Transport of Golgi-localized ß-catenin p-S47 by KIF11 or KIFC3 induces primary ciliogenesis.

Primary cilium is an important hub for cell signaling and dysregulation of primary cilia assembly and disassembly is associated with the development of cancer and chemotherapeutic drug resistance, as well as the genetic disorders collectively known as ciliopathy. ß-Catenin plays a major role in canonical Wnt signaling; however, its association with primary cilia has only recently been highlighted in reports of ß-catenin-mediated primary ciliogenesis. In this study, we found that ß-catenin p-S47 was localized to the Golgi apparatus and the nucleus, and the amount of ß-catenin p-S47 at these locations was significantly higher during primary ciliogenesis compared with asynchronous cell growth conditions. In addition, the novel ß-catenin binding motor proteins KIF11 and KIFC3 were shown to have a lower binding affinity in ß-catenin S47A than in ß-catenin WT. Knockdown of KIF11 or KIFC3 resulted in primary cilia deficiency and increased ß-catenin p-S47 levels in the Golgi apparatus and were accompanied by a decrease in ß-catenin p-S47 at the centrosome. The accumulation of ß-catenin p-S47 in the nucleus was increased during primary ciliogenesis along with ß-catenin-dependent transcriptional activity. The collective findings indicate the existence of a novel mechanism of primary ciliogenesis involving KIF11/KIFC3-associated ß-catenin p-S47 in the Golgi apparatus and ß-catenin p-S47 transcriptional activity in the nucleus. This study revealed a new mechanism for the study of ciliopathies, cancer, and chemotherapeutic drug resistance caused by primary ciliogenesis dysregulation and provides new targets for drug development to treat these diseases.

CRISPR/Cas12a Collateral Cleavage-Driven Transcription Amplification for Direct Nucleic Acid Detection.

The clustered regularly interspaced short palindromic repeat/Cas (CRISPR/Cas) system is a powerful tool for nucleic acid detection owing to specific recognition as well as cis- and trans-cleavage capabilities. However, the sensitivity of CRISPR/Cas-based diagnostic approaches is determined by nucleic acid preamplification, which has several limitations. Here, we present a method for direct nucleic acid detection without preamplification, by combining the CRISPR/Cas12a system with signal enhancement based on light-up RNA aptamer transcription. We first designed two DNA templates to transcribe the light-up RNA aptamer and kleptamer (Kb) RNA: the first DNA template encodes a Broccoli RNA aptamer for fluorescence signal generation, and the Kb DNA template comprises a dsDNA T7 promoter sequence and an ssDNA sequence that encodes an antisense strand for the Broccoli RNA aptamer. Hepatitis B virus (HBV) target recognition activates a CRISPR/Cas12a complex, leading to the catalytic cleavage of the ssDNA sequence. Transcription of the added Broccoli DNA template can then produce several Broccoli RNA aptamer transcripts for fluorescence enhancement. The proposed strategy exhibited excellent sensitivity and specificity with 22.4 fM detection limit, good accuracy, and stability for determining the target HBV dsDNA in human serum samples. Overall, this newly designed signal enhancement strategy can be employed as a universal sensing platform for ultrasensitive nucleic acid detection.

The Potential Role of Aripiprazole Augmentation for Major Depressive Disorder with Anxious Distress in Naturalistic Treatment Setting.

Objective: : This study tried to observe clinical benefit of aripiprazole augmentation (ARPA) treatment for major depressive disorder with anxious distress (MDDA) in routine practice. Methods: : Retrospective chart review (n = 41) was conducted for clinical benefit of ARPA in patients with MDDA in routine practice. The primary endpoint was the mean change of Hamilton Anxiety Rating scale (HAMA) total scores from baseline to the endpoint. Additional secondary endpoints were also retrieved. Results: : The changes of primary endpoint HAMA (t = 5.731, -4.6, p = 0.001), and secondary endpoints including Hamilton Depression Rating scale (HAMD, t = 4.284, -3.4, p ＜ 0.001), Clinical Global Impression-Clinical Benefit (CGI-CB, -0.9, t = 1.821, p = 0.026), and Clinical Global Impression Score-Severity (CGI-S, t = 3.556, -0.4, p ＜ 0.001) scores were also significantly improved during the study. No significant adverse events were observed. Conclusion: : This study has shown additional benefit of ARPA treatment for MDDA patients in routine practice. However, adequately-powered and well-controlled studies are necessary for generalization of the present findings.

