PLM-101 is a novel and potent FLT3/RET inhibitor with less adverse effects in the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a prevalent form of leukemia in adults. As its survival rate is low, there is an urgent need for new therapeutic options. In AML, FMS-like tyrosine kinase 3 (FLT3) mutations are common and have negative outcomes. However, current FLT3-targeting agents, Midostaurin and Gilteritinib, face two significant issues, specifically the emergence of acquired resistance and drug-related adverse events leading to treatment failure. Rearranged during transfection (RET), meanwhile, is a proto-oncogene linked to various types of cancer, but its role in AML has been limited. A previous study showed that activation of RET kinase enhances FLT3 protein stability, leading to the promotion of AML cell proliferation. However, no drugs are currently available that target both FLT3 and RET. This study introduces PLM-101, a new therapeutic option derived from the traditional Chinese medicine indigo naturalis with potent in vitro and in vivo anti-leukemic activities. PLM-101 potently inhibits FLT3 kinase and induces its autophagic degradation via RET inhibition, providing a superior mechanism to that of FLT3 single-targeting agents. Single- and repeated-dose toxicity tests conducted in the present study showed no significant drug-related adverse effects. This study is the first to present a new FLT3/RET dual-targeting inhibitor, PLM-101, that shows potent anti-leukemic activity and fewer adverse effects. PLM-101, therefore, should be considered for use as a potential therapeutic agent for AML.

A phenomenological study on the experiences of patient transfer from the intensive care unit to general wards.

OBJECTIVES: This study aimed to derive an in-depth understanding of the transfer experience of intensive care unit (ICU) patients in South Korea through a phenomenological analysis. METHODS: Participants were 15 adult patients who were admitted to a medical or surgical ICU at a university hospital for more than 48 hours before being transferred to a general ward. Data were collected three to five days after their transfer to the general ward from January to December 2017 through individual in-depth interviews and were analyzed using Colaizzi's phenomenological data analysis method, phenomenological reduction, intersubjective reduction, and hermeneutic circle. Data analysis yielded eight themes and four theme clusters related to the unique experiences of domestic ICU patients in the process of transfer to the general ward. RESULTS: The four main themes of the patients' transfer experiences were "hope amid despair," "gratitude for being alive," "recovery from suffering," and "seeking a return to normality." CONCLUSION: Our findings expand the realistic and holistic understanding from the patient's perspective. This study's findings can contribute to the development of appropriate nursing interventions that can support preparation and adaptation to the transfer of ICU patients.

Cordyceps militaris Induces Immunogenic Cell Death and Enhances Antitumor Immunogenic Response in Breast Cancer.

Cordyceps militaris has been widely used as a traditional medicine in East Asia. Its effects against breast cancer have been reported previously. However, whether C. militaris-induced breast cancer cell death is immunogenic remains unelucidated. This study aimed to determine whether ethanolic extracts of C. militaris (CM-EE) could induce immunogenic cell death (ICD) in breast cancer immunotherapy to improve the efficacy of immune checkpoint inhibitors. Human and mouse breast cancer cells were treated with various concentrations of CM-EE for 72 h, and cytotoxicity was measured using the sulforhodamine B assay. Flow cytometry was used to assess cell death with annexin V/7-AAD staining and measure the surface exposure of damage-associated molecular pattern (DAMP) molecules including calreticulin, HSP70, and HSP90. Western blot for cleaved poly (ADP-ribose) polymerase (PARP) was used to confirm apoptotic cell death. The immunogenicity of CM-EE-induced dead cells was evaluated using the CFSE dilution assay. CM-EE reduced the viability of human (MCF7, MDA-MB-231, HS578T, and SKBR3) and mouse (4T1-neu-HA, TUBO-HA, and TUBO-P2J-HA) breast cancer cells. The IC50 was 25-50 µg/ml in human breast cancer cells and 10-50 µg/ml in mouse breast cancer cells at 72 h. CM-EE-treated breast cancer cells were positively stained by annexin V, cleaved PARP, and cleaved caspase 3/7 which were increased upon CM-EE treatment. Surface exposure of DAMP molecules was increased in dose- and time-dependent manners. The CFSE dilution assay revealed that dendritic cells fed with CM-EE-treated breast cancer cells successfully stimulated tumor-specific T cell proliferation without inhibiting DC function and T cell proliferation. The expression of PD-L1 mRNA and protein level was increased in dose-dependent manners. In addition, CM-EE also potentiated the cytotoxic activity of tumor-specific T cells. CM-EE can induce immunogenic and apoptotic cell death in breast cancer cells, and it is a good candidate for cancer immunotherapy and may improve the efficacy of immune checkpoint inhibitors.

