Relapse in patients with antineutrophil cytoplasmic antibody-associated vasculitis undergoing dialysis: a single-centre retrospective study in South Korea.

OBJECTIVES: The disease activity of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) can decrease after dialysis, and relapse after dialysis is not well-studied. We investigated the clinical manifestations and factors associated with relapse in patients with AAV undergoing dialysis. METHODS: This retrospective study included data of patients with AAV undergoing dialysis due to renal involvement from July 2005 to March 2021 in a single tertiary centre in Seoul, Korea. Cox regression analysis was performed to identify relapse-associated factors. RESULTS: The study cohort included 38 patients with a median age of 64.0 years; 28 (73.7%) were female, and 35 (92.1%) patients were diagnosed with microscopic polyangiitis (MPA). At diagnosis, the mean Birmingham vasculitis activity score (BVAS) was 18.3 and 66.3% of the patients exhibited pulmonary manifestations. During follow-up, 12 patients experienced AAV relapse, including nine patients with diffuse alveolar haemorrhage (DAH), two patients with aggravated interstitial lung disease, and one patient with DAH accompanied with neuropathy. Clinical features including age, sex, and baseline BVAS did not significantly differ between the relapse and non-relapse groups. By univariable analysis, lung infiltration, DAH, corticosteroid pulse therapy for induction, and mean corticosteroid dose were significantly associated with relapse. Multivariable analysis revealed that DAH (adjusted hazard ratio 5.509, 95% CI 1.569-19.339; P=0.008) and mean corticosteroid dose (adjusted hazard ratio 1.381, 95% CI 1.161-1.642; P<0.001) were significantly associated with relapse. CONCLUSIONS: In patients with AAV undergoing dialysis, DAH and mean corticosteroid dose were significantly associated with relapse, highlighting the importance of close monitoring.

Prognostic value of proteinuria monitoring in anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To determine the prognostic significance of proteinuria monitoring in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We retrospectively analyzed the data of kidney biopsy-confirmed patients with AAV. Proteinuria was evaluated by a urine dipstick test. Poor renal outcome was defined as stage 4/5 chronic kidney disease (CKD) (estimated glomerular filtration rate < 30 mL/min/1.73 m2). RESULTS: We enrolled 77 patients with a median follow-up duration of 36 months (interquartile range, 18-79) in this study. Excluding 8 patients on dialysis at 6 months, 59/69 (85.5%) achieved remission after induction therapy. Patients were then divided into two groups according to the presence of proteinuria at 6 months after induction therapy (n = 29 with proteinuria, 40 without proteinuria). There was no significant difference in the rate of relapse or death according to the presence of proteinuria (p = 0.304 relapse, 0.401 death). In contrast, patients with proteinuria had significantly lower kidney function than those without proteinuria (41 vs. 53.5 mL/min/1.73 m2, p = 0.003). Multivariate analysis revealed that eGFR values at 6 months (hazard ratio [HR] 0.925; 95% CI 0.875-0.978, p = 0.006) and proteinuria at 6 months (HR 4.613; 95% CI 1.230-17.298, p = 0.023) were significantly associated with stage 4/5 CKD. CONCLUSION: The presence of proteinuria at 6 months after induction therapy and low renal function was significantly associated with a higher risk of stage 4/5 CKD in patients with AAV. Monitoring for proteinuria after induction therapy may help predict poor renal outcomes in patients with AAV.

When MRI would be useful in patients without evidence of sacroiliitis on radiographs?

