Development of finely tuned liposome nanoplatform for macrophage depletion.

BACKGROUND: Immunotherapy with clodronate-encapsulated liposomes, which induce macrophage depletion, has been studied extensively. However, previously reported liposomal formulation-based drugs (Clodrosome® and m-Clodrosome®) are limited by their inconsistent size and therapeutic efficacy. Thus, we aimed to achieve consistent therapeutic effects by effectively depleting macrophages with uniform-sized liposomes. RESULTS: We developed four types of click chemistry-based liposome nanoplatforms that were uniformly sized and encapsulated with clodronate, for effective macrophage depletion, followed by conjugation with Man-N3 and radiolabeling. Functionalization with Man-N3 improves the specific targeting of M2 macrophages, and radioisotope labeling enables in vivo imaging of the liposome nanoplatforms. The functionalized liposome nanoplatforms are stable under physiological conditions. The difference in the biodistribution of the four liposome nanoplatforms in vivo were recorded using positron emission tomography imaging. Among the four platforms, the clodronate-encapsulated mannosylated liposome effectively depleted M2 macrophages in the normal liver and tumor microenvironment ex vivo compared to that by Clodrosome® and m-Clodrosome®. CONCLUSION: The newly-developed liposome nanoplatform, with finely tuned size control, high in vivo stability, and excellent ex vivo M2 macrophage targeting and depletion effects, is a promising macrophage-depleting agent.

Endoscopic Intervention for Anastomotic Leakage After Gastrectomy.

Anastomotic leaks and fistulas are significant complications of gastric surgery that potentially lead to increased postoperative morbidity and mortality. Surgical intervention is reserved for cases with severe symptoms or hemodynamic instability; however, surgery carries a higher risk of complications. With advancements in endoscopic treatment options, endoscopic approaches have emerged as the primary choice for managing these complications. Endoscopic clipping is a traditional method comprising 2 main categories: through-the-scope clips and over-the-scope clips. Through-the-scope clips are user friendly and adaptable to various clinical scenarios, whereas over-the-scope clips can close larger defects. Another promising approach is endoscopic stent insertion, which has shown a high success rate for leak closure, although vigilant monitoring is required to monitor stent migration. Infection control is essential in post-surgical leakage cases, and endoscopic internal drainage provides a relatively safe and noninvasive means to manage fluids, contributing to infection control and wound healing promotion. Endoscopic suturing offers full-thickness wound closure, but requires additional training and endoscopic versatility. As a promising tool, endoscopic vacuum therapy potentially surpasses stent therapy by draining inflammatory materials and closing defects. Furthermore, the use of tissue sealants, such as fibrin glue and cyanoacrylate, has been reported to be effective in selected situations. The choice of endoscopic device should be tailored to individual cases and specific patient conditions, with careful consideration of the nature of the defect. Further extensive studies involving larger patient populations are required to provide more robust evidence on the efficacy of endoscopic approach in managing post-gastric anastomotic leaks.

Extracranial Vascular Malformations Increase Cardiovascular Disease Risk: A Nationwide Population-Based Cohort Study.

BACKGROUND: Extracranial vascular malformations affect vessel inflammation, clotting, and ischemia. However, the relationship between extracranial vascular malformations and myocardial infarction (MI) or stroke has not been fully elucidated. Limited studies have investigated the association between extracranial vascular malformations and cardiovascular diseases. METHODS: A total of 48,701 patients with extracranial vascular malformations and a control cohort with 487,010 age- and sex-matched participants from the Korean National Health Insurance database were included. The incidence and risk of MI, ischemic stroke (IS), and hemorrhagic stroke (HS) between participants with extracranial vascular malformations and the control cohort was then compared. RESULTS: After adjusting for other cardiovascular disease risk factors, the adjusted hazard ratios (aHRs) for VMs, CMs, AVMs, and LMs in patients with acute MI were 1.25 [CI 1.04-1.50], 1.41 [CI 1.24-1.61], 1.68 [CI 1.18-2.37], and 1.40 [CI 1.31-1.48], respectively. For IS, the aHRs were 1.55 [CI 1.35-1.77], 1.92 [CI 1.74-2.11], 1.13 [CI 0.78-1.64], and 1.51 [CI 1.44-1.58], respectively. For HS, the aHRs were 1.51 [CI 1.12-2.05], 5.63 [CI 4.97-6.38], 2.93 [CI 1.82-4.72], and 1.34 [CI 1.20-1.50], respectively. CONCLUSIONS: Independent of cardiovascular risk factors, extracranial vascular malformations were associated with an increased risk of MI, IS, and HS. For patients with CMs and AVMs, intracerebral hemorrhage risk was particularly high, accounting for 563% and 293%, respectively. Therefore, even in patients with extracranial CMs or AVMs, performing diagnostic evaluations for cerebral AVMs and employing measures to prevent intracerebral hemorrhage are very crucial.