Cisplatin Induces Kidney Cell Death via ROS-dependent MAPK Signaling Pathways by Targeting Peroxiredoxin I and II in African Green Monkey (Chlorocebus aethiops sabaeus) Kidney Cells.

BACKGROUND/AIM: Cisplatin [cis-diamminedichloroplatinum(II), CDDP] is a widely used and effective antitumor drug in clinical settings, notorious for its nephrotoxic side effects. This study investigated the mechanisms of CDDP-induced damage in African green monkey kidney (Vero) cells, with a focus on the role of Peroxiredoxin I (Prx I) and Peroxiredoxin II (Prx II) of the peroxiredoxin (Prx) family, which scavenge reactive oxygen species (ROS). MATERIALS AND METHODS: We utilized the Vero cell line derived from African green monkey kidneys and exposed these cells to various concentrations of CDDP. Cell viability, apoptosis, ROS levels, and mitochondrial membrane potential were assessed. RESULTS: CDDP significantly compromised Vero cell viability by elevating both cellular and mitochondrial ROS, which led to increased apoptosis. Pretreatment with the ROS scavenger N-acetyl-L-cysteine (NAC) effectively reduced CDDP-induced ROS accumulation and subsequent cell apoptosis. Furthermore, CDDP reduced Prx I and Prx II levels in a dose- and time-dependent manner. The inhibition of Prx I and II exacerbated cell death, implicating their role in CDDP-induced accumulation of cellular ROS. Additionally, CDDP enhanced the phosphorylation of MAPKs (p38, ERK, and JNK) without affecting AKT. The inhibition of these pathways significantly attenuated CDDP-induced apoptosis. CONCLUSION: The study highlights the involvement of Prx proteins in CDDP-induced nephrotoxicity and emphasizes the central role of ROS in cell death mediation. These insights offer promising avenues for developing clinical interventions to mitigate the nephrotoxic effects of CDDP.

Efficacy and cost-effectiveness of darbepoetin alfa once every 4 weeks versus continuous erythropoietin receptor activator once every 4 weeks for anemia correction in patients with chronic kidney disease not on dialysis.

BACKGROUND: For anemia management in patients with chronic kidney disease not on dialysis, darbepoetin alfa (DA), which has a shorter half-life but is more inexpensive than continuous erythropoietin receptor activator (CERA), is preferred in Korea. This study evaluated the efficacy, safety, and cost-effectiveness of once-in-4-weeks DA compared with once-in-4-weeks CERA in patients with chronic kidney disease not on dialysis. METHODS: In this randomized, prospective, non-inferiority study, 40 erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis were randomized 1:1 to the DA group and CERA group. They received the study drug once in 4 weeks during 10- or 12-week correction period and 24-week efficacy evaluation period. The primary outcomes were the mean difference in the changes in hemoglobin levels between baseline and efficacy evaluation period and hemoglobin response rates during the correction period. The secondary outcomes included differences in adverse events and costs. RESULTS: DA was non-inferior to CERA for anemia correction; the mean difference in the change in hemoglobin levels between the groups was -0.070 g/dL (95% confidence interval, -0.730 to 0.590 g/dL). Hemoglobin response rates were 100% with DA and 94.1% with CERA. Adverse events were comparable. The mean cost of DA was approximately one-third that of CERA (34,100 ± 7,600 Korean won/4 weeks vs. 115,500 ± 23,600 Korean won/4 weeks; p < 0.001). CONCLUSION: Once-in-4-weeks DA safely corrects anemia in erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis and is more cost-effective than once-in-4-weeks CERA.

A Rare Case of Juvenile Gangrenous Vasculitis of the Scrotum in Korea.

Juvenile gangrenous vasculitis is characterized by the abrupt onset of scrotal ulcerations in young males, preceded by fever and pharyngeal symptoms. The etiology of this disease is poorly understood. The course is benign and self-limiting within a few weeks with no relapse. Because of its rare incidence, physicians often confuse it with Fournier's gangrene, which progresses rapidly to severe systemic symptoms requiring urgent surgical intervention. Herein, we report a rare case of juvenile gangrenous vasculitis of the scrotum and emphasize the importance of awareness of this diagnosis to avoid unnecessary invasive surgical intervention. A 17-year-old boy presented with painful and tender, diffuse erythema and swelling with a necrotic lesion on the scrotum for three days. Preceding the cutaneous manifestations, he had a fever and sore throat. Physical examination showed an about 2 cm-sized well-demarcated necrotic lesion on the anterior scrotum. Laboratory findings revealed neutrophilic leukocytosis with an elevated C-reactive protein and erythrocyte sedimentation rate. On scrotal ultrasonography, only edematous skin thickening and an increase in vascularity were observed. Histopathological examination showed epidermal necrosis and dermal neutrophilic infiltration. Empirical antibiotic treatment with ampicillin/sulbactam and clindamycin was administered and a prompt clinical resolution was observed.