We aimed to identify when magnetic resonance imaging (MRI) would be useful to diagnose patients with suspected axial spondyloarthropathy (AxSpA) without evidence of sacroiliitis on radiographs. We retrospectively reviewed electronic medical records of patients who underwent pelvis MRI after radiographs at the rheumatology clinic in a single tertiary center in Korea. Patients underwent imaging from January 2020 to July 2022. We collected data including complete blood count, erythrocyte sedimentation rate, C-reactive protein (CRP), human leukocyte antigen (HLA)-B27, history of acute anterior uveitis (AAU), peripheral arthritis, dactylitis, inflammatory bowel disease (IBD), enthesopathy, and psoriasis. A total of 105 patients who showed no evidence of sacroiliitis on radiographs were included. The median age of patients was 41.0 years, and 44.8% were male. Of them, 34 showed sacroiliitis on MRI (group 1), and 71 showed no evidence of sacroiliitis even on MRI (group 2). Known AxSpA-related clinical features including AAU, peripheral arthritis, dactylitis, IBD, enthesopathy, and psoriasis were not different between the two groups. HLA-B27 positivity (79.4% vs. 40.0%, p < 0.001), median white blood cell count (7700 vs. 6300, p = 0.007), mean platelet count (307.7 ± 69.7 vs. 265.3 ± 68.9 × 103/µL, p = 0.005), and median CRP level (0.38 vs. 0.10, p = 0.001) showed significant differences between the two groups. In a multivariate analysis, HLA-B27 positivity and platelet count were significantly associated with sacroiliitis on MRI. In our cohort, sacroiliitis was observed on MRI in one-third of patients without radiographic evidence. MRI could be recommended to evaluate sacroiliitis in patients with positive HLA-B27 and a high platelet count.

The Correlation between Waist Circumference and the Pro-Inflammatory Adipokines in Diabetic Retinopathy of Type 2 Diabetes Patients.

Central obesity is one of the major risk factors for type 2 diabetes mellitus (DM), and the most common complication of DM is diabetic retinopathy. However, the exact relationship between obesity and DR remains unknown. In this study, we evaluate the effect of obesity on DR by comparing the aqueous humor-derived adipokines. For the analysis, 37 DR patients and 29 non-DR-patients participated. To evaluate the obesity of the patients, body mass index (BMI) and waist circumference (WC) were used. By comparing the concentrations of adipokines obtained from the aqueous humor of the two groups, the relationship between DR and adipokines was analyzed. In addition, by analyzing the correlation between obesity and adipokines in patients, the relationship between central obesity and DR was finally confirmed. The WC was significantly higher in patients than in the non-patient group. The concentrations of all adipokines compared in this study were significantly higher in the DR group than in the non-DM group (p < 0.05). Among them, adiponectin, leptin, TNF-α, Factor D (adipsin), lipocalin-2 (NGAL), Serpin E1 (PAI-1), and CXCL8 (IL-8) were confirmed to have a positive correlation with central obesity (defined as WC). These findings suggest that central obesity is strongly associated with the risk of DR.

Influencing Factors for Cardiometabolic Risk in Korean Adolescents Based on 2010-2015 Data From the Korea National Health and Nutrition Examination Survey.

BACKGROUND: High academic stress and physical inactivity in Korean adolescents increase cardiometabolic risk factors, such as obesity, making it crucial to identify the factors influencing their risk. OBJECTIVE: Our aims were to determine differences in the prevalence of metabolic syndrome and its 5 components in Korean adolescents according to gender and to identify the influencing factors for cardiometabolic risk (individual risk factor ≥ 1). METHODS: Data related to adolescents from the Korean National Health and Nutrition Examination Survey (2010-2015) were assessed. Bivariate analyses to compare distribution and logistic regression analyses to examine the influencing factors were performed. RESULTS: Cardiometabolic risk (≥1 risk factor) was found in 33.2% and 32.6% of male and female adolescents, respectively, and metabolic syndrome (≥3 risk factors) was found in 2.0% and 2.3%, respectively. Among male adolescents, cardiometabolic risk was 1.66 times higher for the group that did not perform strength exercises ( P = .007). For female adolescents, the cardiometabolic risk was 2.44 times higher in 16- to 18-year-olds than in 12- to 15-year-olds ( P < .001) and 1.50 times higher in the non-aerobic-exercise group ( P = .030). Central obesity (waist-to-height ratio ≥ 0.47) increased cardiometabolic risk by 5.71 and 13.91 times in male and female adolescents, respectively ( P < .001). CONCLUSION: To reduce cardiometabolic risk profiles and future cardiovascular risk in Korean adolescents, school-based physical activity programs should be actively provided not only for students with central obesity but also for students who lack aerobic or strength exercises.

