ANXA2 (annexin A2) is crucial to ATG7-mediated autophagy, leading to tumor aggressiveness in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and metastatic growth. TNBC cells frequently undergo macroautophagy/autophagy, contributing to tumor progression and chemotherapeutic resistance. ANXA2 (annexin A2), a potential therapeutic target for TNBC, has been reported to stimulate autophagy. In this study, we investigated the role of ANXA2 in autophagic processes in TNBC cells. TNBC patients exhibited high levels of ANXA2, which correlated with poor outcomes. ANXA2 increased LC3B-II levels following bafilomycin A1 treatment and enhanced autophagic flux in TNBC cells. Notably, ANXA2 upregulated the phosphorylation of HSF1 (heat shock transcription factor 1), resulting in the transcriptional activation of ATG7 (autophagy related 7). The mechanistic target of rapamycin kinase complex 2 (MTORC2) played an important role in ANXA2-mediated ATG7 transcription by HSF1. MTORC2 did not affect the mRNA level of ANXA2, but it was involved in the protein stability of ANXA2. HSPA (heat shock protein family A (Hsp70)) was a potential interacting protein with ANXA2, which may protect ANXA2 from lysosomal proteolysis. ANXA2 knockdown significantly increased sensitivity to doxorubicin, the first-line chemotherapeutic regimen for TNBC treatment, suggesting that the inhibition of autophagy by ANXA2 knockdown may overcome doxorubicin resistance. In a TNBC xenograft mouse model, we demonstrated that ANXA2 knockdown combined with doxorubicin administration significantly inhibited tumor growth compared to doxorubicin treatment alone, offering a promising avenue to enhance the effectiveness of chemotherapy. In summary, our study elucidated the molecular mechanism by which ANXA2 modulates autophagy, suggesting a potential therapeutic approach for TNBC treatment.Abbreviation: ATG: autophagy related; ChIP: chromatin-immunoprecipitation; HBSS: Hanks' balanced salt solution; HSF1: heat shock transcription factor 1; MTOR: mechanistic target of rapamycin kinase; TNBC: triple-negative breast cancer; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3.

Host-specific growth responses of Larix kaempferi and Quercus acutissima to Asian gypsy moth defoliation in central Korea.

As the risk of gypsy moth outbreaks that have detrimental effects on forest ecosystem in the Northern Hemisphere increase due to climate change, a quantitative evaluation of the impact of gypsy moth defoliation is needed to support the adaptive forest management. To evaluate the host-specific impact of gypsy moth defoliation, radial growth and annual carbon accumulation were compared for one severely defoliated (Larix kaempferi (Lamb.) Carrière) and one moderate defoliated (Quercus acutissima Carruth.) host, in defoliated and non-defoliated site using tree-ring analysis. Finally, the resilience indices of radial growth variables were calculated to assess the ability of sampled trees to withstand defoliation. Gypsy moth defoliation mainly decreased latewood width and caused reduction in annual carbon absorption more than 40% for both tree species. However, L. kaempferi, showed the reduced growth until the year following defoliation, while Q. acutissima, showed no lagged growth depression and rapid growth recover. The findings show how each species reacts differently to gypsy moth defoliation and highlight the need of managing forests in a way that takes resilient tree species into account.

Development of a Protocol for the Direct Breastfeeding of Premature Infants in Neonatal Intensive Care Units.

