Monocarboxylate transporter functions and neuroprotective effects of valproic acid in experimental models of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder for which no successful therapeutics are available. Valproic acid (VPA), a monocarboxylate derivative, is a known antiepileptic drug and a histone deacetylase inhibitor. METHODS: To investigate whether monocarboxylate transporter 1 (MCT1) and sodium-coupled MCT1 (SMCT1) are altered in ALS cell and mouse models, a cellular uptake study, quantitative real time polymerase chain reaction and western blot parameters were used. Similarly, whether VPA provides a neuroprotective effect in the wild-type (WT; hSOD1WT) and ALS mutant-type (MT; hSOD1G93A) NSC-34 motor neuron-like cell lines was determined through the cell viability assay. RESULTS: [3H]VPA uptake was dependent on time, pH, sodium and concentration, and the uptake rate was significantly lower in the MT cell line than the WT cell line. Interestingly, two VPA transport systems were expressed, and the VPA uptake was modulated by SMCT substrates/inhibitors in both cell lines. Furthermore, MCT1 and SMCT1 expression was significantly lower in motor neurons of ALS (G93A) model mice than in those of WT mice. Notably, VPA ameliorated glutamate- and hydrogen peroxide-induced neurotoxicity in both the WT and MT ALS cell lines. CONCLUSIONS: Together, the current findings demonstrate that VPA exhibits a neuroprotective effect regardless of the dysfunction of an MCT in ALS, which could help develop useful therapeutic strategies for ALS.

Modulation of histone H3K4 dimethylation by spermidine ameliorates motor neuron survival and neuropathology in a mouse model of ALS.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to motor neuron degeneration. It has been proposed that epigenetic modification and transcriptional dysregulation may contribute to motor neuron death. In this study, we investigate the basis for therapeutic approaches to target lysine-specific histone demethylase 1 (LSD1) and elucidate the mechanistic role of LSD1-histone H3K4 signaling pathway in ALS pathogenesis. METHODS: In order to examine the role of spermidine (SD), we administered SD to an animal model of ALS (G93A) and performed neuropathological analysis, body weight, and survival evaluation. RESULTS: Herein, we found that LSD1 activity is increased while levels of H3K4me2, a substrate of LSD1, is decreased in cellular and animal models of ALS. SD administration modulated the LSD1 activity and restored H3K4me2 levels in ChAT-positive motor neurons in the lumbar spinal cord of ALS mice. SD prevented cellular damage by improving the number and size of motor neurons in ALS mice. SD administration also reduced GFAP-positive astrogliogenesis in the white and gray matter of the lumbar spinal cord, improving the neuropathology of ALS mice. Moreover, SD administration improved the rotarod performance and gait analysis of ALS mice. Finally, SD administration delayed disease onset and prolonged the lifespan of ALS (G93A) transgenic mice. CONCLUSION: Together, modulating epigenetic targets such as LSD1 by small compounds may be a useful therapeutic strategy for treating ALS.

Efficacy of Post-Operative Medication to Prevent Recurrence of Endometrioma: Cyclic Oral Contraceptive (OC) After Gonadotropin-Releasing Hormone (GnRH) Agonist Versus Dienogest.

BACKGROUND: There are several medical treatment options for endometrioma. Progestin, especially dienogest, is an effective drug for preventing recurrence of endometrioma after surgery. Additionally, oral contraceptive (OC) use after conservative surgery has been reported to reduce significantly the risk of endometrioma recurrence. The aim of this study was to compare the long-term effects of gonadotropin-releasing hormone (GnRH) agonist followed by OC to those of dienogest alone to prevent recurrence of endometrioma after laparoscopic surgery. METHODS: A retrospective cohort study was performed on patients who underwent conservative laparoscopic surgery for endometrioma between January 2000 and December 2020, in the Endometriosis Clinic, Department of Gynecology, Samsung Medical Center. A total of 624 patients who received medical treatment at least six months after laparoscopic conservative surgery for endometrioma was included. Among them, 372 patients used OC after GnRH agonist therapy, and 252 patients used dienogest. Within the OC group, 148 used a 21/7 regiment and 224 used a 24/4 regimen. A cumulative endometrioma recurrence curve was presented using the Kaplan-Meier method to compare the recurrence of those groups. RESULTS: The cumulative recurrence rate of endometrioma for 60 months was 2.08% (n = 4) in the OC after GnRH agonist group and 0.40% (n = 1) in the dienogest group. There was no statistical difference in cumulative recurrence of endometrioma between the two groups. In subgroup analysis, the cumulative recurrence rate of endometrioma over 60 months was 4.21% (n = 2) in the 21/7 OC group and 1.09% (n = 2) in the 24/4 OC group and showed no significant difference. CONCLUSION: Long-term use of OC after GnRH agonist as well as that of dienogest treatment are effective postoperative medical therapies for preventing endometrioma recurrence. Thus, the choice of regimen can be individualized or used interchangeably depending on patient condition, need for contraception, and compliance with drug therapy.

