Search

Cerebral hyperperfusion syndrome (CHS) is a serious complication after bypass surgery in Moyamoya disease (MMD), with autoregulatory dysfunction being a major pathogenesis. This study investigated the change of perioperative autoregulation and preoperative prognostic potentials in MMD with postoperative CHS. Among 26 hemispheres in 24 patients with adult MMD undergoing combined bypass, 13 hemispheres experienced postoperative CHS. Arterial blood pressure and cerebral blood flow velocity were perioperatively measured with transcranial Doppler ultrasound during resting and the Valsalva maneuver (VM). Autoregulation profiles were discovered in both the CHS and non-CHS groups using mean flow index (Mxa), VM Autoregulatory Index (VM AI ), and a new metric termed VM Overshooting Index (VM OI ). The CHS group had inferior autoregulation than the non-CHS group as indicated by VM OI on preoperative day 1 and postoperative 3rd day. Deteriorated autoregulation was observed via Mxa in the CHS group than in the non-CHS group on the postoperative 3rd and discharge days. Postoperative longitudinal autoregulation recovery in the CHS group was found in a logistic regression model with diminished group differences over the time course. This work represents a step forward in utilizing autoregulation indices derived from physiological signals, to predict the postoperative CHS in adult MMD., (© 2024. The Author(s).)

Bidirectional communication between tumours and neurons has emerged as a key facet of the tumour microenvironment that drives malignancy 1,2 . Another hallmark feature of cancer is epigenomic dysregulation, in which alterations in gene expression influence cell states and interactions with the tumour microenvironment 3 . Ependymoma (EPN) is a paediatric brain tumour that relies on epigenomic remodelling to engender malignancy 4,5 ; however, how these epigenetic mechanisms intersect with extrinsic neuronal signalling during EPN tumour progression is unknown. Here we show that the activity of serotonergic neurons regulates EPN tumorigenesis, and that serotonin itself also serves as an activating modification on histones. We found that inhibiting histone serotonylation blocks EPN tumorigenesis and regulates the expression of a core set of developmental transcription factors. High-throughput, in vivo screening of these transcription factors revealed that ETV5 promotes EPN tumorigenesis and functions by enhancing repressive chromatin states. Neuropeptide Y (NPY) is one of the genes repressed by ETV5, and its overexpression suppresses EPN tumour progression and tumour-associated network hyperactivity through synaptic remodelling. Collectively, this study identifies histone serotonylation as a key driver of EPN tumorigenesis, and also reveals how neuronal signalling, neuro-epigenomics and developmental programs are intertwined to drive malignancy in brain cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The COVID-19 pandemic has had a substantial adverse impact on the physical and mental health of pregnant and postpartum women, thereby increasing the risk of postpartum depression (PPD). This study aimed to evaluate the effectiveness of a continuous contactless exercise intervention in reducing the risk of depression during the prenatal and postnatal periods. The study utilized an interactive contactless exercise program consisting of Pilates movement over a 16-week period, with 8 weeks during pregnancy and 8 weeks after childbirth. Metabolic and psychological factors related to postpartum depression, including pain, stress, and stress-response markers, were analyzed. The results showed that the exercise intervention significantly alleviated postpartum depression by improving pain (Oswestry Disability Index: Non-exercise, 11.4 ± 14.8 versus Exercise, - 63.1 ± 18.4, p < .001) and stress factors (Edinburgh Postnatal Depression Scale: Non-exercise, 8.8 ± 8.72 versus Exercise, - 37.6 ± 9.13, p < .001; Perceived Stress Scale: Non-exercise, 9.21 ± 9.35 versus Exercise, - 20.7 ± 14.4, p < .001) caused by physical/structural imbalances in postpartum women. Additionally, the intervention improved the metabolic imbalances commonly observed after childbirth, including reductions in triglyceride (Interaction effect, p = .017), insulin (Interaction effect, p = .032), and cortisol levels (Interaction effect, p < .001), which are recognized risk factors for postpartum depression. Taken together, these findings suggest that contactless online exercise interventions can mitigate postpartum depression by addressing metabolic dysregulation that frequently occurs after delivery, especially in situations of social isolation caused by the pandemic., (© 2024. The Author(s).)

