Photoinduced antibacterial activity of NRC03 peptide-conjugated dopamine/nano-reduced graphene oxide against Staphylococcus aureus.

In recent years, several drugs have become relatively easy to obtain with the rapid development of the economy and improvement in people's living standards. However, pathogenic bacteria have evolved strains that are resistant to certain drugs, such as antibiotics. Peptides are generally considered to be safe, have high tolerance to drugs, and are easy to manufacture. However, peptides are easily decomposed in complex biological environments. To solve this problem, many studies have modified peptides on the surface of nanomaterials to increase their functionality, biocompatibility, and stability. Meanwhile, nanomaterials have exhibited good absorption of near-infrared (NIR) light. When the NIR laser is focused on nanomaterials, photons are absorbed and the energy of the photons is converted into heat. Low-toxicity NRC03 peptide-conjugated dopamine/nano-reduced-graphene oxide (NRC03-DA/nRGO) nanomaterials are synthesized in this study for antibacterial testing using photothermal technology. The strains used in this study were Gram-positive Staphylococcus aureus (S. aureus). Our results indicated that the synthesized NRC03-DA/nRGO exhibits good absorption of NIR light and high photothermal conversion efficiency. Moreover, the synthesized NRC03-DA/nRGO inhibits the growth and survival of S. aureus. When the NRC03 peptide is modified on the surface of DA/nRGO, its biological stability is improved and the photothermal effect generated by NIR light produces additive effects, thereby indicating potential antibacterial applications.

High-quality thulium iron garnet films with tunable perpendicular magnetic anisotropy by off-axis sputtering - correlation between magnetic properties and film strain.

Thulium iron garnet (TmIG) films with perpendicular magnetic anisotropy (PMA) were grown on gadolinium gallium garnet (GGG) (111) substrates by off-axis sputtering. High-resolution synchrotron radiation X-ray diffraction studies and spherical aberration-corrected scanning transmission electron microscope (Cs-corrected STEM) images showed the excellent crystallinity of the films and their sharp interface with GGG. Damping constant of TmIG thin film was determined to be 0.0133 by frequency-dependent ferromagnetic resonance (FMR) measurements. The saturation magnetization (Ms) and the coercive field (Hc) were obtained systematically as a function of the longitudinal distance (L) between the sputtering target and the substrate. A 170% enhancement of PMA field (H⊥) was achieved by tuning the film composition to increase the tensile strain. Moreover, current-induced magnetization switching on a Pt/TmIG structure was demonstrated with an ultra-low critical current density (jc) of 2.5 × 106 A/cm2, an order of magnitude smaller than the previously reported value. We were able to tune Ms, Hc and H⊥ to obtain an ultra-low jc of switching the magnetization, showing the great potential of sputtered TmIG films for spintronics.

How deep is the inflammation in chronic rhinosinusitis? Sinus wall thickness and blood eosinophilia.

Various factors have been proposed to be related to refractory chronic rhinosinusitis (CRS). Treatment for refractory CRS is challenging for ear, nose, and throat (ENT) surgeons. The aim of the study was to determine the clinical features associated with the severity of CRS that may necessitate revision surgery by eliminating the bias of the surgeons technique using standardizing surgical procedures. Sinus wall thickness and blood eosinophilia, which may represent the depth of inflammation in CRS, are associated with the need for revision surgery. We found that, when the thickness of the postero-lateral maxillary sinus wall is more than 3.03 mm, there is an increased probability for a need for revision surgery. CRS patients with thickened sinus walls were found to have poorer outcomes. Further research is needed in order to justify this type of surgical procedure for CRS.

Exercise interventions for patients with gynaecological cancer: a systematic review and meta-analysis.