Non-Cell Autonomous and Epigenetic Mechanisms of Huntington's Disease.

Huntington's disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of Huntingtin (HTT) gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD.

Fermented kimchi rejuvenated precancerous atrophic gastritis via mitigating Helicobacter pylori-associated endoplasmic reticulum and oxidative stress.

Dietary intervention to prevent Helicobacter pylori (H. pylori)-gastric cancer might be ideal by long-term intervention, rejuvenating action, and no risk of bacterial resistance. Stimulated with finding that kimchi prevented H. pylori-gastric cancer, we compared the efficacy of cancer preventive kimchi (cpkimchi) and standard recipe kimchi (skimchi) and the efficacy between fermented kimchi and non-fermented kimchi (kimuchi) in H. pylori-initiated gastric cancer model and explored novel mechanisms hinted from RNAseq transcriptome analysis. Animal models assessing gastric pathology on 24 and 36 weeks after H. pylori initiated, salt diet-promoted gastric mutagenesis model showed fermented cpkimchi afforded the best outcome of either rejuvenating atrophic gastritis or inhibiting tumorigenesis compared to skimchi and kimuchi. Highest inhibition of atrophic gastritis was achieved with cpkimchi, while significantly lower in kimuchi. Transcriptomic analysis showed ameliorated-endoplasmic reticulum (ER) stress, -oxidative stress, and -apoptosis as major rejuvenating action of cpkimchi. Homogenates from animal model showed that elevated expressions of p-PERK, IRE, ATF6, p-elf, and XBP1 in control group, while significantly decreased with dietary intake of only cpkimchi. Significantly increased expressions of HO-1 and γ-GCS were only noted with cpkimchi. Conclusively, long-term dietary intervention of fermented cpkimchi can be potential way preventing H. pylori-associated carcinogenesis via rejuvenation of atrophic gastritis.

Transcriptome profiling implicated in beneficiary actions of kimchi extracts against Helicobacter pylori infection.

Dietary intervention to prevent Helicobacter pylori (H. pylori)-gastric cancer might be ideal because of no risk of bacterial resistance, safety, and rejuvenating action of atrophic gastritis. We have published data about the potential of fermented kimchi as nutritional approach for H. pylori. Hence recent advances in RNAseq analysis lead us to investigate the transcriptome analysis to explain these beneficiary actions of kimchi. gastric cells were infected with either H. pylori or H. pylori plus kimchi. 943 genes were identified as significantly increased or decreased genes according to H. pylori infection and 68 genes as significantly changed between H. pylori infection and H. pylori plus kimchi (p<0.05). Gene classification and Medline database showed DLL4, FGF18, PTPRN, SLC7A11, CHAC1, FGF21, ASAN, CTH, and CREBRF were identified as significantly increased after H. pylori, but significantly decreased with kimchi and NEO1, CLDN8, KLRG1, and IGFBP1 were identified as significantly decreased after H. pylori, but increased with kimchi. After KEGG and STRING-GO analysis, oxidative stress, ER stress, cell adhesion, and apoptosis genes were up-regulated with H. pylori infection but down-regulated with kimchi, whereas tissue regeneration, cellular anti-oxidative response, and anti-inflammation genes were reversely regulated with kimchi (p<0.01). Conclusively, transcriptomes of H. pylori plus kimchi showed significant biological actions.

The first small molecules capable of strongly suppressing proliferation of cancer cells harboring BRAF class I/II/III mutations.