Upper airway collapse can be effectively dealt with positive airway pressure (PAP), and patient adherence is considered as a major determining factor for success of PAP therapy. This study was performed to determine the potential factors affecting the adherence to PAP in patients with OSA by using polysomnography (PSG) parameters recorded for diagnosis of OSA. The data of 158 patients between December 2018 and July 2021 were collected. They were prescribed with PAP and used the device during the adaptation period for 90 days. They were categorized into adherent and non-adherent group according to the criteria of good adherence as use of PAP ≥ 4 h per night on 70% of nights. Demographic, clinical characteristics, and PSG results were reviewed. Among 158 patients engaged in PAP therapy, 121 patients (76.6%) met the criteria of good adherence. No significant differences were found in good adherence rate regarding demographic and clinical characteristics. None of the polysomnographic factors showed significant differences between adherent and non-adherent groups. However, the percentage of sleep time on back in the adherent group was significantly higher than non-adherent group (p = 0.041). The cut-off value was determined to be 41.45% (95% confidence interval 0.43 to 0.79) by receiver operating characteristic curve analysis and the odds ratio was calculated as 2.97. Only the percentage of sleep time on back appeared to be polysomnographic predictor for identifying good adherence to PAP therapy in OSA patients. However, the conclusions may be limited in generalization due to the small sample size., (© 2023. The Author(s).)

Donor against recipient one-way Human leukocyte antigen (HLA) mismatch (D → R one-way HLA MM) seemed strongly associated with graft-versus-host disease (GVHD). The aim of this study is to investigate the relevance of D → R one-way HLA MM in outcome of liver transplantation (LT). We retrospectively analyzed 2670 patients in Korean Organ Transplantation Registry database between April 2014 and December 2020. The patients were categorized into two groups whether D → R one-way HLA MM or not and evaluated the outcomes of LT between the two groups. 18 patients were found to be D → R one-way HLA MM. The incidence of GVHD (0.3% vs. 22.2%, p < 0.001) and mortality rate (11.6% vs. 38.9%, p = 0.003) was much higher in D → R one-way HLA MM group. D → R one-way HLA MM at 3 loci was seemed to be strongly associated with the incidence of GVHD (OR 163.3, p < 0.001), and found to be the strongest risk factor for patient death (HR 12.75, p < 0.001). Patients with D → R one-way HLA MM at 3 loci showed significantly lower overall survival (p < 0.001) but there were no significant differences in rejection-free survival and death-censored graft survival. D → R one-way HLA MM at 3 loci not only affects the overall survival of LT patients but also the incidence of GVHD., (© 2023. The Author(s).)

The clinical effects of tacrolimus (TAC) exposure on hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) remain unclear. In this retrospective single centric study, 512 patients who underwent LT for HCC were divided into four groups according to cumulative exposure to tacrolimus (CET) during 3 months after LT: conventional (n = 218), aggressive minimization (n = 32), minimization (n = 161), and high exposure (n = 101). Impact of CET on HCC recurrence and death were analyzed. Compared with the conventional group, the other three CET groups showed a similar risk of HCC recurrence. The aggressive minimization group showed a higher risk [hazard ratio (HR) 5.64, P < 0.001] and the high exposure group showed a marginal risk (HR 1.67, P = 0.081) of overall death compared to the conventional group. CET during 3 months was not associated with HCC recurrence in the matched cohort and various subgroups. TAC minimization is not effective to prevent HCC recurrence but could result in higher mortality in LT recipients., (© 2023. The Author(s).)

Melatonin is involved in the regulation of various biological functions. Here, we explored a novel molecular mechanism by which the melatonin-induced sestrin2 (SESN2)-small heterodimer partner (SHP) signaling pathway protects against fasting- and diabetes-mediated hepatic glucose metabolism. Various key gene expression analyses were performed and multiple metabolic changes were assessed in liver specimens and primary hepatocytes of mice and human participants. The expression of the hepatic cereblon (CRBN) and b-cell translocation gene 2 (BTG2) genes was significantly increased in fasting mice, diabetic mice, and patients with diabetes. Overexpression of Crbn and Btg2 increased hepatic gluconeogenesis by enhancing cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH), whereas this phenomenon was prominently ablated in Crbn null mice and Btg2-silenced mice. Interestingly, melatonin-induced SESN2 and SHP markedly reduced hepatic glucose metabolism in diabetic mice and primary hepatocytes, and this protective effect of melatonin was strikingly reversed by silencing Sesn2 and Shp. Finally, the melatonin-induced SESN2-SHP signaling pathway inhibited CRBN- and BTG2-mediated hepatic gluconeogenic gene transcription via the competition of BTG2 and the interaction of CREBH. Mitigation of the CRBN-BTG2-CREBH axis by the melatonin-SESN2-SHP signaling network may provide a novel therapeutic strategy to treat metabolic dysfunction due to diabetes., (© 2023. The Author(s).)