OPTICAL COHERENCE TOMOGRAPHY BIOMARKERS FOR REDUCTION OF DRUSENOID PIGMENT EPITHELIUM DETACHMENT.

PURPOSE: To identify the optical coherence tomography biomarkers that can collectively predict the probability of collapse or reduction of drusenoid pigment epithelium detachment (PED). METHODS: This consecutive observational case series reviewed the clinical data of 24 eyes with non-neovascular drusenoid PED. Among the study population, 17 eyes showed collapse or reduction of drusenoid PED. The mean follow-up duration was 44.8 ± 24.6 months. Optical coherence tomography-derived parameters were analyzed at baseline, at the last available visit before reduction of PED, at the first available visit after reduction of PED, and at the final visit. RESULTS: The mean subfoveal choroidal thickness showed a significant decrease after PED reduction and at the most recent visit (P = 0.015). Migration of retinal pigment epithelium cells was detected in 15 (88.2%) after PED reduction; however, there was no significance in the frequency of migration of retinal pigment epithelium cells at each time point (P = 0.392). Non-neovascular subretinal fluid was detected in 7 (41.2%) before PED reduction, 2 (11.8%) after PED reduction, and 2 (11.8%) at the final visit. Interestingly, subretinal fluid appeared more frequently just before reduction of PED (P = 0.029). CONCLUSION: We found evidence of non-neovascular subretinal fluid and choroidal thinning before reduction in PED. This finding might be useful for detection and prediction of the progression of drusenoid PED.

Molecular Mechanisms of Retinal Pigment Epithelium Dysfunction in Age-Related Macular Degeneration.

The retinal pigment epithelium (RPE), situated upon Bruch's membrane, plays multiple roles in the ocular system by interacting with photoreceptors and. Therefore, dysfunction of the RPE causes diseases related to vision loss, such as age-related macular degeneration (AMD). Despite AMD being a global cause of blindness, the pathogenesis remains unclear. Understanding the pathogenesis of AMD is the first step for its prevention and treatment. This review summarizes the common pathways of RPE dysfunction and their effect in AMD. Potential treatment strategies for AMD based on targeting the RPE have also been discussed.

The Predicted Functional Compartmentation of Rice Terpenoid Metabolism by Trans-Prenyltransferase Structural Analysis, Expression and Localization.

Most terpenoids are derived from the basic terpene skeletons of geranyl pyrophosphate (GPP, C10), farnesyl-PP (FPP, C15) and geranylgeranyl-PP (GGPP, C20). The trans-prenyltransferases (PTs) mediate the sequential head-to-tail condensation of an isopentenyl-PP (C5) with allylic substrates. The in silico structural comparative analyses of rice trans-PTs with 136 plant trans-PT genes allowed twelve rice PTs to be identified as GGPS_LSU (OsGGPS1), homomeric G(G)PS (OsGPS) and GGPS_SSU-II (OsGRP) in Group I; two solanesyl-PP synthase (OsSPS2 and 3) and two polyprenyl-PP synthases (OsSPS1 and 4) in Group II; and five FPSs (OsFPS1, 2, 3, 4 and 5) in Group III. Additionally, several residues in "three floors" for the chain length and several essential domains for enzymatic activities specifically varied in rice, potentiating evolutionarily rice-specific biochemical functions of twelve trans-PTs. Moreover, expression profiling and localization patterns revealed their functional compartmentation in rice. Taken together, we propose the predicted topology-based working model of rice PTs with corresponding terpene metabolites: GPP/GGPPs mainly in plastoglobuli, SPPs in stroma, PPPs in cytosol, mitochondria and chloroplast and FPPs in cytosol. Our findings could be suitably applied to metabolic engineering for producing functional terpene metabolites in rice systems.

Cks1 regulates human hepatocellular carcinoma cell progression through osteopontin expression.

