The Impact of Infectious Mononucleosis History on the Risk of Developing Lymphoma and Nasopharyngeal Carcinoma: a Retrospective Large-Scale Cohort Study using National Health Insurance Data in South Korea.

Purpose: This study aimed to assess the long-term risks associated with a history of infectious mononucleosis (IM), primarily caused by the Epstein-Barr virus (EBV). Specifically analyzing the potential increase in developing nasopharyngeal cancer (NPC) and lymphoma in patients with a history of IM and exploring the prevalence of other EBV-associated conditions. Materials and Methods: The Korean National Health Insurance Service (NHIS) database was utilized for a retrospective analysis, covering data from 2002 to 2021. A total of 25,582 IM patients and controls were included, with 1:1 propensity score matching. The study monitored outcomes, including lymphoma, NPC, gastric cancer, multiple sclerosis, and all-cause mortality. Results: Patients with a history of IM demonstrated a significantly higher incidence of lymphoma (HR=5.32, 95% CI 3.208‒8.82, p<0.001) and NPC (HR=7.116, 95% CI 1.617‒31.314, p=0.009) during the follow-up period compared with the control group. Additionally, the IM group showed an increased rate of all-cause mortality (HR=2.225, 95% CI 1.858‒2.663, p<0.001). Conclusion: This study suggests that individuals with a history of IM have an elevated risk of developing lymphoma and NPC in South Korea, emphasizing the importance of vigilant follow-up and monitoring. The results advocate for heightened awareness and potential national monitoring policies to address the long-term health implications of EBV infection and to implement preventive measures.

TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction.

Adipose tissue (AT) adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Among immune cells recruited to AT, lipid-associated macrophages (LAMs) have emerged as key players in obesity and in diseases involving lipid stress and inflammation. Here, we show that LAMs selectively express transmembrane 4 L six family member 19 (TM4SF19), a lysosomal protein that represses acidification through its interaction with Vacuolar-ATPase. Inactivation of TM4SF19 elevates lysosomal acidification and accelerates the clearance of dying/dead adipocytes in vitro and in vivo. TM4SF19 deletion reduces the LAM accumulation and increases the proportion of restorative macrophages in AT of male mice fed a high-fat diet. Importantly, male mice lacking TM4SF19 adapt to high-fat feeding through adipocyte hyperplasia, rather than hypertrophy. This adaptation significantly improves local and systemic insulin sensitivity, and energy expenditure, offering a potential avenue to combat obesity-related metabolic dysfunction.

The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress.

Mitophagy induction upon mitochondrial stress is critical for maintaining mitochondrial homeostasis and cellular function. Here, we found that Mst1/2 (Stk3/4), key regulators of the Hippo pathway, are required for the induction of mitophagy under various mitochondrial stress conditions. Knockdown of Mst1/2 or pharmacological inhibition by XMU-MP-1 treatment led to impaired mitophagy induction upon CCCP and DFP treatment. Mechanistically, Mst1/2 induces mitophagy independently of the PINK1-Parkin pathway and the canonical Hippo pathway. Moreover, our results suggest the essential involvement of BNIP3 in Mst1/2-mediated mitophagy induction upon mitochondrial stress. Notably, Mst1/2 knockdown diminishes mitophagy induction, exacerbates mitochondrial dysfunction, and reduces cellular survival upon neurotoxic stress in both SH-SY5Y cells and Drosophila models. Conversely, Mst1 and Mst2 expression enhances mitophagy induction and cell survival. In addition, AAV-mediated Mst1 expression reduced the loss of TH-positive neurons, ameliorated behavioral deficits, and improved mitochondrial function in an MPTP-induced Parkinson's disease mouse model. Our findings reveal the Mst1/2-BNIP3 regulatory axis as a novel mediator of mitophagy induction under conditions of mitochondrial stress and suggest that Mst1/2 play a pivotal role in maintaining mitochondrial function and neuronal viability in response to neurotoxic treatment.

Role of autophagy in betaine-promoted hepatoprotection against non-alcoholic fatty liver disease in mice.