Association between total cholesterol levels and all-cause mortality among newly diagnosed patients with cancer.

We aimed to determine the association between cholesterol values and the risk of all-cause mortality in newly diagnosed patients with cancer in a large-scale longitudinal cohort. Newly diagnosed patients with cancer were reviewed retrospectively. Cox proportional hazards regression models determined the association between baseline levels of total cholesterol (TC), triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and the risk of all-cause mortality. A restricted cubic spline curve was used to identify the association between total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol with the risk of death on a continuous scale and to present the lowest values of lipid measurements associated with death. The median follow-up duration of the study was 5.77 years. Of the 59,217 patients with cancer, 12,624 patients were expired. The multivariable adjusted hazard ratio (aHR) for all-cause mortality in patients with cancer with 1st-5th (≤ 97 mg/dL) and 96th-100th (> 233 mg/dL) in TC levels was 1.54 (95% CI 1.43-1.66) and 1.28 (95% CI 1.16-1.41), respectively, compared to 61st-80th (172-196 mg/dL). The TC level associated with the lowest mortality risk in the multivariable model was 181 mg/dL. In comparison with LDL-C levels in the 61st-80th (115-136 mg/dL), the multivariable aHR for all-cause mortality in cancer patients with LDL-C levels in the 1st-5th (≤ 57 mg/dL) and 96th-100th (> 167 mg/dL) was 1.38 (95% CI 1.14-1.68) and 0.94 (95% CI 0.69-1.28), respectively. The 142 mg/dL of LDL cholesterol showed the lowest mortality risk. We demonstrated a U-shaped relationship between TC levels at baseline and risk of mortality in newly diagnosed patients with cancer. Low LDL levels corresponded to an increased risk of all-cause death.

The discriminative role of PROX-1 immunohistochemistry between venous malformation and lymphatic malformation of the deep type with no visible diagnostic surface skin lesion.

BACKGROUND: Venous malformations (VMs) are distinguished from lymphatic malformations (LMs) when specific diagnostic skin lesions are present. In the deep type, this is difficult by clinico-radiologic evaluation alone. We aimed to investigate the usefulness of lymphatic vessel endothelial cell (LEC) markers for the differential diagnosis of the deep VMs and LMs. METHODS: A retrospective study was conducted based on the medical records of patients with VMs and LMs who underwent biopsy with both D2-40 and PROX-1 immunohistochemistry. We compared the initial clinico-radiological diagnosis with the final pathological diagnosis and identified which ones showed a difference. RESULTS: From 261 patients who had VMs and LMs, 111 remained after the exclusion of those who showed definite surface diagnostic features. After pathological diagnosis with the expressions of D2-40 and PROX-1, 38 of 111 (34.2%) patients' final diagnoses were changed. Among these 38 cases, diagnosis was not changed by D2-40 positivity alone, but changed by PROX-1 positivity alone (52.6%) or by both (47.4%). The diagnostic changes were more frequent in the deep category (43.7%) than in the superficial category. CONCLUSIONS: Identifying the expression of D2-40, and especially PROX-1, in the differential diagnosis of VMs and LMs may provide important treatment guidelines and understanding their natural course.

Relationships among self-esteem, ego-resilience, and caregiver burden among families of children with hematologic and oncologic disease: A cross-sectional study.