We investigated the correlation between standardized uptake value (SUV) of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and conductivity parameters in breast cancer and explored the feasibility of conductivity as an imaging biomarker. Both SUV and conductivity have the potential to reflect the tumors' heterogeneous characteristics, but their correlations have not been investigated until now. Forty four women diagnosed with breast cancer who underwent breast MRI and 18 F-FDG PET/CT at the time of diagnosis were included. Among them, 17 women received neoadjuvant chemotherapy followed by surgery and 27 women underwent upfront surgery. For conductivity parameters, maximum and mean values of the tumor region-of-interests were examined. For SUV parameters, SUVmax, SUVmean, and SUVpeak of the tumor region-of-interests were examined. Correlations between conductivity and SUV were evaluated, and among them, the highest correlation was observed between mean conductivity and SUVpeak (Spearman's correlation coefficient = 0.381). In a subgroup analysis for 27 women with upfront surgery, tumors with lymphovascular invasion (LVI) showed higher mean conductivity than those without LVI (median: 0.49 S/m vs 0.06 S/m, p < 0.001). In conclusion, our study shows a low positive correlation between SUVpeak and mean conductivity in breast cancer. Furthermore, conductivity showed a potential to noninvasively predict LVI status., (© 2023. The Author(s).)

We compared neural activities and network properties between the antihistamine-induced seizures (AIS) and seizure-free groups, with the hypothesis that patients with AIS might have inherently increased neural activities and network properties that are easily synchronized. Resting-state electroencephalography (EEG) data were collected from 27 AIS patients and 30 healthy adults who had never had a seizure. Power spectral density analysis was used to compare neural activities in each localized region. Functional connectivity (FC) was measured using coherence, and graph theoretical analyses were performed to compare network properties between the groups. Machine learning algorithms were applied using measurements found to be different between the groups in the EEG analyses as input features. Compared with the seizure-free group, the AIS group showed a higher spectral power in the entire regions of the delta, theta, and beta bands, as well as in the frontal areas of the alpha band. The AIS group had a higher overall FC strength, as well as a shorter characteristic path length in the theta band and higher global efficiency, local efficiency, and clustering coefficient in the beta band than the seizure-free group. The Support Vector Machine, k-Nearest Neighbor, and Random Forest models distinguished the AIS group from the seizure-free group with a high accuracy of more than 99%. The AIS group had seizure susceptibility considering both regional neural activities and functional network properties. Our findings provide insights into the underlying pathophysiological mechanisms of AIS and may be useful for the differential diagnosis of new-onset seizures in the clinical setting., (© 2023. The Author(s).)

Septoplasty is one of the most common otolaryngological surgical procedures. The causes of persistent septal deviation after primary septoplasty vary. The purpose of this study was to identify factors associated with failure of primary septoplasty, operative techniques that correct residual septal deviation, and surgical outcomes. Seventy-four adults who underwent revision septoplasty to treat persistent septal deviations were enrolled. The level of hospital in which primary septoplasty was performed, type of septal deviation, septal portion exhibiting persistent deviation, and techniques used to correct the deviation were evaluated. Outcomes were measured subjectively using a visual analog scale (VAS), and objectively using acoustic rhinometry. The first septoplasties were usually performed in primary and secondary hospitals. C-shaped deviations were more common than S-shaped ones in both the anteroposterior and cephalocaudal dimensions. The most common region of persistent septal deviation was the caudal septum (44.6%), followed by multiple sites (20.3%). The corrective techniques included excision of the remnant deviated portion (70.3%), septal cartilage traction suturing (27.0%), spreader grafting (13.5%), and cross-suturing (6.8%). The VAS score improved significantly 6 months after surgery. The minimal cross-sectional area and nasal cavity volume of the convex side increased significantly after revision septoplasty. Patients who underwent septoplasty in primary and secondary hospitals were more likely to require revision septoplasty. The caudal septum was the most common site of persistent septal deviation. Careful preoperative evaluation of the caudal septal deviation and selection of an appropriate surgical technique may reduce the need for revision septoplasty., (© 2022. The Author(s).)