BRAF mutants are categorized into three classes according to dependency on RAS signaling and RAF dimerization-dependency. Class I BRAF V600 mutants (RAS-independent monomer) are sensitive to vemurafenib. In contrast, both class II mutants (RAS-independent dimer) and class III mutants (RAS-dependent heterodimer) are insensitive to vemurafenib. It is not likely that BRAF inhibitors capable of inhibiting all classes of BRAF mutants are currently available. Herein, we report GNF-7 and its novel derivative, SIJ1227 as the first BRAF inhibitors capable of inhibiting all classes of BRAF mutants. Compared with vemurafenib and PLX8394, both GNF-7 and SIJ1227 possess much more strong anti-proliferative activities on melanoma (A375 and C8161) and lung cancer cells (H1755 and H1666) harboring BRAF V600E (class I mutant), BRAF G464E/G469A (class II mutant) and BRAF G466V (class III mutant), respectively. Also, both GNF-7 and SIJ1227 are capable of inhibiting more strongly colony formation than vemurafenib and PLX8394 in 3D soft agar assay using C8161 melanoma cells. In addition, GNF-7 and SIJ1227 suppress more strongly migration/invasion of these cancer cells than vemurafenib and PLX8394. Taken together, both GNF-7 and SIJ1227 are much superior to vemurafenib and PLX8394 in terms of capability to inhibit all classes of BRAF mutants.

Flexible Behavior of the Black-Tailed Godwit Limosa limosa is Key to Successful Refueling during Staging at Rice Paddy Fields in Midwestern Korea.

Successful refueling at staging sites is essential for the survival and reproduction of migratory birds. Understanding their staging ecology is therefore crucial for the conservation of migrant species. Rice fields in the mid-western region of the Korean Peninsula serve as staging habitats for the black-tailed godwit (Limosa limosa). We examined the behavior of staging black-tailed godwits in rice fields located in the East Asian-Australasian Flyway during their northward migration. Specifically, we tested the effect of flock size and water level on the foraging, vigilance, and resting behaviors of black-tailed godwits. Our observations revealed that as flock size increased, stepping rate, pecking rate, and vigilance duration decreased, while probing rate, preening duration, and foraging efficiency increased. Stepping and pecking rates increased at low water levels, compared with high water levels. We determined that the behavior of black-tailed godwits at the staging site is influenced by flock size and water level. These observations suggest that black-tailed godwits form larger flocks to increase foraging efficiency by lowering individual-level vigilance, and to spend more time on preening, which is critical for flight and survival. It can be also inferred, based on the shift in primary foraging mode between probing and pecking depending on the water level, that they obtain higher foraging efficiency by flexibly adapting their foraging mode to the conditions in rice fields that are subject to agricultural activities. Our results are expected to serve as basic data for establishing efficient management strategies for anthropogenic habitats for the conservation of migratory shorebirds such as black-tailed godwit.

Evaluation of the Korean version of the self-assessment of nursing informatics competencies scale.

BACKGROUND: In order to assess nursing students' informatics competency, we need a comprehensive Korean version scale that reflects the important advances in nursing informatics and can make up for the lack of an existing measure. This study aimed to cross-culturally adapt the Self-Assessment of Nursing Informatics Competencies Scale (SANICS) into Korean (K-SANICS) and verify its validity and reliability with nursing students. METHODS: The design of this study was a methodological approach to translate and evaluate the Korean version tool (K-SANICS). A total of 254 nursing students at four universities in Korea completed a structured questionnaire including background characteristics and the K-SANICS. Reliability and validity of the 30-item K-SANICS were evaluated using Cronbach's α, content validity, factor analysis, and contrasted groups approach. RESULTS: Cronbach's α was .95. Exploratory factor analysis was performed to verify the scale's construct validity, identifying 30 items across six categories: advanced skills for clinical informatics, basic application skills, basic computer skills, roles in nursing informatics, skills for clinical applications, and attitude toward computers in nursing. CONCLUSION: The K-SANICS may be used as a reliable assessment tool of nursing students' nursing informatics competencies. It is expected that the K-SANICS will contribute to establishing, operating, and evaluating nursing informatics curricula and also can be used in a clinical setting.

Dietary intake of probiotic kimchi ameliorated IL-6-driven cancer cachexia.