Betaine, a compound found in plants and sea foods, is known to be beneficial against non-alcoholic fatty liver disease (NAFLD), but its hepatoprotective and anti-steatogenic mechanisms have been not fully understood. In the present study, we investigated the mechanisms underlying betaine-mediated alleviation of NAFLD induced by a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) in mice, with special focus on the contribution of betaine-stimulated autophagy to NAFLD prevention. Male ICR mice were fed a CDAHFD with or without betaine (0.2-1% in drinking water) for 1 week. Betaine ameliorated the CDAHFD-induced fatty liver by restoring sulfur amino acid (SAA)-related metabolites, such as S-adenosylmethionine and homocysteine, and the phosphorylation of AMPK and ACC. In addition, it reduced the CDAHFD-induced ER stress (BiP, ATF6, and CHOP) and apoptosis (Bax, cleaved caspase-3, and cleaved PARP); however, it induced autophagy (LC3II/I and p62) which was downregulated by CDAHFD. To determine the role of autophagy in the improvement of NAFLD, chloroquine (CQ), an autophagy inhibitor, was injected into the mice fed a CDAHFD and betaine (0.5 % in drinking water). CQ did not affect SAA metabolism but reduced the beneficial effects of betaine as shown by the increases of hepatic lipids, ER stress, and apoptosis. Notably, the betaine-induced improvements in lipid metabolism determined by protein levels of p-AMPK, p-ACC, PPARα, and ACS1, were reversed by CQ. Thus, the results of this study suggest that the activation of autophagy is an important upstream mechanism for the inhibition of steatosis, ER stress, and apoptosis by betaine in NAFLD.

Sudden Sensorineural Hearing Loss and Facial Palsy in Patients with Vestibular Schwannoma Based on the Population Data of Korea.

BACKGROUND: The prevalence of sudden sensorineural hearing loss and facial palsy in patients with vestibular schwannoma and the association of sudden sensorineural hearing loss or facial palsy with vestibular schwannoma were investigated based on the population data of Korea. METHODS: This retrospective study used the Korean National Health Insurance Service data. Patients with vestibular schwannoma and those with a previous history of sudden sensorineural hearing loss or facial palsy were identified based on diagnostic, medication, magnetic resonance imaging, or audiometric codes from 2005 to 2020. The control group was established with propensity score matching. The risk for vestibular schwannoma in patients with a previous history of sudden sensorineural hearing loss or facial palsy was analyzed. RESULTS: There were 5751 patients in the vestibular schwannoma group and 23004 in the control group. The rate of patients with a previous history of sudden sensorineural hearing loss in the vestibular schwannoma group (25.8%) was significantly higher than in the control group (P -lt; .0001), as was the rate of patients with a previous history of facial palsy in the vestibular schwannoma group (4.7%) (P -lt; .0001). Previous history of sudden sensorineural hearing loss was a significant risk factor for vestibular schwannoma (hazard ratio=7.109, 95% confidence interval=6.696-7.547). Previous history of facial palsy was also a significant risk factor for vestibular schwannoma (hazard ratio=3.048, 95% confidence interval=2.695-3.447). CONCLUSION: The prevalence of sudden sensorineural hearing loss or facial palsy was significantly higher in patients with vestibular schwannoma than in those without vestibular schwannoma. Based on the population data of Korea, sudden sensorineural hearing loss and facial palsy were significant risk factors for vestibular schwannoma.

Longitudinal Analyses of Mutational Subclonal Architecture and Tumor Subtypes in Recurrent Bladder Cancer.

Longitudinal tumor sequencing of recurrent bladder cancer (BC) can facilitate the investigation of BC progression-associated genomic and transcriptomic alterations. In this study, we analyzed 18 tumor specimens including distant and locoregional metastases obtained during tumor progression for five BC patients using whole-exome and transcriptome sequencing. Along with the substantial level of intratumoral mutational heterogeneity across the cases, we observed that clonal mutations were enriched with known BC driver genes and apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC)-associated mutation signatures compared with subclonal mutations, suggesting the genetic makeup for BC tumorigenesis associated with APOBEC deaminase activity was accomplished early in the cancer evolution. Mutation-based phylogenetic analyses also revealed temporal dynamics of mutational clonal architectures in which the number of mutational clones varied along the BC progression and notably was often punctuated by clonal sweeps associated with chemotherapy. The bulk-level transcriptome sequencing revealed frequent subtype switching in which transcriptionally defined BC subtypes may vary during tumor progression. Longitudinal whole-exome and transcriptome sequencing of recurrent BC may advance our understanding into the BC heterogeneity in terms of somatic mutations, cell clones and transcriptome-based tumor subtypes during disease progression.