Manually delineating upper abdominal organs at risk (OARs) is a time-consuming task. To develop a deep-learning-based tool for accurate and robust auto-segmentation of these OARs, forty pancreatic cancer patients with contrast-enhanced breath-hold computed tomographic (CT) images were selected. We trained a three-dimensional (3D) U-Net ensemble that automatically segments all organ contours concurrently with the self-configuring nnU-Net framework. Our tool's performance was assessed on a held-out test set of 30 patients quantitatively. Five radiation oncologists from three different institutions assessed the performance of the tool using a 5-point Likert scale on an additional 75 randomly selected test patients. The mean (± std. dev.) Dice similarity coefficient values between the automatic segmentation and the ground truth on contrast-enhanced CT images were 0.80 ± 0.08, 0.89 ± 0.05, 0.90 ± 0.06, 0.92 ± 0.03, 0.96 ± 0.01, 0.97 ± 0.01, 0.96 ± 0.01, and 0.96 ± 0.01 for the duodenum, small bowel, large bowel, stomach, liver, spleen, right kidney, and left kidney, respectively. 89.3% (contrast-enhanced) and 85.3% (non-contrast-enhanced) of duodenum contours were scored as a 3 or above, which required only minor edits. More than 90% of the other organs' contours were scored as a 3 or above. Our tool achieved a high level of clinical acceptability with a small training dataset and provides accurate contours for treatment planning., (© 2022. The Author(s).)

Tacrolimus is the mainstay of immunosuppression in liver transplantation to prevent rejection. However, the clinical use of tacrolimus is complicated by its narrow therapeutic window and significant intra-patient variability (IPV). High tacrolimus IPV is associated with overexposure and adverse effects, including malignancy. The effects of tacrolimus IPV in liver transplant recipients with and without hepatocellular carcinoma (HCC) are unknown. We investigated the association between tacrolimus IPV and transplant outcomes in 636 liver transplant patients. Tacrolimus IPV was determined by calculating the coefficient of variance (CV) of outpatient tacrolimus trough levels from 3 to 12 months after transplantation. High tacrolimus IPV was defined as CV > 30%. Patients were grouped according to tacrolimus IPV and HCC status. Among 636 liver transplant patients, 349 had HCC and 287 had no HCC. Overall survival in HCC patients was significantly reduced with high tacrolimus IPV (P < 0.001), whereas survival of non-HCC patients was not associated with tacrolimus IPV. Multivariable analysis confirmed the independent association between high tacrolimus IPV and overall mortality in HCC patients (HR, 3.010; 95% CI, 1.084-4.918). HCC recurred in 59 patients (16.9%) post-transplantation. After adjusting for donor/recipient factors, immunosuppression, and tumor characteristics, high tacrolimus IPV was independently associated with an increased risk of HCC recurrence (HR, 2.196; 95% CI, 1.272-3.791). High tacrolimus IPV was associated with significantly increased risks of overall mortality and HCC recurrence in liver transplant recipients with HCC., (© 2022. The Author(s).)

Obesity is a global health problem that is associated with adverse consequences such as the development of metabolic disorders, including cardiovascular disease, neurodegenerative disorders, and type 2 diabetes. A major cause of obesity is metabolic imbalance, which results from insufficient physical activity and excess energy intake. Understanding the pathogenesis of obesity, as well as other metabolic disorders, is important in the development of methods for prevention and therapy. The coordination of energy balance takes place in the hypothalamus, a major brain region that maintains body homeostasis. The primary cilium is an organelle that has recently received attention because of its role in controlling energy balance in the hypothalamus. Defects in proteins required for ciliary function and formation, both in humans and in mice, have been shown to cause various metabolic disorders. In this review, we provide an overview of the critical functions of primary cilia, particularly in hypothalamic areas, and briefly summarize the studies on the primary roles of cilia in specific neurons relating to metabolic homeostasis., (© 2021. The Author(s).)

Serum bilirubin, a potent endogenous antioxidant, has been associated with decreased risks of cardiovascular disease, diabetes, and kidney disease. However, the effects of serum bilirubin on kidney transplant outcomes remain undetermined. We analyzed 1628 patients who underwent kidney transplantations between 2003 and 2017. Patients were grouped into sex-specific quartiles according to mean serum bilirubin levels, 3-12 months post-transplantation. Median bilirubin levels were 0.66 mg/dL in males and 0.60 mg/dL in females. The intra-individual variability of serum bilirubin levels was low (9%). Serum bilirubin levels were inversely associated with graft loss, death-censored graft failure, and all-cause mortality, independent of renal function, donor status, and transplant characteristics. Multivariable analysis revealed that the lowest serum bilirubin quartile was associated with increased risk of graft loss (HR 2.64, 95% CI 1.67-4.18, P < 0.001), death-censored graft failure (HR 2.97, 95% CI 1.63-5.42, P < 0.001), and all-cause mortality (HR 2.07, 95% CI 1.01-4.22, P = 0.046). Patients with lower serum bilirubin were also at greater risk of rejection and exhibited consistently lower glomerular filtration rates than those with higher serum bilirubin. Serum bilirubin levels were significantly associated with transplantation outcomes, suggesting that bilirubin could represent a therapeutic target for improving long-term transplant outcomes.