The complete chloroplast genome of Paeonia lactiflora Pall. (Paeoniaceae).

The complete chloroplast genome sequence of Paeonia lactiflora was obtained by de novo assembly using next-generation sequencing. The circular molecule of the genome constituted of four parts, with 152,731 bp in the complete chloroplast genome, including a large single-copy (LSC) region of 84,402 bp, a small single-copy (SSC) region of 16,969 bp, and two inverted repeat (IRa and IRb) regions of 25,680 bp each. The genome annotation predicted a total of 111 genes, including 77 protein-coding genes, 30 tRNA genes, and 4 rRNA genes. Phylogenetic analysis showed the close taxonomical relationship to P. veitchii.

Characterization of a Major Allergen from Mongolian Oak, Quercus mongolica, a Dominant Species of Oak in Korea.

BACKGROUND: Oaks are the most common trees in Korean forests, and Mongolian oak, Quercus mongolica, is the dominant species. However, no allergen has been characterized from Mongolian oak. In this study, we tried to characterize a major allergen from Mongolian oak. METHODS: A molecule homologous to pathogenesis-related 10 (PR-10)-like protein, Que m 1, was cloned by RT-PCR. Its recombinant protein, along with Que a 1, an allergen from white oak (Q. alba), was produced. The allergenicity and diagnostic value of recombinant Que m 1, Que a 1, and Bet v 1 proteins were compared by ELISA using sera from oak-sensitized subjects. A basophil activation test was also performed using CD63 expression as an activation marker. RESULTS: Que m 1 sequence shares 57.5-96.2% amino acid sequence identity with PR-10-like allergens from various plants. Specific IgE to recombinant Que m 1, Que a 1, and Bet v 1 were detected in 92.0, 74.0, and 38.0% of 50 serum samples from Korean tree pollinosis patients. Recombinant Que m 1 was able to inhibit IgE reactivity to Que a 1 and Bet v 1, indicating its strong cross-reactivity. The activation patterns of basophils from 5 patients were similar in terms of the CD63 expression and protein concentration of challenged Bet v 1 and Que m 1. CONCLUSIONS: A major allergen, Que m 1, was cloned, and its recombinant protein was produced from Mongolian oak, a dominant species in Korea. Recombinant Que m 1 is potentially useful for the diagnosis and treatment of tree pollinosis in Korea.

Heavy Metal Distribution in Street Dust from Traditional Markets and the Human Health Implications.

Street dust is a hazard for workers in traditional markets. Exposure time is longer than for other people, making them vulnerable to heavy metals in street dust. This study investigated heavy metal concentrations in street dust samples collected from different types of markets. It compared the results with heavy metal concentrations in heavy traffic and rural areas. Street dust was significantly enriched with most heavy metals in a heavy traffic area while street dust from a fish market was contaminated with cupper (Cu), lead (Pb) and zinc (Zn). Street dust from medicinal herb and fruit markets, and rural areas were not contaminated. Principal component and cluster analyses indicated heavy metals in heavy traffic road and fish market dust had different sources. Relatively high heavy metal concentration in street dust from the fish market may negatively affect worker's mental health, as depression levels were higher compared with workers in other markets. Therefore, intensive investigation of the relationship between heavy metal concentrations in street dust and worker's health in traditional marketplaces should be conducted to elucidate the effect of heavy metals on psychological health in humans.

