Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

Continuous, Spontaneous, and Directional Water Transport in the Trilayered Fibrous Membranes for Functional Moisture Wicking Textiles.

Directional water transport is a predominant part of functional textiles used for continuous sweat release in daily life. However, it has remained a great challenge to design such textiles which ensure continuous directional water transport and superior prevention of water penetration in the reverse direction. Here, a scalable strategy is reported to create trilayered fibrous membranes with progressive wettability by introducing a transfer layer, which can guide the directional water transport continuously and spontaneously, thus preventing the skin from being rewetted. The resulting trilayered fibrous membranes exhibit a high one-way transport index R (1021%) and a desired breakthrough pressure (16.1 cm H2 O) in the reverse direction, indicating an ultrahigh directional water transport capacity. Moreover, on the basis of water transport behavior, a plausible mechanism is proposed to provide insight into the integrative and cooperative driving forces at the interfaces of trilayered hydrophobic/transfer/superhydrophilic fibrous membranes. The successful synthesis of such fascinating materials would be valuable for the design of functional textiles with directional water transport properties for personal drying applications.

Epithelial-specific knockout of the Rac1 gene leads to enamel defects.

The Ras-related C3 botulinum toxin substrate 1 (Rac1) gene encodes a 21-kDa GTP-binding protein belonging to the RAS superfamily. RAS members play important roles in controlling focal adhesion complex formation and cytoskeleton contraction, activities with consequences for cell growth, adhesion, migration, and differentiation. To examine the role(s) played by RAC1 protein in cell-matrix interactions and enamel matrix biomineralization, we used the Cre/loxP binary recombination system to characterize the expression of enamel matrix proteins and enamel formation in Rac1 knockout mice (Rac1(-/-)). Mating between mice bearing the floxed Rac1 allele and mice bearing a cytokeratin 14-Cre transgene generated mice in which Rac1 was absent from epithelial organs. Enamel of the Rac1 conditional knockout mouse was characterized by light microscopy, backscattered electron imaging in the scanning electron microscope, microcomputed tomography, and histochemistry. Enamel matrix protein expression was analyzed by western blotting. Major findings showed that the Tomes' processes of Rac1(-/-) ameloblasts lose contact with the forming enamel matrix in unerupted teeth, the amounts of amelogenin and ameloblastin are reduced in Rac1(-/-) ameloblasts, and after eruption, the enamel from Rac1(-/-) mice displays severe structural defects with a complete loss of enamel. These results support an essential role for RAC1 in the dental epithelium involving cell-matrix interactions and matrix biomineralization.

[A pilot study of peginterferon alfa-2a combined with short-term lamivudine therapy in HBeAg-positive chronic hepatitis B patients].

OBJECTIVES: To investigate the efficacy of by combining a 12-week course of lamivudine in those HBeAg-positive hepatitis B patients receiving peginterferon alfa-2a (peg-IFN alpha-2a) therapy. METHODS: A total of 58 patients initiated a 52-week course of peginterferon alfa-2a were enrolled and divided into 3 groups. The patients with HBV DNA undetectable or HBeAg negative at week 12 were divided into group A, in this group treatment continued to week 52 with peg-IFN alpha-2a alone; The rest patients were divided into group B1 and B2, in group B1, lamivudine was combined at a course of 12 weeks, while in group B2 treatment continued to week 52 with peg-IFN alpha-2a alone. Clinical responses were assessed at week 52. RESULTS: 8 out of 58 patients achieved undetectable HBV DNA or HBeAg loss at week 12 and divide into group A. In this group the HBV DNA loss rate, HBeAg seroconversion rate, HBsAg loss rate and ALT normalization rate were 100% (8/8), 75% (6/8), 0% (0/8) and 100% (8/8) respectively at the end of treatment. In this group the HBV DNA loss rate, HBeAg seroconversion rate, HBsAg loss rate and ALT normalization rate were 100% (8/8), 75% (6/8), 0% (0/8) and 100%(8/8) respectively at the end of treatment. The rest 50 patients without early response to peg-IFN alpha-2a at week 12 were divided into group B1 (24 patients enrolled) and B2 (26 patients). At the end of treatment, the HBV DNA loss rate, HBeAg seroconversion rate, HBsAg loss rate and ALT normalization rate in Group B1 were 50% (12/24), 38% (9/24), 4% (1/24) and 63% (15/24) respectively, and 31% (8/26), 27% (7/26), 0% (0/26) and 35% (9/26) respectively in group B2. CONCLUSION: Those patients with early responses to peg-IFN alpha-2a therapy can achieve high clinical responses at the end of 52-week treatment. The combining therapy of lamivudine for a course of 12-weeks can improve the clinical responses for the patients without early responses to peg-IFN alpha-2a.

