cost-effectiveness, ultrasound (US) is usually accepted as the first choice in suspicious AC patients. A meta-analysis comparing methods of diagnosis for AC reported that the US has 81% of sensitivity and 83% of specificity. Abdominal computed tomography is recommended for diagnosing emphysematous or gangrenous cholecystitis. Meanwhile, acute acalculous cholecystitis (AAC) is a life-threatening disease mainly in severely ill patients. It usually affects the patients hospitalized for multiple trauma, burns, cardiopulmonary bypass surgery, long-term total parenteral nutrition or sepsis. The diagnosis of AAC is quite challenging and requires a high index of suspicion. Currently, cholecystectomy is the treatment of choice for AC, although the optimal time for surgery is still controversial. Due to high morbidity and mortality in high surgical risk groups, percutaneous gallbladder drainage can be a safe and feasible alternative to cholecystectomy, particularly for patients unfit for the surgery.
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Vascular calcification increases morbidity and mortality in patients with cardiovascular and renal diseases. Previously, we reported that histone deacetylase 1 prevents vascular calcification, whereas its E3 ligase, mouse double minute 2 homolog (MDM2), induces vascular calcification. In the present study, we identified the upstream regulator of MDM2. By utilizing cellular models and transgenic mice, we confirmed that E3 ligase activity is required for vascular calcification. By promoter analysis, we found that both msh homeobox 1 (Msx1) and msh homeobox 2 (Msx2) bound to the MDM2 promoter region, which resulted in transcriptional activation of MDM2. The expression levels of both Msx1 and Msx2 were increased in mouse models of vascular calcification and in calcified human coronary arteries. Msx1 and Msx2 potentiated vascular calcification in cellular and mouse models in an MDM2-dependent manner. Our results establish a novel role for MSX1/MSX2 in the transcriptional activation of MDM2 and the resultant increase in MDM2 E3 ligase activity during vascular calcification.
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Proteínas de Homeodominio/metabolismo , Factor de Transcripción MSX1/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Ubiquitina-Proteína Ligasas/genética , Calcificación Vascular/etiología , Calcificación Vascular/metabolismo , Animales , Biomarcadores , Calcio/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Ratones Noqueados , Modelos Biológicos , Mutación , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Elementos de Respuesta , Ubiquitina-Proteína Ligasas/metabolismo , Calcificación Vascular/patologíaRESUMEN
BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak has markedly influenced the endoscopic patterns. Endoscopic retrograde cholangiopancreatography (ERCP) is an essential technique for pancreatobiliary disease but increases the risk of exposure to the virus-containing body fluid; however, the impact of COVID-19 on ERCP is unknown. AIM: To compare the number of endoscopic activities and to analyze the clinical outcomes of ERCPs before and during the COVID-19 outbreak in Daegu, South Kore. METHODS: This retrospective cohort study included patients aged ≥ 18 years who underwent ERCP between February 18 and March 28, 2020, at a tertiary hospital. ERCP indications and endoscopic details were compared with those from the same period in 2018 and 2019 as control groups. RESULTS: Of the 269 ERCP procedures, 113 (42.0%) cases were performed as emergency procedures. The number of ERCP procedures in 2018 and 2019 decreased by 20.2% and 56.6%, respectively, compared with that in 2020 (P < 0.01); among the 113 emergency ERCPs, the observed numbers in 2018 (n = 42) and 2019 (n = 55) dramatically dropped by 61.9% and 70.9%, respectively, compared with that in 2020 (n = 16). Of the 16 cases in 2020, stone removal was performed in five, biliary stenting in five, sphincterotomy in five, and nasobiliary drainage in one. No case of ERCP-related infection in medical workers or other patients has been reported. CONCLUSION: The COVID-19 outbreak significantly reduced the number of ERCPs; however, there is no difference in the indications and endoscopic interventions before and during the COVID-19 outbreak.
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Various heart diseases cause cardiac remodeling, which in turn leads to ineffective contraction. Although it is an adaptive response to injury, cardiac fibrosis contributes to this remodeling, for which the reactivation of quiescent myofibroblasts is a key feature. In the present study, we investigated the role of the p300/CBP-associated factor (PCAF), a histone acetyltransferase, in the activation of cardiac fibroblasts. An intraperitoneal (i.p.) injection of a high dose (160 mg/kg) of isoproterenol (ISP) induced cardiac fibrosis and reduced the amount of the PCAF in cardiac fibroblasts in the mouse heart. However, the PCAF activity was significantly increased in cardiac fibroblasts, but not in cardiomyocytes, obtained from ISP-administered mice. An in vitro study using human cardiac fibroblast cells recapitulated the in vivo results; an treatment with transforming growth factor-ß1 (TGF-ß1) reduced the PCAF, whereas it activated the PCAF in the fibroblasts. PCAF siRNA attenuated the TGF-ß1-induced increase in and translocation of fibrosis marker proteins. PCAF siRNA blocked TGF-ß1-mediated gel contraction and cell migration. The PCAF directly interacted with and acetylated mothers against decapentaplegic homolog 2 (SMAD2). PCAF siRNA prevented TGF-ß1-induced phosphorylation and the nuclear localization of SMAD2. These results suggest that the increase in PCAF activity during cardiac fibrosis may participate in SMAD2 acetylation and thereby in its activation.
