Cytotoxic Peptaibols from Trichoderma guizhouense, a Fungus Isolated from an Urban Soil Sample.

Soil sustains human life by nourishing crops, storing food sources, and housing microbes, which may affect the nutrition and biosynthesis of secondary metabolites, some of which are used as drugs. To identify lead compounds for a new class of drugs, we collected soil-derived fungal strains from various environments, including urban areas. As various human pathogens are assumed to influence the biosynthetic pathways of metabolites in soil fungi, leading to the production of novel scaffolds, we focused our work on densely populated urban areas and tourist attractions. A soil-derived fungal extract library was screened against MDA-MB-231 cells to derive their cytotoxic activity. Notably, 10 µg/mL of the extract of Trichoderma guizhouense (DS9-1) was found to exhibit an inhibitory effect of 71%. Fractionation, isolation, and structure elucidation efforts led to the identification of nine new peptaibols, trichoguizaibols A-I (1-9), comprising 14 amino acid residues (14-AA peptaibols), and three new peptaibols, trichoguizaibols J-L (10-12), comprising 18 amino acid residues (18-AA peptaibols). The chemical structures of 1-12 were determined based on their 1D and 2D NMR spectra, HRESIMS, electronic circular dichroism data, and results of the advanced Marfey's method. The 18-AA peptaibols were found to exhibit cytotoxicity against MDA-MB-231, SK-Hep1, SKOV3, DU145, and HCT116 cells greater than that of the 14-AA peptaibols. Among these compounds, 10-12 exhibited potent sub-micromolar IC50 values. These results are expected to shed light on a new direction for developing novel scaffolds as anticancer agents.

Germline Mutations and Phenotypic Associations in Korean Patients With Pheochromocytoma and Paraganglioma: A Multicenter Study and Literature Review.

Genetic testing is recommended for all patients with pheochromocytomas and paragangliomas (PPGL) to establish genotype-phenotype associations. We investigated germline mutations in 59 patients with PPGL at six Korean university hospitals using next-generation sequencing (NGS) targeting 38 PPGL-associated genes, including those recommended by the Korean PPGL Task Force. Germline mutations were identified in 13 patients (22%), and affected four genes: RET, NF1, VHL, and SDHD. Germline mutations were significantly associated with a family history of PPGL, smaller tumor size, and the presence of other types of tumors. Using 95 Korean PPGL cases with germline mutations identified through a literature review and 13 cases from our cohort, we characterized genotype-phenotype correlations. Mutation hotspots were identified in specific codons of RET (codons 631 and 634), VHL (157 and 167), and SDHB (131 and 253). NF1 mutations varied, indicating the absence of common hotspots. These findings highlight the efficacy of the recommended NGS panel for Korean patients with PPGL and the importance of genetic testing in establishing clinical management and personalized therapeutic strategies.

Long-term efficacy and safety of enavogliflozin in Korean people with type 2 diabetes: A 52-week extension of a Phase 3 randomized controlled trial.

AIMS: To evaluate the long-term safety and efficacy of enavogliflozin monotherapy (0.3 mg/day) in individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Following a 24-week randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 77) or placebo (n = 69), consenting participants received enavogliflozin 0.3 mg/day for an additional 28 weeks during an open-label extension (OLE) period. The safety and efficacy of enavogliflozin were assessed at Week 52. RESULTS: A total of 37 participants continued enavogliflozin (maintenance group), and 26 participants switched from placebo to enavogliflozin (switch group). No additional adverse drug reactions related to enavogliflozin were observed during the OLE period. At Week 52, glycated haemoglobin (HbA1c) and fasting plasma glucose were significantly lower than at the baseline, by 0.9% and 24.9 mg/dL, respectively, in the maintenance group (p < 0.0001 for both), and by 0.7% and 18.0 mg/dL, respectively, in the switch group (p < 0.0001 and p = 0.002). The proportions of participants reaching HbA1c 7.0% (53 mmol/mol) at Week 52 were 69.4% in the maintenance group and 65.4% in the switch group. A significant increase in urine glucose-to-creatinine ratio was observed at Week 52, by 84.9 g/g and 67.1 g/g in the maintenance and switch groups, respectively (p < 0.0001 for both). Body weight in both groups decreased significantly (p < 0.0001) from baseline to Week 52, by 3.5 kg and 3.8 kg in the maintenance and switch groups, respectively. CONCLUSIONS: Enavogliflozin 0.3 mg monotherapy provides long-term glycaemic control in T2DM and is safe and well tolerated during a 52-week treatment period.

Cytotoxic Peptaibols from Trichoderma strigosum.

Five new lipopeptaibols (1-5) and eight new 19-residue peptaibols (8-15) along with two known lipopeptaibols, lipovelutibols C (6) and D (7) were isolated from Trichoderma strigosum. The planar structures of the newly discovered peptaibols (1-5, 8-15) were elucidated using 1D and 2D NMR, and UPLC-MS/MS data. The absolute configurations for new peptaibols (1-5, 8-15) were elucidated using the advanced Marfey's method and GITC (2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl isothiocyanate) derivatization. Through analysis of CD spectra, these peptabols were found to have right-handed helical conformations. While most of the new compounds were significantly more active than the positive control, 9, 10, 12, and 15 containing Ser and Leu at positions 10 and 11, respectively, were the most cytotoxic against MDA-MB-231, SNU449, SKOV3, DU145, and HCT116 cancer cell lines, and the 19-residue peptaibols were generally more potent than lipopeptaibols.

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.

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.

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.

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.

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.

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.

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.