PURPOSE: This study aimed to develop a direct breastfeeding protocol for premature infants admitted to neonatal intensive care units (NICUs) and investigate its efficacy. BACKGROUND: Direct breastfeeding increases the amount and duration of breastfeeding. However, NICUs have low direct feeding rates owing to medical staff anxiety, lack of knowledge and experience, and fear of overwork. Accordingly, this study developed a protocol for direct breastfeeding in the NICU and evaluated its effect. METHODS: The protocol was developed through a literature review, expert validation, and preliminary investigation. Its application effects were identified using a nonexperimental, evidence-based research design targeting premature infants, their mothers, and NICU nurses. RESULTS: The protocol comprised 5 areas and 23 items. Application of the protocol resulted in continuous weight gain of the infants and increased self-efficacy in the mothers' direct breastfeeding ( t = 3.219, P = .004). Significant increases were noted in NICU nurses' direct breastfeeding activities ( t = 3.93, P < .001), breastfeeding rates in the NICU ( P = .037), and direct breastfeeding rates ( P = .007). CONCLUSIONS: Results underscore the value of an evidence-based protocol for improving breastfeeding rates in premature infants. This study highlights the need for continuous nursing education on protocol applications and human resource support.

Selection of climate variables in ant species distribution models: case study in South Korea.

The selection of explanatory variables is important in modeling prediction of changes in species distribution in response to climate change. In this study, we evaluated the importance of variable selection in species distribution models. We compared two different types of models for predicting the distribution of ant species: temperature-only and both temperature and precipitation. Ants were collected at 343 forest sites across South Korea from 2006 through 2009. We used a generalized additive model (GAM) to predict the future distribution of 16 species that showed significant responses to changes in climatic factors (temperature and/or precipitation). Four types of GAMs were constructed: temperature, temperature with interaction of precipitation, temperature and precipitation without interaction, and temperature and precipitation with interaction. Most species displayed similar results between the temperatureonly and the temperature and precipitation models. The results for predicted changes in species richness were different from the temperature-only model. This indicates higher uncertainty in the prediction of species richness, which is obtained by combining the prediction results of distribution change for each species, than in the prediction of distribution change. The turnover rate of the ant assemblages was predicted to increase with decreases in temperature and increases in elevation, which was consistent with other studies. Finally, our results showed that the prediction of the distribution or diversity of organisms responding to climate change is uncertain because of the high variability of the model outputs induced by the variables used in the models.

Palliative Care for Infants in the Neonatal Intensive Care Unit: A Scoping Review.

This scoping review aimed to explore the characteristics of neonatal palliative care in the neonatal intensive care unit, including the features, contents, and experiences of infants, parents, and nurses during palliative care. Five databases (PubMed, Cochrane, CINAHL, Research Information Sharing Service, and Korean Studies Information Service System) were searched to identify relevant articles published between 2011 and 2020. From the systematic search and review process, 13 studies that met the eligibility criteria were selected for the analysis. From the literature review, 2 key principles were found to facilitate neonatal palliative care: family-centered care and integrative care in the neonatal intensive care unit. In addition, the themes found in this review included (1) providing comfortable care to dying infants with respect to infants and offering parents choices, (2) therapeutic communication, (3) support with respect, and (4) bereavement care for parents of dying infants in the neonatal intensive care unit. Caregivers require effective communication, manpower support, emotional support, educational programs, and well-defined protocols. The evidence mapped and synthesized in this review indicates the need to facilitate the provision of palliative care in the neonatal intensive care unit in line with the unique needs of infants, parents, and nurses.

Value of circulating neutrophil elastase for detecting recurrence of differentiated thyroid cancer.

Objective: The inflammatory microenvironment has been implicated in differentiated thyroid cancer (DTC). Inflammatory stimuli induce the release of components of neutrophils into extracellular space, leading to formation of neutrophil extracellular trap (NET), which can stimulate growth and progression of cancer. Generation of activated factor XII and thrombin is also involved in cancer progression. This study attempted to determine whether the level of circulating markers of NET, activated factor XII, and endogenous thrombin potential may be useful for detecting the recurrence of DTC. Methods: A total of 122 patients with DTC were recruited during the postoperative follow-up period. Measurement of the levels of circulating markers of NET (neutrophil elastase, histone-DNA complex, cell-free dsDNA), activated factor XII, and endogenous thrombin potential was performed. Results: A significantly elevated level of neutrophil elastase was detected in patients with recurrence (n = 12) compared to those without recurrence (n = 110), while significant elevation of the levels of other markers was not observed. The value for area under the curve (0.717, P = 0.018) of neutrophil elastase for detecting recurrence of DTC was superior to that (0.661, P = 0.051) of serum thyroglobulin. An elevated level of neutrophil elastase was significantly associated with recurrence of DTC independent of serum thyroglobulin. Conclusions: Because an elevated level of neutrophil elastase was detected in patients with recurrence of DTC and showed a significant association with recurrence of DTC, it can be proposed as a novel biomarker for use in detecting recurrence of DTC along with other tests.