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Fibroblastos/metabolismo , Miocardio/citología , Proteína Smad2/metabolismo , Factores de Transcripción p300-CBP/metabolismo , Acetilación , Actinas/metabolismo , Animales , Movimiento Celular , Núcleo Celular/metabolismo , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Fibrosis , Humanos , Isoproterenol , Masculino , Metaloproteinasas de la Matriz/metabolismo , Ratones Endogámicos C57BL , Fosforilación , Transporte de Proteínas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factores de Transcripción p300-CBP/genéticaRESUMEN
BACKGROUND: Arterial pressure-based cardiac output (APCO) is a less invasive method for estimating cardiac output without concerns about complications from the pulmonary artery catheter (PAC). However, inaccuracies of currently available APCO devices have been reported. Improvements to the algorithm by researchers are impossible, as only a subset of the algorithm has been released. OBJECTIVE: In this study, an open-source algorithm was developed and validated using a convolutional neural network and a transfer learning technique. METHODS: A retrospective study was performed using data from a prospective cohort registry of intraoperative bio-signal data from a university hospital. The convolutional neural network model was trained using the arterial pressure waveform as input and the stroke volume (SV) value as the output. The model parameters were pretrained using the SV values from a commercial APCO device (Vigileo or EV1000 with the FloTrac algorithm) and adjusted with a transfer learning technique using SV values from the PAC. The performance of the model was evaluated using absolute error for the PAC on the testing dataset from separate periods. Finally, we compared the performance of the deep learning model and the FloTrac with the SV values from the PAC. RESULTS: A total of 2057 surgical cases (1958 training and 99 testing cases) were used in the registry. In the deep learning model, the absolute errors of SV were 14.5 (SD 13.4) mL (10.2 [SD 8.4] mL in cardiac surgery and 17.4 [SD 15.3] mL in liver transplantation). Compared with FloTrac, the absolute errors of the deep learning model were significantly smaller (16.5 [SD 15.4] and 18.3 [SD 15.1], P<.001). CONCLUSIONS: The deep learning-based APCO algorithm showed better performance than the commercial APCO device. Further improvement of the algorithm developed in this study may be helpful for estimating cardiac output accurately in clinical practice and optimizing high-risk patient care.
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Coupled signaling between bone-forming osteoblasts and bone-resorbing osteoclasts is crucial to the maintenance of bone homeostasis. We previously reported that v-crk avian sarcoma virus CT10 oncogene homolog-like (CrkL), which belongs to the Crk family of adaptors, inhibits bone morphogenetic protein 2 (BMP2)-mediated osteoblast differentiation, while enhancing receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation. In this study, we investigated whether CrkL can also regulate the coupling signals between osteoblasts and osteoclasts, facilitating bone homeostasis. Osteoblastic CrkL strongly decreased RANKL expression through its inhibition of runt-related transcription factor 2 (Runx2) transcription. Reduction in RANKL expression by CrkL in osteoblasts resulted in the inhibition of not only osteoblast-dependent osteoclast differentiation but also osteoclast-dependent osteoblast differentiation, suggesting that CrkL participates in the coupling signals between osteoblasts and osteoclasts via its regulation of RANKL expression. Therefore, CrkL bifunctionally regulates osteoclast differentiation through both a direct and indirect mechanism while it inhibits osteoblast differentiation through its blockade of both BMP2 and RANKL reverse signaling pathways. Collectively, these data suggest that CrkL is involved in bone homeostasis, where it helps to regulate the complex interactions of the osteoblasts, osteoclasts, and their coupling signals.
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Proteínas Adaptadoras Transductoras de Señales/fisiología , Remodelación Ósea/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Animales Recién Nacidos , Diferenciación Celular/genética , Células Cultivadas , Células HEK293 , Humanos , Ratones , Ratones Endogámicos ICR , Osteoblastos/fisiología , Osteoclastos/fisiología , Osteogénesis/genéticaRESUMEN
Extrahepatic recurrence (EHR) after curative hepatectomy for hepatocellular carcinoma (HCC) is associated with a poor prognosis. We investigated the features of EHR and identified its predictive factors. This retrospective study included 398 treatment-naive patients who underwent curative hepatectomy for HCC at two tertiary hospitals. Multivariate Cox-regression analysis was performed to identify the variables associated with EHR. EHR was diagnosed in 94 patients (23.6%) over a median follow-up period of 5.92 years, most commonly in the lungs (42.6%). The 5-/10-year cumulative rates of HCC recurrence and EHR were 63.0%/75.6% and 18.1%/35.0%, respectively. The median time to EHR was 2.06 years. Intrahepatic HCC recurrence was not observed in 38.3% of patients on EHR diagnosis. On multivariate analysis, pathologic modified Union for International Cancer Control stage (III, IVa), surgical margin involvement, tumor necrosis, sum of tumor size > 7 cm, and macrovascular invasion were predictive factors of EHR. Four risk levels and their respective EHR rates were defined as follows: very low risk, 1-/5-year, 3.1%/11.6%; low risk, 1-/5-year, 12.0%/27.7%; intermediate risk, 1-/5-year, 36.3%/60.9%; and high risk, 1-year, 100.0%. Our predictive model clarifies the clinical course of EHR and could improve the follow-up strategy to improve outcomes.