MiR-640 inhibition alleviates acute liver injury via regulating WNT signaling pathway and LRP1.

OBJECTIVE: Acute liver injury (ALI) is associated with the Kupffer cells (KCs) inflammation and hepatocytes apoptosis. Previous studies have shown that miR-640 is a valid regulator of the Low-density lipoprotein receptor-related protein 1 (LRP 1) which expressed much lower in an inflammatory condition. However, it is unclear whether MiR-640 inhibition protects against ALI by the up-regulation of LRP 1. To explore the regulated mechanism of miR-640 on acute liver injury. MATERIALS AND METHODS: We analyzed the expression of miR-640 in different times of acute injured liver tissues. Lipopolysaccharide (LPS) was employed in provoking the KCs inflammation to injure liver. We used miR-640 mimic or inhibitor to improve or resist the function of miR-640 to explore miR-640 function to ALI via the target of LRP1. RESULTS: We showed that the expression of miR-640 markedly increased in LPS-induced acute injured liver tissues. LPS promoted the progress of ALI, and the inhibition of miR-640 could reverse the injured effects of LPS. Moreover, WNT signaling pathway and LRP1 were significantly enhanced by miR-640 inhibition. CONCLUSIONS: These results suggested that miR-640 promotes KCs inflammation via restraining LRP 1 and WNT signaling pathway. But inhibiting miR-640 prevents inflammation damage and ameliorates ALI. MiR-640 inhibition may become a novel target for the therapy of ALI in the future.

Identifying characteristics of an effective fracture liaison service: systematic literature review.

Fracture liaison services (FLS) have been demonstrated to improve outcomes following osteoporotic fracture. The aim of this systematic literature review (SLR) was to determine the characteristics of an FLS that lead to improved patient outcomes. We conducted a SLR, including articles published between 2000 and February 2017, using global (Medline, EMBASE, PubMed and Cochrane Library) and local databases. Studies including patients aged ≥ 50 years with osteoporotic fractures enrolled in an FLS were assessed. Information extracted from each article included key person coordinating the FLS (physician, nurse or other healthcare professional), setting (hospital vs community), intensity (single vs multiple), duration (long vs short term), fracture type and gender. A meta-analysis of randomised controlled trials was conducted based on the key person coordinating the FLS. Out of 7236 articles, 57 were considered to be high quality and identified for further analysis. The SLR identified several components which contributed to FLS success, including multidisciplinary involvement, driven by a dedicated case manager, regular assessment and follow-up, multifaceted interventions and patient education. Meta-analytic data confirm the effectiveness of an FLS following an osteoporotic fracture: approximate 27% increase in the likelihood of BMD testing and up to 21% increase in the likelihood of treatment initiation compared with usual care. The balance of evidence indicates that the multifaceted FLS and dedicated coordination are important success factors that contribute to effective FLS interventions which reduce fracture-related morbidity and mortality.

Survival outcome of weak estrogen/progesterone receptor expression in HER2 negative breast cancer is similar to triple negative breast cancer.

BACKGROUND: Recent publications have suggested that human epidermal growth factor receptor 2 (HER2)-negative breast cancers with "weak" estrogen receptor (ER)/progesterone receptor (PR) expression levels by immunohistochemical (IHC) analysis were considered as the triple-negative (TN) subtype. This study aimed to evaluate the overall survival (OS), disease-free survival rates (DFS), and disease-specific survival (DSS) based on ER and PR expression levels into one of three groups, ER and PR <1%, ER and PR 1%-20%, and ER or PR >20% by hormone therapy. METHODS: Medical records of 3353 breast cancer patients treated from 2006 to 2013 were retrospectively reviewed. Tumor characteristics, type of treatment, OS, DFS and DSS were evaluated among the three patient groups. RESULTS: Regarding OS, there were significant differences according to the received hormone therapy in the different groups: ER and PR <1% (P = 0.972), ER and PR 1%-20% (P = 0.264), and ER or PR >20% (P = 0.014). Regarding DFS and DSS, there were also significant differences in the different groups: ER and PR <1% (P = 0.611, 0.766), ER and PR 1%-20% (P = 0.847, 0.629), and ER or PR >20% (P = 0.031, 0.002). CONCLUSIONS: In HER2 negative breast cancer patient with hormone therapy, ER and PR expression level of 1%-20% has similar survival outcome to the ER and PR expression level of <1% by IHC analysis.