Effects of Thinning Intensity on Litterfall Production, Soil Chemical Properties, and Fine Root Distribution in Pinus koraiensis Plantation in Republic of Korea.

It is crucial to evaluate the effects of thinning on litterfall production, soil chemical properties, and fine root dynamics when implementing thinning as a silvilcultural technique to enhance tree growth and timber yield in Pinus koraiensis plantations. Thus, we determined the 10-year effects (2007-2017) of different thinning intensities on litterfall production, soil chemical properties, and fine root biomass and necromass within a P. koraiensis plantation in South Korea. The soil chemical parameters and fine root biomass and necromass were also compared across three soil depths (0-10, 10-20, and 20-30 cm). Three thinning treatments were employed: no thinning (CON), light thinning (32% removed, LT), and heavy thinning (64% removed, HT). Results revealed that litterfall was consistent across all thinning treatments, but broadleaf species had considerably higher litterfall production at HT stands than at CON/LT stands. Soil chemical properties, except exchangeable K+, were generally lower at LT stands, particularly at a depth of 20-30 cm soil. After ten years, there was a decrease in fine root biomass and necromass with increasing soil depth. Over 80% of fine roots were found in the upper layer (0-20 cm), while very fine roots (0-1 mm) consisted mainly of 47% pine and 53% other species and were concentrated in the 0-10 cm soil depth in HT. In conclusion, different thinning intensities had diverse effects on the parameters measured within the plantation. Future studies can explore how the effects of thinning intensities on litterfall production, soil chemistry, and fine root dynamics affect species diversity, carbon storage, and understory vegetation in P. koraiensis plantations.

A novel isoxazole compound CM2-II-173 inhibits the invasive phenotype of triple-negative breast cancer cells.

Invasion and metastasis are important hallmarks of breast cancer and are the leading cause of patient mortality. Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer characterized by a poor prognosis and a lack of effective targeted therapies. The present study investigated the inhibitory effect of a novel FTY720 derivative on the invasive phenotype of TNBC cells. Here, we showed that a novel compound with an isoxazole ring, 4-(3-Decylisoxazol-5-yl)-1-hydroxy-2-(hydroxymethyl)butan-2-aminium chloride (CM2-II-173), significantly inhibited invasiveness of MDA-MB-231 TNBC cells. Expression of matrix metalloproteinase (MMP)-9 and invasiveness of MCF10A normal breast cells induced by sphingosine-1-phosphate (S1P) were reduced by CM2-II-173 treatment. Activations of pMEK1, pAkt, pERK, and p38 MAPK by S1P were inhibited by treatment with CM2-II-173. Proliferation and anchorage-independent growth of MDA-MB-231 TNBC cells were significantly decreased by CM2-II-173. CM2-II-173 efficiently induced apoptosis in MDA-MB-231 TNBC cells. CM2-II-173 significantly inhibited invasive phenotypes of breast, liver, prostate, and ovarian cancer cells. CM2-II-173 exhibited a more potent effect on the invasiveness of MDA-MB-231 TNBC cells compared to FTY720. Taken together, this study demonstrated that CM2-II-173 has the potential to be a lead compound that can inhibit cancer progression of not only TNBC cells, but also of liver, prostate, and ovarian cancer cells.

