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The identification of molecular events underlying the pathogenesis of neuroblastoma can likely result in improved clinical outcomes for this disease. In this study, a translocation within chromosome 2p and 4q was found to bring about the formation of an in-frame fusion gene that was composed of portions of the teneurin transmembrane protein 3 (TENM3, also known as ODZ3) gene and the anaplastic lymphoma kinase (ALK) gene in tumor cells from patients with neuroblastoma. Expression of the full length TENM3-ALK cDNA in NIH-3T3 cells led to the formation of a fusion protein that: (1) possesses constitutive tyrosine kinase activity, (2) induces strong activation of the downstream targets of extracellular signal-regulated kinase (ERK), protein kinase B (a.k.a. AKT), and signal transducer and activator of transcription 3 (STAT3), (3) provokes oncogenic transformation in NOD.Cg-Prkdc

Linear polysiloxanes were synthesized by using organometallic carboxylic acid catalysts containing tin, zinc, or iron. By optimizing the amount of catalyst and the reaction temperature, polysiloxan...

We prepared a dielectric elastomer actuator composed of hydrogenated carboxylated acrylonitrile-butadiene rubber (HXNBR)/nitrile group (CN)-modified and non-modified titanium oxide (TiO2) particles with insulation properties. The CN group-containing silane coupling agent was synthesized via a thiol–ene reaction between acrylonitrile and 3-mercaptpropyltrimethoxysilane and immobilized onto the TiO2 particle surface. The HXNBR/CN-modified and non-modified TiO2 particle composite elastomer showed a high relative dielectric constant and generated stress in a low electric field. The relative dielectric constant increased proportionally with the amount of CN-modified TiO2 particles, showing a value of 22 at 100 Hz. As the dielectric constant increased, the volumetric resistivity decreased; however, the dielectric breakdown strength was maintained at 95 V/mm. The generated stress of the composite elastomer increased in proportion to the relative dielectric constant, showing a maximum of 1.9 MPa. The card-house structure of TiO2 particles in the composite elastomer is assumed to suppress the dielectric breakdown in a low electric field. Thus, we demonstrated that an elastomer containing a high dipole group on an insulating particle surface is capable of improving the power performance of soft actuators.

Neuroblastoma is the most common extracranial solid tumor that occurs in childhood and the most common cancer in infancy. Fewer than 5% of neuroblastomas occur in adolescents and young adults (AYAs), for whom the disease has an indolent and fatal course. Chen et al. previously reported that missense mutations in the protein- tyrosine kinase domain of anaplastic lymphoma kinase (ALK) occur in approximately 10% of cases of sporadic neuroblastoma, and these missense mutations result in the activation of the ALK protein kinase domain, which plays a key role in the tumorigenic process as seen in ALK fusion proteins. Since the initial discovery of the NPM-ALK fusion protein in human anaplastic lymphoma cell lines, more than 24 different ALK fusion proteins have been discovered in various malignancies. Till date, ALK-containing chimeric proteins have not been reported in neuroblastoma. In this study, a translocation within chromosome 2p and 4q was found to bring about the formation of an in-frame fusion gene that was composed of portions of the teneurin transmembrane protein 3 (TENM3) gene and ALK gene in tumor cells from an AYA patient with neuroblastoma. The patient was 19-year-old female diagnosed with stage 4 neuroblastoma (unfavorable histology, poorly differentiated subtype, MYCN DNA not amplified). Computed tomography revealed a mass in the left adrenal gland with bone, spine, liver, and lung metastasis. ALK rearrangement was confirmed via FISH analysis. Crizotinib resulted in no disease progression for 5 months, except for metastatic spinal disease, but it did not exhibit high efficacy compared with its effects against lymphoma and lung cancer. This 5′ in-frame fusion partner gene in neuroblastoma has not yet been identified, and its role is not well-known in oncogenesis. We generated the cell line with the expression of the full length TENM3-ALK cDNA in NIH-3T3 cells led to the formation of a fusion protein. A cell-based evaluation of this predicted ALK protein variant revealed activation of downstream targets-STAT3, AKT and ERK- and ALK inhibitors, crizotinib or lorlatinib, treatment inhibited the growth of xenograft tumors with stable TENM3-ALK expression. We determined whether TENM3-ALK affects transformation and proliferation using a soft agar colony formation assay. As expected, the cells that expressed an empty vector and wild type ALK line did not produce a considerable number of colonies, whereas TENM3-ALK transfected cells showed anchorage-independent growth, resulting in the production of a higher number of colonies. The evidence for the role of ALK receptor signaling in stimulating neuroblastoma tumor cell growth and the demonstrated in vitro and in vivo efficacy of the ALK selective inhibitors in this study provide biological and clinical justification for the further exploration of this combination and testing in patients with recurrent or refractory neuroblastoma. Citation Format: Mitsuteru Hiwatari, Masafumi Seki, Ryosuke Matsuno, Kenichi Yoshida, Takeshi Nagasawa, Aiko Sato-Otsubo, Shohei Yamamoto, Motohiro Kato, Kentaro Watanabe, Masahiro Sekiguchi, Satoru Miyano, Seishi Ogawa, Junko Takita. Identification of the novel TENM3-ALK fusion in an AYA case with ALK rearranged neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6734.

