Miracle-dz/UniFAR-FTUs huggingface dataset:
MicroRNA‐492 is processed from the keratin 19 gene and up‐regulated in metastatic hepatoblastoma

MicroRNAs (miRNAs) are well‐known regulators of proliferation, apoptosis, and differentiation and are recognized to play an important role in the development of cancers. Here we aimed to identify the functional contribution of miRNAs to the biology of hepatoblastoma (HB), the most common malignant liver tumor in childhood. As overexpression of the oncogene PLAG1 (pleomorphic adenoma gene 1) is a characteristic phenomenon in HB, we used RNA interference and subsequent miRNA array analysis to identify miR‐492 as most strongly influenced by PLAG1. We provide novel experimental evidence that miR‐492 can originate from the coding sequence of the HB marker gene keratin 19 (KRT19). In agreement with these in vitro observations, significantly elevated levels of coexpressed KRT19 and miR‐492 were particularly found in metastatic HB tumor samples. Stable overexpression of miR‐492 in HB cell clones served to identify a broad range of differentially expressed transcripts, including several candidate targets of miR‐492 predicted by computational algorithms. Among those the liver enzyme BAAT showed significant association with miR‐492 expression in HB tumor samples. Conclusion: A close functional relationship between KRT19 and miR‐492 was identified that may play an important role in the progression of malignant embryonal liver tumors. Additionally, miR‐492 and its associated targets might serve as new HB biomarkers of clinical utility and could assist to explore targeted therapies, especially in metastatic HB with a poor prognosis. (HEPATOLOGY 2011)
Activation of v‐Myb avian myeloblastosis viral oncogene homolog‐like2 (MYBL2)‐LIN9 complex contributes to human hepatocarcinogenesis and identifies a subset of hepatocellular carcinoma with mutant p53

Up‐regulation of the v‐Myb avian myeloblastosis viral oncogene homolog‐like2 B‐Myb (MYBL2) gene occurs in human hepatocellular carcinoma (HCC) and is associated with faster progression of rodent hepatocarcinogenesis. We evaluated, in distinct human HCC prognostic subtypes (as defined by patient survival length), activation of MYBL2 and MYBL2‐related genes, and relationships of p53 status with MYBL2 activity. Highest total and phosphorylated protein levels of MYBL2, E2F1‐DP1, inactivated retinoblastoma protein (pRB), and cyclin B1 occurred in HCC with poorer outcome (HCCP), compared to HCC with better outcome (HCCB). In HCCP, highest LIN9‐MYBL2 complex (LINC) and lowest inactive LIN9‐p130 complex levels occurred. MYBL2 positively correlated with HCC genomic instability, proliferation, and microvessel density, and negatively with apoptosis. Higher MYBL2/LINC activation in HCC with mutated p53 was in contrast with LINC inactivation in HCC harboring wildtype p53. Small interfering RNA (siRNA)‐mediated MYBL2/LINC silencing reduced proliferation, induced apoptosis, and DNA damage at similar levels in HCC cell lines, irrespective of p53 status. However, association of MYBL2/LINC silencing with doxorubicin‐induced DNA damage caused stronger growth restraint in p53−/− Huh7 and Hep3B cells than in p53+/+ Huh6 and HepG2 cells. Doxorubicin triggered LIN9 dissociation from MYBL2 in p53+/+ cell lines and increased MYBL2‐LIN9 complexes in p53−/− cells. Doxorubicin‐induced MYBL2 dissociation from LIN9 led to p21WAF1 up‐regulation in p53+/+ but not in p53−/− cell lines. Suppression of p53 or p21WAF1 genes abolished DNA damage response, enhanced apoptosis, and inhibited growth in doxorubicin‐treated cells harboring p53+/+. Conclusion: We show that MYBL2 activation is crucial for human HCC progression. In particular, our data indicate that MYBL2‐LIN9 complex integrity contributes to survival of DNA damaged p53−/− cells. Thus, MYBL2 inhibition could represent a valuable adjuvant for treatments against human HCC with mutated p53. (HEPATOLOGY 2011;)
Plasma miR-183 predicts recurrence and prognosis in patients with colorectal cancer