Background: Pediatric hematology and oncology disease is a physically and emotionally demanding health condition for families. High self-esteem and ego-resilience among caregivers, which have recently gained increased recognition, might help ease caregiver burdens. Few studies, however, have simultaneously investigated the relationships between self-esteem, ego-resilience, and caregiver burden among caregivers of children with hematologic and oncologic disease. Objective: The purpose of this study is to investigate the relationships between caregiver burden, self-esteem, and ego-resilience and examine whether ego-resilience plays a role in mediating the relationship between self-esteem and caregiver burden among family caregivers of children with hematologic and oncologic disease. Design: Descriptive correlational study. Setting: The outpatient clinic of the department of pediatric hematology and oncology at a flagship university hospital in a metropolitan city in South Korea. Participants: The sample comprised 109 primary family caregivers of children with hematologic and oncologic disease. Convenience sampling method was used. Methods: The participants completed the Ego-Resiliency Scale, Rosenberg Self-Esteem Scale, and Family Burden Questionnaire. One-way analysis of variance, independent t-tests, and correlation analyses were conducted using IBM SPSS 25.0. The mediating effect of ego-resilience was estimated using the PROCESS macro and bootstrap method in SPSS. Results: Caregiver burden showed significant negative associations with self-esteem and ego-resilience, with moderate effect sizes (r = -.391 and -0.361, respectively, p = .001). Ego-resilience mediated the relationship between self-esteem and caregiver burden (b = -0.019; 95 % bias-corrected bootstrap confidence interval -0.035 and -0.001). Conclusions: Self-esteem and ego-resilience may lessen caregiver burden among families of children with hematologic and oncologic disease, and self-esteem of caregivers tends to promote their ego-resilience. Therefore, self-esteem and ego-resilience should be improved among family caregivers to reduce their caregiver burden.

ß-Cyclodextrin Nanophotosensitizers for Redox-Sensitive Delivery of Chlorin e6.

The aim of this study is to prepare redox-sensitive nanophotosensitizers for the targeted delivery of chlorin e6 (Ce6) against cervical cancer. For this purpose, Ce6 was conjugated with ß-cyclodextrin (bCD) via a disulfide bond, creating nanophotosensitizers that were fabricated for the redox-sensitive delivery of Ce6 against cancer cells. bCD was treated with succinic anhydride to synthesize succinylated bCD (bCDsu). After that, cystamine was attached to the carboxylic end of bCDsu (bCDsu-ss), and the amine end group of bCDsu-ss was conjugated with Ce6 (bCDsu-ss-Ce6). The chemical composition of bCDsu-ss-Ce6 was confirmed with 1H and 13C NMR spectra. bCDsu-ss-Ce6 nanophotosensitizers were fabricated by a dialysis procedure. They formed small particles with an average particle size of 152.0 ± 23.2 nm. The Ce6 release rate from the bCDsu-ss-Ce6 nanophotosensitizers was accelerated by the addition of glutathione (GSH), indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive photosensitizer delivery capacity. The bCDsu-ss-Ce6 nanophotosensitizers have a low intrinsic cytotoxicity against CCD986Sk human skin fibroblast cells as well as Ce6 alone. However, the bCDsu-ss-Ce6 nanophotosensitizers showed an improved Ce6 uptake ratio, higher reactive oxygen species (ROS) production, and phototoxicity compared to those of Ce6 alone. GSH addition resulted in a higher Ce6 uptake ratio, ROS generation, and phototoxicity than Ce6 alone, indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive biological activity in vitro against HeLa human cervical cancer cells. In a tumor xenograft model using HeLa cells, the bCDsu-ss-Ce6 nanophotosensitizers efficiently accumulated in the tumor rather than in normal organs. In other words, the fluorescence intensity in tumor tissues was significantly higher than that of other organs, while Ce6 alone did not specifically target tumor tissue. These results indicated a higher anticancer activity of bCDsu-ss-Ce6 nanophotosensitizers, as demonstrated by their efficient inhibition of the growth of tumors in an in vivo animal tumor xenograft study.

Association between lipid variability and the risk of mortality in cancer patients not receiving lipid-lowering agents.