Efficacy and Safety of Evogliptin Add-on Therapy to Dapagliflozin/Metformin Combinations in Patients with Poorly Controlled Type 2 Diabetes Mellitus: A 24-Week Multicenter Randomized Placebo-Controlled Parallel-Design Phase-3 Trial with a 28-Week Extension.

BACKGRUOUND: This study investigates the long-term efficacy and safety of evogliptin add-on therapy in patients with inadequately controlled type 2 diabetes mellitus (T2DM) previously received dapagliflozin and metformin (DAPA/MET) combination. METHODS: In this multicenter randomized placebo-controlled phase 3 trial, patients with glycosylated hemoglobin (HbA1c) levels 7.0% to 10.5% (n=283) previously used DAPA 10 mg plus MET (≥1,000 mg) were randomly assigned to the evogliptin 5 mg once daily or placebo group (1:1). The primary endpoint was the difference in the HbA1c level from baseline at week 24, and exploratory endpoints included the efficacy and safety of evogliptin over 52 weeks (trial registration: ClinicalTrials.gov NCT04170998). RESULTS: Evogliptin add-on to DAPA/MET therapy was superior in HbA1c reduction compared to placebo at weeks 24 and 52 (least square [LS] mean difference, -0.65% and -0.55%; 95% confidence interval [CI], -0.79 to -0.51 and -0.71 to -0.39; P<0.0001). The proportion of patients achieving HbA1c <7% was higher in the triple combination group at week 52 (32.14% vs. 8.51% in placebo; odds ratio, 5.62; P<0.0001). Evogliptin significantly reduced the fasting glucose levels and mean daily glucose levels with improvement in homeostatic model assessment of ß-cell function (LS mean difference, 9.04; 95% CI, 1.86 to 16.21; P=0.0138). Adverse events were similar between the groups, and no serious adverse drug reactions were reported in the evogliptin group. CONCLUSION: Long-term triple combination with evogliptin added to DAPA/MET showed superior HbA1c reduction and glycemic control compared to placebo at 52 weeks and was well tolerated.

C-Reactive Protein Signaling Pathways in Tumor Progression.

Many cancers arise from sites of chronic inflammation, which creates an inflammatory microenvironment surrounding the tumor. Inflammatory substances secreted by cells in the inflammatory environment can induce the proliferation and survival of cancer cells, thereby promoting cancer metastasis and angiogenesis. Therefore, it is important to identify the role of inflammatory factors in cancer progression. This review summarizes the signaling pathways and roles of C-reactive protein (CRP) in various cancer types, including breast, liver, renal, and pancreatic cancer, and the tumor microenvironment. Mounting evidence suggests the role of CRP in breast cancer, particularly in triple-negative breast cancer (TNBC), which is typically associated with a worse prognosis. Increased CRP in the inflammatory environment contributes to enhanced invasiveness and tumor formation in TNBC cells. CRP promotes endothelial cell formation and angiogenesis and contributes to the initiation and progression of atherosclerosis. In pancreatic and kidney cancers, CRP contributes to tumor progression. In liver cancer, CRP regulates inflammatory responses and lipid metabolism. CRP modulates the activity of various signaling molecules in macrophages and monocytes present in the tumor microenvironment, contributing to tumor development, the immune response, and inflammation. In the present review, we overviewed the role of CRP signaling pathways and the association between inflammation and cancer in various types of cancer. Identifying the interactions between CRP signaling pathways and other inflammatory mediators in cancer progression is crucial for understanding the complex relationship between inflammation and cancer.

Alcohol-induced increase in BMP levels promotes fatty liver disease in male prediabetic stage Otsuka Long-Evans Tokushima Fatty rats.