BACKGROUND: People with gynaecological cancer commonly suffer from physical and psychological symptoms related to their cancer and cancer treatment. OBJECTIVE: To evaluate and synthesise the evidence examining the effect of interventions with an exercise component for females with gynaecological cancer. DATA SOURCES: Medline, CINAHL, EMBASE, PubMed, PEDro, PsycINFO and Cochrane Library were searched systematically in September 2014. STUDY SELECTION: Randomised controlled trials were included if they investigated the effects of interventions with an exercise component in patients with gynaecological cancer. STUDY APPRAISAL: Two reviewers independently assessed the risk of bias of studies using the PEDro scale. RESULTS: Seven randomised controlled trials on five patient groups involving 221 participants were included. The mean PEDro score was 5.3 (standard deviation 1.5) out of 10. Compared with control groups, the intervention groups showed significantly greater improvements in physical activity levels and body mass index. No significant effects were found for fatigue, depression and health-related quality of life. A meta-analysis of functional exercise capacity and muscle strength was not possible due to insufficient data in the included trials. LIMITATIONS: The majority of studies provided exercise as part of multicomponent intervention programmes. CONCLUSIONS: Interventions with an exercise component appear to be effective at improving physical activity levels and body mass index among patients with gynaecological cancer. Further research is required to examine the effects of exercise interventions alone in this population. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42014014019.

Genome-wide screen identified let-7c/miR-99a/miR-125b regulating tumor progression and stem-like properties in cholangiocarcinoma.

Cholangiocarcinoma (CCA), which is a poor prognosis malignancy that arises from the malignant transformation of cholangiocytes, is associated with chronic inflammation of the biliary epithelium. Thus far, the molecular mechanisms of the origin and neoplastic processes of CCA that are promoted by inflammation are still unclear and need to be fully elucidated. Here using small RNA sequencing to determine the microRNA (miRNA) expression profiles in CCA, we found that let-7c, miR-99a and miR-125b, which are three miRNAs of the same cluster, were downregulated in CCA and targeted interleukin 6 (IL-6), IL-6R and type 1 insulin-like growth factor, which are important cytokines and receptors of the IL-6/signal transducer and activator 3 (STAT3) pathway and have key roles in inflammation and CCA initiation. We also found that enforced expression of let-7c, miR-99a or miR-125b could reduce the activity of STAT3 and further suppress CCA tumorigenicity in vivo and inhibit the migration and invasion of CCA cells in vitro. Surprisingly, let-7c/miR-99a/miR-125b cluster also significantly decreased the ability of CCA cells for cancer stem cell-like mammosphere generation by downregulating CD133 and CD44, which suggests the pivotal roles of let-7c, miR-99a and miR-125b in CCA by regulating both inflammation and stem-like properties. Our findings showed potential links between miRNAs and inflammation, and provide a potential treatment strategy for developing an miRNA-based therapy via IL-6/STAT3 targeting for CCA.

YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells.

BACKGROUND AND PURPOSE: The aim of this study was to determine the potency and molecular mechanism of action of YM155, a first-in-class survivin inhibitor that is currently under phase I/II clinical investigations, in various drug-resistant breast cancers including the oestrogen receptor positive (ER(+) ) tamoxifen-resistant breast cancer and the caspase-3-deficient breast cancer. EXPERIMENTAL APPROACH: The potency of YM155 in SK-BR-3, MDA-MB-231, MCF7 and its tamoxifen-resistant sublines, TamR6, TamR7, TamR8, TamC3 and TamC6, were determined by MTT assay. Western blot analysis, flow cytometric analysis, reverse transcription-PCR, fluorescent microscopy and comet assay were used to determine the molecular mechanism of action of YM155 in different breast cancer cell lines. KEY RESULTS: YM155 was equally potent towards the parental ER(+) /caspase-3-deficient MCF7 breast cancer cells and its tamoxifen-resistant sublines in vitro. The ER(-) /HER2(+) SK-BR-3 breast cancer cells and the triple-negative/caspase-3-expressing metastatic aggressive MDA-MB-231 breast cancer cells were also sensitive to YM155 with IC50 values in the low nanomolar range. Targeting survivin by YM155 modulated autophagy, induced autophagy-dependent caspase-7 activation and autophagy-dependent DNA damage in breast cancer cells. Interestingly, YM155 also induced XIAP degradation and the degradation of XIAP might play an important role in YM155-induced autophagy in breast cancer cells. CONCLUSIONS AND IMPLICATIONS: YM155 is a potent survivin inhibitor that has potential for the management of various breast cancer subtypes regardless of the expression of ER, HER2 and caspase-3. Importantly, this study provides new insights into YM155's molecular mechanism of action and therapeutic potential in the treatment of tamoxifen-resistant breast cancer.