Aim: We investigated the association between total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride (TG) variability and cancer patient mortality risk. Methods: We retrospectively analyzed 42,539 cancer patients who were not receiving lipid-lowering agents and who had at least three TC measurements within 2 years of their initial cancer diagnosis. Using a multivariable Cox regression model, the risk of mortality was evaluated. Results: In multivariable analysis, Q2 (adjusted hazard ratio [aHR]: 1.32, 95% confidence interval (CI): 1.24-1.41), Q3 (aHR: 1.66, 95% CI: 1.56-1.76), and Q4 (aHR: 1.96, 95% CI: 1.84-2.08) of coefficient of variation (CV) in TC were significantly associated with mortality risk compared to Q1, showing a linear association between higher TC variability and mortality (P for trend<0.001). Q2 (aHR: 1.34, 95% CI: 1.06-1.77), Q3 (aHR: 1.40, 95% CI: 1.06-1.85), and Q4 (aHR: 1.50, 95% CI: 1.14-1.97) were all significantly associated with a higher risk of death compared to Q1 in multivariable Cox regression for the association between CV in LDL and all-cause mortality (P for trend=0.005). Conclusion: In cancer patients who do not receive lipid-lowering agents, high variability in total cholesterol and LDL cholesterol levels was found to pose significant role in mortality risk.

The stress-responsive protein REDD1 and its pathophysiological functions.

Regulated in development and DNA damage-response 1 (REDD1) is a stress-induced protein that controls various cellular functions, including metabolism, oxidative stress, autophagy, and cell fate, and contributes to the pathogenesis of metabolic and inflammatory disorders, neurodegeneration, and cancer. REDD1 usually exerts deleterious effects, including tumorigenesis, metabolic inflammation, neurodegeneration, and muscle dystrophy; however, it also exhibits protective functions by regulating multiple intrinsic cell activities through either an mTORC1-dependent or -independent mechanism. REDD1 typically regulates mTORC1 signaling, NF-κB activation, and cellular pro-oxidant or antioxidant activity by interacting with 14-3-3 proteins, IκBα, and thioredoxin-interacting protein or 75 kDa glucose-regulated protein, respectively. The diverse functions of REDD1 depend on cell type, cellular context, interaction partners, and cellular localization (e.g., mitochondria, endomembrane, or cytosol). Therefore, comprehensively understanding the molecular mechanisms and biological roles of REDD1 under pathophysiological conditions is of utmost importance. In this review, based on the published literature, we highlight and discuss the molecular mechanisms underlying the REDD1 expression and its actions, biological functions, and pathophysiological roles.

The landscape of PBMC methylome in canine mammary tumors reveals the epigenetic regulation of immune marker genes and its potential application in predicting tumor malignancy.

BACKGROUND: Genome-wide dysregulation of CpG methylation accompanies tumor progression and characteristic states of cancer cells, prompting a rationale for biomarker development. Understanding how the archetypic epigenetic modification determines systemic contributions of immune cell types is the key to further clinical benefits. RESULTS: In this study, we characterized the differential DNA methylome landscapes of peripheral blood mononuclear cells (PBMCs) from 76 canines using methylated CpG-binding domain sequencing (MBD-seq). Through gene set enrichment analysis, we discovered that genes involved in the growth and differentiation of T- and B-cells are highly methylated in tumor PBMCs. We also revealed the increased methylation at single CpG resolution and reversed expression in representative marker genes regulating immune cell proliferation (BACH2, SH2D1A, TXK, UHRF1). Furthermore, we utilized the PBMC methylome to effectively differentiate between benign and malignant tumors and the presence of mammary gland tumors through a machine-learning approach. CONCLUSIONS: This research contributes to a better knowledge of the comprehensive epigenetic regulation of circulating immune cells responding to tumors and suggests a new framework for identifying benign and malignant cancers using genome-wide methylome.

JP-1366: A novel and potent potassium-competitive acid blocker that is effective in the treatment of acid-related diseases.