Alcohol consumption exacerbates liver abnormalities in animal models, but whether it increases the severity of liver disease in early diabetic or prediabetic rats is unclear. To investigate the molecular mechanisms underlying alcohol-induced liver steatosis or hepatitis, we used a prediabetic animal model. Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Fatty (LETO) rats were pair-fed with an ethanol-containing liquid diet for 6 weeks. Compared with controls, OLETF and LETO rats displayed more pronounced liver steatosis and higher plasma levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SPGT), indicating liver injury. Ethanol-fed LETO (Pd-L-E) rats showed mild liver steatosis and no inflammation compared with ethanol-fed OLETF (Pd-O-E) rats. Although precursor and active SREBP-1 levels in the liver of ethanol-fed OLETF rats significantly increased compared with control diet-fed OLETF rats (Pd-O-C), those of Pd-L-E rats did not. Bone morphogenetic protein (BMP) and TGF-ß1 balance in Pd-O-E rats was significantly altered because BMP signaling was upregulated by inducing BMP2, BMP4, BMP7, BMP9, Smad1, and Smad4, whereas TGF-ß1, Smad3, and Erk were downregulated. Activation of TGF-ß/Smad signaling inhibited BMP2 and BMP9 expression and increased epithelial-mesenchymal transition (EMT) marker levels (Hepcidin, Snail, and Twist) in the liver of LETO rats. Livers of ethanol-fed OLETF rats showed increased levels of vimentin, FSP-1, α-SMA, MMP1, MMP13, and collagen III compared with rats of other groups, whereas EMT marker levels did not change. Thus, BMP exerted anti- and/or pro-fibrotic effects in ethanol-fed rats. Therefore, BMP and TGF-ß, two key members of the TGF-ß superfamily, play important but diverse roles in liver steatosis in young LETO and OLETF rats.

Psychometric properties of the Korean version of the Palliative Care Nursing Self-Competence scale for infant use.

BACKGROUND: Despite the significant advances in neonatal treatment and care over the past 30 years, palliative care in the neonatal intensive care unit has not been fully provided in South Korea. Neonatal nurses are essential professionals in palliative care as they are directly involved in the care, but there is little information on their palliative care competency because no assessment instrument is available in Korea. OBJECTIVES: The aim of this study was to develop and test the validity and reliability of the Korean version of the Palliative Care Nursing Self-Competence scale for neonatal palliative care. METHODS: This scale for infant care was developed through parallel translation techniques and revised based on cognitive interviews. Survey data were then collected from 220 neonatal nurses who worked in 13 neonatal intensive care units in Korea. Internal consistency reliability, construct validity based on exploratory factor analysis, and criterion-related validity were tested. RESULTS: The final version of the scale included 40 items in five domains that explained 53.4% of the variance. Criterion-related validity was confirmed based on a positive correlation with the Korean version of the attitudes towards neonatal palliative care measurement tool. The Cronbach's alpha for the scale was 0.95. CONCLUSIONS: The Korean version of the Palliative Care Nursing Self-Competence scale for infant care has satisfactory construct validity and reliability to measure palliative care self-competence of neonatal nurses in Korea and evaluate an education program in future studies.

Association of Depression, Poor Mental Health Status and Asthma Control Patterns in US Adults Using a Data-Reductive Latent Class Method.

Objectives To explore the association between depression, poor mental health status, and asthma control patterns among US adults using a latent class analysis (LCA) approach. Methods We used data from 10,337 adults aged 18 years and above from the 2016 Behavioral Risk Factor Surveillance System (BRFSS) Asthma Call-back Survey. Data-reductive LCA was used to derive asthma control patterns in the population using class variables indicative of asthma control. Besides univariate analysis, adjusted and unadjusted logistic regression models were used to examine the association of depression and poor mental health on the derived asthma control patterns.  Results About 27.8% of adults aged <55 reported depression, while 27.3% aged ≥55 years were depressed. The latent class prevalence of asthma control patterns was 42.8%, 31.1%, and 26.1%, corresponding to good, fair, and poor asthma control patterns, respectively. In adults aged <55 years, odds of depression (OR=1.52, 95% CI=1.27-1.82) and poor mental health (OR=1.58, 95% CI=1.27-1.96) were higher in the poor asthma control group compared to the good asthma control group. Odds for depression (OR=1.28, 95% CI=1.06-1.53) were also higher in the moderate asthma control group compared to the good asthma control group. Among those aged ≥55 years, depression odds (OR=1.57, 95% CI=1.31-1.87) were higher in only the poor asthma control group. Conclusions These findings may have public health implications. Detecting, screening, and treating depression and mental health disorders may help improve asthma control in people with asthma.