MicroRNA-149 targets GIT1 to suppress integrin signaling and breast cancer metastasis.

Metastasis is the predominant cause of death in breast cancer patients. Several lines of evidence have shown that microRNAs (miRs) can have an important role in cancer metastasis. Using isogenic pairs of low and high metastatic lines derived from a human breast cancer line, we have identified miR-149 to be a suppressor of breast cancer cell invasion and metastasis. We also identified GIT1 (G-protein-coupled receptor kinase-interacting protein 1) as a direct target of miR-149. Knockdown of GIT1 reduced migration/invasion and metastasis of highly invasive cells. Re-expression of GIT1 significantly rescued miR-149-mediated inhibition of cell migration/invasion and metastasis. Expression of miR-149 impaired fibronectin-induced focal adhesion formation and reduced phosphorylation of focal adhesion kinase and paxillin, which could be restored by re-expression of GIT1. Inhibition of GIT1 led to enhanced protein degradation of paxillin and α5ß1 integrin via proteasome and lysosome pathways, respectively. Moreover, we found that GIT1 depletion in metastatic breast cancer cells greatly reduced α5ß1-integrin-mediated cell adhesion to fibronectin and collagen. Low level of miR-149 and high level of GIT1 was significantly associated with advanced stages of breast cancer, as well as with lymph node metastasis. We conclude that miR-149 suppresses breast cancer cell migration/invasion and metastasis by targeting GIT1, suggesting potential applications of the miR-149-GIT1 pathway in clinical diagnosis and therapeutics.

MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia.

Acute myeloblastic leukemia (AML) is characterized by the accumulation of abnormal myeloblasts (mainly granulocyte or monocyte precursors) in the bone marrow and blood. Though great progress has been made for improvement in clinical treatment during the past decades, only minority with AML achieve long-term survival. Therefore, further understanding mechanisms of leukemogenesis and exploring novel therapeutic strategies are still crucial for improving disease outcome. MicroRNA-100 (miR-100), a small non-coding RNA molecule, has been reported as a frequent event aberrantly expressed in patients with AML; however, the molecular basis for this phenotype and the statuses of its downstream targets have not yet been elucidated. In the present study, we found that the expression level of miR-100 in vivo was related to the stage of the maturation block underlying the subtypes of myeloid leukemia. In vitro experiments further demonstrated that miR-100 was required to promote the cell proliferation of promyelocytic blasts and arrest them differentiated to granulocyte/monocyte lineages. Significantly, we identified RBSP3, a phosphatase-like tumor suppressor, as a bona fide target of miR-100 and validated that RBSP3 was involved in cell differentiation and survival in AML. Moreover, we revealed a new pathway that miR-100 regulates G1/S transition and S-phase entry and blocks the terminal differentiation by targeting RBSP3, which partly in turn modulates the cell cycle effectors pRB/E2F1 in AML. These events promoted cell proliferation and blocked granulocyte/monocyte differentiation. Our data highlight an important role of miR-100 in the molecular etiology of AML, and implicate the potential application of miR-100 in cancer therapy.

CD8+ T cells, NK cells and IFN-gamma are important for control of tumor with downregulated MHC class I expression by DNA vaccination.