Peroxiredoxin II regulates exosome secretion from dermal mesenchymal stem cells through the ISGylation signaling pathway.

BACKGROUND: Exosomes are small extracellular vesicles that play important roles in intercellular communication and have potential therapeutic applications in regenerative medicine. Dermal mesenchymal stem cells (DMSCs) are a promising source of exosomes due to their regenerative and immunomodulatory properties. However, the molecular mechanisms regulating exosome secretion from DMSCs are not fully understood. RESULTS: In this study, the role of peroxiredoxin II (Prx II) in regulating exosome secretion from DMSCs and the underlying molecular mechanisms were investigated. It was discovered that depletion of Prx II led to a significant reduction in exosome secretion from DMSCs and an increase in the number of intracellular multivesicular bodies (MVBs), which serve as precursors of exosomes. Mechanistically, Prx II regulates the ISGylation switch that controls MVB degradation and impairs exosome secretion. Specifically, Prx II depletion decreased JNK activity, reduced the expression of the transcription inhibitor Foxo1, and promoted miR-221 expression. Increased miR-221 expression inhibited the STAT signaling pathway, thus downregulating the expression of ISGylation-related genes involved in MVB degradation. Together, these results identify Prx II as a critical regulator of exosome secretion from DMSCs through the ISGylation signaling pathway. CONCLUSIONS: Our findings provide important insights into the molecular mechanisms regulating exosome secretion from DMSCs and highlight the critical role of Prx II in controlling the ISGylation switch that regulates DMSC-exosome secretion. This study has significant implications for developing new therapeutic strategies in regenerative medicine. Video Abstract.

Primary cilia: a novel research approach to overcome anticancer drug resistance.

Primary cilia are cellular organelles that consist of a microtubule skeleton surrounded by a membrane filled with cell signaling receptors. Many studies have shown that primary cilia are cellular antennas, which serve as signaling hubs and their assembly and disassembly are dynamically regulated throughout the cell cycle, playing an important role in regulating cellular homeostasis. Aberrant control of primary cilia dynamics causes a number of genetic disorders known as ciliopathies and is closely associated with tumorigenesis. Anticancer drug resistance is a primary cause of chemotherapy failure, although there is no apparent remedy. The recent identification of a relationship between anticancer drug resistance and primary ciliary dynamics has made primary cilia an important target subcellular organelle for overcoming anticancer drug resistance. Therefore, the research on primary ciliary dynamics may provide new strategies to overcome anticancer drug resistance, which is urgently needed. This review aims to summarize research on the relevance of primary cilia and anticancer drug resistance, as well as future possibilities for research on overcoming anticancer drug resistance utilizing primary cilia dynamics.

Additional Clinical Benefit of Agomelatine Treatment for Major Depressive Disorder in Naturalistic Treatment Setting.

Objective: This study tried to observe additional benefit of agomelatine (AGO) treatment for major depressive disorder (MDD) in routine practice. Methods: Retrospective chart review (n = 63) was conducted for additional benefit of combination with or switching to AGO in MDD patients without full remission. The primary endpoint was the mean change of Clinical Global Impression-Clinical Benefit (CGI-CB) total scores from baseline to the endpoint. Additional secondary endpoints were also collected. Results: The changes of CGI-CB (Z = -3.073, p = 0.002) and Montgomery-Åsberg Depression Rating Scale (Z = -3.483, p < 0.001) total scores were significantly decreased from baseline to the endpoint, respectively. At the endpoint, the remission rate was 22.6% (n = 18) and 28.6% of patient had improvement in CGI-CB total scores at the endpoint. No significant adverse events were observed. Conclusion: This study has shown additional benefit of AGO treatment as combination or switching agent for MDD patients without full remission in routine practice. However, adequately-powered and well-controlled studies are necessary for generalization of the present findings.