Cross-Reactivity between Oak and Birch Pollens in Korean Tree Pollinosis.

Oak and birch trees belong to Fagales order. Specific IgE to pollen allergens of both trees are frequently found in Korea pollinosis patients. Oak trees which comprise 40% of forest area are common in Korea. However, birch trees are sparse. We compared the allergenicity of pollen extracts of white oak, sawtooth and Mongolian oaks which are prevalent species in Korea, with the pollen extract of birch. The cross-reactivity of four pollen extracts was examined with pooled sera of 12 patients by ELISA, immunoblotting and CAP inhibitions. A protein of 17 kDa, putatively homologous to a major birch allergen Bet v 1, displayed strong IgE reactivity from white oak and sawtooth oak pollen extract but not from Mongolian oak pollen. Notably, a 23-kDa protein from sawtooth and white oaks showed strong IgE reactivity and inhibited by Bet v 1. IgE binding to white oak was inhibited a maximum of 94.6% by white oak, 93.4% by sawtooth oak, 83.2% by Mongolian oak, and 68.8% by birch. Furthermore, sawtooth oak, white oak, and Mongolian oak extracts were able to inhibit up to 78.5%, 76.6% and 67.3% of IgE binding to birch extract, while birch extract itself inhibited up to 94.3%. Specific IgE to Bet v 1 was inhibited a maximum of 79.1% by sawtooth oak, 77.4% by white oak, and 72.7% by Mongolian oak, while 81.5% inhibition was shown by birch. Bet v 1 was able to partially inhibit its homologous molecules from sawtooth oak and white oak in immunoblotting. Birch pollen extract was found to be cross-reactive primarily with Bet v 1-homologous allergen from oak pollens in Korea pollinosis patients. Considering the sparseness of birch tree in Korea, oak, especially sawtooth oak may be the main cause of tree pollinosis in Korea, rather than birch.

Effects of Korean red ginseng extracts on neural tube defects and impairment of social interaction induced by prenatal exposure to valproic acid.

Ginseng is one of the most widely used medicinal plants, which belongs to the genus Panax. Compared to uncured white ginseng, red ginseng has been generally regarded to produce superior pharmacological effects with lesser side/adverse effects, which made it popular in a variety of formulation from tea to oriental medicine. Using the prenatal valproic acid (VPA)-injection model of autism spectrum disorder (ASD) in rats, which produces social impairrment and altered seizure susceptibility as in human ASD patients as well as mild neural tube defects like crooked tail phenotype, we examined whether chronic administration of red ginseng extract may rescue the social impairment and crooked tail phenotype in prenatally VPA-exposed rat offspring. VPA-induced impairment in social interactions tested using sociability and social preference paradigms as well as crooked tail phenotypes were significantly improved by administration of Korean red ginseng (KRG) in a dose dependent manner. Rat offspring prenatally exposed to VPA showed higher sensitivity to electric shock seizure and increased locomotor activity in open-field test. KRG treatment reversed abnormal locomotor activity and sensitivity to electric shock to control level. These results suggest that KRG may modulate neurobehavioral and structural organization of nervous system adversely affected by prenatal exposure to VPA.

Hwanggeumchal sorghum induces cell cycle arrest, and suppresses tumor growth and metastasis through Jak2/STAT pathways in breast cancer xenografts.