Differential signaling through p190 and p210 BCR-ABL fusion proteins revealed by interactome and phosphoproteome analysis.

Two major types of leukemogenic BCR-ABL fusion proteins are p190BCR-ABLand p210BCR-ABL. Although the two fusion proteins are closely related, they can lead to different clinical outcomes. A thorough understanding of the signaling programs employed by these two fusion proteins is necessary to explain these clinical differences. We took an integrated approach by coupling protein-protein interaction analysis using biotinylation identification with global phosphorylation analysis to investigate the differences in signaling between these two fusion proteins. Our findings suggest that p190BCR-ABL and p210BCR-ABL differentially activate important signaling pathways, such as JAK-STAT, and engage with molecules that indicate interaction with different subcellular compartments. In the case of p210BCR-ABL, we observed an increased engagement of molecules active proximal to the membrane and in the case of p190BCR-ABL, an engagement of molecules of the cytoskeleton. These differences in signaling could underlie the distinct leukemogenic process induced by these two protein variants.

Combination therapy targeting ectopic ATP synthase and 26S proteasome induces ER stress in breast cancer cells.

F1Fo ATP synthase is present in all organisms and is predominantly located on the inner membrane of mitochondria in eukaryotic cells. The present study demonstrated that ATP synthase and electron transport chain complexes were ectopically expressed on the surface of breast cancer cells and could serve as a potent anticancer target. We investigated the anticancer effects of the ATP synthase inhibitor citreoviridin on breast cancer cells through proteomic approaches and revealed that differentially expressed proteins in cell cycle regulation and in the unfolded protein response were functionally enriched. We showed that citreoviridin triggered PERK-mediated eIF2α phosphorylation, which in turn attenuated general protein synthesis and led to cell cycle arrest in the G0/G1 phase. We further showed that the combination of citreoviridin and the 26S proteasome inhibitor bortezomib could improve the anticancer activity by enhancing ER stress, by ameliorating citreoviridin-caused cyclin D3 compensation, and by contributing to CDK1 deactivation and PCNA downregulation. More interestingly, the combined treatment triggered lethality through unusual non-apoptotic caspase- and autophagy-independent cell death with a cytoplasmic vacuolization phenotype. The results imply that by boosting ER stress, the combination of ATP synthase inhibitor citreoviridin and 26S proteasome inhibitor bortezomib could potentially be an effective therapeutic strategy against breast cancer.

Radiation induces senescence and a bystander effect through metabolic alterations.

Cellular senescence is a state of irreversible growth arrest; however, the metabolic processes of senescent cells remain active. Our previous studies have shown that radiation induces senescence of human breast cancer cells that display low expression of securin, a protein involved in control of the metaphase-anaphase transition and anaphase onset. In this study, the protein expression profile of senescent cells was resolved by two-dimensional gel electrophoresis to investigate associated metabolic alterations. We found that radiation induced the expression and activation of glyceraldehyde-3-phosphate dehydrogenase that has an important role in glycolysis. The activity of lactate dehydrogenase A, which is involved in the conversion of pyruvate to lactate, the release of lactate and the acidification of the extracellular environment, was also induced. Inhibition of glycolysis by dichloroacetate attenuated radiation-induced senescence. In addition, radiation also induced activation of the 5'-adenosine monophosphate-activated protein kinase (AMPK) and nuclear factor kappa B (NF-κB) pathways to promote senescence. We also found that radiation increased the expression of monocarboxylate transporter 1 (MCT1) that facilitates the export of lactate into the extracellular environment. Inhibition of glycolysis or the AMPK/NF-κB signalling pathways reduced MCT1 expression and rescued the acidification of the extracellular environment. Interestingly, these metabolic-altering signalling pathways were also involved in radiation-induced invasion of the surrounding, non-irradiated breast cancer and normal endothelial cells. Taken together, radiation can induce the senescence of human breast cancer cells through metabolic alterations.