Precise cell cycle regulation is critical to prevent aberrant cell proliferation and cancer progression. Cks1 was reported to be an essential accessory factor for SCFSkp2, the ubiquitin ligase that targets p27Kip1 for proteasomal degradation; these actions drive mammalian cell transition from G1 to S phase. In this study, we investigated the role played by Cks1 in the growth and progression of human hepatocellular carcinoma (HCC) cells. Silencing Cks1 expression abrogated osteopontin (OPN) expression in a p27Kip1-dependent manner in Huh7 HCC cells. OPN increased the proliferation, migration and invasion of Huh7 cells. Pharmacological inhibitor studies demonstrated that ERK1/2 signaling is responsible mainly for Cks1-mediated OPN expression. Cks1 appears to regulate ERK1/2 signaling through the expression of dual-specificity phosphatase 16 (DUSP16) because both Cks1 knockdown, which leads to DUSP16 upregulation, and DUSP16 overexpression decreased ERK1/2 phosphorylation and the resulting OPN expression. The same is true for the Cks1-mediated increases in p27Kip1, suggesting that Cks1 regulates OPN expression through activating ERK1/2 signaling either by suppressing DUSP16 expression or by a p27Kip1-dependent mechanism. Cks1 and OPN expression levels were significantly higher, but DUSP16 expression levels were significantly lower in HCC tissues than in normal liver tissues. Both Cks1 and OPN expression were negatively correlated with DUSP16 expression, whereas Cks1 expression was positively correlated with OPN expression. Moreover, combined panels for the expression levels of Cks1, DUSP16 and OPN showed significant prognostic power for the risk assessment of HCC patient overall survival. In conclusion, our data propose a novel function for Cks1 as a tumor promoter through the expression of the strongly oncogenic protein OPN in HCC.

Plastoglobule-Targeting Competence of a Putative Transit Peptide Sequence from Rice Phytoene Synthase 2 in Plastids.

Plastoglobules (PGs) are thylakoid membrane microdomains within plastids that are known as specialized locations of carotenogenesis. Three rice phytoene synthase proteins (OsPSYs) involved in carotenoid biosynthesis have been identified. Here, the N-terminal 80-amino-acid portion of OsPSY2 (PTp) was demonstrated to be a chloroplast-targeting peptide by displaying cytosolic localization of OsPSY2(ΔPTp):mCherry in rice protoplast, in contrast to chloroplast localization of OsPSY2:mCherry in a punctate pattern. The peptide sequence of a PTp was predicted to harbor two transmembrane domains eligible for a putative PG-targeting signal. To assess and enhance the PG-targeting ability of PTp, the original PTp DNA sequence (PTp) was modified to a synthetic DNA sequence (stPTp), which had 84.4% similarity to the original sequence. The motivation of this modification was to reduce the GC ratio from 75% to 65% and to disentangle the hairpin loop structures of PTp. These two DNA sequences were fused to the sequence of the synthetic green fluorescent protein (sGFP) and drove GFP expression with different efficiencies. In particular, the RNA and protein levels of stPTp-sGFP were slightly improved to 1.4-fold and 1.3-fold more than those of sGFP, respectively. The green fluorescent signals of their mature proteins were all observed as speckle-like patterns with slightly blurred stromal signals in chloroplasts. These discrete green speckles of PTp-sGFP and stPTp-sGFP corresponded exactly to the red fluorescent signal displayed by OsPSY2:mCherry in both etiolated and greening protoplasts and it is presumed to correspond to distinct PGs. In conclusion, we identified PTp as a transit peptide sequence facilitating preferential translocation of foreign proteins to PGs, and developed an improved PTp sequence, a stPTp, which is expected to be very useful for applications in plant biotechnologies requiring precise micro-compartmental localization in plastids.

Differentiation between mucus secretion and endoluminal tumors in the airway: analysis and comparison of CT findings.