Current study is a case report of a 5-year-old patient with T-cell acute lymphoblastic leukemia (ALL) and multiple urolithiasis. Complex factors, including glucocorticoid-induced hypercalciuria, fluid restriction for the syndrome of inappropriate secretion of antidiuretic hormone, and long-term bed rest, predispose children with ALL to develop urolithiasis. To prevent urinary urolithiasis formation, urinary calcium excretion should be monitored during chemotherapy and when administering glucocorticoids.

We synthesized silica-coated barium titanate (BaTiO3) particles with different silica shell thicknesses and evaluated the effect of silica coating on the relative dielectric properties of silica-coated BaTiO3 particles. Furthermore, composite elastomers were prepared using hydrogenated carboxylated acrylonitrile-butadiene rubber (HXNBR) with a high relative dielectric constant (er) and silica-coated BaTiO3 particles, and their performance as an actuator was evaluated. Both er and relative dielectric loss of non-coated BaTiO3 particles increased at low frequencies (

We synthesized rubbers including cyanoethyl groups and evaluated the effect of side-chain structures on dielectric properties, electrical properties at room temperature, and glass-transition temper...

Acrylonitrile-butadiene rubbers (NBRs) have a lower glass transition temperature (T g) and a higher dielectric constant than other rubbers. To understand how a low T g and a high dielectric constant are compatible, we focused on the acrylonitrile (AN) monomer sequence in rubber and synthesized random and alternating copolymers to evaluate the effect of the sequence. The AN monomer sequence dependence of the relative dielectric constant was investigated by the C-N stretching vibration of the nitrile group through Fourier transform infrared spectroscopy and internal rotation potential energy measurements around the C-C bond within the nitrile group based on dimer model calculations. The alternating copolymers, including NBR, showed a higher dielectric constant than random copolymers. The alternating copolymer shifted from ∼2243 cm-1 for polyAN to ∼2236 cm-1 for NBRs, while the random copolymer only shifted to ∼2239 cm-1. The peak of the C-N stretching vibration was correlated with the AN sequence. The sequence dependence of the shift can be explained by the C-N bond length calculation. The internal rotation potential energy between gauche and trans of the NBR model was the lowest, indicating that the NBR main chain is flexible and that AN in the main chain rotates easily. Therefore, NBR has a high dielectric constant and a low T g because of the presence of an alternating sequence and the flexibility of the NBR main chain.

In this study, the effects of ion-pair interaction energy and the alkyl chain length of acryl-ionic copolymers on the dispersion state of supergrowth single-walled carbon nanotubes (SG-SWCNTs) in c...

Ionic liquid monomers with ion pair interaction energies ranging from 73.0 to 101.4 kcal/mol were designed by using the calculated electrostatic potential (ESP) values of the component ions. The io...

It is desirable that noninvasive differential diagnosis takes place without lymph node biopsy for histiocytic necrotizing lymphadenitis (HNL) or malignant lymphoma (ML). In this study, we propose a novel scoring model for the differential diagnosis of these diseases using clinical information and clinical findings. We retrospectively analyzed the data from 15 HNL and 13 ML pediatric patients. First, a univariate analysis identified 14 clinical factors with significant differences. Second, a subsequent analysis using receiver operating characteristic (ROC) curve analysis identified three factors among them with area under the ROC curve values of >0.95: body temperature (°C), maximum lymph node size (cm), and serum β2-microglobulin level (mg/L). Finally, the cut-off values of each of these three factors were determined and examined for the 28 cases. All 15 HNL cases were within 2–3 of the cut-off values among the three factors, no ML case was within two or more cut-off values. Thus, the diagnostic sensitivity and specificity of this novel scoring system were both 100%, indicating that clinical scoring with body temperature, maximum lymph node size, and β2-microglobulin are useful for distinguishing between HNL and ML.

