Multidisciplinary Tool Kit for Febrile Neutropenia: Stewardship Guidelines, Staphylococcus aureus Epidemiology, and Antibiotic Use Ratios.

PURPOSE: Inappropriate vancomycin for febrile neutropenia (FN) is an ideal antimicrobial stewardship target. To improve vancomycin prescribing, we instituted a multifaceted intervention, including an educational guideline with audit for compliance; an antibiotic use audit; and an assessment of local burden of methicillin-resistant Staphylococcus aureus (MRSA) colonization and infection. MATERIALS AND METHODS: We conducted a quasi-experimental pre-post intervention review of vancomycin initiation for FN on a 32-bed hematology/oncology unit. A retrospective chart review was conducted from November 2015 to May 2016 (preintervention period). In January 2017, we implemented an institutional FN guideline emphasizing criteria for appropriate use. Vancomycin audit was conducted from February 2017 to October 2017 (postintervention period). The primary outcome was appropriateness of vancomycin initiation. We then compared average antibiotic use (days of therapy per 1,000 patient days) for vancomycin and cefepime before and after intervention. Finally, unit-wide MRSA screening cultures were obtained upon admission and bimonthly for 6 weeks (October 2, 2017, to November 9, 2017). Screened patients were followed for 12 months for clinical MRSA infection. RESULTS: Forty-three (49%) of 88 preintervention patients were started on empiric vancomycin appropriately, compared with 59 (66%) of 90 postintervention patients (P = .02). There was a significant decrease in vancomycin use after intervention. Six (7.1%) of 85 patients screened positive for MRSA colonization. During the 12-month follow-up, no colonized patients developed clinical MRSA infections (positive predictive value, 0.0%). Of the 79 noncolonized patients, 2 developed a clinically significant infection (negative predictive value, 97.5%). CONCLUSION: Guideline-focused education can improve vancomycin appropriateness in FN and should be bundled with education and feedback about local MRSA epidemiology and antibiotic use rates for maximal stewardship impact.

Sequence analysis of Jembrana disease virus strains reveals a genetically stable lentivirus.

Jembrana disease virus (JDV) is a lentivirus associated with an acute disease syndrome with a 20% case fatality rate in Bos javanicus (Bali cattle) in Indonesia, occurring after a short incubation period and with no recurrence of the disease after recovery. Partial regions of gag and pol and the entire env were examined for sequence variation in DNA samples from cases of Jembrana disease obtained from Bali, Sumatra and South Kalimantan in Indonesian Borneo. A high level of nucleotide conservation (97-100%) was observed in gag sequences from samples taken in Bali and Sumatra, indicating that the source of JDV in Sumatra was most likely to have originated from Bali. The pol sequences and, unexpectedly, the env sequences from Bali samples were also well conserved with low nucleotide (96-99%) and amino acid substitutions (95-99%). However, the sample from South Kalimantan (JDV(KAL/01)) contained more divergent sequences, particularly in env (88% identity). Phylogenetic analysis revealed that the JDV(KAL/01)env sequences clustered with the sequence from the Pulukan sample (Bali) from 2001. JDV appears to be remarkably stable genetically and has undergone minor genetic changes over a period of nearly 20 years in Bali despite becoming endemic in the cattle population of the island.

Negative regulation of MHC class II gene expression by CXCR4.

OBJECTIVE: CXCR4 is overexpressed in 23 types of cancers of both hematopoietic and nonhematopoietic origin. Based on the known role of CXCR4 and its ligand CXCL12 in homing of hematopoietic cells, CXCR4 is likely to play a role in metastasis. We have initiated a study aimed at dissecting additional functions of CXCR4 in cancer cells, particularly in relation to the immune system. MATERIALS AND METHODS: RNA from CXCR4+ and CXCR4- subpopulations of MDA-MB-231 breast cancer cells was subjected to microarray analysis. Cell surface expression of CXCR4 and MHC class II proteins were determined by flow cytometry. Real-time PCR was used for measuring mRNA levels of MHC class II and CIITA, the master regulator of MHC class II gene expression. RESULTS: 1988 genes were differentially expressed (p < 0.001) between CXCR4+ and CXCR4- cells. The expression of class II genes HLA-DPalpha1, HLA-DQbeta1, HLA-DRalpha, HLA-DRbeta1, HLA-DRbeta3, and CD74 was lower by 2.6-fold to eightfold in CXCR4+ cells compared to CXCR4- cells. Basal and IFN-gamma-inducible HLA-DR mRNA and protein levels were lower in CXCR4+ cells than in CXCR4- cells. HLA-DR mRNA expression in both cell types was reduced by CXCL12; the ability of CXCL12 to reduce HLA-DR was lower in cells expressing short interfering RNA against CXCR4. PKA inhibitor H89 and the SRC kinase inhibitor PP2 increased HLA-DR expression in CXCR4+ cells. The basal but not IFN-gamma-inducible expression of CIITA was 2.5-fold higher in CXCR4- cells compared to CXCR4+ cells. CD34+/CD38- hematopoietic cells from the human bone marrow contain a distinct CXCR4+/HLA-DR- subpopulation of cells. CONCLUSION: CXCR4 may influence the immune system under physiologic and pathologic conditions through negative regulation of MHC class II expression, possibly through PKA and SRC kinase.

CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis.

INTRODUCTION: A subpopulation (CD44+/CD24-) of breast cancer cells has been reported to have stem/progenitor cell properties. The aim of this study was to investigate whether this subpopulation of cancer cells has the unique ability to invade, home, and proliferate at sites of metastasis. METHODS: CD44 and CD24 expression was determined by flow cytometry. Northern blotting was used to determine the expression of proinvasive and 'bone and lung metastasis signature' genes. A matrigel invasion assay and intracardiac inoculation into nude mice were used to evaluate invasion, and homing and proliferation at sites of metastasis, respectively. RESULTS: Five among 13 breast cancer cell lines examined (MDA-MB-231, MDA-MB-436, Hs578T, SUM1315, and HBL-100) contained a higher percentage (>30%) of CD44+/CD24- cells. Cell lines with high CD44+/CD24- cell numbers express basal/mesenchymal or myoepithelial but not luminal markers. Expression levels of proinvasive genes (IL-1alpha, IL-6, IL-8, and urokinase plasminogen activator [UPA]) were higher in cell lines with a significant CD44+/CD24- population than in other cell lines. Among the CD44+/CD24(-)-positive cell lines, MDA-MB-231 has the unique property of expressing a broad range of genes that favor bone and lung metastasis. Consistent with previous studies in nude mice, cell lines with CD44+/CD24- subpopulation were more invasive than other cell lines. However, only a subset of CD44+/CD24(-)-positive cell lines was able to home and proliferate in lungs. CONCLUSION: Breast cancer cells with CD44+/CD24- subpopulation express higher levels of proinvasive genes and have highly invasive properties. However, this phenotype is not sufficient to predict capacity for pulmonary metastasis.

The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer.

Parthenolide, a sesquiterpene lactone, shows antitumor activity in vitro, which correlates with its ability to inhibit the DNA binding of the antiapoptotic transcription factor nuclear factor kappaB (NF-kappaB) and activation of the c-Jun NH(2)-terminal kinase. In this study, we investigated the chemosensitizing activity of parthenolide in vitro as well as in MDA-MB-231 cell-derived xenograft metastasis model of breast cancer. HBL-100 and MDA-MB-231 cells were used to measure the antitumor and chemosensitizing activity of parthenolide in vitro. Parthenolide was effective either alone or in combination with docetaxel in reducing colony formation, inducing apoptosis and reducing the expression of prometastatic genes IL-8 and the antiapoptotic gene GADD45beta1 in vitro. In an adjuvant setting, animals treated with parthenolide and docetaxel combination showed significantly enhanced survival compared with untreated animals or animals treated with either drug. The enhanced survival in the combination arm was associated with reduced lung metastases. In addition, nuclear NF-kappaB levels were lower in residual tumors and lung metastasis of animals treated with parthenolide, docetaxel, or both. In the established orthotopic model, there was a trend toward slower growth in the parthenolide-treated animals but no statistically significant findings were seen. These results for the first time reveal the significant in vivo chemosensitizing properties of parthenolide in the metastatic breast cancer setting and support the contention that metastases are very reliant on activation of NF-kappaB.

Recombinant Jembrana disease virus gag proteins identify several different antigenic domains but do not facilitate serological differentiation of JDV and nonpathogenic bovine lentiviruses.