Effect of Isoquercitrin on Free Fatty Acid-Induced Lipid Accumulation in HepG2 Cells.

Liver metabolic disorders and oxidative stress are crucial factors in the development of nonalcoholic fatty liver disease (NAFLD); however, treatment strategies to combat NAFLD remain poorly established, presenting an important challenge that needs to be addressed. Herein, we aimed to examine the effect of isoquercitrin on lipid accumulation induced by exogenous free fatty acids (FFA) using HepG2 cells and elucidate the underlying molecular mechanism. The cells were exposed to 0.5 mM FFA to induce intracellular lipid accumulation, followed by co-treatment with isoquercitrin to confirm the potential inhibitory effect on FFA-induced lipid production. HepG2 cells exposed to FFA alone exhibited intracellular lipid accumulation, compromised endoplasmic reticulum (ER) stress, and enhanced expression of proteins and genes involved in lipid synthesis; however, co-treatment with isoquercitrin decreased the expression of these molecules in a dose-dependent manner. Furthermore, isoquercitrin could activate AMP-activated protein kinase (AMPK), a key regulatory protein of hepatic fatty acid oxidation, suppressing new lipid production by phosphorylating acetyl-CoA carboxylase (ACC) and inhibiting sterol regulatory element-binding transcription factor 1 (SREBP-1)/fatty acid synthase (FAS) signals. Overall, these findings suggest that isoquercitrin can be employed as a therapeutic agent to improve NAFLD via the regulation of lipid metabolism by targeting the AMPK/ACC and SREBP1/FAS pathways.

Green tea extract exhibits antidiabetic effects partly through regulating dipeptidyl peptidase-4 expression in adipose tissue.

The antidiabetic effects of green tea have been demonstrated in clinical trials and epidemiological studies. This study investigated the antidiabetic effects of green tea extract (GTE) and its underlying molecular mechanisms using a leptin receptor-deficient db/db mouse model (Leprdb/db). Treatment with GTE for 2 weeks improved glucose tolerance and insulin sensitivity in Leprdb/db mice. In addition, GTE treatment reduced the body weight and adiposity of Leprdb/db mice. Furthermore, GTE treatment reduced pro-inflammatory gene expression, including nuclear factor kappa B (NF-κB) in white adipose tissue (WAT), and also reduced dipeptidyl peptidase-4 (DPP4) expression levels in WAT as well as in the serum. The promoter region of Dpp4 contains the NF-κB binding site, and DPP4 was found to be a direct target of NF-κB. Consistently, in vitro treatment of cells with GTE or its main constituent epigallocatechin gallate reduced lipopolysaccharide-induced NF-κB/DPP4 expression in 3T3-L1 adipocytes and RAW264.7 cells. Overall, our data demonstrated that GTE exerts an anti-diabetic effect by regulating the expression levels of NF-κB and DPP4 in WAT.

Incidence and Risk Factors of Vestibular Schwannoma in Korea : A Population-Based Study.

OBJECTIVE: This study aims to investigate the incidence of vestibular schwannoma (VS) and demographic characteristics in Korea using population-based National Health Insurance Service data. METHODS: This study analyzed Korean National Health Insurance Service data from 2005 to 2020, based on the International Classification of Diseases, 10th version, Clinical Modification codes D333 and D431. Only those patients who had undergone magnetic resonance imaging and audiologic tests were considered definitive cases. Demographic variables included age, sex, treatment modality, hypertension, diabetics, dyslipidemia, smoking history, alcohol history, and income status. RESULTS: The total number of VS patients was 5751. The average incidence rate was 0.71 per 100000 from 2005 to 2020, and the annual incidence rate increased from 0.33 in 2005 to 1.32 in 2019 but decreased to 0.80 in 2020. Incidence was highest in those aged 60-69 years (1.791) and lowest in those younger than 20 years (0.041). Incidence was higher in females, and the number of patients who received radiosurgery (46.64%) was largest compared to the wait and scan group (37.96%), microsurgery group (12.85%), or the group who received both (2.56%). Diabetes, dyslipidemia, and alcohol consumption increased the risk of VS, while cigarette smoking reduced the risk of VS. CONCLUSION: The incidence of VS exhibited an increasing trend from 2005 to 2019. Radiosurgery (46.64%) was the most common treatment modality. Diabetes, dyslipidemia, and alcohol consumption increased the risk of VS, while cigarette smoking reduced the risk of VS.