Lipid raft protein flotillin-1 is important for the interaction between SOS1 and H-Ras/K-Ras, leading to Ras activation.

Ras mutations have been frequently observed in human cancer. Although there is a high degree of similarity between Ras isomers, they display preferential coupling in specific cancer types. The binding of Ras to the plasma membrane is essential for its activation and biological functions. The present study elucidated Ras isoform-specific interactions with the membrane and their role in Ras-mediated biological activities. We investigated the role of a lipid raft protein flotillin-1 (Flot-1) in the activations of Ras. We found that Flot-1 was co-localized with H-Ras, but not with N-Ras, in lipid rafts of MDA-MB-231 human breast cells. The amino-terminal hydrophobic domain (1-38) of Flot-1 interacted with the hypervariable region of H-Ras. The epidermal growth factor-stimulated activation of H-Ras required Flot-1 which was not necessary for that of N-Ras in breast cancer cells. Flot-1 interacted with son of sevenless (SOS)-1, which promotes the conversion of Ras-bound GDP to GTP. Notably, Flot-1 was crucial for the interaction between SOS1 and H-Ras/K-Ras in breast and pancreatic cancer cells. Stable knockdown of Flot-1 reduced the in vivo metastasis in a mouse xenograft model with human breast carcinoma cells. A tissue microarray composed of 61 human pancreatic cancer samples showed higher levels of Flot-1 expression in pancreatic tumor tissues compared to normal tissues, and a correlation between K-Ras and Flot-1. Taken together, our findings suggest that Flot-1 may serve as a membrane platform for the interaction of SOS1 with H-Ras/K-Ras in human cancer cells, presenting Flot-1 as a potential target for Ras-driven cancers.

Papillary thyroid cancer with Hashimoto's thyroiditis attenuates the tumour aggressiveness through the up-regulation of E-cadherin and TGF-ß expression.

Human papillary thyroid cancer (PTC) is often associated with Hashimoto's thyroiditis (HT), and their coexistence improves the prognosis of PTC. Aim of the study. The objective of our study is to investigate the expression of cadherins and TGF-ß which are regulators in the tumour aggressiveness with metastatic spread in PTC patients and its relationship with HT. The expression of E-cadherin and N-cadherin was measured in thyroid tissues of healthy volunteers and PTC patients with HT (PTC/HT) or without. The E-cadherin expression was also determined in thyroid cancer cells (TPC1, SNU373, SNU790, 8505C, CAL62, and FTC133). Cell migration was measured by wound healing assay. The expression of N-cadherin, ICAM1, and TGF-ß was measured in thyroid tissues and plasma. The E-cadherin expression was significantly increased in PTC/HT patients compared with PTC alone. Meanwhile, the N-cadherin expression was significantly decreased in PTC/HT patients. The E-cadherin expression was only observed in FTC cells, and the overexpression of E-cadherin inhibited cancer cell migration. The TGF-ß expression was significantly increased in PTC/HT patients, and the plasma levels were higher in PTC/HT patients than in PTC alone. The expression of N-cadherin and ICAM-1 was significantly decreased in PTC/HT patients. Our results indicate that the expression of E-cadherin and TGF-ß was higher in PTC/HT patients than in PTC alone. This suggests that the presence of PTC with HT may attenuate the tumour aggressiveness and metastasis through the up-regulation of E-cadherin and TGF-ß expression.

Body mass index, waist circumference and cardiovascular diseases in transitional ages (40 and 66 years).