The global prevalence of GERD is substantially increasing each year, and GERD is a chronic disease that reduces the quality of life of patients. The efficacy of conventional drugs is diverse, and most require long-term or lifetime administration; thus, the development of more effective therapeutic agents is needed. Herein, a more effective treatment for GERD was tested. We investigated whether JP-1366 affected gastric H+/K+-ATPase activity and used the Na+/K+-ATPase assay to confirm the selectivity of H+/K+-ATPase inhibition. To clarify the mechanism of enzyme inhibition, JP-1366 and TAK-438 were analyzed by Lineweaver-Burk. Also, we investigated the effects of JP-1366 in various models involving reflux esophagitis. We found that JP-1366 mediates strong, selective, and dose-dependent inhibition of H+/K+-ATPase. We found that JP-1366 significantly suppressed gastric acid secretion in histamine-treated pylorus-ligated rats in a dose-dependent manner. Additionally, we confirmed that JP-1366 inhibited histamine-stimulated gastric acid secretion in the HPD model. JP-1366 exhibited a more than 2-fold higher inhibitory effect on esophageal injury than TAK-438 in GERD lesions and had a more potent inhibitory effect in indomethacin- or aspirin-induced gastric ulcer rat models than TAK-438. Additionally, JP-1366 inhibited gastric ulcers. These results support the possibility that JP-1366 is a good candidate drug for treating acid-related diseases.

HDAC8 Deacetylates HIF-1α and Enhances Its Protein Stability to Promote Tumor Growth and Migration in Melanoma.

Melanoma is the most lethal type of skin cancer, and it causes more than 55,000 deaths annually. Although regional melanoma can be surgically removed, once melanoma metastasizes to other regions of the body, the survival rate drops dramatically. The current treatment options are chemotherapy, immunotherapy, and targeted therapy. However, the low response rate and the development of resistance necessitate the search for a novel therapeutic target in melanoma. Hypoxia-inducible factor-1 α (HIF-1α) is overexpressed in melanoma and plays a crucial role in driving malignant transformation in cancer cells. Here, we identified that histone deacetylase 8 (HDAC8) enhances the protein stability of HIF-1α. HDAC8 directly binds to and deacetylates HIF-1α, thereby promoting its protein stability. This, in turn, upregulates the transcriptional activity of HIF-1α and promotes the expressions of its target genes, such as hexokinase 2 (HK2) and glucose transporter 1 (GLUT1). The inhibition of HDAC8 suppresses the proliferation and metastasis of melanoma cells. Furthermore, HDAC8 is correlated with HIF1A expression and poor prognosis in samples from patients with melanoma. These findings uncover a novel epigenetic mechanism that maintains HIF-1α stability and implicates the potential of HDAC8 inhibitors for melanoma therapy.

Efficacy and safety of transarterial bleomycin sclerotherapy of early-stage facial arteriovenous malformation: Single-center multidisciplinary team experience.

BACKGROUND: To evaluate the efficacy and safety of transarterial bleomycin sclerotherapy of early-stage facial arteriovenous malformation (AVM). METHODS: A retrospective review was performed of patients who underwent bleomycin sclerotherapy for early-stage AVM (Schobinger stage I or II) in a single-referral vascular anomalies center. Bleomycin was slowly infused transarterially with flow control techniques to prolong the effects of bleomycin. Procedure details, AVM characteristics, and previous treatments were reviewed. Initial therapeutic outcomes were determined by 5 categories using both radiological and clinical findings in a 6-month follow-up. Further follow-up outcomes were reviewed to evaluate the long-term efficacy and safety of the treatment. Procedure-related complications were also analyzed. RESULTS: Nineteen patients (mean age 22.4 ± 14.0 years, 14 females) with 31 sessions of sclerotherapies were enrolled. All AVMs were Cho-Do classification type III (type IIIa [n = 13], type IIIb [n = 2], and type IIIa+b [n = 4]). Patients received a mean of 1.6 (range, 1-4) sessions of treatment. The mean cumulative bleomycin dose was 23,600 IU ± 14,500 (range, 8000 - 60,000 IU). The results showed that 14 patients (74%) were responsive to transarterial bleomycin sclerotherapy, including complete response (n = 3), marked improvement (n = 1), and partial improvement (n = 10). The remaining 5 (26%) showed no response. During a mean follow-up of 32.6 months, 5 (26%) showed slight progression compared with 6-month outcomes and 14 (74%) were stable. There were only 2 minor complications [hyperpigmentation (n = 1) and cellulitis (n = 1)]. CONCLUSIONS: Transarterial bleomycin sclerotherapy using flow control techniques can be a safe and feasible alternative treatment option for facial early-stage AVM.