Longitudinal Transcription Profiling of Bladder Cancers Dictate the Response to BCG Treatment and Disease Progression.

Although the intravesical instillation of Bacillus Calmette-Guerin (BCG) is widely used as adjuvant treatment for nonmuscle-invasive bladder cancers, the clinical benefit is variable across patients, and the molecular mechanisms underlying the sensitivity to BCG administration and disease progression are poorly understood. To establish the molecular signatures that predict the responsiveness and disease progression of bladder cancers treated with BCG, we performed transcriptome sequencing (RNA-seq) for 13 treatment-naïve and 22 post-treatment specimens obtained from 14 bladder cancer patients. To overcome disease heterogeneity, we used non-negative matrix factorization to identify the latent molecular features associated with drug responsiveness and disease progression. At least 12 molecular features were present, among which the immune-related feature was associated with drug responsiveness, indicating that pre-treatment anti-cancer immunity might dictate BCG responsiveness. We also identified disease progression-associated molecular features indicative of elevated cellular proliferation in post-treatment specimens. The progression-associated molecular features were validated in an extended cohort of BCG-treated bladder cancers. Our study advances understanding of the molecular mechanisms of BCG activity in bladder cancers and provides clinically relevant gene markers for evaluating and monitoring patients.

Anti-obesity effects of the dual-active adenosine A2A/A3 receptor-ligand LJ-4378.

BACKGROUND AND OBJECTIVES: A2A adenosine receptor (A2AAR)-mediated signaling in adipose tissues has been investigated as a potential target for obesity-related metabolic diseases. LJ-4378 has been developed as a dual-acting ligand with A2AAR agonist and A3 adenosine receptor (A3AR) antagonist activity. The current study aimed to investigate the anti-obesity effects of LJ-4378 and its underlying molecular mechanisms. METHODS: Immortalized brown adipocytes were used for in vitro analysis. A high-fat diet (HFD)-induced obesity and cell death-inducing DFFA-like effector A reporter mouse models were used for in vivo experiments. The effects of LJ-4378 on lipolysis and mitochondrial metabolism were evaluated using immunoblotting, mitochondrial staining, and oxygen consumption rate analyses. The in vivo anti-obesity effects of LJ-4378 were evaluated using indirect calorimetry, body composition analyses, glucose tolerance tests, and histochemical analyses. RESULTS: In vitro LJ-4378 treatment increased the levels of brown adipocyte markers and mitochondrial proteins, including uncoupling protein 1. The effects of LJ-4378 on lipolysis of adipocytes were more potent than those of the A2AAR agonist or A3AR antagonist. In vivo, LJ-4378 treatment increased energy expenditure by 17.0% (P value < 0.0001) compared to vehicle controls. LJ-4378 (1 mg/kg, i.p.) treatment for 10 days reduced body weight and fat content by 8.24% (P value < 0.0001) and 24.2% (P value = 0.0044), respectively, and improved glucose tolerance in the HFD-fed mice. LJ-4378 increased the expression levels of brown adipocyte markers and mitochondrial proteins in interscapular brown and inguinal white adipose tissue. CONCLUSION: These findings support the in vivo anti-obesity effects of LJ-4378, and suggest a novel therapeutic approach to combat obesity and related metabolic diseases.

Adipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism.