First Report of Acidovorax avenae subsp. citrulli as the Causal Agent of Bacterial Leaf Blight of Betelvine in Taiwan.

In November 2008, betelvines (Piper betle L., Piperaceae) exhibiting leaf blight symptoms were observed in central Taiwan. Infections resulted in a 30 to 70% loss of leaf yield in the investigated betel leaf-producing facilities. Symptoms began with small, necrotic, water-soaked spots that progressed to circular to irregularly shaped brown lesions, 5 to 10 mm in diameter, with chlorotic halos on leaves; some lesions started from the edge of leaves and later fused to form dried, necrotic margins. Bacteria-like streaming fluid was visible from the edges of freshly cut lesions at the junctions of chlorotic and necrotic leaf tissues when observed with a light microscope at ×100. When the streaming fluid was streaked onto King's medium B (3), a slow-growing, gram-negative, nonfluorescent bacterium was identified from the whitish colonies that consistently developed on the medium. Five bacterial isolates from three lesions were characterized with fatty acid methyl ester analysis (Agilent Technologies, Santa Clara, CA) and Sherlock Microbial Identification System (Microbial IDentification Inc., Newark, DE), and for each isolate, the bacterium was confirmed as Acidovorax avenae subsp. citrulli with a similarity index >0.70. In addition, the Biolog system (Biolog, Hayward, CA) and 16S ribosomal RNA sequence identity comparison were performed to confirm that the five betelvine-isolated bacteria were A. avenae subsp. citrulli based on a similarity of 0.54 with Biolog and 99% sequence identity for 16S rRNA gene. Koch's postulates were fulfilled by infiltrating a bacterial suspension of 3 × 105 CFU/ml into 40 leaves of four greenhouse-grown, disease-free, mature betelvine plants. After inoculation, plants were kept in a humidified greenhouse at 28°C to favor symptom development and symptoms similar to those observed in the greenhouse were evident at 7 days post inoculation (dpi) on all bacterium-infiltrated leaves. Control leaves infiltrated with distilled water remained symptomless. Bacteria showing morphological and biochemical similarities (2) to the ones used for inoculation were isolated from all of the inoculated betelvine leaves. In addition, a bacterial suspension at 3 × 108 CFU/ml was sprayed at the amount of 5 ml per plant onto 6 to 10 plants each of 4-week-old disease-free seedlings of watermelon (Citrullus lanatus (Thunb.) Matsum & Nakai, cv. Empire No. 2), oriental sweet melon (Cucumis melo L. var. saccharinus Naudin, cv. Silver Beam), and waxgourd (Benincasa hispida (Thunb.) Cogn., cv. Cheerer) for bioassays, and the inoculated seedlings were enclosed in plastic bags for 36 h at 28°C. Water-soaked lesions were observed on leaves of watermelon and waxgourd at 2 dpi and on sweet melon at 4 dpi on all inoculated plants but not on distilled water-sprayed control plants, indicating that A. avenae subsp. citrulli strains from betelvine could also infect melon plants. A. avenae subsp. citrulli was previously identified as the causal agent of bacterial fruit blotch on melon and bitter gourd in Taiwan (1). To our knowledge, this is the first report that A. avenae subsp. citrulli can naturally infect betelvine, a noncucurbit crop, to elicit bacterial leaf blight disease. References: (1) A.-H. Cheng and T.-C. Huang. Plant Pathol. Bull. 7:216, 1998. (2) J. B. Jones et al. Page 121 in: Laboratory Guide for Identification of Plant Pathogenic Bacteria. 3rd ed. The American Phytopathological Society, St. Paul, MN, 2001. (3) E. O. King et al. J. Lab. Clin. Med. 44:301, 1954.

Mediastinitis and mediastinitis-like symptoms associated with mal-positioning of a Port-A catheter.

