FGF5 is expressed in melanoma and enhances malignancy in vitro and in vivo.

Although FGF5 mRNA was previously found expressed in some melanoma cell lines in contrast to normal human melanocytes, neither its contribution to melanoma growth nor its expression in melanoma tissue has been investigated. Here we demonstrate that ectopic overexpression of FGF5 in human melanoma cells with low endogenous FGF5 expression increased clonogenicity and invasion but not short-term growth in vitro. Silencing of FGF5 in melanoma cells with high endogenous FGF5 expression had the opposite effect on clonogenicity. FGF overexpression led to increased signaling along the MAPK and NFAT axis but had no effect on STAT3 signaling. In an in vivo experiment in immunocompromised mice, human melanoma xenografts overexpressing FGF5 showed enhanced tumor growth, a higher Ki-67 proliferation index, decreased apoptosis and enhanced angiogenesis. Immunohistochemistry performed on a tissue microarray demonstrated FGF5 protein expression in more than 50% of samples of melanoma and benign nevi. These data suggest that FGF5 has oncogenic potential in melanoma cells and contributes to melanoma growth in a subset of patients. This highlights the importance of further evaluating FGF5 as potential biomarker and therapy target in melanoma.

Evaluating the effect of Matricaria recutita and Mentha piperita herbal mouthwash on management of oral mucositis in patients undergoing hematopoietic stem cell transplantation: A randomized, double blind, placebo controlled clinical trial.

OBJECTIVES: To investigate the effects of Matricaria recutita and Mentha piperita on oral mucositis (OM) in patients undergoing hematopoietic stem cell transplantation (HSCT). DESIGN: Randomized double blind placebo controlled clinical trial. SETTING: Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, and Bone Marrow Transplantation Center at Taleghani Teaching Hospital, Tehran, Iran. PARTICIPANTS: Sixty patients undergoing HSCT were randomly assigned to two groups: placebo (n=33), and herbal mouthwash group (n=27). INTERVENTIONS: All patients received the mouthwash one week before HSCT and were instructed to use it three times daily for at least 30s. MAIN OUTCOME MEASURES: OM was graded using National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale (grade 0-5). The Numerical Rating Scale (NRS: 0-10 scale) measured the severity of OM symptoms. RESULTS: The duration, maximum and average daily grade of OM were significantly reduced in the treatment group (P<0.05). The use of herbal mouthwash led to significant improvements in pain intensity (P=0.009), dryness (P=0.04) and dysphagia (P=0.009). Other significant results included: reduced need for complementary medications (P=0.03), narcotic analgesics (P=0.047), total parenteral nutrition (TPN) (P=0.02) and the duration of TPN (P=0.03). CONCLUSION: This study shows that patients receiving the herbal mouthwash experienced less complications and symptoms associated with OM. In summary, it seems that the use of our prepared herbal mouthwash is beneficial for patients undergoing HSCT.

Effects of Pharmacist Intervention on the Utilization of Vancomycin in a Teaching Hospital.

In order to investigate the effect of pharmacist intervention on vancomycin use, this study was performed on all patients receiving vancomycin in the intensive care unit (ICU) and hematology-oncology ward of Taleghani Educational Hospital in Tehran, Iran. Vancomycin use was assessed during a pre- and post-intervention period in accordance with the Center of Disease Control and prevention (CDC) and Infectious Diseases Society of America (IDSA) guidelines. Following the intervention, there was a significant change in appropriate initiation of vancomycin (P = 0.009) and no significant improvement was observed in adequate dosage and the duration of therapy (P = 0.15 and P = 0.54 respectively); however, informing the physician resulted in discontinuation of the drug in 50% of inappropriate cases and vancomycin dosage was adjustedin 31% of cases. Temperature charts, culture results and pre-treatment CBC tests changed significantly (P = 0.02, P = 0.009 and P = 0.04 respectively). The rate of infusion related adverse drug reactions did not decrease significantly (P = 0.06); yet in 100% of patients, these reactions were resolved after notifying the nursing team. After pharmacist intervention,vancomycin use improved in some aspects. A significant improvement in appropriate initiation of therapy was observed; however, treatments continued despite negative cultures. It is necessary to optimize the use of vancomycin by performing more educational interventions.

The ß-importin KAP8 (Pse1/Kap121) is required for nuclear import of the cellulase transcriptional regulator XYR1, asexual sporulation and stress resistance in Trichoderma reesei.