Clinical Application of Intravitreal Aflibercept Injection for Diabetic Macular Edema Comparing Two Loading Regimens.

Background and Objectives: We investigated and compared the efficacy of three and five monthly loading regimens of an intravitreal aflibercept injection (IVA) in patients with diabetic macular edema (DME). Materials and Methods: This was a retrospective study that included patients diagnosed with DME and treated with an either three or five monthly aflibercept loading regimen from July 2018 to March 2022. Information on clinical characteristics and changes in the central retinal thickness (CRT) were obtained from medical records. Results: In total, 44 eyes of 44 patients with DME treated with IVA were included in this study, with 30 eyes treated with 3-monthly loadings (three-loading group) and 14 eyes with 5-monthly loadings (five-loading group). The mean CRT significantly decreased from the baseline one month after loading in both the three-loading and five-loading groups (p < 0.001). Four cases were refractory to treatment in the three-loading group, while there were no cases of refractory DME in the five-loading group. The stability rate was significantly higher in the five-loading group at three months after loading (p = 0.033). Conclusions: Five-monthly loading regimens of IVA might be favorable for DME considering the rate of refractory cases, stable duration, and the importance of early responsiveness to IVA in DME.

Surgical Outcomes of Vitrectomy for Primary Treatment of Rhegmatogenous Retinal Detachment in Patients with Atopic Dermatitis.

PURPOSE: To investigate the clinical results of vitrectomy alone as the primary treatment for rhegmatogenous retinal detachment (RD) in patients with atopic dermatitis (AD). METHODS: The medical records of patients with AD treated for rhegmatogenous retinal detachment (RD) were retrospectively reviewed. We investigated the characteristics of retinal breaks and detachments, applied surgical methods, and results. RESULTS: Twenty eyes of 14 patients with AD who presented with rhegmatogenous RD and treated by vitrectomy were included in this analysis. Sixteen eyes (80%) were treated with vitrectomy, either alone or in combination with cataract surgery, and the retina was successfully attached to 94% of the eyes. There were four cases in which vitrectomy was combined with encircling. Reoperation was needed in half of the eyes that received vitrectomy with encircling, which presented nearly total detachment, severe proliferative vitreoretinopathy, and pseudophakia. CONCLUSIONS: Vitrectomy alone, in combination with cataract surgery, may be sufficient to treat rhegmatogenous RD in patients with AD. Additional encircling or buckling should still be considered in complicated cases.

Synergistic effect of anticancer drug resistance and Wnt3a on primary ciliogenesis in A549 cell-derived anticancer drug-resistant subcell lines.

Primary cilia, antenna-like cellular sensor structures, are generated from the mother centriole in the G0/G1 cell-cycle phase under control by cellular signaling pathways involving Wnt, hedgehog, and platelet-derived growth factor. Although primary ciliary dynamics have been reported to be closely related to ciliopathy and tumorigenesis, the molecular basis for the role of primary cilia in human disease is lacking. To clarify how Wnt3a affects primary ciliogenesis in anticancer drug-resistant cells, we derived specific drug-resistant subcell lines from A549 human lung cancer cells using anticancer drugs doxorubicin, dasatinib, and paclitaxel (A549/Dox, A549/Das, and A549/Pac, respectively). The primary cilia-containing cell population and primary cilia length increased in the A549/Dox and A549/Pac subcell lines under increased MDR1 expression, when compared to those in the parental A549 cells. In the A549/Das subcell line, primary cilia length increased but the cell population was not affected. In addition, Wnt3a increased primary cilia-containing cell population and primary cilia length in A549/Dox, A549/Das, and A549/Pac cells, without change of cell growth. Abnormal shapes of primary cilia were frequently observed by anticancer drug resistance and Wnt3a stimulation. Taken together, our results indicate that anticancer drug resistance and Wnt3a affect primary ciliogenesis synergistically, suggesting a potential new strategy for overcoming anticancer drug resistance.

Prediction of Heart Function and Volume Status in End-Stage Kidney Disease Patients through N-Terminal Pro-Brain Natriuretic Peptide.