Cancer cachexia is a syndrome accompanying weight loss, skeletal muscle atrophy, and loss of adipose tissue in patients with advanced cancer. Since interleukin-6 (IL-6) is one of core mediators causing cancer cachexia and kimchi can modulate IL-6 response, we hypothesized dietary intake of kimchi can ameliorate cancer cachexia. In this study, we studied preemptive administration of kimchi can ameliorate mouse colon carcinoma cells colon (C26) adenocarcinoma-induced cancer cachexia and explored anti-cachexic mechanisms of kimchi focused on the changes of muscle atrophy, cachexic inflammation, and catabolic catastrophe. As results, dietary intake of kimchi significantly attenuated the development of cancer cachexia, presented with lesser weight loss, higher muscle preservation as well as higher survival from cancer cachexia in mice. Starting from significant inhibition of IL-6 and its signaling, kimchi afforded significant inhibition of muscle specific ubiquitin-proteasome system including inhibition of atrogin-1 and muscle ring finger protein-1 (MuRF-1) with other muscle related genes including mitofusin-2 (Mfn-2) and PGC-1α. Significant inhibition of lipolysis gene such as adipose triglyceride lipase (ATGL) and hormone-sensitive ligase (HSL) accompanied with significant induction of fatty acid synthase (FAS) and sterol response element binding protein 1 (SREBP1) was achieved with kimchi. As gene regulation, IL-6 and their receptor as well as Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were significantly attenuated with kimchi. In conclusion, dietary intake of cancer preventive kimchi can be an anticipating option to ameliorate cancer cachexia via suppressive action of IL-6 accompanied with decreased muscle atrophy and lipolysis.

Workplace violence against nurses in Korea and its impact on professional quality of life and turnover intention.

AIM: To inform countermeasures against nurses' workplace violence by reviewing the experience of violence. BACKGROUND: Violence is an important issue in medical settings that influences turnover intention of nurses. However, few studies have dealt with the effects of violence experienced by nurses on professional quality of life and turnover intention. METHOD: A descriptive study using a structured questionnaire and data were analysed using t-test, one-way anova and hierarchical multiple regression analysis. RESULTS: Of 358 nurses 95.5% reported that they had experienced workplace violence during the previous 1 year. Findings indicated that turnover intention was positively associated with years worked as a nurse, functional nursing delivery system, exposure types of violence with physical threats, and mild or severe burnout. CONCLUSIONS: Nurses experienced diverse workplace violence, which could decrease their professional quality of life and be a factor affecting their turnover intention. IMPLICATIONS FOR NURSING MANAGEMENT: Role of leadership in creating a positive work environment is needed. Prevention of workplace violence should focus on at-risk groups to reduce workplace violence. Workplace violence should be communicated regularly and feedback should be given if there is unintentional non-physical violence. In particular it is important to investigate post-violence management in nurses who have experienced violence to reduce secondary trauma.

Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice.

Genetic changes and epigenetic modifications are associated with neuronal dysfunction in the pathogenesis of neurodegenerative disorders. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Here, we identified an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element, using convolutional neural network. The enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.

Astrocytic autophagy plasticity modulates Aß clearance and cognitive function in Alzheimer's disease.

BACKGROUND: Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aß) in Alzheimer's disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aß-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aß-induced autophagy-associated genes are involved Aß clearance in astrocytes of animal model of AD. METHODS: Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aß-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR). RESULTS: Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aß. Aß transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aß-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aß plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aß aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients. CONCLUSIONS: Taken together, our data indicates that Aß-induced astrocytic autophagic plasticity is an important cellular event to modulate Aß clearance and maintain cognitive function in AD mice.

Synbiotic impact of tagatose on viability of Lactobacillus rhamnosus strain GG mediated by the phosphotransferase system (PTS).

Synbiotics, the combination of prebiotics and probiotics, has been shown to produce synergistic effects that promote gastrointestinal well-being of host. Tagatose is a low calorie food ingredient with putative health-promoting benefits. Herein, we investigated its synbiotic impact on the viability of Lactobacillus casei 01 and Lactobacillus rhamnosus strain GG and the potential mechanism involved. Tagatose, as a synbiotic substrate, enhanced the growth of L. casei 01 and L. rhamnosus strain GG compared to other prebiotics. Other gut-indigenous such as Clostridium spp. readily utilized fructooligosaccharide (FOS), the most widely used functional prebiotics, but not tagatose. Additionally, tagatose enhanced probiotic functions of L. casei 01 and L. rhamnosus strain GG by reinforcing their attachment on HT-29 intestine epithelial cells and enhancing their cholesterol-lowering activities. Whole transcriptome study and quantitative real-time polymerase chain reaction (qRT-PCR) test showed that the presence of tagatose in L. rhamnosus strain GG caused induction of a large number of genes associated with carbohydrate metabolism including the phosphotransferase system (PTS). Collectively, these results indicate the tagatose enhanced the growth of L. casei 01 and L. rhamnosus strain GG and their probiotic activities by activating tagatose-associated PTS networks. Importantly, this study highlights the potential application of tagatose and L. casei 01 and/or L. rhamnosus strain GG as a synbiotic partner in functional dairy foods (i.e. yogurt and cheese) and therapeutic dietary supplements.

