Surface-modified poly(lactide- co -glycolide) nanospheres for targeted bone imaging with enhanced labeling and delivery of radioisotope

Surface-modified nanospheres can be utilized for targeting drugs and diagnostic agents to the bone and bone marrow while extending their circulation time in the blood stream. The surface modification of poly(lactide- co -glycolide) (PLGA) nanospheres by radioisotope carrying poly(ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) triblock copolymers (Poloxamer 407) has been assessed by in vitro characterization and in vivo biodistribution studies after intravenous administration of the nanospheres to the mouse. A hydroxyphenylpropionic acid, a ligand for 125 I and 131 I labeling, was conjugated to the hydroxyl group of the Poloxamer 407 by using dicyclohexyl carbodiimide. The ligand-conjugated Poloxamer 407 was adsorbed onto the surface of PLGA nanospheres. Surface coating was confirmed by measuring both size distribution and the surface charge of the nanospheres. Besides, 125 I-labeling efficiency, radiolabeling stability, whole body imaging, and biodistribution of the radioisotope-labeled nanospheres were examined. Ligand-labeled, surface-modified PLGA nanospheres were in 100-nm size ranges, which may be adequate for long-circulation and further bone imaging. 125 I-labeling efficiency was >90% and was more stable at human serum for 24 h. A noticeable decrease in liver or spleen uptake was obtained by the surface-modified nanospheres. 125 I-labeled nanospheres showed higher blood maintenance and bone uptake compared with stannous colloid with the same size distribution. Therefore, a fully biodegradable, radioisotope-carrying, surface-modified nanosphere system has been developed as a promising tool for targeting bone and bone marrows. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 67A: 751–760, 2003Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34431/1/10167_ftp.pd

Amniotic fluid embolism that took place during an emergent Cesarean section -A case report-

Amniotic fluid embolism (AFE) is a rare but fatal obstetric emergency, characterized by sudden cardiovascular collapse, dyspnea or respiratory arrest and altered mentality, disseminated intravascular coagulation (DIC). It can lead to severe maternal morbidity and mortality, but the prediction of its occurrence and treatment are very difficult. We experienced a case of AFE during emergent Cesarean section in a 40+6 weeks healthy pregnant woman, age 33. Sudden dyspnea, hypotension, signs of pulmonary edema and DIC were developed during Cesarean section, and cardiac arrest followed after these events. The course of these events was so rapid and catastrophic, which was consistent with AFE. Thus, we report this case precisely and review pathophysiology, diagnosis, treatment of AFE by referring to up-to-date literatures

Effect of immobilized cell-binding peptides on chitosan membranes for osteoblastic differentiation of mesenchymal stem cells

Two cell-binding domains from FGF-2 (fibroblast growth factor-2) were shown to increase cell attachment and osteoblastic differentiation. Two synthetic peptides derived from FGF-2, namely residues 36-41 (F36; PDGRVD) and 77-83 (F77; KEDGRLL), were prepared and their N-termini further modified for ease of surface immobilization. Chitosan membranes were used in the present study as mechanical supportive biomaterials for peptide immobilization. Peptides could be stably immobilized on to the surface of chitosan membranes. The adhesion of mesenchymal stem cells to the peptide (F36 and F77)-immobilized chitosan membrane was increased in a dose-dependent manner and completely inhibited by soluble RGD (Arg-Gly-Asp) and anti-integrin antibody, indicating the existence of an interaction between F36/F77 and integrin. Peptide-immobilized chitosan supported human bone-marrow-derived mesenchymal-stem-cell differentiation into osteoblastic cells, as demonstrated by alkaline phosphate expression and mineralization. Taken together, the identified peptide-immobilized chitosan membranes were able to support cell adhesion and osteoblastic differentiation; thus these peptides might be useful as bioactive agents for osteoblastic differentiation and surface-modification tools in bone regenerative therapy.This study was supported in part by the KOSEF (Korea Science and Technology Foundation) Nanobiotechnology Development Program [no. 2007-00952] entitled Regenomics (innovative surface activation of regenerative biomaterials), in part by the Korea Research Foundation [grant no. D00192] and in part by an Engineering Research Center grant from KOSEF through the IBEC (Intelligent Biointerface Engineering Center) [grant no. R11-2000-084-09001-0]

Phase II Study of Low-dose Paclitaxel and Cisplatin as a Second-line Therapy after 5-Fluorouracil/Platinum Chemotherapy in Gastric Cancer

This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel/cisplatin chemotherapy in patients with metastatic or recurrent gastric cancer that had failed 5-fluorouracil/platinum-based chemotherapy. Thirty-two patients with documented progression on or within 6 months after discontinuing 5-fluorouracil/platinum-based chemotherapy were enrolled. As a second-line treatment, paclitaxel (145 mg/m2) and cisplatin (60 mg/m2) was administered on day 1 every 3 weeks. Among 32 patients enrolled, 8 (25%) responded partially to paclitaxel/cisplatin, 8 (25%) had stable disease, and 14 (44%) had progressive disease. Two patients (6%) were not evaluable. The median time to progression (TTP) and overall survival for all patients were 2.9 months and 9.1 months, respectively. The most common hematologic toxicity was anemia (47%). Grade 3 neutropenia developed in three patients (9%), but no other grade 3/4 hematologic toxicity occurred. The most common non-hematologic toxicities were emesis (31%) and peripheral neuropathy (38%). Three cases (9%) of grade 3/4 emesis and 2 cases (6%) of grade 3 peripheral neuropathy developed. In conclusion, low-dose paclitaxel and cisplatin chemotherapy showed moderate activity with favorable toxicity profiles. However, relatively short TTP of this regimen warrants the development of more effective paclitaxel-based regimens other than combination with cisplatin in these patients as second-line therapies