BACKGROUND: There is lack of data on effect modification by age on the association between body mass index (BMI) or waist circumference (WC) and cardiovascular diseases (CVDs). We aimed to investigate the impact of BMI and WC on incident CVDs in individuals aged 40 and 66 years. METHODS: Overall, 2 430 510 participants who underwent a national health screening for transitional ages provided by the Korean National Health Insurance Service between 2009 and 2012 were included. The adjusted hazard ratios and 95% confidence intervals for myocardial infarction (MI), ischaemic stroke and CVDs as a composite outcome of MI and ischaemic stroke were calculated using multivariable Cox proportional hazard regression analysis. RESULTS: During a mean follow-up of 7.7 years, 24 884 MI and 29 415 ischaemic stroke events occurred. Among participants aged 40 years, there was a J-shaped association of BMI with incident CVDs, MI and ischaemic stroke with nadir at BMI 18.5-22.9 kg/m2 (P for trend < 0.001 for all). Among those aged 66 years, there were significant U-shaped associations of BMI with CVDs and MI with nadir at a BMI of 23.0-24.9 kg/m2 (P for trend 0.013 and 0.017, respectively). WC was linearly associated with all study outcomes in both age groups (P for trend < 0.001). The impact of general and abdominal obesity on both study outcomes was more prominent in those aged 40 years than in those aged 66 years (P for interaction < 0.001). CONCLUSIONS: To prevent cardiovascular risk, weight loss intervention should be cautiously implemented and individualized according to age. The maintenance of muscle mass may be essential in managing weight loss particularly in older population.

USP37 Deubiquitinates CDC73 in HPT-JT Syndrome.

The CDC73/HRPT2 gene, a defect which causes hyperparathyroidism-jaw tumor (HPT-JT) syndrome, encodes CDC73/parafibromin. We aimed to investigate whether CDC73 would be a target for ubiquitin-proteasome degradation. We cloned full-length cDNAs encoding a family of 58 ubiquitin-specific deubiquitinating enzymes (DUBs), also known as ubiquitin-specific proteases (USPs). Use of the yeast two-hybrid system then enabled us to identify USP37 as interacting with CDC73. The biochemical interaction between the USP37 and CDC73 and their reciprocal binding domains were studied. Co-localization of CDC73 and USP37 was observed in cells. CDC73 was found to be polyubiquitinated, and polyubiquitination of CDC73 was prominent in mutants. CDC73 was deubiquitinated via K48-specific ubiquitin chains by USP37, but not by the catalytically inactive USP37C350S mutant. Observation of the binding between deletion mutants of CDC73 and USP37 revealed that the ß-catenin binding site of CDC73 and the ubiquitin-interacting motifs 2 and 3 (UIM2 and 3) of USP37 were responsible for the interaction between the two proteins. Moreover, these two enzymes co-existed within the nucleus of COS7 cells. We conclude that USP37 is a DUB for CDC73 and that the two proteins interact through specific domains, suggesting that USP37 is responsible for the stability of CDC73 in HPT-JT syndrome.

A double-blind, Randomized controlled trial on glucose-lowering EFfects and safety of adding 0.25 or 0.5 mg lobeglitazone in type 2 diabetes patients with INadequate control on metformin and dipeptidyl peptidase-4 inhibitor therapy: REFIND study.