Prognostic influences of B-cell lymphoma 2-positive expression on late recurrence in breast cancer.

Purpose: B-cell lymphoma 2 (BCL2) has an antiapoptotic role, however, has resulted in it being a powerful favorable prognostic factor in breast cancer. Several studies revealed BCL2 is strongly associated with a lower rate of early recurrence after initial treatment in breast cancer patients, but study of a prolonged effect after 5 years is lacking. We investigated BCL2 as a prognostic factor in breast cancer in comparison to early and late recurrence. Methods: We retrieved data from 2,198 patients with primary breast cancer who underwent surgical treatment and adjuvant treatment at the breast cancer center between 2005 and 2015. Each molecular subtype was classified, and Ki-67 and BCL2 were also assessed by immunohistochemistry. BCL2 and the association between molecular subtypes were assessed in early and late recurrences, respectively. Five-year postrecurrence survival and BCL2 were also assessed. Results: The BCL2-positive group was associated with favorable clinicopathologic characteristics. The time to recurrence was significantly longer in the BCL2-positive group (P = 0.035). Late recurrence after 5 years was higher in the BCL2-positive group (P = 0.029). In multivariate survival analysis, tumor size and BCL2-positive expression were the only independent prognostic factors for late recurrence (P = 0.004). In the patients with recurrence, 5-year postrecurrence survival was significantly higher in the BCL2-positive group (P < 0.001). Conclusion: Our result showed that prognosis was better in BCL2-positive patients compared to BCL2-negative patients at late recurrence. We suggested that BCL2 expression could be used as a marker to help determine additional adjuvant therapy or extended hormone therapy in hormone-dependent breast cancer.

Impact of rice paddy agriculture on habitat usage of migratory shorebirds at the rice paddy scale in Korea.

Approximately 58 shorebird species, including endangered and threatened species, use various habitats while traveling on their long-distance migratory routes in the East Asian-Australasian Flyway (EAAF). Coastal rice paddies in midwestern Korea, which are located in the EAAF, serve as inland wetlands and provide important stopover sites for long-distance migratory shorebirds. We studied how shorebird population density is affected across periods, time since habitat formation, and field type, at the rice field scale. The shorebirds most frequently observed in rice paddies were, in order, black-tailed godwits (Limosa limosa), common greenshanks (Tringa nebularia), and wood sandpipers (T. glareola). Black-tailed godwits and wood sandpipers were affected by time since formation, field type, and water level, whereas field type affected common greenshanks. We propose that (1) flooding time, (2) shallow water level, (3) harrowed field type, and (4) 5-7 days of management intervals at paddy fields are important factors influencing shorebird species density, although all the factors did not influence common greenshank density. We propose that environmental characteristics derived from field management in rice paddies influence habitat use by migratory shorebirds. These factors need to be considered to systematically protect and manage shorebirds that use rice paddies as stopovers during their migration events.

Antioxidant and Neuroprotective Effects of Paeonol against Oxidative Stress and Altered Carrier-Mediated Transport System on NSC-34 Cell Lines.