Infection by hepatitis E virus (HEV) via the oral route causes acute hepatitis. Extra-hepatic manifestations of HEV infection may stem from various causes; however, its distribution in organs such as the liver, as well as the mechanisms underlying HEV-induced cell injury, remain unclear. The objective of this study was to determine the chronological distribution of HEV in various tissues of HEV-challenged miniature pigs and to investigate the mechanisms underlying HEV-induced cell death in the pancreas and liver. Virological and serological analyses were performed on blood and faecal samples. Histopathology of the liver and extra-hepatic tissues was analysed. Cell death pathways and immune cell characterisation in inflammatory lesions were analysed using immunohistochemistry. The liver and pancreas displayed inflammation and cellular injury, and a large amount of HEV was observed in the lesions. The liver was infiltrated by T and natural killer cells. HEV was identified in all organs except the heart, and was associated with immune cells. Although the liver and the pancreas strongly expressed TNF-α and TRAIL, TUNEL assay results were negative. RIP3 and pMLKL were expressed in the pancreas. RIP3, but not pMLKL, was expressed in the liver. Pancreatitis induced in HEV-infected miniature pigs is associated with necroptosis.

No distinct guidelines are available regarding the effect of pretransplant locoregional treatment (LRT) in hepatocellular carcinoma (HCC) staging system. The aim of this study was to investigate the prognosis of pathologic downstaging (PDS) by the exclusion of total necrosis after liver transplantation. We conducted a study of 326 HCC patients who underwent liver transplantation between September 2005 and December 2016. Two hundred twenty-two patients received pretransplant LRT and 102 patients did not. Among the former group, 74 (33.0%) achieved PDS while 150 (67.0%) showed unchanged T stage after the exclusion of total necrosis. Five-year HCC recurrent free survival (RFS) of PDS group (85.1%) was similar to that of the no LRT group (88.8%) but higher than that of the non-PDS group (68.9%; P < 0.001). Based on T stage adjusted with total necrosis and PDS status, RFS was similar in the PDS T1 (82.4%) and non-PDS T1 (86.5%) groups. Non-PDS T2 cancers had worse outcome regardless of the Milan (P = 0.982) or University of California San Francisco criteria (P = 0.466). On preoperative examination, parameters like less than 1 viable tumor, less than 1 cm of tumor size, and less than 20 ng/mL of serum alpha fetoprotein were associated with PDS. This study showed that PDS by LRT was associated with favorable outcome in HCC patients after liver transplantation.

The previous Korean liver allocation system was based on Child-Turcotte-Pugh scores, but increasing numbers of deceased donors created a pressing need to develop an equitable, objective allocation system based on model for end-stage liver disease scores (MELD scores). A nationwide, multicenter, retrospective cohort study of candidates registered for liver transplantation from January 2009 to December 2011 was conducted at 11 transplant centers. Classification and regression tree (CART) analysis was used to stratify MELD score ranges according to waitlist survival. Of the 2702 patients that registered for liver transplantation, 2248 chronic liver disease patients were eligible. CART analysis indicated several MELD scores significantly predicted waitlist survival. The 90-day waitlist survival rates of patients with MELD scores of 31-40, 21-30, and ≤20 were 16.2%, 64.1%, and 95.9%, respectively (P < 0.001). Furthermore, the 14-day waitlist survival rates of severely ill patients (MELD 31-40, n = 240) with MELD scores of 31-37 (n = 140) and 38-40 (n = 100) were 64% and 43.4%, respectively (P = 0.001). Among patients with MELD > 20, presence of HCC did not affect waitlist survival (P = 0.405). Considering the lack of donor organs and geographic disparities in Korea, we proposed the use of a national broader sharing of liver for the sickest patients (MELD ≥ 38) to reduce waitlist mortality. HCC patients with MELD ≤ 20 need additional MELD points to allow them equitable access to transplantation. Based on these results, the Korean Network for Organ Sharing implemented the MELD allocation system in 2016.

Phosphoinositide 3-kinase (PI3K) signaling in hypothalamic neurons integrates peripheral metabolic cues, including leptin and insulin, to coordinate systemic glucose and energy homeostasis. PI3K is composed of different subunits, each of which has several unique isoforms. However, the role of the PI3K subunits and isoforms in the ventromedial hypothalamus (VMH), a prominent site for the regulation of glucose and energy homeostasis, is unclear. Here we investigated the role of subunit p110β in steroidogenic factor-1 (SF-1) neurons of the VMH in the regulation of metabolism. Our data demonstrate that the deletion of p110β in SF-1 neurons disrupts glucose metabolism, rendering the mice insulin resistant. In addition, the deletion of p110β in SF-1 neurons leads to the whitening of brown adipose tissues and increased susceptibility to diet-induced obesity due to blunted energy expenditure. These results highlight a critical role for p110β in the regulation of glucose and energy homeostasis via VMH neurons.