OBJECTIVE: The objective of our study was to suggest CT features that help differentiate transient mucus secretion from airway tumors in the evaluation of soft-tissue nodular lesions confined within the airway lumen. MATERIALS AND METHODS: Forty-two patients with airway tumors (mean age, 57.6 ± 14.9 [SD] years) and 48 patients with secretion (mean age, 67.8 ± 13.4 years) were included. Two observers analyzed the following features on contrast-enhanced CT in consensus readings: shape (round, ovoid, lobulating, or complex); margin (circumscribed or uncircumscribed); size (including change in size between mediastinal and lung window images); location (anterior, posterior, or unclear); angle between the lesion and contacting airway wall (acute, obtuse, or unclear); attenuation (quantitative and qualitative analyses); and presence of air, fat, or calcification within the lesion. The positive predictive value (PPV) of each CT finding was calculated for secretion and tumor, respectively. RESULTS: Round (90.0%) or lobulating (92.9%) shape, uncircumscribed margin (100.0%), unclear location (87.5%), unclear angle (87.5%), a CT number of 21.7 HU or more (91.7%), and internal features such as fat (100.0%) or calcification (100.0%) showed high PPVs for tumors. Complex shape (100.0%), change in size of more than 15.9% (96.8%), a CT number of less than 21.7 HU (83.3%), and internal air density (100.0%) showed high PPVs for secretion. CONCLUSION: On contrast-enhanced CT, the evaluation of shape, change in size between mediastinal and lung window images, the measurement of CT number, and internal features such as air, fat, or calcification might help differentiate secretion from tumors.

Effect of belimumab in patients with systemic lupus erythematosus treated with low dose or no corticosteroids.

BACKGROUND/AIMS: Systemic lupus erythematosus (SLE) responder index (SRI)-4 response has been achieved with belimumab treatment in patients with moderate disease activity in cornerstone clinical trials and following studies. However, most studies involved patients treated with a mean prednisolone-equivalent dose of approximately 10 mg/d and focused on the steroid-sparing effect of belimumab. We aimed to identify the effect of belimumab in patients with mild-to-moderate SLE who were treated with low-dose or no corticosteroids. METHODS: We retrospectively reviewed the electronic medical records of patients treated with belimumab for at least 6 months between May 2021 and June 2022. The primary endpoint was SRI-4 response at 6 months. RESULTS: Thirty-one patients were included (13 low dose- and 18 steroid non-users). The mean age was 39.2 ± 11.4 years, and 90.3% of patients were female. The baseline Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 6.0 (4.0-9.0). The primary endpoint was achieved in 32.3% (10/31) of patients. Significant improvements in anemia, C4 levels, and SELENA-SLEDAI score were observed during treatment. Univariate analysis showed that the baseline SELENA-SLEDAI and arthritis were significantly associated with SRI-4 response at 6 months, and only the SELENA-SLEDAI remained significant (p = 0.014) in multivariate analysis. CONCLUSION: This cohort study is the first to report the efficacy of belimumab after minimizing the effect of corticosteroids. Belimumab showed efficacy in improving the SELENA-SLEDAI score, anemia, and low C4 in patients who did not receive corticosteroids or received only low doses.

Progression to ANCA-associated vasculitis in patients with idiopathic interstitial pneumonia and positive ANCA.

OBJECTIVE: This study explored the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and its risk factors in patients with idiopathic interstitial pneumonia (IIP) and positive ANCA results. METHODS: Data of patients diagnosed with IIP with positive ANCA results at a single tertiary center in South Korea were retrospectively reviewed from January 2013 to August 2023. Cox regression analysis was performed to identify variables associated with AAV occurrence following IIP diagnosis. Kaplan-Meier curves were employed to investigate the relationship between autoantibodies and the occurrence of AAV. RESULTS: In a cohort of 154 IIP-diagnosed patients with positive ANCA results but without AAV, 10.4 % of them eventually developed AAV. The AAV and non-AAV groups did not significantly differ by sex, age, smoking status, urinalysis, or chest computed tomography findings. All the patients who subsequently developed AAV were anti-myeloperoxidase (MPO) positive, while 48.8 % of the non-AAV patients were anti-MPO positive (P < 0.001). Rheumatoid factor (RF) positivity differed significantly (62.5 % vs. 29.2 %, P = 0.007) between the AAV and non-AAV groups. Multivariate Cox regression and Kaplan-Meier analyses revealed RF (HR 4.02; P = 0.004) and anti-MPO (HR 38.10; P < 0.001) positivity as risk factors associated with AAV occurrence. CONCLUSION: Approximately 10 % of ANCA-positive IIP patients developed AAV after an IIP diagnosis. Anti-MPO or co-occurring positive RF poses a significant risk for subsequent AAV occurrence. This emphasizes the importance of careful monitoring in patients with high-risk antibody profiles, even if the complete features of AAV are not present at IIP diagnosis.