The ascomycete Trichoderma reesei is an industrial producer of cellulolytic and hemicellulolytic enzymes, and serves as a prime model for their genetic regulation. Most of its (hemi-)cellulolytic enzymes are obligatorily dependent on the transcriptional activator XYR1. Here, we investigated the nucleo-cytoplasmic shuttling mechanism that transports XYR1 across the nuclear pore complex. We identified 14 karyopherins in T. reesei, of which eight were predicted to be involved in nuclear import, and produced single gene-deletion mutants of all. We found KAP8, an ortholog of Aspergillus nidulans KapI, and Saccharomyces cerevisiae Kap121/Pse1, to be essential for nuclear recruitment of GFP-XYR1 and cellulase gene expression. Transformation with the native gene rescued this effect. Transcriptomic analyses of Δkap8 revealed that under cellulase-inducing conditions 42 CAZymes, including all cellulases and hemicellulases known to be under XYR1 control, were significantly down-regulated. Δkap8 strains were capable of forming fertile fruiting bodies but exhibited strongly reduced conidiation both in light and darkness, and showed enhanced sensitivity towards abiotic stress, including high osmotic pressure, low pH and high temperature. Together, these data underscore the significance of nuclear import of XYR1 in cellulase and hemicellulase gene regulation in T. reesei, and identify KAP8 as the major karyopherin required for this process.

The effects of earmuff on physiologic and motor responses in premature infants admitted in neonatal intensive care unit.

BACKGROUND: Continuous high-intensity noise in the Neonatal Intensive Care Unit (NICU) is stressful for premature infants and its reduction is considered as a nursing care. This study aimed to evaluate the effects of earmuffs' use on the physiologic and motor responses of premature infants. MATERIALS AND METHODS: This is a clinical trial conducted on 64 premature infants admitted to the NICU, who met the inclusion criteria, and were randomly assigned to study and control groups. Earmuffs were used for premature infants for 2 h in the morning and 2 h in the afternoon for two consecutive days to reduce the noise intensity in the busiest time of the NICU. The group with earmuff (study group) was compared with the control group receiving only routine care. Infants' physiologic and motor responses were observed before, during, immediately, and 1 h after the intervention. Analysis of covariance and repeated measure analysis of variance (ANOVA) were used to analyze the data. RESULTS: When infants wore the earmuffs, they had significantly higher mean arterial oxygen saturation, the less frequent motor response, and a decrease in their pulse and respiratory rate. CONCLUSION: Paying attention to environmental noise can help the patients, especially the neonates in the NICU, and can be considered as a nursing care. Wearing earmuffs can protect premature infants against noise in the NICU and improve their physiological and motor state.

Effects of Scrophularia extracts on tumor cell proliferation, death and intravasation through lymphoendothelial cell barriers.

Different studies describe the anti-inflammatory effects of Scrophularia species, a medicinal plant widely used in folk medicine since ancient times. As knowledge regarding the anti-neoplastic properties of this species is rather limited, we investigated the influence of methanol extracts of different Scrophularia species on cell proliferation, cell death, and tumour cell intravasation through the lymph endothelial barrier. HL-60 leukaemia cells were treated with methanol extracts of different Scrophularia species leading to strong growth inhibition and high cell death rates. The expression of cell cycle regulators, oncogenes and cell death inducers was determined by Western blot analysis. Furthermore the effect of S. lucida was studied in an NF-κB reporter assay, and in a novel assay measuring 'circular chemo-repellent-induced defects' (CCID) in lymph endothelial monolayers that were induced by MCF-7 breast cancer spheroids. Methanol extracts of Scrophularia species exhibited strong anti-proliferative properties. S. floribunda extract inhibited G2/M- and later on S-phase and S. lucida inhibited S-phase and in both cases this was associated with the down-regulation of c-Myc expression. Extracts of S. floribunda and S. lucida led to necrosis and apoptosis, respectively. Furthermore, S. lucida, but not S. floribunda, effectively attenuated tumour cell intravasation through lymph endothelial cell monolayers, which correlated with the inhibition of NF-κB. S. lucida exhibited promising anti-neoplastic effects and this was most likely due to the down-regulation of various cell cycle regulators, proto-oncogenes and NF-κB and the activation of caspase-3.

Fibroblast growth factor receptors as therapeutic targets in human melanoma: synergism with BRAF inhibition.

Cutaneous melanoma is a tumor with rising incidence and a very poor prognosis at the disseminated stage. Melanomas are characterized by frequent mutations in BRAF and also by overexpression of fibroblast growth factor 2 (FGF2), offering opportunities for therapeutic intervention. We investigated inhibition of FGF signaling and its combination with dacarbazine or BRAF inhibitors as an antitumor strategy in melanoma. The majority of melanoma cell lines displayed overexpression of FGF2 but also FGF5 and FGF18 together with different isoforms of FGF receptors (FGFRs) 1-4. Blockade of FGF signals with dominant-negative receptor constructs (dnFGFR1, 3, or 4) or small-molecule inhibitors (SU5402 and PD166866) reduced melanoma cell proliferation, colony formation, as well as anchorage-independent growth, and increased apoptosis. DnFGFR constructs also significantly inhibited tumor growth in vivo. Combination of FGF inhibitors with dacarbazine showed additive or antagonistic effects, whereas synergistic drug interaction was observed when combining FGFR inhibition with the multikinase/BRAF inhibitor sorafenib or the V600E mutant-specific BRAF inhibitor RG7204. In conclusion, FGFR inhibition has antitumor effects against melanoma cells in vitro and in vivo. Combination with BRAF inhibition offers a potential for synergistic antimelanoma effects and represents a promising therapeutic strategy against advanced melanoma.