[Studies on secretion function of normal and transferred submandibular glands].

In order to investigate the secretion mechanism of denervated submandibular gland(SMG) and artificially regulate the secretion of transferred SMG,serial studies on the secretion function of normal and transferred SMG have been performed. The results showed that functional alpha(1A-) and alpha(1B-) adrenoceptors(AR) were expressed in human SMG, and might contribute to the regulation of saliva synthesis and secretion. Both beta(1)- and beta(2)-AR were expressed in rabbit SMG. beta(1)-AR was the predominant subtype and might play an important role in regulating saliva and alpha-amylase secretion. Vanilloid receptor1(VR1) mRNA and protein were detected in rabbit SMG. Capsaicin could induce a significant increase in secretion of rabbit SMG via activitation of VR1. On the rabbit model of microvascular transfer of SMG, phenylephrine(10(-7) mol/L) was infused into SMG through the Wharton's duct. The secretion of transferred SMG was significantly increased without significant changes of cardiovascular function. The effective mechanism of phenylephrine might involve the increased expression of alpha1-AR, translocation of AQP(5) from cytoplasm to apical membrane, activation of signal molecules related to cell proliferation, and moderate the atrophy of the gland. These results provided a experimental basis for deeply understanding of secretion mechanism of normal and transferred SMG, and effective regulation of secretion of the transferred SMG.

Bioactive nanofibers enable the identification of thrombospondin 2 as a key player in enamel regeneration.

Tissue regeneration and development involves highly synchronized signals both between cells and with the extracellular environment. Biomaterials can be tuned to mimic specific biological signals and control cell response(s). As a result, these materials can be used as tools to elucidate cell signaling pathways and candidate molecules involved with cellular processes. In this work, we explore enamel-forming cells, ameloblasts, which have a limited regenerative capacity. By exposing undifferentiated cells to a self-assembling matrix bearing RGDS epitopes, we elicited a regenerative signal at will that subsequently led to the identification of thrombospondin 2 (TSP2), an extracellular matrix protein that has not been previously recognized as a key player in enamel development and regeneration. Targeted disruption of the thrombospondin 2 gene (Thbs2) resulted in enamel formation with a disordered architecture that was highly susceptible to wear compared to their wild-type counterparts. To test the regenerative capacity, we injected the bioactive matrix into the enamel organ and discovered that the enamel organic epithelial cells in TSP-null mice failed to polarize on the surface of the artificial matrix, greatly reducing integrin ß1 and Notch1 expression levels, which represent signaling pathways known to be associated with TSP2. These results suggest TSP2 plays an important role in regulating cell-matrix interactions during enamel formation. Exploiting the signaling pathways activated by biomaterials can provide insight into native signaling mechanisms crucial for tooth development and cell-based strategies for enamel regeneration.

Methane hydrates with a high capacity and a high formation rate promoted by biosurfactants.

Lignosulfonates, which are byproducts of the pulp and paper industry, can be used as promoters for the formation of methane hydrates with a high capacity up to 170 v/v and a high formation rate.

Biological synthesis of tooth enamel instructed by an artificial matrix.