BACKGROUND: Cancer is one of the highly virulent diseases known to humankind with a high mortality rate. Breast cancer is the most common cancer in women worldwide. Sorghum is a principal cereal food in many parts of the world, and is critical in folk medicine of Asia and Africa. In the present study, we analyzed the effects of HSE in metastatic breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: Preliminary studies conducted on MDA-MB 231 and MCF-7 xenograft models showed tumor growth suppression by HSE. Western blotting studies conducted both in vivo and in vitro to check the effect of HSE in Jak/STAT pathways. Anti-metastatic effects of HSE were confirmed using both MDA-MB 231 and MCF-7 metastatic animal models. These studies showed that HSE can modulate Jak/STAT pathways, and it hindered the STAT5b/IGF-1R and STAT3/VEGF pathways not only by down-regulating the expression of these signal molecules and but also by preventing their phosphorylation. The expression of angiogenic factors like VEGF, VEGF-R2 and cell cycle regulators like cyclin D, cyclin E, and pRb were found down-regulated by HSE. In addition, it also targets Brk, p53, and HIF-1α for anti-cancer effects. HSE induced G1 phase arrest and migration inhibition in MDA-MB 231 cells. The metastasis of breast cancer to the lungs also found blocked by HSE in the metastatic animal model. CONCLUSIONS/SIGNIFICANCE: Usage of HS as a dietary supplement is an inexpensive natural cancer therapy, without any side effects. We strongly recommend the use of HS as an edible therapeutic agent as it possesses tumor suppression, migration inhibition, and anti-metastatic effects on breast cancer.

Ethyl acetate extract of Psidium guajava inhibits IgE-mediated allergic responses by blocking FcεRI signaling.

Psidium guajava (P. guajava) is an important food crop and medicinal plant with antioxidant, anti-inflammatory, and anti-allergic activities, supporting its traditional uses. However, its precise effects remain unknown. We investigated the effects of P. guajava ethyl acetate extract (PGEA) on IgE-mediated allergic responses in rat mast RBL-2H3 cells. PGEA reduced antigen (DNP-BSA)-induced release of ß-hexosaminidase and histamine in IgE-sensitized RBL-2H3 cells. In addition, it inhibited antigen-induced IL-4 and TNF-α mRNA expression and protein production in IgE-sensitized RBL-2H3 cells. PGEA also suppressed antigen-induced COX-2 mRNA and protein expression in these cells, as well as antigen-induced activation of NFAT and reactive oxygen species. Moreover, it inhibited antigen-induced activation of NF-κB and degradation of IκB-α. To identify the mechanisms underpinning the inhibition of degranulation and cytokine production by PGEA, we examined the activation of intracellular FcεRI signaling molecules. PGEA suppressed antigen-induced phosphorylation of Syk, LAT, Gab2, and PLCγ2 but not Lyn, and inhibited antigen-induced phosphorylation of downstream signaling intermediates including MAP kinases and Akt. Collectively, the anti-allergic effects of PGEA in vitro suggest its possible therapeutic application to inflammatory allergic diseases, in which its inhibition of inflammatory cytokine production and FcεRI-dependent signaling events in mast cells may be hugely beneficial.

Comparative value of phosphate sources on the immobilization of lead, and leaching of lead and phosphorus in lead contaminated soils.

The mobility and bioavailability of lead (Pb) in soils can be mitigated by its immobilization using both soluble and insoluble phosphate (P) compounds. The effectiveness of insoluble P sources on Pb immobilization depends on their rate of dissolution which can be enhanced by phosphate solubilizing bacteria (PSB). In this study, the effect of soluble (potassium dihydrogen phosphate) and insoluble (rock phosphate in the presence and absence of PSB) P compounds on the immobilization of Pb, and leaching of Pb and P was examined using both naturally contaminated (SR soil: NH4NO3 extractable Pb: 28.7 mg/kg, pH: 5.88, organic matter: 0.7%) and Pb spiked (AH soil: NH(4)NO(3) extractable Pb: 42.7 mg/kg, pH: 5.23, organic matter: 10.9%) soils. Phosphate compounds were added at the rate of 200 mg P/kg and 800 mg P/kg for SR and AH soils, respectively. Soluble P treatment immobilized 80% and 57% of Pb in SR and AH soils, respectively. Insoluble rock phosphate immobilized 40% and 9% of Pb without PSB, and 60% and 17% with PSB in SR and AH soils, respectively. Lead leaching was the lowest when soils were amended with rock phosphate in the presence of PSB, which reduced Pb leaching by 36% for SR soil and 18% for AH soil compared to the control. The leaching of Pb increased when the soils were amended with soluble P because soluble P treatment increased dissolved organic carbon (DOC) concentration of soil, thereby increasing Pb mobility. Soluble P treatment significantly increased P leaching and 9% of total added P was leached from low P retaining AH soil. The optimum level of P amendment is a critical issue when soluble P is used as a Pb immobilizing agent because of eutrophication resulting from excessive P leaching to surface and ground water. While the soluble P compound was effective in the immobilization of Pb, it resulted in P leaching which increased with increasing levels of P addition. However, rock phosphate amendment with PSB achieved the immobilization of Pb with a minimum effect on both Pb and P leaching.