The exact incidence of acute kidney injury (AKI) during chemotherapy for acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) is unknown. Furthermore, childhood cancer survivors are at risk of AKI-chronic kidney disease transition. Thus, early diagnosis of AKI is crucial. This study aimed to elucidate the incidence of AKI in patients undergoing chemotherapy for pediatric ALL/LBL and to compare the usefulness of serum cystatin C (CysC)- and creatinine (Cr)-based estimated glomerular filtration rate (eGFR) as diagnostic measures. Data of 16 patients with ALL/LBL treated with a total of 75 courses of chemotherapy were retrospectively analyzed. CysC- and Cr-based eGFR were measured before and three times per week during therapy. To calculate the eGFR, an equation for Japanese children was used. AKI was diagnosed when eGFR dropped by ≥ 25% from the highest eGFR value obtained during the latest 2 weeks since the start of chemotherapy. AKI was graded based on the pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease scale. All patients developed AKI during chemotherapy; however, more than 90% of the cases were mild and eventually recovered. No significant differences were found in the incidence of AKI between CysC- and Cr-based eGFR (p = 0.104). The median time to AKI diagnosis was significantly shorter in the CysC-based eGFR than in the Cr-based eGFR (8 vs. 17 days, p < 0.001). In this study, all patients with pediatric ALL/LBL could develop mild AKI during treatment. CysC-based eGFR is a more effective measure than Cr-based eGFR for the early diagnosis of AKI.

Background We describe a continuous monitoring method aimed at preserving nerve function during biopsy of lesions on the oculomotor nerve using stimulation of the oculomotor nerve proximal to the lesion. Case Description A 5-year-old girl with a recurrent left oculomotor nerve palsy and contrast-enhancing left oculomotor nerve mass on magnetic resonance imaging underwent a biopsy of the lesion to aid in its diagnosis. At the time of surgery, needle electrodes were inserted into the superior and inferior rectus muscles percutaneously, and cotton-covered electrodes were implanted into the oculomotor nerve proximal to the lesion. Compound muscle action potentials of the oculomotor nerve were measured continuously by monopolar stimulation. The lesion was mapped by direct stimulation, and the unresponsive area was excised. The amplitude of the compound muscle action potentials decreased during the resection but recovered postoperatively. After resection of the lesion, the compound muscle action potentials remained the same as they were preoperatively. No obvious postoperative oculomotor nerve palsy was observed. Conclusions This method of continuous monitoring of the function of the oculomotor nerve is simple to use and is suitable for lesions in close proximity to the oculomotor nerve.

Pediatric acute lymphoblastic leukemia regimens include large L-asparaginase dosages and steroids, which are associated with an increased risk of venous thromboemboli in adolescents and young adults. Herein, we report the case of an 18-year-old male with acute lymphoblastic leukemia, who was treated with the pediatric regimen, in which edoxaban was employed as a prophylaxis against cerebral sinus venous thrombosis. The event happened on day 20 of induction therapy, when brain magnetic resonance imaging demonstrated a cerebral sinus venous thrombosis in the superior sagittal sinus. Anticoagulation therapy was initiated, and the patient’s symptoms disappeared 3 days later. The induction therapy was restarted after an interruption of 16 days, and the consolidation therapies, which included L-asparaginase and steroids, were completed. Edoxaban was administered as a prophylaxis during the consolidation therapy. There were no further adverse events. Edoxaban could be an effective prophylaxis for coagulation complications in adolescents and young adults with acute lymphoblastic leukemia.