Paeonol is a naturally occurring phenolic agent that attenuates neurotoxicity in neurodegenerative diseases. We aimed to investigate the antioxidant and protective effects of paeonol and determine its transport mechanism in wild-type (WT; NSC-34/hSOD1WT) and mutant-type (MT; NSC-34/hSOD1G93A) motor neuron-like amyotrophic lateral sclerosis (ALS) cell lines. Cytotoxicity induced by glutamate, lipopolysaccharides, and H2O2 reduced viability of cell; however, the addition of paeonol improved cell viability against neurotoxicity. The [3H]paeonol uptake was increased in the presence of H2O2 in both cell lines. Paeonol recovered ALS model cell lines by reducing mitochondrial oxidative stress induced by glutamate. The transport of paeonol was time-, concentration-, and pH-dependent in both NSC-34 cell lines. Kinetic parameters showed two transport sites with altered affinity and capacity in the MT cell line compared to the WT cell line. [3H]Paeonol uptake increased in the MT cell line transfected with organic anion transporter1 (Oat1)/Slc22a6 small interfering RNA compared to that in the control. Plasma membrane monoamine transporter (Pmat) was also involved in the uptake of paeonol by ALS model cell lines. Overall, paeonol exhibits neuroprotective activity via a carrier-mediated transport system and may be a beneficial therapy for preventing motor neuronal damage under ALS-like conditions.

The different prognostic impact of age according to individual molecular subtypes in breast cancer.

Purpose: Young age at diagnosis has been considered a poor prognostic factor. However, considering young age itself as an independent poor prognostic factor for all breast cancers is unwarranted. We analyzed the different prognostic effects of age as a prognostic factor according to molecular subtype. Methods: We retrieved data from 1,819 patients with primary breast cancer at the breast cancer center between 2007 and 2012. We classified each molecular subtype in 3 age cohorts (<40, 40-50, and >50 years). The associations of age and molecular subtypes with relapse-free survival (RFS) and disease-specific survival (DSS) were assessed. Results: Patients aged <40 years showed a poor histologic grade, hormone receptor negative expression than older patients, and had a higher proportion of triple-negative breast cancer (TNBC) (P < 0.001). This was thought to have led to a significantly shorter RFS than that of older patients (P < 0.001). In the subgroup analysis according to molecular subtypes, the poorer RFS was observed only in patients aged <40 years with luminal type breast cancer (P < 0.001). Age was an independent prognostic factor of RFS in luminal-type breast cancer (P = 0.001). However, no difference in RFS between age groups was found for patients with other subtypes (human epidermal growth factor receptor 2 overexpression, TNBC). No significant effect between age groups was found in DSS for patients with all molecular subtypes. Conclusion: Age at diagnosis of breast cancer affected prognosis differently according to molecular subtype. Age itself is not an independent prognostic factor. Age of <40 years showed a limited worse prognostic impact of recurrence in luminal type breast cancer only.

Metastatic breast cancer from a hepatocellular carcinoma: a case report.

Breast metastases from extramammary malignancies are rare. Here, we report a case of breast metastasis from hepatocellular carcinoma (HCC) after breast mass excision in a 63-year-old woman. A new breast nodule was noticed after transarterial chemoembolization, transarterial radioembolization, and stereotactic body radiation therapy for HCC. Breast ultrasound and core needle biopsy were performed to differentiate between the breast tumors. The biopsy result was invasive breast carcinoma, and wide excision of the breast was performed. The final pathological diagnosis was HCC breast metastasis based on histological findings and immunohistochemical staining results. After 9 months of follow-up, HCC and breast metastasis recurred. Despite palliative treatment, the patient died due to complications and general health deterioration. Although breast metastasis due to HCC is very rare, HCC breast metastasis should be considered when a new breast mass is discovered in a patient with a history of HCC for effective treatment and management.

Small heat shock protein as a multifunctional scaffold: integrated tumor targeting and caspase imaging within a single cage.

Protein cages have the potential to serve as biomaterials for the targeted therapeutic and imaging systems. As an effort to exploit small heat shock protein (Hsp) cages as multifunctional biomaterials, we demonstrate that chemically and genetically modified Hsp cages permeate the cells via cancer cell binding and subsequent endocytic internalization and can image caspase activity in the live cells. Moreover, we report here that these functional Hsp cages can be specifically accumulated to tumor tissues of tumor-bearing mice when administered intravenously through the lateral tail vein. These tumor-targeting properties could be explained by the prolonged in vivo circulation and enhanced permeability and retention (EPR) effect as well as the ligand-mediated binding to cancer cells. Furthermore, when combined with the caspase sensing ability, our Hsp cage allows us to monitor the therapeutic evaluation after anticancer drug treatment by imaging the caspase activity within tumors. Therefore, we demonstrate that the Hsp cages have multifunctional scaffolds amenable to genetic and chemical modifications without loss of the cagelike architecture and can be exploited as biomedical materials including drug or imaging agent carriers.