Colorectal cancer (CRC) is one of the most common malignancies worldwide. The prognosis for this cancer is poor, and the development of novel biomarkers, particularly non-invasive surrogate biomarkers, is urgently needed. Recent studies have demonstrated that microRNAs (miRNAs) are stably detectable in the blood and can serve as useful biomarkers for various types of cancer. In this study, the miR-183 expression levels were found to be significantly overexpressed in plasma samples from CRC patients compared with controls, and the postoperative plasma miR-183 levels were significantly reduced compared with the preoperative levels. The value of the area under the receiver operating characteristic (ROC) curve obtained for miR-183 was 0.829, which was higher than those for carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). High plasma miR-183 expression was significantly associated with lymph node metastasis, distant metastasis, higher pTNM stage (III-IV), and tumor recurrence. CRC patients with elevated miR-183 expression in plasma displayed shorter disease-free survival (DFS) and lower overall survival (OS). More importantly, plasma miR-183 was independently correlated with tumor recurrence and a lower OS. Collectively, our results suggested that the elevated miR-183 in the plasma could be a promising biomarker for predicting the risk of tumor recurrence and poor survival in CRC patients.
Glycaemic control in patients with type 2 diabetes switching from premixed insulin to long‐acting basal insulin analogue plus oral antidiabetic drugs: an observational study

Aim: To evaluate whether administration of long‐acting basal insulin analogue plus oral antidiabetic drugs (OADs) improves glycaemic control in type 2 diabetic patients with glycosylated haemoglobin (HbA1c) > 7% (53 mmol/mol) under premixed insulin therapy.
A novel plant protein disulfide isomerase family homologous to animal P5 – molecular cloning and characterization as a functional protein for folding of soybean seed‐storage proteins

The protein disulfide isomerase is known to play important roles in the folding of nascent polypeptides and in the formation of disulfide bonds in the endoplasmic reticulum (ER). In this study, we cloned a gene of a novel protein disulfide isomerase family from soybean leaf (Glycine max L. Merrill. cv Jack) mRNA. The cDNA encodes a protein called GmPDIM. It is composed of 438 amino acids, and its sequence and domain structure are similar to that of animal P5. Recombinant GmPDIM expressed in Escherichia coli displayed an oxidative refolding activity on denatured RNase A. The genomic sequence of GmPDIM was also cloned and sequenced. Comparison of the soybean sequence with sequences from Arabidopsis thaliana and Oryza sativa showed significant conservation of the exon/intron structure. Consensus sequences within the promoters of the GmPDIM genes contained a cis‐acting regulatory element for the unfolded protein response, and other regulatory motifs required for seed‐specific expression. We observed that expression of GmPDIM was upregulated under ER‐stress conditions, and was expressed ubiquitously in soybean tissues such as the cotyledon. It localized to the lumen of the ER. Data from co‐immunoprecipitation experiments suggested that GmPDIM associated non‐covalently with proglycinin, a precursor of the seed‐storage protein glycinin. In addition, GmPDIM associated with the α′ subunit of β‐conglycinin, a seed‐storage protein in the presence of tunicamycin. These results suggest that GmPDIM may play a role in the folding of storage proteins and functions not only as a thiol‐oxidoredactase, but also as molecular chaperone.
Eating Disorders & Breastfeeding

Disordered eating is a concern for clinicians providing care to adolescent female patients, yet the concern seems to drift from the forefront as the patient matures toward motherhood. As women become pregnant, they may adopt a negative body image that persists throughout the postnatal period with pregnancy-related weight gain. For women with a history of an eating disorder (ED), these physical changes may reactivate past coping strategies such as food restriction, binge eating, or induced vomiting to maintain prepregnancy weight. There is evidence that long-term breastfeeding fosters a positive maternal–child bond, aids in postpartum weight loss, and provides the mother with an opportunity to reestablish healthy eating habits for her infant. Because clinicians providing care for pregnant and postpartum women develop trusting relationships through frequent and prolonged contact with their patients, nurses can provide screening for ED symptoms and educate their patients about the positive effects of breastfeeding as it applies to her recovery from pregnancy and ED. This article discusses how breastfeeding can positively influence complications present in pregnant mothers with EDs and provides nurses with tools to cultivate the mother's positive self-image.
Lpx1p is a peroxisomal lipase required for normal peroxisome morphology