Background and Objectives: N-terminal pro-brain natriuretic peptide (NT-proBNP) is a biomarker used to predict heart failure and evaluate volume status in hemodialysis (HD) patients. However, it is difficult to determine the cutoff value for NT-proBNP in HD patients. In this study, we analyzed whether NT-proBNP helps predict heart function and volume status in HD patients. Materials and Methods: This prospective observational study enrolled 96 end-stage kidney disease patients with HD. All patients underwent echocardiography and bioimpedance spectroscopy (BIS) after an HD session. Overhydration (OH) was measured by BIS. Laboratory data were obtained preHD, while serum NT-proBNP was measured after HD. Interventions for blood pressure control and dry weight control were performed, and NT-proBNP was re-assessed after a month. Results: There was an inverse correlation between NT-proBNP and ejection fraction (EF) (ß = -0.34, p = 0.001). OH (ß = 0.331, p = 0.001) and diastolic dysfunction (ß = 0.226, p = 0.027) were associated with elevated NT-proBNP. In a subgroup analysis of diastolic dysfunction grade, NT-proBNP increased according to dysfunction grade (normal, 4177 pg/mL [2637-10,391]; grade 1, 9736 pg/mL [5471-21,110]; and grades 2-3, 26,237 pg/mL [16,975-49,465]). NT-proBNP showed a tendency toward a decrease in the 'reduced dry weight' group and toward an increase in the 'increased dry weight' group compared to the control group (ΔNT-proBNP, -210 pg/mL [-12,899 to 3142], p = 0.104; 1575 pg/mL [-113 to 6439], p = 0.118). Conclusions: We confirmed that NT-proBNP is associated with volume status as well as heart function in HD patients.

Comparison of Th1 and Th17 Inflammatory Cytokine Profiles Between Chronic Plaque and Acute Guttate Psoriasis.

Background: The phenotypic heterogeneity of psoriasis is suspected to reflect differences in its pathogenesis, but not yet completely elucidated. Studies of the Th1 and Th17 cytokines associated with different phenotypes of psoriasis have yielded inconsistent results. Objective: To investigate the tissue expression levels of Th1 and Th17 cytokines among patients with chronic plaque psoriasis, acute guttate psoriasis, and healthy control. Methods: A total of 20 patients with psoriasis (10 with chronic plaque type and 10 with acute guttate type) and 5 healthy controls were enrolled. The tissue mRNA and protein levels of following cytokines were measured: interleukin (IL)-12, IL-2, interferon (IFN)-γ, IL-23, IL-17A, and IL-22. Results: The tissue mRNA levels of IL-12, IFN-γ, IL-23, IL-17A, IL-22 and the protein levels of IL-12, IL-2, IFN-γ, IL-17A, IL-22 were significantly increased in the psoriasis patients compared with the healthy controls. In comparisons of the subtypes, the tissue mRNA level of IFN-γ was increased in acute guttate psoriasis, whereas the protein levels of IL-12 and IL-17A were significantly increased in chronic plaque psoriasis. The cytokine ratios of IL-17A/IL-2 and IL-22/IL-2 were significantly higher in chronic plaque psoriasis than in acute guttate psoriasis. Conclusion: We confirmed that the tissue levels of Th1 and Th17 cytokines were increased in psoriasis patients compared with healthy controls. The increased IFN-γ mRNA level in acute guttate psoriasis and increased IL-12 and IL-17A protein levels in chronic plaque psoriasis suggest that an imbalance between Th1 and Th17 cytokines may play a role in the phenotypic transition of psoriasis.

Is gas/air tamponade essential for eyes with small peripheral retinal breaks without detachment during vitrectomy?

BACKGROUND: To investigate the safety of vitrectomy with laser photocoagulation in eyes with small peripheral retinal breaks without air or gas tamponade. METHODS: Among patients who underwent vitrectomy for various retinal disorders, those with small peripheral retinal breaks treated by laser photocoagulation without air or gas tamponade were included in this study. Their medical records were assessed retrospectively, and we investigated the characteristics of small peripheral retinal breaks and the incidence of postoperative retinal detachment (RD). RESULTS: Thirty-one eyes of 31 patients who presented with small peripheral retinal breaks requiring endolaser photocoagulation during vitrectomy were included in this analysis. There were two cases of iatrogenic retinal breaks that occurred during vitrectomy, while others were preexisting lesions, including retinal tears, atrophic retinal holes, and retinal holes with lattice degeneration. There were no cases of RD during the follow-up period of at least 6 months. CONCLUSIONS: Adequate laser treatment without gas or air tamponade may be sufficient during vitrectomy in cases with small peripheral retinal breaks without concurrent RD, along with complete removal of vitreoretinal traction.