In Indonesia, it is suspected that there are two bovine lentiviruses circulating in the cattle population: a pathogenic Jembrana disease virus (JDV), and a nonpathogenic bovine immunodeficiency-like virus (BIV). Both viruses cross-react antigenically and cannot be differentiated by current serological tests using JDV antigens. To identify possible type-specific epitopes, a series of recombinant protein constructs including the matrix, capsid and nucleocapsid proteins were produced from JDV gag and the expressed proteins were tested by Western blot using JDV and BIV hyperimmune sera. JDV matrix and truncated capsid proteins were recognised by both JDV and BIV hyperimmune sera indicating that there were multiple cross-reactive epitopes present in JDV gag. At least three epitopic regions were identified in these constructs, including the major homology region, by monoclonal antibody binding studies. JDV nucleocapsid recombinant protein was not recognised by either JDV or BIV hyperimmune sera and none of the recombinant gag proteins were able to differentiate between JDV positive sera from Jembrana disease endemic and Jembrana disease-free areas. Additionally, a 40 amino acid recombinant subunit protein encompassing the region recently found to contain an epitope unique to BIV [Zheng, L., Zhang, S., Wood, C., Kapil, S., Wilcox, G.E., Loughin, T.A., Minocha, H.C., 2001. Differentiation of two bovine lentiviruses by a monoclonal antibody on the basis of epitope specificity. Clin. Diagn. Lab. Immunol. 8, 283-287] was tested but was not recognised by either JDV positive sera from Jembrana disease-endemic or Jembrana disease-free areas.

The science of patient safety: implications for oncology nursing practice.

Patient safety is one of the most frequent terms used in health care today. Patients and their families are, first and foremost, focused on receiving effective and safe care, and oncology nurses strive to incorporate clinical evidence into day-to-day practice. This article provides a road map on how to incorporate emerging patient safety science into daily clinical practice to best serve patients and their families.

The music of your emotions: neural substrates involved in detection of emotional correspondence between auditory and visual music actions.

In humans, emotions from music serve important communicative roles. Despite a growing interest in the neural basis of music perception, action and emotion, the majority of previous studies in this area have focused on the auditory aspects of music performances. Here we investigate how the brain processes the emotions elicited by audiovisual music performances. We used event-related functional magnetic resonance imaging, and in Experiment 1 we defined the areas responding to audiovisual (musician's movements with music), visual (musician's movements only), and auditory emotional (music only) displays. Subsequently a region of interest analysis was performed to examine if any of the areas detected in Experiment 1 showed greater activation for emotionally mismatching performances (combining the musician's movements with mismatching emotional sound) than for emotionally matching music performances (combining the musician's movements with matching emotional sound) as presented in Experiment 2 to the same participants. The insula and the left thalamus were found to respond consistently to visual, auditory and audiovisual emotional information and to have increased activation for emotionally mismatching displays in comparison with emotionally matching displays. In contrast, the right thalamus was found to respond to audiovisual emotional displays and to have similar activation for emotionally matching and mismatching displays. These results suggest that the insula and left thalamus have an active role in detecting emotional correspondence between auditory and visual information during music performances, whereas the right thalamus has a different role.

Adipose tissue production of hepatocyte growth factor contributes to elevated serum HGF in obesity.

Serum HGF is elevated in obese individuals. This study examined the contribution of excess adipose tissue to increased circulating HGF levels in obesity. Serum HGF was measured by ELISA before and after weight loss due to bariatric surgery or a 24-h fast. At 6.1 +/- 0.1 mo following surgery, BMI (50.6 +/- 1.6 vs. 35.1 +/- 1.3 kg/m(2); P < 0.0001) and serum HGF were significantly decreased (1,164 +/- 116 vs. 529 +/- 39 pg/ml, P < 0.001). A 24-h fast did not change serum HGF, but serum leptin was significantly reduced (67.7 +/- 7.1 vs. 50.3 +/- 8.3 ng/ml, P = 0.02). HGF secretion in vitro from adipocytes of obese (BMI 40.3 +/- 2.8 kg/m(2)) subjects was significantly greater (80.9 +/- 10.4 vs. 21.5 +/- 4.0 pg/10(5) cells, P = 0.008) than release from adipocytes of lean (BMI 23.3 +/- 1.4 kg/m(2)) subjects. HGF mRNA levels determined by real-time RT-PCR were not different in adipocytes from lean (BMI 24.0 +/- 0.8 kg/m(2)) and obese (45.7 +/- 3.0 kg/m(2)) subjects, but serum HGF was significantly elevated in the obese individuals studied (787 +/- 61 vs. 489 +/- 49 pg/ml, P = 0.001). TNF-alpha (24 h treatment) significantly increased HGF release from subcutaneous adipocytes 23.6 +/- 8.3% over control (P = 0.02). These data suggest that elevated serum HGF in obesity is in part attributable to excess adipose tissue and that this effect can be reversed by reducing adipose tissue mass through weight loss. Increased HGF secretion from adipocytes of obese subjects may be due to posttranscriptional events possibly related to adipocyte size and stimulation by elevated TNF-alpha in the adipose tissue of obese individuals.