Dysregulation of adipose tissue plasmalogen metabolism is associated with obesity-related metabolic diseases. We report that feeding mice a high-fat diet reduces adipose tissue lysoplasmalogen levels and increases transmembrane protein 86 A (TMEM86A), a putative lysoplasmalogenase. Untargeted lipidomic analysis demonstrates that adipocyte-specific TMEM86A-knockout (AKO) increases lysoplasmalogen content in adipose tissue, including plasmenyl lysophosphatidylethanolamine 18:0 (LPE P-18:0). Surprisingly, TMEM86A AKO increases protein kinase A signalling pathways owing to inhibition of phosphodiesterase 3B and elevation of cyclic adenosine monophosphate. TMEM86A AKO upregulates mitochondrial oxidative metabolism, elevates energy expenditure, and protects mice from metabolic dysfunction induced by high-fat feeding. Importantly, the effects of TMEM86A AKO are largely reproduced in vitro and in vivo by LPE P-18:0 supplementation. LPE P-18:0 levels are significantly lower in adipose tissue of human patients with obesity, suggesting that TMEM86A inhibition or lysoplasmalogen supplementation might be therapeutic approaches for preventing or treating obesity-related metabolic diseases.

Effects of dietary restriction on hepatic sulfur-containing amino acid metabolism and its significance in acetaminophen-induced liver injury.

Dietary restriction (DR) has been revealed to have health benefits as it induces reduction in oxidative stress. Glutathione (GSH), an important cellular antioxidant, is increased in rodent livers owing to DR; however, the exact mechanism and clinical relevance of DR are yet to be fully understood. In this study, male C57BL/6 mice were administered a 50% restricted diet for 7 d, and the hepatic sulfur-containing amino acid (SAA) metabolism was determined to assess the biosynthesis of GSH. The hepatic methionine level was found to decrease, while the homocysteine, cysteine, and GSH levels were increased owing to decreased betaine-homocysteine methyltransferase (BHMT) and increased CßS, CγL, and glutamate cysteine ligase catalytic subunit (GCLC) proteins in the livers of mice subjected to DR. To determine the effects of DR on drug-induced oxidative liver injury, mice subjected to DR were injected with a toxic dose (300 mg/kg) of acetaminophen (APAP). DR significantly alleviated APAP-induced liver damage and oxidative stress, which might be attributed to the higher levels of GSH and related antioxidant enzyme (GPx, GSTα, and GSTµ) in the livers. The decrease in the levels of hepatic CYP1A, 2E1, and 3A, which imply the inhibition of APAP metabolic activation, could contribute to the lower hepatotoxicity in mice subjected to DR. Overall, our findings revealed that DR stimulated the hepatic transsulfuration pathway and GSH synthesis. The consequent elevation of GSH could thus serve as an important mechanism of DR-mediated liver protection against APAP intoxication.

Relationship between Bone Mineral Density and Dental Caries in Koreans by Sex and Menopausal State.

We aimed to investigate the relationship between bone mineral density and dental caries in adults of over 19 years of age who were categorized according to their sex and menopausal status. The Korea National Health and Nutrition Examination Survey (KNHANES) dataset was used for the study. Bone mineral density (BMD) and oral health examination data were collected between 2008 and 2011. A total of 17,141 adults of ≥19 years old were eligible for inclusion in the present study. Multiple regression analysis was performed after adjustment for age, household income, educational level, smoking status, and alcohol drinking status for men, and pre- and post-menopausal women. In men, the ß-value for the mean decayed, missing, and filled teeth (DMFT) index was 0.98 (95% confidence interval (CI) = 0.71−1.25), and was significantly higher in osteoporotic participants than in participants with normal BMD (p < 0.05). In post-menopausal women, the ß-value for the mean DMFT index was 0.86, and was higher in the osteoporotic participants than in the participants with normal BMD (p < 0.05). Men and post-menopausal women with osteoporosis had higher DMFT indexes than those with normal BMD. In addition, there was a correlation between DMFT index and BMD in men and post-menopausal women. Therefore, the prevention of osteoporosis should be implemented alongside proper oral care.

Type I IFN stimulates IFI16-mediated aromatase expression in adipocytes that promotes E2-dependent growth of ER-positive breast cancer.