One of the major hurdles facing cancer immunotherapy is that cancers may downregulate expression of MHC class I molecules. The development of a suitable tumor model with downregulated MHC class I expression is critical for designing vaccines and immunotherapeutic strategies to control such tumors. We developed an E7-expressing murine tumor model with downregulated MHC class I expression, TC-1 P3 (A15). Using this model, we tested DNA and vaccinia vaccines for their ability to control tumors with downregulated MHC class I expression. We found that vaccination with DNA encoding E7 linked to Mycobacterial heat shock protein 70 (HSP70) generated a significant antitumor effect against TC-1 P3 (A15), while vaccination with E7/HSP70 vaccinia did not generate an appreciable antitumor effect. Lymphocyte depletion experiments revealed that both CD8+ T cells and NK cells were essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Furthermore, tumor protection experiments using IFN-gamma knockout mice revealed that IFN-gamma was essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Our results demonstrate that vaccination with E7/HSP70 DNA results in a significant antitumor effect against a neoplasm with downregulated MHC class I expression and the importance of CD8+ T cells, NK cells, and IFN-gamma in generating this antitumor effect.

An outcome study of breast reconstruction: presurgical identification of risk factors for complications.

BACKGROUND: Breast reconstruction following mastectomy has been shown to have a salutary effect on the overall psychological well-being of women being treated for breast cancer. Unfortunately, however, not every patient is an ideal candidate for reconstruction. Complications stemming from reconstructive surgery can cause significant morbidity, the most important of which may be the delay of subsequent adjuvant antineoplastic therapies, and therefore may not be in the best interests of the patient. METHODS: A retrospective study was performed on a consecutive series of 123 breast reconstructions in 98 patients, performed by one of two plastic surgeons, in a university setting over a 5-year period, for all surgical outcomes. Specifically, wound-healing complications, infections, and reoperations leading to the potential delay of subsequent chemotherapy or radiotherapy were recorded, and possible risk factors leading to these were sought. RESULTS: Three presurgical risk factors were found to have a statistically significant influence on the development of complications following breast reconstruction. These were: (1) increasing obesity, defined by the body mass index, (2) an active or recent (<5 year) history of cigarette smoking, and (3) a history of previous radiation exposure. Odds ratios were used to describe the magnitude of the effect of each factor for the development of complications. An ordinal regression analysis was used to create a nomogram based on this information that can be used to calculate any individual patient's presurgical risk for developing major complications following breast reconstruction, based on the presence of these factors. CONCLUSIONS: It is possible, based on the presence of specific presurgical risk factors, to predict the probability of developing major complications following breast reconstruction. This information can be useful to the referring physician and plastic surgeon alike in determining which patients are the best candidates for breast reconstruction and which type of reconstruction would be best suited for each individual patient.

The scientific basis for selecting surgical sutures.

The purpose of this study was to examine the handling properties of synthetic absorbable and monofilament polypropylene sutures made by two different manufacturers and to compare a subjective evaluation by surgeons to the results of standardized biomechanical performance tests. The surgeons' clinical subjective evaluation of the monofilament polypropylene sutures correlated with the results of the biomechanical performance studies, whereas the biomechanical evaluation of the two synthetic absorbable sutures detected notable differences in their performance. These distinct differences in biomechanical performance of the absorbable sutures did not alter their performance in the subjective clinical evaluation.

Evidence for inhibition of low density lipoprotein oxidation and cholesterol accumulation by apolipoprotein H (beta2-glycoprotein I).

Low density lipoprotein (LDL) oxidation and lipid accumulation are thought to enhance the progression of atherosclerosis. Apolipoprotein H (apoH) has been implicated in the development of human atherosclerosis. However, the roles of apoH in the oxidative modification of LDL and cellular accumulation of lipid constituents remained uncharacterized. In this study, the level of plasma apoH was found to be significantly associated with the oxidative susceptibility of LDL in human subjects. Plasma levels of apoH were positively correlated with the lag time but negatively correlated with LDL oxidation rate in conjugated diene formation. By using a J774 A.1 macrophage culture system, we found that apoH could not only inhibit the formation of conjugated diene and thiobarbituric acid-reactive substances, but also reduce the electrophoretic mobility of oxidized LDL. Furthermore, apoH decreased cellular accumulation of cholesterol via a reduction in cholesterol influx and an increase in cholesterol efflux. This is the first demonstration that apoH appears to have "antioxidant"-like effects on LDL oxidation. The results also suggest that apoH can inhibit the translocation of cholesterol from extracellular pools to macrophages, suggesting that apoH may play an important role in the prevention of atherosclerosis.