Subchondral insufficiency fracture of the femoral head in a patient with ankylosing spondylitis: Case report and literature review.

Subchondral insufficiency fracture (SIF) of the femoral head occurs in patients with osteoporosis, elderly women, and renal or liver transplant recipients. Although SIF has been reported in several patients with rheumatic disease, SIF of the femoral head has not been reported in patients with ankylosing spondylitis (AS), and the association between AS and SIF has not been determined. A 48-year-old man with AS presented with pain in his left hip for 2 months. He had been diagnosed with AS and radiographic bilateral grade 3 sacroiliitis 11 years earlier. He had been treated with subcutaneous adalimumab 40 mg biweekly for more than 10 years, during which time his condition remained stable. This patient was obese but had no other known predisposing conditions, such as old age, overexertion, osteoporosis, steroid use, or transplantation. He had never taken steroids. X-rays showed no specific findings, other than mild osteoarthritis in both hips. However, pelvic magnetic resonance imaging demonstrated flattening and subchondral irregularity with a large amount of bone marrow edema, confirming a diagnosis of SIF of the femoral head. Thus, even in patients with AS having no significant risk factors, SIF should be considered as part of the differential diagnosis of hip pain.

Stepwise protein targeting into plastoglobules are facilitated by three hydrophobic regions of rice phytoene synthase 2.

Plastoglobules (PGs) are plastidial lipid droplets enclosed by a polar monolayer born from the thylakoid membrane when plants require active lipid metabolism, including carotenogenesis, under the environmental stress and during plastid transition. Despite the fact that many proteins are reported to target PGs, their translocation mechanism has remained largely unexplored. To elucidate this process, we studied the influence of three hydrophobic regions (HR)-HR1 (1-45th aa), HR2 (46-80th aa), and HR3 (229-247th aa)-of rice phytoene synthase 2 (OsPSY2, 398 aa), which has previously shown to target PGs. As results, HR1 includes the crucial sequence (31-45th aa) for chloroplast import and the stromal cleavage occurs at a specific alanine site (64th aa) within HR2, verifying that a N-terminal 64-aa-region works as the transit peptide (Tp). HR2 has a weak PG-targeting signal by showing synchronous and asynchronous localization patterns in both PGs and stroma of chloroplasts. HR3 exhibited a strong PG-targeting role with the required positional specificity to prevent potential issues such as non-accumulation, aggregation, and folding errors in proteins. Herein, we characterized a Tp and two transmembrane domains in three HRs of OsPSY2 and propose a spontaneous pathway for its PG-translocation with a shape embedded in the PG-monolayer. Given this subplastidial localization, we suggest six sophisticated tactics for plant biotechnology applications, including metabolic engineering and molecular farming.

Recovery and long-term renal outcome of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis who are on dialysis at presentation.