[Factors influencing relocation stress syndrome in patients following transfer from intensive care units].

PURPOSE: The purpose of this study was to identify the levels of relocation stress syndrome (RSS) and influencing the stress experienced by Intensive Care Unit (ICU) patients just after transfer to general wards. METHODS: A cross-sectional study was conducted with 257 patients who transferred from the intensive care unit. Data were collected through self-report questionnaires from May to October, 2009. Data were analyzed using the Pearson correlation coefficient, t-test, one-way ANOVA, and stepwise multiple linear regression with SPSS/WIN 12.0. RESULTS: The mean score for RSS was 17.80+/-9.16. The factors predicting relocation stress syndrome were symptom experience, differences in scope and quality of care provided by ICU and ward nursing staffs, satisfaction with transfer process, length of stay in ICU and economic status, and these factors explained 40% of relocation stress syndrome (F=31.61, p<.001). CONCLUSION: By understanding the stress experienced by ICU patients, nurses are better able to provide psychological support and thus more holistic care to critically ill patients. Further research is needed to consider the impact of relocation stress syndrome on patients' health outcomes in the recovery trajectory.

High dose concentration administration of ascorbic acid inhibits tumor growth in BALB/C mice implanted with sarcoma 180 cancer cells via the restriction of angiogenesis.

To test the carcinostatic effects of ascorbic acid, we challenged the mice of seven experimental groups with 1.7 x 10(-4) mol high dose concentration ascorbic acid after intraperitoneal administrating them with sarcoma S-180 cells. The survival rate was increased by 20% in the group that received high dose concentration ascorbic acid, compared to the control. The highest survival rate was observed in the group in which 1.7 x 10(-4) mol ascorbic acid had been continuously injected before and after the induction of cancer cells, rather than just after the induction of cancer cells. The expression of three angiogenesis-related genes was inhibited by 0.3 times in bFGF, 7 times in VEGF and 4 times in MMP2 of the groups with higher survival rates. Biopsy Results, gene expression studies, and wound healing analysis in vivo and in vitro suggested that the carcinostatic effect induced by high dose concentration ascorbic acid occurred through inhibition of angiogenesis.

Houttuynia cordata water extract suppresses anaphylactic reaction and IgE-mediated allergic response by inhibiting multiple steps of FcepsilonRI signaling in mast cells.