Although, cisplatin resistance is a major challenge in the treatment of ovarian cancer, the precise mechanisms underlying cisplatin resistance are not fully understood. Collagen type XI alpha 1 (COL11A1), a gene encoding a minor fibrillar collagen of the extracellular matrix, is identified as one of the most upregulated genes in cisplatin-resistant ovarian cancer and recurrent ovarian cancer. However, the exact functions of COL11A1 in cisplatin resistance are unknown. Here we demonstrate that COL11A1 binds to integrin α1β1 and discoidin domain receptor 2 (DDR2) and activates downstream signaling pathways to inhibit cisplatin-induced apoptosis in ovarian cancer cells. Mechanistically, we show that COL11A1 activates Src-PI3K/Akt-NF-kB signaling to induce the expression of three inhibitor apoptosis proteins (IAPs), including XIAP, BIRC2, and BIRC3. Genetic and pharmacological inhibition of XIAP, BIRC2, and BIRC3 is sufficient to restore cisplatin-induced apoptosis in ovarian cancer cells in the presence of COL11A1 in ovarian cancer cells and xenograft mouse models, respectively. We also show that the components of COL11A1- integrin α1β1/DDR2- Src-PI3K/Akt-NF-kB-IAP signaling pathway serve as poor prognosis markers in ovarian cancer patients. Taken together, our results suggest novel mechanisms by which COL11A1 confers cisplatin resistance in ovarian cancer. Our study also uncovers IAPs as promising therapeutic targets to reduce cisplatin resistance in ovarian cancer, particularly in recurrent ovarian cancer expressing high levels of COL11A1.

Development of metabolic syndrome is associated with hyperactivity of the HPA axis characterized by elevated levels of circulating adrenal hormones including cortisol and aldosterone. However, the molecular mechanism leading to the dysregulation of the HPA axis is not well elucidated. In this study, we found that insulin regulates adrenal steroidogenesis by increasing the expression and activity of steroidogenic factor 1 (SF-1) both in vitro and in vivo and this insulin effect was partly through inhibition of FoxO1. Specifically, insulin increased the protein and RNA levels of SF-1 and steroidogenic target genes. Further, adrenal SF-1 expression was significantly increased by hyperactivation of insulin signaling in mice. Together with the elevated SF-1 expression in adrenal glands, hyperactivation of insulin signaling led to increased aldosterone and corticosterone levels. On the other hand, suppressing the insulin signaling using streptozotocin markedly reduced the expression of adrenal SF-1 in mice. In addition, overexpression of FoxO1 significantly suppressed SF-1 and its steroidogenic target genes implying that the positive effect of insulin on SF-1 activity might be through suppression of FoxO1 in the adrenal gland. Taken together, these results indicate that insulin regulates adrenal steroidogenesis through coordinated control of SF-1 and FoxO1.

4-hydroxy-3-methoxycinnamic acid (ferulic acid, FA) is known to have numerous beneficial health effects, including anti-obesity and anti-hyperglycemic properties. However, the molecular networks that modulate the beneficial FA-induced metabolic effects have not been well elucidated. In this study, we explored the molecular mechanisms mediating the beneficial metabolic effects of FA. In mice, FA protected against high-fat diet-induced weight gain, reduced food intake and exhibited an overall improved metabolic phenotype. The food intake suppression by FA was accompanied by a specific reduction in hypothalamic orexigenic neuropeptides, including agouti-related protein and neuropeptide Y, with no significant changes in the anorexigenic peptides pro-opiomelanocortin and cocaine and amphetamine-regulated transcript. FA treatment also inhibited fat accumulation in the liver and white adipose tissue and suppressed the expression of gluconeogenic genes, including phosphoenolpyruvate carboxylase and glucose-6-phosphatase. Furthermore, we show that FA phosphorylated and inactivated the transcription factor FoxO1, which positively regulates the expression of gluconeogenic and orexigenic genes, providing evidence that FA might exert its beneficial metabolic effects through inhibition of FoxO1 function in the periphery and the hypothalamus.