The regenerative capability of enamel, the hardest tissue in the vertebrate body, is fundamentally limited due to cell apoptosis following maturation of the tissue. Synthetic strategies to promote enamel formation have the potential to repair damage, increase the longevity of teeth and improve the understanding of the events leading to tissue formation. Using a self-assembling bioactive matrix, we demonstrate the ability to induce ectopic formation of enamel at chosen sites adjacent to a mouse incisor cultured in vivo under the kidney capsule. The resulting material reveals the highly organized, hierarchical structure of hydroxyapatite crystallites similar to native enamel. This artificially triggered formation of organized mineral demonstrates a pathway for developing cell fabricated materials for treatment of dental caries, the most ubiquitous disease in man. Additionally, the artificial matrix provides a unique tool to probe cellular mechanisms involved in tissue formation further enabling the development of tooth organ replacements.

Structure and haemocompatibility of ZnO films deposited by radio frequency sputtering.

ZnO films were first deposited on silicon and glass substrates using radio frequency sputtering and then annealed in air at different temperatures from 300 to 700 degrees C. The microstructures, surface energy and optical properties of ZnO films were examined by x-ray diffraction, Raman spectroscopy, contact angle test and UV-visible optical absorption spectroscopy, respectively. Results show that a perfectly oriented ZnO (0 0 2) thin film is obtained in all ZnO samples. Raman spectroscopy, in combination with those derived by UV-visible optical absorption spectroscopy, provides us with an accurate description of ZnO nature, revealing that, after annealing, ZnO films exhibit better crystallinity and narrower optical energy gap. The contact angle test denotes that the adhesive work and polar component of the surface energy of ZnO films increase steadily with the annealing temperature, which leads to more active interaction between annealed ZnO films and blood plasma. The platelet adhesion experiment shows that there are fewer platelets adhered to the surface of ZnO films compared to the polyurethane (PU) used in clinical application, suggesting ZnO's better compatibility with blood. As the annealing temperature increases, the number of platelets adhered to ZnO films increases correspondingly, which we believe is due to the narrower optical energy gap. Therefore, the appropriate surface properties and the wide optical energy gap of ZnO thin films are believed to be the main factors responsible for the excellent haemocompatibility.

Bioactive nanofibers instruct cells to proliferate and differentiate during enamel regeneration.

During tooth development, ectoderm-derived ameloblast cells create enamel by synthesizing a complex protein mixture serving to control cell to matrix interactions and the habit of hydroxyapatite crystallites. Using an in vitro cell and organ culture system, we studied the effect of artificial bioactive nanostructures on ameloblasts with the long-term goal of developing cell-based strategies for tooth regeneration. We used branched peptide amphiphile molecules containing the peptide motif Arg-Gly-Asp, or "RGD" (abbreviated BRGD-PA), known to self-assemble in physiologic environments into nanofibers that display on their surfaces high densities of this biological signal. Ameloblast-like cells (line LS8) and primary enamel organ epithelial (EOE) cells were cultured within PA hydrogels, and the PA was injected into the enamel organ epithelia of mouse embryonic incisors. The expression of amelogenin, ameloblastin, integrin alpha 5, and integrin alpha 6 was detected by quantitative real-time PCR and immunodetection techniques. We performed cell proliferation assay using BrdU labeling and a biomineralization assay using Alizarin red S staining with quantitative Ca(2+) measurements. In the cell culture model, ameloblast-like cells (LS8) and primary EOE cells responded to the BRGD-PA nanostructures with enhanced proliferation and greater amelogenin, ameloblastin, and integrin expression levels. At the site of injection of the BRGD-PA in the organ culture model, we observed EOE cell proliferation with differentiation into ameloblasts as evidenced by their expression of enamel specific proteins. Ultrastructural analysis showed the nanofibers within the forming extracellular matrix, in contact with the EOE cells engaged in enamel formation and regeneration. This study shows that BRGD-PA nanofibers present with enamel proteins participate in integrin-mediated cell binding to the matrix with delivery of instructive signals for enamel formation.