Houttuynia cordata has been used as a traditional medicine in Korea and is known to have antioxidant, anti-cancer and anti-allergic activities. The precise effect of H. cordata, however, remains unknown. In this study, we investigated the effects of H. cordata water extract (HCWE) on passive cutaneous anaphylaxis (PCA) in mice and on IgE-mediated allergic response in rat mast RBL-2H3 cells. Oral administration of HCWE inhibited IgE-mediated systemic PCA in mice. HCWE also reduced antigen (DNP-BSA)-induced release of beta-hexosaminidase, histamine, and reactive oxygen species in IgE-sensitized RBL-2H3 cells. In addition, HCWE inhibited antigen-induced IL-4 and TNF-alpha production and expression in IgE-sensitized RBL-2H3 cells. HCWE inhibited antigen-induced activation of NF-kappaB and degradation of IkappaB-alpha. To investigate the inhibitory mechanism of HCWE on degranulation and cytokine production, we examined the activation of intracellular FcepsilonRI signaling molecules. HCWE suppressed antigen-induced phosphorylation of Syk, Lyn, LAT, Gab2, and PLC gamma2. Further downstream, antigen-induced phosphorylation of Akt and MAP kinases (ERK1/2 and JNK1/2 but not p38 MAP kinase) were inhibited by HCWE. Taken together, the in vivo/in vitro anti-allergic effect of HCWE suggests possible therapeutic applications of this agent in inflammatory allergic diseases through inhibition of cytokines and multiple events of FcepsilonRI-dependent signaling cascades in mast cells.

Berberine inhibits rat vascular smooth muscle cell proliferation and migration in vitro and improves neointima formation after balloon injury in vivo. Berberine improves neointima formation in a rat model.

Berberine, an alkaloid isolated from Chinese medicinal herbs, long been known for its anti-microbial activity and used to treat various infectious disorders in traditional Chinese medicine. In the present study, we have tested the hypothesis that berberine could inhibit vascular smooth muscle cell (VSMC) proliferation as it did in endothelial cells or cancer cells. Our results show that berberine significantly inhibits growth factor, mainly angiotensin II (AngII) and heparin binding epidermal growth factor (HB-EGF), induced VSMC proliferation and migration in vitro, and this effect is achieved by delaying or partially suppressing activation of Akt pathway rather than ERK pathway. Furthermore, we have examined its effect in vivo using a rat carotid artery injury model. A 28 days of chronic berberine treatment using an osmotic pump (100 microg kg(-1)d(-1), 2 weeks before and 2 weeks after the injury) improved neointima formation. The Neointima/Media ratio for control group and berberine treated group were 1.14+/-0.11 and 0.85+/-0.06 (p<0.05), respectively, and the reduction was approximately 25%. The result of the present study suggests a possibility of berberine being a potent agent to control restenosis after balloon angioplasty and warrants further study to gain a more complete understanding of its underlying mechanisms at a cellular level.

Effect of genistein on the expression of bone metabolism genes in ovariectomized mice using a cDNA microarray.

Osteoporosis associated with estrogen deficiency is defined as an abnormal decrease in bone mass leading to an increased fracture risk. Genistein (GEN), as a phytoestrogen, is a type of soybean-derived isoflavone that possesses structural similarity to estrogen. In this study, we assessed the effect of GEN in ovariectomized (OVX) mice. To determine the effect of GEN on bone metabolism, we investigated gene expression profiles using a radioactive cDNA microarray. Eight-week-old female mice were either sham operated (SHAM) or OVX. From 1 week after the operation, OVX mice were injected daily with intraperitoneal GEN (0.1, 0.5, 1.5 and 3.0 mg/day) or 17beta-estradiol (E2, 0.03 microg/day) for 4 weeks. A cDNA microarray was used to evaluate changes in the expression of 1,152 genes. OVX mice showed bone mineral density (BMD) loss versus SHAM mice (5.8+/-0.4 vs. 6.9+/-0.6 mg/cm2). However, femur BMDs were completely restored by GEN and by E2 administration in OVX mice. Serum osteocalcin in OVX mice treated with 0.5 mg/day of GEN was 1.6-fold (44.30+/-5.73 ng/ml) higher than that in untreated mice. GEN treatment up-regulated 38 genes (e.g., mitogen-activated protein kinase 10) and down-regulated 18 (e.g., matrix metalloproteinase 13). Moreover, GEN was found to have a protective effect on bone loss caused by estrogen deficiency in OVX mice. The present study suggests that GEN modulates bone metabolism-related gene expression, including calciotropic receptor, cytokines, growth factors and bone matrix proteins.