Lpx1p (systematic name: Yor084wp) is a peroxisomal protein from Saccharomyces cerevisiae with a peroxisomal targeting signal type 1 (PTS1) and a lipase motif. Using mass spectrometry, we have identified Lpx1p as present in peroxisomes, and show that Lpx1p import is dependent on the PTS1 receptor Pex5p. We provide evidence that Lpx1p is piggyback‐transported into peroxisomes. We have expressed the Lpx1p protein in Escherichia coli, and show that the enzyme exerts acyl hydrolase and phospholipase A activity in vitro. However, the protein is not required for wild‐type‐like steady‐state function of peroxisomes, which might be indicative of a metabolic rather than a biogenetic role. Interestingly, peroxisomes in deletion mutants of LPX1 have an aberrant morphology characterized by intraperoxisomal vesicles or invaginations.
Brox, a novel farnesylated Bro1 domain‐containing protein that associates with charged multivesicular body protein 4 (CHMP4)

Human Brox is a newly identified 46 kDa protein that has a Bro1 domain‐like sequence and a C‐terminal thioester‐linkage site of isoprenoid lipid (CAAX motif) (C standing for cysteine, A for generally aliphatic amino acid, and X for any amino acid). Mammalian Alix and its yeast ortholog, Bro1, are known to associate with charged multivesicular body protein 4 (CHMP4), a component of endosomal sorting complex required for transport III, via their Bro1 domains and to play roles in sorting of ubiquitinated cargoes. We investigated whether Brox has an authentic Bro1 domain on the basis of its capacity for interacting with CHMP4s. Both Strep Tactin binding sequence (Strep)‐tagged wild‐type Brox (Strep–BroxWT) and Strep‐tagged farnesylation‐defective mutant (Cys→Ser mutation; Strep–BroxC408S) pulled down FLAG‐tagged CHMP4b that was coexpressed in HEK293 cells. Treatment of cells with a farnesyltransferase inhibitor, FTI‐277, caused an electrophoretic mobility shift of Strep–BroxWT, and the mobility coincided with that of Strep–BroxC408S. The inhibitor also caused a mobility shift of endogenous Brox detected by western blotting using polyclonal antibodies to Brox, suggesting farnesylation of Brox in vivo. Fluorescence microscopic analyses revealed that Strep–BroxWT exhibited accumulation in the perinuclear area and caused a punctate pattern of FLAG–CHMP4b that was constitutively expressed in HEK293 cells. On the other hand, Strep–BroxC408S showed a diffuse pattern throughout the cell, including the nucleus, and did not cause accumulation of FLAG–CHMP4b. Fluorescent signals of monomeric green fluorescent protein (mGFP)‐fused BroxWT merged partly with those of Golgi markers and with those of abnormal endosomes induced by overexpression of a dominant negative mutant of AAA type ATPase SKD1/Vps4B in HeLa cells, but such colocalization was less efficient for mGFP–BroxC408S. These results suggest a physiological significance of farnesylation of Brox in its subcellular distribution and efficient interaction with CHMP4s in vivo.
Faculty and Staff Development Strategies to Prevent Childhood Obesity

AbstractChildhood obesity prevention and management is currently a priority health focus in the United States. Graduates of nursing programs and practicing registered nurses must be competent to implement interventions and programs to assess, prevent, and manage childhood obesity in acute care and community settings. This article provides an overview of the scope of the problem and recommendations from relevant health organizations. Nurse and staff educators are provided with specific content and teaching strategies for the prevention and management of childhood obesity for developing the knowledge and skills of nursing students, staff nurses, and advanced practice nurses.
The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91phox mediate hepatic fibrosis in mice

Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a multicomponent enzyme that mediates electron transfer from nicotinamide adenine dinucleotide phosphate to molecular oxygen, which leads to the production of superoxide. NOX2/gp91phox is a catalytic subunit of NOX expressed in phagocytic cells. Several homologues of NOX2, including NOX1, have been identified in nonphagocytic cells. We investigated the contributory role of NOX1 and NOX2 in hepatic fibrosis. Hepatic fibrosis was induced in wild‐type (WT) mice, NOX1 knockout (NOX1KO) mice, and NOX2 knockout (NOX2KO) mice by way of either carbon tetrachloride (CCl4) injection or bile duct ligation (BDL). The functional contribution of NOX1 and NOX2 in endogenous liver cells, including hepatic stellate cells (HSCs), and bone marrow (BM)‐derived cells, including Kupffer cells (KCs), to hepatic reactive oxygen species (ROS) generation and hepatic fibrosis was assessed in vitro and in vivo using NOX1 or NOX2 BM chimeric mice. Hepatic NOX1 and NOX2 messenger RNA expression was increased in the two experimental mouse models of hepatic fibrosis. Whereas NOX1 was expressed in HSCs but not in KCs, NOX2 was expressed in both HSCs and KCs. Hepatic fibrosis and ROS generation were attenuated in both NOX1KO and NOX2KO mice after CCl4 or BDL. Liver fibrosis in chimeric mice indicated that NOX1 mediates the profibrogenic effects in endogenous liver cells, whereas NOX2 mediates the profibrogenic effects in both endogenous liver cells and BM‐derived cells. Multiple NOX1 and NOX2 components were up‐regulated in activated HSCs. Both NOX1‐ and NOX2‐deficient HSCs had decreased ROS generation and failed to up‐regulate collagen α1(I) and transforming growth factor β in response to angiotensin II. Conclusion: Both NOX1 and NOX2 have an important role in hepatic fibrosis in endogenous liver cells, including HSCs, whereas NOX2 has a lesser role in BM‐derived cells. (HEPATOLOGY 2011;)
RN181 suppresses hepatocellular carcinoma growth by inhibition of the ERK/MAPK pathway