Electrophysiologic Patterns of Symptomatic Vincristine-Induced Peripheral Neuropathy in Children with Acute Lymphocytic Leukemia.

Acute lymphocytic leukemia is one of the most common cancers in children. Multi-drug chemotherapy is used for treatment, and the representative drug is vincristine. Although various side effects may occur due to vincristine, the association with peripheral neuropathy is high compared to that of other drugs. This study focused on children under the age of 18 years of age with ALL who received chemotherapy containing vincristine. We retrospectively analyzed the results of a nerve conduction study and a cumulative dose of vincristine in 30 children diagnosed with peripheral neuropathy. The average cumulative dose until diagnosis of vincristine-induced peripheral neuropathy was 14.99 ± 1.21 mg/m2, and motor nerves were predominantly involved. Additionally, a marked decrease in average amplitude was also observed in motor nerves. In addition, when the relationship between the incidence of peripheral neuropathy and the cumulative dose was analyzed through the survival curve, about 50% of children developed peripheral neuropathy at a dose of 15.5 ± 1.77 mg/m2. Based on the electrophysiological characteristics of pediatric vincristine-induced peripheral neuropathy, as well as the relationship between the incidence rate and the cumulative dose, it is possible to observe more closely the vincristine-induced peripheral neuropathy occurrence in children with ALL at an appropriate time.

Detection of increased intracranial pressure in trans-oral robotic thyroidectomy using optic nerve sheath diameter measurement.

BACKGROUND: During transoral robot-assisted thyroidectomy, there is a risk of increasing intracranial pressure because the site of CO2 insufflation is narrow and close to the brain. METHODS: We analyzed the pre- to post-CO2 neck insufflation change in the optic nerve sheath diameter during transoral robot-assisted thyroidectomy. Changes in vital-signs, airway pressure, and arterial carbon dioxide pressure were analyzed along with postoperative complications. RESULTS: Among the 30 participants, the post-CO2 inflation mean optic nerve sheath diameter (5.64 ± 0.54 mm) was higher than the pre-induction diameter (4.81 ± 0.37 mm) with a mean difference of 0.83 (95% CI, 0.69-0.97; p < 0.001), but returned to baseline after CO2 deflation in most cases. One participant had sustained increased optic nerve sheath diameter (6.35 mm) associated with severe new-onset postoperative headache. CONCLUSION: Transient elevation in the intracranial pressure during low-pressure CO2 neck insufflation in the transoral robot-assisted thyroidectomy did not appear to adversely affect patients.

Epidemiologic and Clinical Outcomes of Pediatric Renal Tumors in Korea: A Retrospective Analysis of The Korean Pediatric Hematology and Oncology Group (KPHOG) Data.

PURPOSE: Renal tumors account for approximately 7% of all childhood cancers. These include Wilms tumor (WT), clear cell sarcoma of the kidney (CCSK), malignant rhabdoid tumor of the kidney (MRTK), renal cell carcinoma (RCC), congenital mesoblastic nephroma (CMN) and other rare tumors. We investigated the epidemiology of pediatric renal tumors in Korea. MATERIALS AND METHODS: From January 2001 to December 2015, data of pediatric patients (0-18 years) newly-diagnosed with renal tumors at 26 hospitals were retrospectively analyzed. RESULTS: Among 439 patients (male, 240), the most common tumor was WT (n=342, 77.9%), followed by RCC (n=36, 8.2%), CCSK (n=24, 5.5%), MRTK (n=16, 3.6%), CMN (n=12, 2.7%), and others (n=9, 2.1%). Median age at diagnosis was 27.1 months (range 0-225.5) and median follow-up duration was 88.5 months (range 0-211.6). Overall, 32 patients died, of whom 17, 11, 1, and 3 died of relapse, progressive disease, second malignant neoplasm, and treatment-related mortality. Five-year overall survival and event free survival were 97.2% and 84.8% in WT, 90.6% and 82.1% in RCC, 81.1% and 63.6% in CCSK, 60.3% and 56.2% in MRTK, and 100% and 91.7% in CMN, respectively (p < 0.001). CONCLUSION: The pediatric renal tumor types in Korea are similar to those previously reported in other countries. WT accounted for a large proportion and survival was excellent. Non-Wilms renal tumors included a variety of tumors and showed inferior outcome, especially MRTK. Further efforts are necessary to optimize the treatment and analyze the genetic characteristics of pediatric renal tumors in Korea.