Effects of external beam irradiation on the TRAM flap: an experimental model.

The rat model of the transverse rectus abdominis musculocutaneous (TRAM) flap was used in the present study to determine the effects of external beam radiation on myocutaneous flap histology and pathophysiology. A total of 57 adult Sprague-Dawley rats underwent a TRAM procedure. A pilot study with 17 animals was first performed to determine proper radiation dosages, and the remaining 40 rats were then used in the definitive study. In half of the definitive study group, the flaps were subjected to fractionated doses of external beam radiation, whereas the other half served as controls. Six weeks after the last radiation dose, all animals were killed and the flaps were harvested for mechanical assessment and histopathologic evaluation. All TRAM flaps survived in both groups. The irradiated and nonirradiated flaps were minimally distinguishable in viscoelastic properties, as well as by histopathologic examination. Growth of the flap in the irradiated animals was significantly diminished (48 percent average surface area increase in irradiated flaps, versus 92 percent increase in nonirradiated flaps, p < 0.05). These findings suggest that the myocutaneous flap is relatively resistant to some of the known adverse affects of radiation on living tissues.

Complete breast absence revisited.

Congenital absence of the breast is a rare condition. The literature shows that there is much heterogeneity in its presentation as well as its inheritance. We described a mother and daughter with the condition and how the mother underwent breast reconstruction with use of bilateral transverse rectus abdominis myocutaneous flaps.

Targeting human papillomavirus type 16 E7 to the endosomal/lysosomal compartment enhances the antitumor immunity of DNA vaccines against murine human papillomavirus type 16 E7-expressing tumors.

DNA vaccination is an attractive approach for tumor immunotherapy because of its stability and simplicity of delivery. Advances demonstrate that helper T cell responses play a critical role in initiating immune responses. The aim of the current study is to test whether targeting HPV-16 E7 to the endosomal/lysosomal compartment can enhance the potency of DNA vaccines. We linked the lysosome-associated membrane protein 1 (LAMP-1) to HPV-E7 to construct a chimeric DNA, Sig/E7/LAMP-1 DNA. For in vivo tumor prevention experiments, mice were vaccinated with E7 DNA or Sig/E7/LAMP-1 DNA via gene gun, followed by tumor challenge. For in vivo tumor regression experiments, mice were first challenged with tumor cells and then vaccinated with E7-DNA or Sig/E7/LAMP-1 DNA. Intracellular cytokine staining with flow cytometry analysis, cytotoxic T lymphocyte (CTL) assays, enzyme-linked immunoabsorbent assay (ELISA), and enzyme-linked immunospot (ELISPOT) assays were used for in vitro E7-specific immunological studies. In both tumor prevention and tumor regression assays, Sig/E7/LAMP-1 DNA generated greater antitumor immunity than did wild-type E7 DNA. In addition, mice vaccinated with Sig/E7/LAMP-1 DNA had greater numbers of E7-specific CD4+ helper T cells, higher E7-specific CTL activity, and greater numbers of CD8+ T cell precursors than did mice vaccinated with Sig/E7 or wild-type E7 DNA. Sig/E7 generated a stronger E7-specific antibody response than did Sig/E7/LAMP-1 or wild-type E7 DNA. Our results indicate that linkage of the antigen gene to an endosomal/lysosomal targeting signal may greatly enhance the potency of DNA vaccines.

Long-term outcome analysis of two treatment methods for cleft palate: combined levator retropositioning and pharyngeal flap versus double-opposing Z-plasty.