The activation of oncogenes and the inactivation of tumor suppressor genes by mutations or chronic hepatitis virus infections play key roles in the pathogenesis of hepatocellular carcinoma (HCC). Here we report that RN181, a really interesting new gene finger domain‐containing protein, was down‐regulated in highly malignant cell lines and in tumor cells of 139 HCC clinical samples in comparison with adjacent normal liver tissues. The expression of RN181 was strongly associated with the pathological grade of HCC. Alterations of the expression of RN181 by retrovirus‐transduced up‐regulation and short hairpin RNA–mediated down‐regulation demonstrated the function of RN181 as a tumor suppressor because it decreased the proliferation and colony formation of HCC cells in vitro and inhibited tumor growth in vivo by suppressing cell proliferation and enhancing cell apoptosis in xenografted tumors. Proteomic analyses showed that RN181 regulates the expression of many proteins that are important in many cellular processes. Statistical analyses identified 33 proteins with consistent changes (≥2‐fold) in RN181‐transformed cells. Ten of these proteins were up‐regulated by RN181, and 23 were down‐regulated. Representative proteins were validated by western blotting. Interaction network investigations revealed that 20 RN181‐regulated proteins could integrate several key biological processes such as survival, metabolism, and mitogen‐activated protein kinase (MAPK) pathways. Remarkably, 11 of the 33 proteins are associated with MAPK signaling in one or more ways. RN181 suppressed the tyrosine phosphorylation of extracellular signal‐regulated kinase 1/2 (ERK1/2) in cell lines and in tumor cells of xenografts and HCC clinical samples, and removing the suppression increased tumor growth.
Obstetric Float Nurse Role Redesign in a Small Rural Community Hospital

Purpose: The purpose of this process improvement project in a rural community hospital with a small volume perinatal service was to foster a cooperative working environment between the obstetric and medical–surgical nursing teams and promote quality nursing care by evaluating, revising, and clearly defining the obstetric float nurse role. Scope of the Problem: Members of the obstetric and medical–surgical nursing team were convened to evaluate the obstetric float nurse role and develop plans for improvement. Nurses from both units participated in a written survey before and after the project was completed. Based on issues identified from review of the surveys and group discussion, a guideline was developed that defined the expectations and responsibilities of the obstetric float nurse on the medical–surgical unit. Result: The redesigned obstetric float nurse role helped nurses of both units understand the expectations and responsibilities of the obstetric float nurse and promoted better working relationships. An additional benefit was improved communication regarding care and needs of the medical–surgical patients. Clinical Implications: Clearly defined obstetric float nurse guidelines were successful in our small rural community hospital and may be of benefit to other similar volume perinatal units.
Order within a mosaic distribution of mitochondrial c‐type cytochrome biogenesis systems?