Drawing a line between histone demethylase KDM5A and KDM5B: their roles in development and tumorigenesis.

Distinct epigenetic modifiers ensure coordinated control over genes that govern a myriad of cellular processes. Growing evidence shows that dynamic regulation of histone methylation is critical for almost all stages of development. Notably, the KDM5 subfamily of histone lysine-specific demethylases plays essential roles in the proper development and differentiation of tissues, and aberrant regulation of KDM5 proteins during development can lead to chronic developmental defects and even cancer. In this review, we adopt a unique perspective regarding the context-dependent roles of KDM5A and KDM5B in development and tumorigenesis. It is well known that these two proteins show a high degree of sequence homology, with overlapping functions. However, we provide deeper insights into their substrate specificity and distinctive function in gene regulation that at times divert from each other. We also highlight both the possibility of targeting KDM5A and KDM5B to improve cancer treatment and the limitations that must be overcome to increase the efficacy of current drugs.

Pathological Role of HDAC8: Cancer and Beyond.

Histone deacetylase 8 (HDAC8) is a class I HDAC that catalyzes the deacetylation of histone and non-histone proteins. As one of the best-characterized isoforms, numerous studies have identified interacting partners of HDAC8 pertaining to diverse molecular mechanisms. Consequently, deregulation and overexpression of HDAC8 give rise to diseases. HDAC8 is especially involved in various aspects of cancer progression, such as cancer cell proliferation, metastasis, immune evasion, and drug resistance. HDAC8 is also associated with the development of non-cancer diseases such as Cornelia de Lange Syndrome (CdLS), infectious diseases, cardiovascular diseases, pulmonary diseases, and myopathy. Therefore, HDAC8 is an attractive therapeutic target and various HDAC8 selective inhibitors (HDAC8is) have been developed. Here, we address the pathological function of HDAC8 in cancer and other diseases, as well as illustrate several HDAC8is that have shown anti-cancer effects.

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells.

HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors.

Hypoxia Promotes Angiogenic Effect in Extracranial Arteriovenous Malformation Endothelial Cells.

Arteriovenous malformation (AVM) is characterized by high-flow blood vessels connecting arteries and veins without capillaries. This disease shows increased angiogenesis and a pathophysiological hypoxic environment in proximal tissues. Here, we analyzed the effects of hypoxia on angiogenesis in the endothelial cells (ECs) of AVM and normal tissues. ECs from human normal and AVM tissues were evaluated using immunocytochemistry with CD31. In vitro tube formation under hypoxia was tested in both ECs using Matrigel. The relative expression of angiogenesis-related genes was measured using real-time PCR. Under normoxia, CD31 was significantly higher in AVM ECs (79.23 ± 0.65%) than in normal ECs (74.15 ± 0.70%). Similar results were observed under hypoxia in AVM ECs (63.85 ± 1.84%) and normal ECs (60.52 ± 0.51%). In the tube formation test under normoxic and hypoxic conditions, the junction count and total vessel length were significantly greater in AVM ECs than normal ECs. Under both normoxia and hypoxia, the angiogenesis-related gene FSTL1 showed a significantly higher expression in AVM ECs than in normal ECs. Under hypoxia, CSPG4 expression was significantly lower in AVM ECs than in normal ECs. Accordingly, the angiogenic effect was increased in AVM ECs compared with that in normal ECs. These results provide a basic knowledge for an AVM treatment strategy.