Pneumocystis jirovecii pneumonia (PJP) is a potentially life-threatening infection that occurs in immunocompromised patients. The aim of this study was to evaluate risk factors for PJP in kidney transplantation recipients. We conducted a retrospective analysis of patient data from 500 consecutive kidney transplants performed at Severance Hospital between April 2011 and April 2014. Eighteen kidney transplantation recipients (3.6%) were diagnosed with PJP. In the univariate analysis, acute graft rejection, CMV infection, use of medication for diabetes mellitus, and lowest lymphocyte count were associated with PJP. Recipients who experienced acute graft rejection (odds ratio [OR] 11.81, 95% confidence interval [CI] 3.06-45.57, P < 0.001) or developed CMV infection (OR 5.42, 95% CI 1.69-17.39, P = 0.005) had high odds of PJP in multivariate analysis. In the acute graft rejection subgroup, patients treated with anti-thymocyte globulin (ATG) had significantly higher odds of PJP (OR 5.25, 95% CI 1.01-27.36, P = 0.006) than those who were not. Our data suggest that acute graft rejection and CMV infection may be risk factors for PJP in kidney transplant patients. The use of ATG for acute graft rejection may increase the risk of PJP.

Some G-protein-coupled receptors have been reported to require accessory proteins with specificity for proper functional expression. In this study, we found that CXCR1 interacted with REEP5 and REEP6, but CXCR2 did not. Overexpression of REEP5 and REEP6 enhanced IL-8-stimulated cellular responses through CXCR1, whereas depletion of the proteins led to the downregulation of the responses. Although REEPs enhanced the expression of a subset of GPCRs, in the absence of REEP5 and REEP6, CXCR1 was expressed in the plasma membrane, but receptor internalization and intracellular clustering of β-arrestin2 following IL-8 treatment were impaired, suggesting that REEP5 and REEP6 might be involved in the ligand-stimulated endocytosis of CXCR1 rather than membrane expression, which resulted in strong cellular responses. In A549 lung cancer cells, which endogenously express CXCR1, the depletion of REEP5 and REEP6 significantly reduced growth and invasion by downregulating IL-8-stimulated ERK phosphorylation, actin polymerization and the expression of genes related to metastasis. Furthermore, an in vivo xenograft model showed that proliferation and metastasis of A549 cells lacking REEP5 and REEP6 were markedly decreased compared to the control group. Thus, REEP5 and REEP6 could be novel regulators of G-protein-coupled receptor signaling whose functional mechanisms differ from other accessory proteins.

Macrophages mediate atheroma expansion and disruption, and denote high-risk arterial plaques. Therefore, they are substantially gaining importance as a diagnostic imaging target for the detection of rupture-prone plaques. Here, we developed an injectable near-infrared fluorescence (NIRF) probe by chemically conjugating thiolated glycol chitosan with cholesteryl chloroformate, NIRF dye (cyanine 5.5 or 7), and maleimide-polyethylene glycol-mannose as mannose receptor binding ligands to specifically target a subset of macrophages abundant in high-risk plaques. This probe showed high affinity to mannose receptors, low toxicity, and allowed the direct visualization of plaque macrophages in murine carotid atheroma. After the scale-up of the MMR-NIRF probe, the administration of the probe facilitated in vivo intravascular imaging of plaque inflammation in coronary-sized vessels of atheromatous rabbits using a custom-built dual-modal optical coherence tomography (OCT)-NIRF catheter-based imaging system. This novel imaging approach represents a potential imaging strategy enabling the identification of high-risk plaques in vivo and holds promise for future clinical implications.

Steroidogenic factor 1 (SF-1) is a transcription factor expressed in the ventral medial nucleus of the hypothalamus that regulates energy homeostasis. However, the molecular mechanisms of SF-1 in the control of energy balance are largely unknown. Here, we show that nutritional conditions, such as the presence or absence of serum, affect SF-1 action. Serum starvation significantly decreased hypothalamic SF-1 levels by promoting ubiquitin-dependent degradation, and sumoylation was required for this process. SF-1 transcriptional activity was also differentially regulated by nutritional status. Under normal conditions, the transcriptional activity of hypothalamic SF-1 was activated by SUMO, but this was attenuated during starvation. Taken together, these results indicate that sumoylation and ubiquitination play crucial roles in the regulation of SF-1 function and that these effects are dependent on nutritional conditions, further supporting the importance of SF-1 in the control of energy homeostasis.