Weekly Paclitaxel and Trastuzumab as a First-Line Therapy in Patients with HER2-Overexpressing Metastatic Breast Cancer: Magnitude of HER2/neu Amplification as a Predictive Factor for Efficacy

We evaluated the efficacy and safety of weekly paclitaxel plus trastuzumab as firs-tline chemotherapy in women with HER2-overexpressing metastatic breast cancer (MBC), and we investigated the prognostic factors including magnitude of HER2/neu amplification in this population. We analyzed 54 patients with HER2-overexpressing MBC that were treated with weekly paclitaxel plus trastuzumab as first-line chemotherapy from February 2004 to December 2006. At a median follow-up of 28 months, median time to progression (TTP) was 16.6 months (95% CI, 9.4 to 23.7 months) and median overall survival was 25.6 months (95% CI, 21.8 to 27.3 months). Therapy was generally well tolerated, although three patients (5.5%) experienced reversible, symptomatic heart failure. Of the 27 patients evaluable for the HER2 FISH, patients with a HER2/CEP17 ratio of ≤4.0 had significantly shorter TTP than those with a HER2/CEP17 ratio of >4.0 (10.8 vs. 23.2 months, P=0.034). A HER2/CEP17 ratio of >4.0 was identified as significant predictive factor of TTP by multivariate analysis (P=0.032). The combination of weekly paclitaxel plus trastuzumab as first-line chemotherapy is an effective regimen in patients with HER2-FISH-positive MBC. Furthermore, the magnitude of HER2 amplification is an independent predictive factor of TTP

Enhanced bone formation by controlled growth factor delivery from chitosan-based biomaterials

For the purpose of obtaining high bone forming efficacy, development of chitosan was attempted as a tool useful as a scaffolding device. Porous chitosan matrices, chitosan–poly(-lactide) (PLLA) composite matrices and chitosan coated on PLLA matrices were dealt with in this research. Porous chitosan matrix was fabricated by freeze-drying and cross-linking aqueous chitosan solution. Porous chitosan matrix combined with ceramics and constituents of extracellular matrices were prepared and examined for their bone regenerative potential. Composite porous matrix of chitosan–PLLA was prepared by mixing polylactide with chitosan and freeze-drying. All chitosan based devices demonstrated improved bone forming capacity by increasing mechanical stability and biocompatibility. Release of platelet-derived growth factor-BB (PDGF-BB) from these matrices exerted significant osteoinductive effect in addition to the high osteoconducting capacity of the porous chitosan matrices. The hydrophobic surface of PLLA matrices was modified by chitosan to enhance cell affinity and wettability. The chitosan coated PLLA matrix induced increased osteoblast attachment as compared with intact PLLA surface. Overall results in this study demonstrated the usefulness of chitosan as drug releasing scaffolds and as modification tools for currently used biomaterials to enhance tissue regeneration efficacy. These results may expand the feasibility of combinative strategy of controlled local drug delivery concept and tissue engineered bone formation in reconstructive therapy in the field of periodontics, orthopedics and plastic surgery

The Synthetic Collagen-Binding Peptide NIPEP-OSS Delays Mouse Myeloma Progression

Multiple myeloma (MM) is the second most common hematological malignancy. It is a clonal B-cell disorder characterized by the proliferation of malignant plasma cells in the bone marrow, the presence of monoclonal serum immunoglobulin, and osteolytic lesions. An increasing amount of evidence shows that the interactions of MM cells and the bone microenvironment play a significant role, suggesting that these interactions may be good targets for therapy. The osteopontin-derived collagen-binding motif-bearing peptide NIPEP-OSS stimulates biomineralization and enhances bone remodeling dynamics. Due to its unique targeted osteogenic activity with a broad safety margin, we evaluated the potential of NIPEP-OSS for anti-myeloma activity using MM bone disease (MMBD) animal models. In a 5TGM1-engrafted NSG model, the survival rates of the control and treated groups were significantly different (p = 0.0014), with median survival times of 45 and 57 days, respectively. The bioluminescence analyses showed that myeloma slowly developed in the treated mice compared to the control mice in both models. NIPEP-OSS enhanced bone formation by increasing biomineralization in the bone. We also tested NIPEP-OSS in a well-established 5TGM1-engrafted C57BL/KaLwRij model. Similar to the previous model, the median survival times of the control and treated groups were significantly different (p = 0.0057), with 46 and 63 days, respectively. In comparison with the control, an increase in p1NP was found in the treated mice. We concluded that NIPEP-OSS delays mouse myeloma progression via bone formation in MMBD mouse models

Rapidly developing T-cell posttransplantation lymphoproliferative disorder

Posttransplantation lymphoproliferative disorder (PTLD) of T-cell origin has been rarely described in chronically immunosuppressed allograft recipients. We report a case of renal PTLD of a T lineage that occurred shortly after transplantation under a triple-immunosuppressive regimen. Renal graft biopsy performed 58 days posttransplantation showed extensive interstitial infiltrates of polymorphic lymphoid cells, which expressed the UCHL-1 and CD3 markers for T-cell lineage. The clonal nature of the T cells in renal tissue was identified by showing rearrangement of the T-cell receptor gamma chain genes using a polymerase chain reaction (PCR). DNA extracted from the graft biopsy specimen did not show the sequences of human T-cell leukemia virus type 1 (HTLV-I) by PCR, Signals for Epstein-Barr virus (EBV) infection in renal tissue were not shown by in situ hybridization, After the reduction of immunosuppressive therapy, regression of PTLD lesion and development of rejection were shown in the second graft biopsy and graftectomy specimen. The extreme rarity of rapidly developing T-cell PTLD in a renal allograft prompted us to write this report. (C) 1999 by the National Kidney Foundation, Inc