Although type I interferons (IFNs) play multifaceted roles during tumorigenesis and cancer treatment, the interplay between type I IFNs and estrogen signaling in breast cancer (BC) microenvironment is not well understood. Here, we report a novel function of type I IFNs in inducing aromatase expression in adipose tissues surrounding BC, which potentiates the E2-dependent growth of estrogen receptor (ER)-positive BC. First, we found that expression levels of type I IFNs correlate negatively with clinical outcome but positively with tumor grade in patients with ER-positive BC. Levels of type I IFNs were elevated in cocultured media of immune cells and BC cells, which increased aromatase expression and E2 production in Simpson-Golabi-Behmel syndrome preadipocytes. The type I IFN-induced aromatase expression was dependent on IFN-γ-inducible protein 16 (IFI16), which is encoded by an interferon-stimulated gene. At the molecular level, type I IFNs led to recruitment of HIF1α-IFI16-PRMT2 complex to the hypoxia-response element located in the aromatase PI.3/PII promoter. Next, we generated an adipocyte-specific Ifi204, which is a mouse ortholog of human IFI16, knockout mouse (Ifi204-AKO). IFNß induced E2 production in the preadipocytes isolated from the control mice, but such E2 production was far lower in the Ifi204-AKO preadipocytes. Importantly, the growth of orthotopically inoculated E0771 ER-positive mammary tumors was reduced significantly in the Ifi204-AKO mice. Taken together, our findings provide novel insights into the crosstalk between type I IFNs and estrogen signaling in the progression of ER-positive BC.

Comparison of treatment outcomes of pelvis external radiotherapy with and without vaginal brachytherapy for cervical cancer patients with positive or close vaginal resected margins.

BACKGROUND: We evaluated whether there is a difference in the local recurrence and survival after pelvic external radiotherapy (ERT) with and without boost vaginal brachytherapy (VB) in cervical cancer patients with positive or close vaginal resected margins (RM). METHODS: We retrospectively reviewed FIGO stage IA-IIB cervical cancer patients treated with postoperative ERT between 1997 and 2018. The sixty patients showing close (safety margin < 5 mm) or positive vaginal RM were included. ERT was delivered with median 50.4 Gy in 28 fractions to the pelvis and VB with median 30 Gy in 6 fractions. RESULTS: The median follow-up duration was 46 months. Five out of 30 patients treated with ERT alone experienced vaginal recurrence within 2 years after surgery. The 5-year local control (LC) was 100% in patients receiving ERT + VB compared with 81.3% in patients receiving ERT alone (log rank p = 0.022). The 5-year pelvic control (PC) was 95.8% for patients receiving ERT + VB and 76.8% for ERT alone (p = 0.041). The 5-year overall survival and recurrence-free survival (RFS) were not significantly different between treatment groups. In multivariate analysis, perineural invasion was a significant risk factor for PC (p = 0.024). Parametrial involvement (p = 0.044) and vascular invasion (p = 0.032) were unfavorable prognostic factors for RFS. Late toxicity occurrences were not significant in both groups. CONCLUSION: VB after ERT improved LC and PC in cervical cancer patients with close or positive RM after hysterectomy. The toxicities were not increased after VB was added to ERT.

Lymphedema in Endometrial Cancer Survivor: A Nationwide Cohort Study.

BACKGROUND: Endometrial cancer is the most common gynecological cancer in developed countries. Treatment-related lymphedema negatively affects the quality of life and function of patients. This study investigated the cumulative incidence and risk factors of, and utilization of health care resources for, lymphedema in patients with endometrial cancer. METHODS: We conducted a nationwide, retrospective cohort study of women with endometrial cancer who underwent cancer-direct treatment using the Korean National Health Insurance Service (NHIS) database. Patients were categorized by age, region, income, and treatment modality. Cox proportional hazards regression models were used to analyze the incidence and risk factors of lymphedema. We also analyzed utilization of health care resources for lymphedema using diagnostic and treatment claim codes. RESULTS: A total of 19,027 patients with endometrial cancer were evaluated between January 2004 and December 2017. Among them, 2493 (13.1%) developed lymphedema. Age (<40 years, adjusted odds ratio [aOR] = 1 vs. 40-59 years, aOR = 1.413; 95% confidence interval (CI) 1.203-1.66 vs. 60+ years, aOR = 1.472; 95% CI 1.239-1.748) and multimodal treatment (surgery only, aOR = 1 vs. surgery + radiation + chemotherapy, aOR = 2.571; 95% CI 2.27-2.912) are considered to be possible risk factors for lymphedema in patients with endometrial cancer (p < 0.001). The utilization of health care resources for the treatment of lymphedema has increased over the years. CONCLUSIONS: Lymphedema is a common complication affecting women with endometrial cancer and leads to an increase in national healthcare costs. Post-treatment surveillance of lymphedema, especially in high-risk groups, is needed.