Central pulse pressure is correlated with carotid atherosclerosis and the incidence of cardiovascular events more significantly than brachial pulse pressure. Augmentation index (Aix) has been shown to be an independent predictor of cardiovascular morbidity and mortality. Pulse wave analysis using the Gaon system allows for the estimation of central blood pressure (CBP), corrected augmentation index (Aix@HR75), ejection duration (ED) and subendocardial viability ratio (SEVR), and is widely used in clinical research in Korea. However, the accuracy of this system is controversial. From February 2008 to March 2011, 99 patients were recruited for this study. Measurements were taken both by the Gaon system and the SphygmoCor system on the same day for all study participants. The estimated values of CBP, Aix@HR75, ED and SEVR for the two systems were compared using paired t-tests, simple correlation analyses and Bland-Altman plots. Systolic blood pressure (SBP) estimated by the two systems was significantly (P<0.001) correlated; the coefficient was 0.982. The two s.d. of the difference in SBP between these systems was quite small--<7 mm Hg. Aix@HR75, ED and SEVR as estimated by the two systems were also significantly correlated, although they, especially SEVR, showed much weaker correlations than were observed in SBP: coefficients for Aix@HR75, ED and SEVR were 0.727, 0.648 and 0.230, respectively. We assessed the CBP of Korean patients estimated by the two systems and observed that the correlations of Aix, ED and SEVR were weaker than that of CBP. Such variations may be due to the difference in measuring methods between the devices. As even a slight change in pulse waveforms may result in a large difference in estimations, parameters, including Aix@HR75, ED and SEVR, should be carefully interpreted by experienced clinicians.

The potassium channels are ubiquitous multisubunit membrane proteins, and potassium-dependent alterations in the membrane potential play an important role in the proliferation of many types of cells. This study analyzed the mutation, allelic loss and expression patterns of the KCNRG gene in 77 HCCs in order to determine if the KCNRG gene, which encodes the potassium channel regulating protein, is involved in the tumorigenesis of hepatocellular carcinoma (HCC). One KCNRG missense mutation, CGT CAT (Arg His) was found at codon 92 within the T1 domain. Hep3B hepatoma cells were transfected with the wild- or mutant-KCNRG to determine the effect of this mutation in KCNRG. Interestingly, the suppressive cell growth activity of the mutant-type KCNRG was significantly lower than that of the wild-type KCNRG. In addition, allelic loss was detected in 17 out of 64 (26.5%) informative HCC cases, and all were hepatitis B virus (HBV)-positive. Moreover, the allelic loss was closely related to an intrahepatic metastasis (P=0.0247), higher grade (P=0.0078) and clinical stage (P=0.0071). Expression analysis revealed 22 tumor tissues to have a loss of expression of the KCNRG transcript. These results suggest that genetic alterations and the expression of KCNRG might play an important role in the development and/or progression of a subset of HCCs.

NF-kappaB promotes cell survival against external stress such as radiation. We examined whether NF-kappaB decoy transfection enhances the antiproliferative effects of radiation on vascular smooth muscle cells (VSMCs) in vitro. The irradiation induced activation or nuclear translocation of NF-kappaB p65 in VSMCs was confirmed by immunofluorescence. NF-kappaB decoy transfection resulted in inhibition of the radiation-induced NF-kappaB activation in VSMCs and the subsequent reduction of transcription and translocation of ICAM, iNOS, and TNF-alpha, downstream molecules under the control of NF-kappaB. By using MTT assay, NF-kappaB decoy augmented the antiproliferative effects of radiation, where the effect of low dose radiation (2 and 8-Gy) of the cells transfected with NF-kappaB decoy was equivalent to the high dose (16-Gy) irradiated non-transfected cells at 48 h after irradiation: 1.06+/-0.16, 1.11+/-0.22, 1.20+/-0.25, respectively. The decrease in proliferation and survival of the radiation treated cells by flow cytometry analysis showed that NF-kappaB inhibition did not show any additive effects on the cell cycle of the irradiated VSMCs, while apoptosis was significantly increased after NF-kappaB decoy transfection in the irradiated VSMCs (apoptosis fraction: 13.33+/-2.08% vs. 26.29+/-7.43%, for radiation only vs. radiation+NF-kappaB decoy transfection, P < 0.05). In addition, at 48 h, NF-kappaB decoy transfection dose dependently (10 microM vs. 20 microM) inhibited proliferation of 16Gy-irradiated VSMCs, and showed greater antiproliferative efficacy than 100 microM sulfasalazine, a specific NF-kappaB inhibitor. These results indicate that NF-kappaB inhibition reduces proliferation and survival of irradiated VSMCs, likely by increased apoptosis rather than additive cell cycle arrest and suggest the possibility of adjunctive gene therapy using NF-kappaB decoy to improve efficacy and to decrease the adverse effects of intracoronary radiation therapy.