AIMS: To compare the efficacy and safety of adding low-dose lobeglitazone (0.25 mg/day) or standard-dose lobeglitazone (0.5 mg/day) to patients with type 2 diabetes mellitus (T2DM) with inadequate glucose control on metformin and dipeptidyl peptidase (DPP4) inhibitor therapy. MATERIALS AND METHODS: In this phase 4, multicentre, double-blind, randomized controlled, non-inferiority trial, patients with T2DM insufficiently controlled by metformin and DPP4 inhibitor combination therapy were randomized to receive either low-dose or standard-dose lobeglitazone. The primary endpoint was non-inferiority of low-dose lobeglitazone in terms of glycaemic control, expressed as the difference in mean glycated haemoglobin levels at week 24 relative to baseline values and compared with standard-dose lobeglitazone, using 0.5% non-inferiority margin. RESULTS: At week 24, the mean glycated haemoglobin levels were 6.87 ± 0.54% and 6.68 ± 0.46% in low-dose and standard-dose lobeglitazone groups, respectively (p = .031). The between-group difference was 0.18% (95% confidence interval 0.017-0.345), showing non-inferiority of the low-dose lobeglitazone. Mean body weight changes were significantly greater in the standard-dose group (1.36 ± 2.23 kg) than in the low-dose group (0.50 ± 1.85 kg) at week 24. The changes in HOMA-IR, lipid profile and liver enzyme levels showed no significant difference between the groups. Overall treatment-emergent adverse events (including weight gain, oedema and hypoglycaemia) occurred more frequently in the standard-dose group. CONCLUSIONS: Adding low-dose lobeglitazone to metformin and DPP4 inhibitor combination resulted in a non-inferior glucose-lowering outcome and fewer adverse events compared with standard-dose lobeglitazone. Therefore, low-dose lobeglitazone might be one option for individualized strategy in patients with T2DM.

Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2).

BACKGROUND/AIMS: Germline mutations of the rearranged during transfection (RET) gene cause multiple endocrine neoplasia type 2 (MEN2). About 85% of RET mutations in MEN2 occur in codon Cys634. The RET D631Y mutation has recently been discovered, and we have studied its molecular expression and clinical consequences. METHODS: We analyzed the clinical characteristics of a total of 34 D631Y variant MEN2 individuals from seven families. We also constructed wild-type and mutant C630Y, D631Y, and C634R/W expression vectors and investigated their effects on signaling pathways and ability to correct the phenotypes of RET mutant cells. RESULTS: The median ages at diagnosis of pheochromocytoma and medullary thyroid carcinoma (MTC) were higher in patients with RET D631Y variant MEN2 than in those with the C634R/W variant (49:53.5 years vs. 33.5:27 years, respectively), and the penetration of the D631Y mutation with respect to MTC was lower than that of the C634R/W mutation (32.3% vs. 90%). The effects of the mutant vectors on phosphorylation of RET signaling molecules and focus formation were significantly different from those of wild type, but there were no significant differences between the mutants. D631Y scored significantly higher for chemotaxis and wound healing than C630Y, but lower than C634R and C634W. CONCLUSION: We suggest that the tumorigenic potential conferred by the D631Y mutation is lower than that conferred by the C634R/W mutation, but higher than that conferred by C630Y. Thus, the risk level of the RET D631Y variant appears to be higher than that of C630Y and lower than that of C634R/W.

A Study on the Fabrication of an Effective Natural Substance Based on Schisandra chinensis Extracted Fermentation.

PURPOSE: In this study, a high-efficiency Schisandra chinensis extract (SCE) produced by the fermentation of effective microorganisms (EM) was used as an antioxidant material in preparing cosmetic products. SUBJECTS AND METHODS: We conducted the study by extracting S. chinensis via EM fermentation to increase the efficiency. Tyrosinase inhibitory factor analysis, pH, and thermal stability were measured to verify the properties of the prepared products. RESULTS: The efficacy and whitening effects of the prepared substances were verified using tyrosinase inhibitory factor analysis. As a result, it was found that both the SCE and SCE fermentation (SCEF) exhibited high, naturally originating, antioxidation ability. In addition, the pH and thermal stability of the substances were evaluated to optimize the cosmetic fabrication conditions. In this context, as the concentration of the added extract increased, the pH value decreased. The evaluation of safety and stability indicated that the substances contained effective chemical components having antioxidant activity, suppressing skin aging, and whitening effects in a weak acid range consistent with a pH of 6.25-2.98. Furthermore, there were no safety problems with the use of the obtained products even after they had been stored for 60 days. CONCLUSION: The SCE substance is demonstrated as a possible material for cosmetic application.