OBJECTIVE: Two surgical techniques for repair of a cleft palate include levator retropositioning in combination with a pharyngeal flap and the Furlow double-opposing Z-plasty. This study compared morbidity and speech results from the use of these two methods in an effort to determine which was the superior technique. DESIGN: Patient records from 1986 to 1996 were retrospectively reviewed, and 10 patients with a cleft palate who underwent repair with a levator retropositioning and pharyngeal flap were compared to 14 patients who underwent a double-opposing Z-plasty repair. Postoperative complications including fistula formation, obstructive sleep apnea, and residual velopharyngeal insufficiency were recorded. Speech was assessed perceptually and through the use of nasometry. RESULTS: Both surgical techniques resulted in good speech in the majority of patients. Only two patients in the study, both in the Z-plasty group, had severe postoperative hypernasality. Two patients in the levator retropositioning and pharyngeal flap group developed severe postoperative obstructive sleep apnea, requiring additional surgery. CONCLUSION: The levator retropositioning and pharyngeal flap technique was successful in achieving good speech results, but it also caused more serious postoperative complications when compared to the double-opposing Z-plasty technique.

A cytosine analog that confers enhanced potency to antisense oligonucleotides.

Antisense technology is based on the ability to design potent, sequence-specific inhibitors. The G-clamp heterocycle modification, a cytosine analog that clamps on to guanine by forming an additional hydrogen bond, was rationally designed to enhance oligonucleotide/RNA hybrid affinity. A single, context-dependent substitution of a G-clamp heterocycle into a 15-mer phosphorothioate oligodeoxynucleotide (S-ON) targeting the cyclin-dependent kinase inhibitor, p27(kip1), enhanced antisense activity as compared with a previously optimized C5-propynyl-modified p27(kip1) S-ON and functionally replaced 11 C5-propynyl modifications. Dose-dependent, sequence-specific antisense inhibition was observed at nanomolar concentrations of the G-clamp S-ONs. A single nucleotide mismatch between the G-clamp S-ON and the p27(kip1) mRNA reduced the potency of the antisense ON by five-fold. A 2-base-mismatch S-ON eliminated antisense activity, confirming the sequence specificity of G-clamp-modified S-ONs. The G-clamp-substituted p27(kip1) S-ON activated RNase H-mediated cleavage and demonstrated increased in vitro binding affinity for its RNA target compared with conventional 15-mer S-ONs. Furthermore, incorporation of a single G-clamp modification into a previously optimized 20-mer phosphorothioate antisense S-ON targeting c-raf increased the potency of the S-ON 25-fold. The G-clamp heterocycle is a potent, mismatch-sensitive, automated synthesizer-compatible antisense S-ON modification that will have important applications in the elucidation of gene function, the validation of gene targets, and the development of more potent antisense-based pharmaceuticals.

Wound complications of abdominoplasty in obese patients.

The records of 90 patients who underwent an abdominoplasty at the University of Virginia Health Sciences Center were analyzed to determine the effect of obesity on the incidence of complications after this surgery. The study patients were divided into three groups-obese, borderline, and nonobese-based on the degree to which their preoperative weights varied from their ideal body weight. A history of previous bariatric surgery was also analyzed to determine what impact that might have on subsequent abdominoplasty. Results showed that 80% of obese patients had complications compared with the borderline and nonobese patients, who had complication rates of 33% and 32.5% respectively (p = 0.001). Previous gastric bypass surgery had no significant effect on the incidence of postabdominoplasty complications. Based on these findings the authors conclude that obesity at the time of abdominoplasty has a profound influence on the wound complication rate following surgery, regardless of any previous weight reduction surgery.

The use of ultrasound-assisted liposuction in the treatment of an involuted hemangioma.

The authors report a case of a large, residual involuted hemangioma of the facial region in a 10-year-old girl. Ultrasound-assisted liposuction was used to debulk the tumor mass and to avoid the possibility of inadvertent iatrogenic damage to the facial nerve during surgical excision.

Distraction osteogenesis of the midface: a new implantable distraction device.

This report describes the use of a new implantable device for distraction osteogenesis of the maxilla in treatment of midface hypoplasia seen in craniofacial syndromes. The technique of distraction osteogenesis is a recent advance in plastic surgery for treatment of bone growth disorders. The device is totally implantable except for the activating pin and can provide up to 30 mm of total advancement. We will describe our surgical technique and distraction protocol, illustrated by a case report of the device successfully used in a child with Crouzon syndrome.