Ginsenoside Rg4 Enhances the Inductive Effects of Human Dermal Papilla Spheres on Hair Growth Via the AKT/GSK-3ß/ß-Catenin Signaling Pathway.

Ginsenoside Rg4 is a rare ginsenoside that is naturally found in ginseng, and exhibits a wide range of biological activities including antioxidant and anti-inflammatory properties in several cell types. The purpose of this study was to use an in vivo model of hair follicle (HF)-mimic based on a human dermal papilla (DP) spheroid system prepared by three-dimensional (3D) culture and to investigate the effect of Rg4 on the hair-inductive properties of DP cells. Treatment of the DP spheroids with Rg4 (20 to 50 µg/ml) significantly increased the viability and size of the DP spheres in a dose-dependent manner. Rg4 also increased the mRNA and protein expression of DP signature genes that are related to hair growth including ALP, BMP2, and VCAN in the DP spheres. Analysis of the signaling molecules and luciferase reporter assays further revealed that Rg4 induces the activation of phosphoinositide 3-kinase (PI3K)/AKT and the inhibitory phosphorylation of GSK3ß, which activates the WNT/ß-catenin signaling pathway. These results correlated with not only the increased nuclear translocation of ß-catenin following the treatment of the DP spheres with Rg4 but also the significant elevation of mRNA expression of the downstream target genes of the WNT/ß-catenin pathway including WNT5A, ß-catenin, and LEF1. In conclusion, these results demonstrated that ginsenoside Rg4 promotes the hair-inductive properties of DP cells by activating the AKT/GSK3ß/ß-catenin signaling pathway in DP spheres, suggesting that Rg4 could be a potential natural therapy for hair growth.

Cytokine Profiles of Non-Small Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy with Regards to Radiation Pneumonitis Severity.

The immunologic aspects of radiation pneumonitis (RP) are unclear. We analyzed variations in cytokine profiles between patients with grade (Gr) 0-1 and Gr ≥ 2 RP. Fifteen patients undergoing concurrent chemoradiotherapy for non-small cell lung cancer were included. Blood samples of 9 patients with Gr 0-1 and 6 with Gr ≥ 2 RP were obtained from the Biobank. Cytokine levels were evaluated using an enzyme linked immunosorbent assay at before radiotherapy (RT) initiation, 1, 3, and 6 weeks post-RT initiation, and 1 month post-RT completion. Concentrations of granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, IL-10, IL-13, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-ß were analyzed; none were related to the occurrence of Gr ≥ 2 RP at pre-RT initiation. At 3 weeks, relative changes in the G-CSF, IL-6, and IFN-γ levels differed significantly between the groups (p = 0.026, 0.05 and 0.026, respectively). One month post-RT completion, relative changes of IL-17 showed significant differences (p = 0.045); however, relative changes in TNF-α, IL-10, IL-13, and TGF-ß, did not differ significantly. Evaluation of changes in IL-6, G-CSF, and IFN-γ at 3 weeks after RT initiation can identify patients pre-disposed to severe RP. The mechanism of variation in cytokine levels in relation to RP severity warrants further investigation.

Regulatory roles of G-protein coupled receptors in adipose tissue metabolism and their therapeutic potential.

The high incidence of obesity has increased the need to discover new therapeutic targets to combat obesity and obesity-related metabolic diseases. Obesity is defined as an abnormal accumulation of adipose tissue, which is one of the major metabolic organs that regulate energy homeostasis. However, there are currently no approved anti-obesity therapeutics that directly target adipose tissue metabolism. With recent advances in the understanding of adipose tissue biology, molecular mechanisms involved in brown adipose tissue expansion and metabolic activation have been investigated as potential therapeutic targets to increase energy expenditure. This review focuses on G-protein coupled receptors (GPCRs) as they are the most successful class of druggable targets in human diseases and have an important role in regulating adipose tissue metabolism. We summarize recent findings on the major GPCR classes that regulate thermogenesis and mitochondrial metabolism in adipose tissue. Improved understanding of GPCR signaling pathways that regulate these processes could facilitate the development of novel pharmacological approaches to treat obesity and related metabolic disorders.