Objective: Renal involvement in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) can lead to severe renal dysfunction requiring dialysis at diagnosis. We aimed to study the clinical and pathologic characteristics of patients with AAV dependent on dialysis at presentation and the long-term renal outcomes of patients who recovered from dialysis. Methods: This retrospective study analyzed data of patients diagnosed with AAV who were on dialysis from July 2005 to May 2021 at a single tertiary center in Korea. Results: Thirty-four patients were included in the study (median age 64.5 years, females 61.8%), of which 13 discontinued and 21 continued dialysis. The proportion of normal glomeruli (p<0.001) and interstitial fibrosis (p=0.024) showed significant differences between both groups. Multivariable analysis showed that the proportion of normal glomeruli was associated with dialysis discontinuation (odds ratio=1.29, 95% confidence interval 0.99~1.68, p=0.063), although without statistical significance. Treatment modalities, including plasmapheresis, did not show significance with dialysis discontinuation. In the follow-up analysis of 13 patients who had discontinued dialysis for a median of 81 months, 12 did not require dialysis, and their glomerular filtration rate values significantly increased at follow-up time compared to when they stopped dialysis (37.5 [28.5~45.5] vs. 24.0 [18.5~30.0] mL/min/1.73 m²; p=0.008). Conclusion: Approximately 38% of AAV patients on dialysis discontinued dialysis, and the recovered patients had improved renal function without dialysis during longer follow-up. Patients with AAV on dialysis should be given the possibility of dialysis discontinuation and renal recovery, especially those with normal glomeruli in kidney pathology.

The EDN1/EDNRA/ß­arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation.

Endothelin receptor A (EDNRA) has been reported to play various crucial physiological roles and has been shown to be associated with the pathology of several diseases, including colorectal cancer (CRC). However, the molecular mechanisms of EDNRA in the development of human CRC have not been fully elucidated to date. In this context, the present study was performed to investigate biological functions and novel downstream signaling pathways affected by EDNRA, during CRC progression. First, using public data repositories, it was observed that the EDRNA expression levels were markedly increased in CRC tissues, as compared to normal tissues. Patients with CRC with an increased EDNRA expression exhibited a significantly decreased survival rate in comparison with those with a lower EDNRA expression. Furthermore, a positive correlation between the levels of EDNRA and its ligand, EDN1, was found in CRC tissues. The ectopic expression of EDNRA or its ligand, EDN1, promoted, whereas the silencing of EDNRA or EDN1 decreased cell proliferation and migration in vitro. To elucidate the signaling pathways involved in the regulation of EDNRA expression in CRC cells, a phosphokinase array analysis was performed, and it was observed that the knockdown of EDNRA substantially suppressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in CRC cells. Of note, STAT3 silencing simultaneously decreased EDN1 and EDNRA expression, with the expression of EDN1 and/or EDNRA appearing to be directly regulated by binding STAT3 to their promoter region, according to chromatin immunoprecipitation and promoter assays, ultimately indicating a positive feedback loop in the expression of EDNRA and EDN1. It was also observed that treatment with an EDNRA antagonist (macitentan), alone or in combination with cisplatin, suppressed cell growth and migration ability, and induced cell apoptosis. Collectively, these data suggest a critical role of the EDN1/EDNRA signaling pathway in CRC progression. Thus, the pharmacological intervention of this signaling pathway may prove to be a potential therapeutic approach for patients with CRC.

Enhancement patterns of hepatocellular carcinoma after transarterial chemoembolization using drug-eluting beads on arterial phase CT images: a pilot retrospective study.

OBJECTIVE: The purpose of this article is to assess CT enhancement patterns of hepatocellular carcinoma (HCC) within 1 month after transarterial chemoembolization (TACE) using drug-eluting beads and to determine whether enhancement patterns may be useful for predicting local tumor progression. MATERIALS AND METHODS: Forty-one patients with 50 HCCs underwent CT within 1 month after TACE with drug-eluting beads. Two blinded readers independently reviewed the arterial phase images and classified enhancement patterns as follows: no enhancement, peripheral ring enhancement, and peripheral nodulelike enhancement. Enhancement patterns were correlated with time to tumor progression of enhancing tissue by log-rank test. RESULTS: In the group with no enhancement, 92.3% (24/26) had not progressed and 7.7% (2/26) showed progression; for peripheral ring enhancement, 83.3% (10/12) had not progressed and 16.7% (2/12) showed progression; and for peripheral nodulelike enhancement, 16.7% (2/12) had not progressed and 83.3% (10/12) showed progression. The time to progression of enhancing tissue was significantly different between the group with no enhancement plus peripheral ring enhancement and the group with peripheral nodulelike enhancement (p < 0.001). CONCLUSION: Analysis of enhancement patterns at the arterial phase of the first follow-up CT after TACE with drug-eluting beads is helpful for predicting progression of treated HCC.