Mitochondrial cytochromes c and c1 are present in all eukaryotes that use oxygen as the terminal electron acceptor in the respiratory chain. Maturation of c‐type cytochromes requires covalent attachment of the heme cofactor to the protein, and there are at least five distinct biogenesis systems that catalyze this post‐translational modification in different organisms and organelles. In this study, we use biochemical data, comparative genomic and structural bioinformatics investigations to provide a holistic view of mitochondrial c‐type cytochrome biogenesis and its evolution. There are three pathways for mitochondrial c‐type cytochrome maturation, only one of which is present in prokaryotes. We analyze the evolutionary distribution of these biogenesis systems, which include the Ccm system (System I) and the enzyme heme lyase (System III). We conclude that heme lyase evolved once and, in many lineages, replaced the multicomponent Ccm system (present in the proto‐mitochondrial endosymbiont), probably as a consequence of lateral gene transfer. We find no evidence of a System III precursor in prokaryotes, and argue that System III is incompatible with multi‐heme cytochromes common to bacteria, but absent from eukaryotes. The evolution of the eukaryotic‐specific protein heme lyase is strikingly unusual, given that this protein provides a function (thioether bond formation) that is also ubiquitous in prokaryotes. The absence of any known c‐type cytochrome biogenesis system from the sequenced genomes of various trypanosome species indicates the presence of a third distinct mitochondrial pathway. Interestingly, this system attaches heme to mitochondrial cytochromes c that contain only one cysteine residue, rather than the usual two, within the heme‐binding motif. The isolation of single‐cysteine‐containing mitochondrial cytochromes c from free‐living kinetoplastids, Euglena and the marine flagellate Diplonema papillatum suggests that this unique form of heme attachment is restricted to, but conserved throughout, the protist phylum Euglenozoa.
CORRELATIONS BETWEEN VIDEO CAPSULE ENDOSCOPIC FINDINGS AND CLINICAL ACTIVITY IN CROHN’S DISEASE

Background and Aims: Video capsule endoscopy (VCE) has become increasingly important as a simple method for observing the entire small intestine. The indications for VCE are obscure gastrointestinal bleeding and investigation of Crohn’s disease (CD). However, the correlation between endoscopic findings obtained by VCE and clinical findings in known cases of CD is not clear, and we therefore investigated this in the present study.
Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment

ABSTRACT Many types of tumors are organized in a hierarchy of heterogeneous cell populations. The cancer stem-like cells (CSCs) hypothesis suggests that tumor development and metastasis are driven by a minority population of cells, which are responsible for tumor initiation, growth and recurrences. The inability to efficiently eliminate CSCs during chemotherapy, together with CSCs being highly tumorigenic and invasive, may result in treatment failure due to cancer relapse and metastases. CSCs are emerging as a promising target for the development of translational cancer therapies. Ideal panacea for cancer would kill all malignant cells, including CSCs and bulk tumor cells. Since both chemotherapy and CSCs-specific therapy are insufficient to cure cancer, we propose combination therapy with CSCs-targeted agents and chemotherapeutics for improved breast cancer treatment. We generated in vitro mammosphere of 2 breast cancer cell lines, and demonstrated ability of mammospheres to grow and enrich cancer cells with stem-like properties, including self-renewal, multilineage differentiation and enrichment of cells expressing breast cancer stem-like cell biomarkers CD44+/CD24−/low. The formation of mammospheres was significantly inhibited by salinomycin, validating its pharmacological role against the cancer stem-like cells. In contrast, paclitaxel showed a minimal effect on the proliferation and growth of breast cancer stem-like cells. While combination therapies of salinomycin with conventional chemotherapy (paclitaxel or lipodox) showed a potential to improve tumor cell killing, different subtypes of breast cancer cells showed different patterns in response to the combination therapies. While optimization of combination therapy is warranted, the design of combination therapy should consider phenotypic attributes of breast cancer types.
Two CYP17 genes in the South African Angora goat (Capra hircus) – the identification of three genotypes that differ in copy number and steroidogenic output

In mammals, cytochrome P450 17α‐hydroxylase/17–20 lyase (CYP17), which is encoded by a single gene, plays a critical role in the production of mineralocorticoids, glucocorticoids and androgens by the adrenal cortex. Two CYP17 isoforms with unique catalytic properties have been identified in the South African Angora goat (Capra hircus), a subspecies that is susceptible to cold stress because of the inability of the adrenal cortex to produce sufficient levels of cortisol. A real‐time‐based genotyping assay was used in this study to identify the distribution of the two CYP17 alleles in the South African Angora population. These data revealed that the two CYP17 isoforms were not the product of two alleles of the same gene, but two separate CYP17 genes encoding the two unique CYP17 isoforms. This novel finding was subsequently confirmed by quantitative real‐time PCR. Goats were divided into three unique genotypes which differed not only in the genes encoding CYP17, but also in copy number. Furthermore, in vivo assays revealed that the identified genotypes differed in their ability to produce cortisol in response to intravenous insulin injection. This study clearly demonstrates the presence of two CYP17 genes in the South African Angora goat, and further implicates CYP17 as the primary cause of the observed hypocortisolism in this subspecies.