Mediastinitis is a life-threatening condition and would appear to have been rarely reported as arising as a central-venous catheter-associated complication. Here we report on one cancer patient featuring a Port-A catheter tip positioned within the innominate vein, who developed mediastinitis and mediastinitis-like symptoms subsequent to chemotherapeutic-agent infusion through this catheter. The relevant literature pertaining to this condition was reviewed, and the possible pathophysiology of the condition was discussed.

Comparison of hypoplastic myelodysplastic syndrome (MDS) with normo-/hypercellular MDS by International Prognostic Scoring System, cytogenetic and genetic studies.

The differences in clinical features and prognosis between hypoplastic myelodysplastic syndrome (h-MDS) and normo-/hypercellular MDS (NH-MDS) remain unsettled. In this study, the characteristics of 37 h-MDS patients and 152 NH-MDS patients were compared. Peripheral-blood white blood cell counts and bone marrow blast percentage were lower in h-MDS patients than in NH-MDS patients (P=0.012 and 0.016, respectively). Refractory anemia (RA) was predominant (56.8%) in h-MDS, whereas RA with excess of blast (RAEB) was most common (44.7%) in NH-MDS. Chromosomal abnormalities -7/7q- occurred less frequently in h-MDS patients than in NH-MDS patients (0 vs 18.3%, P=0.022). There was no significant difference in the prevalence of mutations of RAS, AML1, JAK2, PTPN11, FLT3/ITD, and hypermethylation of SOCS1 and SHP1 between these two groups. International Prognostic Scoring System (IPSS) was ideal for predicting prognoses in h-MDS patients (P=0.002). In low- or intermediate-1 (Int-1)-risk MDS patients, h-MDS patients had a superior survival than NH-MDS patients (P=0.01). In conclusion, distinct from NH-MDS, h-MDS patients have different patterns of hemogram, distribution of French-American-British subtypes, cytogenetic changes and prognoses. IPSS is applicable in h-MDS as in NH-MDS. In patients with low- or Int-1-risk MDS, h-MDS patients have a better prognosis than NH-MDS patients.

Coronary artery fistulas in neonates, infants, and children: clinical findings and outcome.

Ten patients were diagnosed with coronary artery fistula (CAF) between 1991 and 1998 in our department. The ages of patients ranged from 3 days to 12 years. Five patients were male and five patients were female. Nine patients had single CAF and 1 patient had dual CAFs. CAFs of 7 patients originated from the left coronary artery, and CAFs of 3 patients originated from the right coronary artery. CAFs of 7 patients terminated at the right ventricle, CAFs of 2 patients terminated at the right atrium, and the CAF of 1 patient terminated at the pulmonary artery. Four patients were diagnosed with CAF in the neonate period. All presented with congestive heart failure. Medical therapy was successful in treating congestive heart failure in 2 of these patients, but the other 2 needed operations. One patient presented with subacute bacterial endocarditis at 12 years of age requiring surgical intervention. One patient had a large left-to-right shunt that was surgically repaired. One patient with dual CAFs underwent coil embolization and the larger CAF achieved complete embolization, but the smaller CAF failed. Follow-up data revealed that 1 patient who received an operation died of sepsis due to recurrent bronchiolitis 6 months later. Nine patients were asymptomatic. Because complications including endocarditis may be encountered in later life, we suggest early closure with coil embolization.

Priority of light/dark entrainment over temperature in setting the circadian rhythms of the prokaryote Synechococcus RF-1.

Light/dark (L/D) and temperature are two major factors in the entrainment of circadian rhythms. The input pathways of these two environmental factors for the entrainment of circadian rhythms in Synechococcus RF-1 are different since the overt rhythms in mutant CR-1, one of the circadian-rhythm mutants of Synechococcus RF-1, could be established by temperature cycles but not by L/D. Therefore, it was of interest to investigate the phases of Synechococcus RF-1 cells entrained simultaneously by L/D and temperature. The circadian rhythms of nitrogenase activity and protein synthesis in RF-1 cells entrained by L/D, and by lowered or raised temperatures differed in their peaks of activity. Comparison of the phases of RF-1 cells entrained by L/D and temperature independently, and by L/D and temperature simultaneously indicated that L/D entrainment has priority over the temperature effect.