Comprehensive analysis of head-shaking nystagmus in patients with vestibular neuritis.

Although biphasic head-shaking nystagmus (HSN) is a basic response to head shaking in patients with unilateral vestibular loss, monophasic HSN is commonly seen in patients with dizziness of undetermined etiology. Since the clinical significance of HSN remains unclear, we sought to characterize different types of HSN in patients with vestibular neuritis (VN) during the acute stage (within 7 days after the onset of vertigo) and at follow-up (about 2 months after the onset of vertigo), and to compare HSN and caloric responses. We analyzed HSN, spontaneous nystagmus and caloric tests in 66 patients with VN. Overall, HSN showed high abnormal rates (94 and 89%) during the acute and follow-up stages and could detect vestibular hypofunction even when canal paresis (CP) had normalized at follow-up. All patients in the acute stage and most patients at follow-up showed HSN with the slow phase to the lesioned side (paretic). Biphasic HSN was common at follow-up, and many patients with a monophasic paretic pattern during the acute stage had evolved to a biphasic paretic pattern at follow-up. Initial slow-phase eye velocities (SPVs) in biphasic HSN were larger than those in monophasic HSN at follow-up. Absence of HSN or reversal of its direction was closely related to normalized caloric responses, but SPVs of HSN did not correlate with the severity of CP. These findings indicate that the HSN test is a sensitive detector of vestibular hypofunction upon 2-Hz head rotation. HSN may reveal previous vestibular hypofunction in the 2-Hz frequency range even at follow-up, when caloric responses detecting vestibular hypofunction in the low-frequency range had normalized. The two tests utilize different mechanisms to assess vestibular hypofunction and are complementary. Biphasic paretic HSN is the most common pattern at follow-up and occurs when the initial SPVs induced by head rotation are large enough to induce the adaptation of primary vestibular afferent activity. Monophasic HSN, which is commonly found in dizzy patients, indicates less severe vestibular hypofunction than biphasic HSN in the 2-Hz frequency range, and the caloric tests can provide further information about the side and presence of vestibular hypofunction at lower frequencies.

Differential Regulation of an OsIspH1, the Functional 4-Hydroxy-3-Methylbut-2-Enyl Diphosphate Reductase, for Photosynthetic Pigment Biosynthesis in Rice Leaves and Seeds.

The methylerythritol 4-phosphate (MEP) pathway is responsible for providing common precursors for the biosynthesis of diverse plastidial terpenoids, including chlorophylls, carotenoids, and phytohormones, in plants. In rice (Oryza sativa), the last-step genes encoding 4-hydroxy-3-methylbut-2-enyl diphosphate reductase [HDR/isoprenoid synthesis H (IspH)] have been annotated in two genes (OsIspH1 and OsIspH2) in the rice genome. The spatial transcript levels indicated that OsIspH1 is highly expressed in all tissues at different developmental stages, whereas OsIspH2 is barely expressed due to an early stop in exon 1 caused by splicing error. OsIspH1 localized into plastids and osisph1, a T-DNA inserted knockout mutant, showed an albino phenotype, indicating that OsIspH1 is the only functional gene. To elucidate the role of OsIspH1 in the MEP pathway, we created two single (H145P and K407R) and double (H145P/K407R) mutations and performed complementation tests in two hdr mutants, including Escherichia coli DLYT1 strains and osisph1 rice plants. The results showed that every single mutation retained HDR function, but a double mutation lost it, proposing that the complementary relations of two residues might be important for enzyme activity but not each residue. When overexpressed in rice plants, the double-mutated gene, OsIspH1MUT , reduced chlorophyll and carotenoid biosynthesis in the leaves and seeds. It confirmed the crucial role of OsIspH1 in plastidic terpenoid biosynthesis, revealing organ-specific differential regulation of OsIspH1 in rice plants.