Synthesis of Platinum Ultrafine Particles in AOT Reverse Micelles.

The synthesis of platinum ultrafine particles by the reduction of H2PtCl6 with hydrazine in AOT/isooctane reverse micellar solutions has been studied. By high-resolution electron microscope, electron diffraction pattern, and XRD analyses, the resultant particles have been found to be pure platinum of fcc structure. Their sizes were observed to increase with the increases in the molar ratio of water to AOT (omegaO) and in the concentration of H2PtCl6, while they decreased with the increase of hydrazine concentration. At a constant omegaO value, the size of platinum ultrafine particles was not affected significantly when the concentration ratio of hydrazine to H2PtCl6 was above 10, the AOT concentration increased from 0.1 to 0.6 M, and the temperature varied from 15 to 35 degrees C. Furthermore, the kinetic study of particle formation indicated that the nucleation time needed several minutes. The time for the growth of platinum ultrafine particles to their final size after nucleation was about one to several hours. It was observed that the formation rates increased with the increase of omegaO value and the concentrations of AOT and H2PtCl6, but they were not affected by hydrazine concentration when the concentration ratio of hydrazine to H2PtCl6 was above 10. Copyright 1999 Academic Press.

Preparation of Palladium Ultrafine Particles in Reverse Micelles.

The preparation of palladium ultrafine particles by the reduction of Pd(NH3)4Cl2 with hydrazine in AOT/isooctane reverse micellar solutions has been studied. By the analyses of high-resolution electron microscope, electron diffraction pattern, and XRD, the resultant particles have been found to be pure fcc palladium. Their sizes were observed to increase first and then approach constant values with increases in the molar ratio of water to AOT (omega0) and in the concentration of Pd(NH3)4Cl2, but were not significantly affected when the concentration ratio of hydrazine to Pd(NH3)4Cl2 was above 10, the AOT concentration increased from 0.1 to 1.0 M, the temperature varied from 15 to 35 degreesC, and the pH of aqueous phase of Pd(NH3)4Cl2 was between 7 and 12. In addition, the kinetic study of particle formation indicated that the nucleation time needed several minutes. After nucleation, the particles grew to their final sizes within several to tens of minutes. The formation rates were found to be faster at larger omega0 values and higher AOT and Pd(NH3)4Cl2 concentrations. Copyright 1999 Academic Press.

Mechanistic Studies on Thiazolidine Formation in Aldehyde/Cysteamine Model Systems.

A mechanism was proposed to elucidate the formation of a thiazolidine in aldehyde/cysteamine model systems. Buffer dramatically promotes thiazolidine formation from formaldehyde and cysteamine. Phosphate tends to stabilize the primary carbocation formed, and this may lead to completion of the cyclization by attack of the amino nitrogen on the activated carbon. Protic solvent, by removing the water molecule, further enhances thiazolidine formation. Redox reaction catalyzed by phosphate ions results in the conversion of thiazolidine to the corresponding thiazoline through hydride transfer.

Mechanistic Studies on the Formation of Thiazolidine and Structurally Related Thiazines in a Cysteamine/2,3-Butanedione Model System.

Phosphate was found to dramatically enhance the formation of 2-methyl-2-acetylthiazolidine from a cysteamine/2,3-butanedione model system. In addition to the major component, 2-methyl-2-acetylthiazolidine, significant amounts of two structurally closely related compounds, 2-acetyl-2,3,5,6-tetrahydro-1,4-thiazine and 5-acetyl-2,3-dihydro-1,4-thiazine, were characterized by using GC/MS (CI and EI). There was an oxidative transformation of 2-acetyl-2,3,5,6-tetrahydro-1,4-thiazine to 5-acetyl-2,3-dihydro-1,4-thiazine in the presence of azodicarbonamide. A formation mechanism for 2-methyl-2-acetylthiazolidine and structurally related 2-acetyl-2,3,5,6-tetrahydro-1,4-thiazine and 5-acetyl-2,3-dihydro-1,4-thiazine is proposed.