Polystyrene (PS)-grafted-titanium oxide (TiO2) nanoparticles with a diameter of 15 nm were prepared by the ‘grafting-from’ method using the surface initiator for nitroxide-mediated radical polymerization (NMRP). The graft densities were estimated to be 0.04–0.28 chains nm−2. Under this graft dense region it is assumed that surface polymer chains form a polymer brush structure in good solvents. Wide-angle X-ray diffraction suggested that the tacticity of the PS chains on the nanoparticle surface is mainly atactic. PS-grafted-TiO2 nanoparticles were stably dispersed in good solvents for PS chains due to the steric repulsion between the grafted chains derived from the osmotic pressure effect and their affinity for the solvents. When the PS-grafted-TiO2 particles were finely dispersed, the ultraviolet absorption due to TiO2 was strong and the difference in absorbance between the visible and ultraviolet regions was ten or more times greater than that for non-grafted TiO2. By adding PS-grafted-TiO2 particles with PS matrix powder in CHCl3, hybrid films were prepared by solvent casting. The PS-grafted-TiO2–PS hybrid films showed high transmittance in the visible light region accompanied by ultraviolet absorption characteristic of TiO2 due to the fine dispersion of nanoparticles in the PS matrix. Furthermore, friction tests revealed that the wear resistance of PS thin films with PS-grafted-TiO2 was improved compared with PS film.

Prognosis in pediatric patients with refractory/relapsed acute myeloid leukemia (AML) is grim, and there is no standard treatment for such patients. Combined treatment with intensive chemotherapy and gemtuzumab ozogamicin (GO), a monoclonal anti-CD33 antibody conjugated with calicheamicin, is useful as reinduction therapy in refractory/relapsed AML. Here, we describe three cases of pediatric refractory/relapsed AML that were successfully managed with FLAG-IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), with or without GO, as reinduction therapy before a KIR-ligand-mismatched cord blood transplant. This strategy relies on the fact that killer cell immunoglobulin-like receptors (KIR) on cord blood natural killer (NK) cells recognize human leukocyte antigen (HLA) class I alleles, and that donor KIR-ligand incompatibility may be associated with lower incidence of relapse and improved survival in AML, as cells that lack these inhibitory HLA ligands can activate NK cells. All three patients are currently alive and have been disease-free for 24–65 months, although one patient developed severe sinusoidal obstructive syndrome (SOS). Thus, our strategy can result in excellent outcomes in pediatric patients with refractory/relapsed AML.

Background Although MYCN (aka N-myc) amplification is reported in ∼20% of neuroblastomas, MYC (aka C-myc) amplification appears to be a rare event in this disease. As of today, only 2 MYC-amplified neuroblastomas have been briefly mentioned in the literature. Methods We studied here the clinicopathological features of 3 MYC-amplified neuroblastomas. Results All 3 patients (2 females and 1 male) had stage 4 disease. One female is currently alive and well 52 months after the diagnosis, while the other female and male patients died of disease 24 and 20 months after the diagnosis, respectively. Further analysis on 2 tumors revealed unfavorable histology with MYC protein overexpression but with neither MYCN amplification nor MYCN protein overexpression. Both of these tumors exhibited “large cell neuroblastoma” histology with enlarged, uniquely open nuclei and nucleolar hypertrophy, along with “aberrant” desmin expression. Conclusions MYC-amplified neuroblastomas are extremely rare and seem to present with distinct clinicopathological features.

Background This study evaluated the utility of Phox2b in pediatric tumors. Previously tyrosine hydroxylase (TH) was the most widely utilized sympathoadrenal marker specific for neural crest tumors with neuronal/neuroendocrine differentiation. However, its sensitivity is insufficient. Recently Phox2b has emerged as another specific marker for this entity. Methods Phox2b IHC was performed on 159 pediatric tumors including (1) 65 neural crest tumors with neuronal differentiation [peripheral neuroblastic tumors (pNT)]: 15 neuroblastoma undifferentiated (NB-UD), 10 NB poorly differentiated (NB-PD), 10 NB differentiating (NB-D), 10 ganglioneuroblastoma intermixed (GNBi), 10 GNB nodular (GNBn), and 10 ganglioneuroma (GN); (2) 23 neural crest tumors with neuroendocrine differentiation [pheochromocytoma/paraganglioma (PCC/PG)]; (3) 27 other neural crest tumors including one composite rhabdomyosarcoma/neuroblastoma; and (4) 44 non-neural crest tumors. TH IHC was performed on group (1), (2) and (3). Results Phox2b was diffusely expressed in pNT (n=65/65): strongly in NB-UD and NB-PD, and in NB-D, GNB and GN with less intensity. Diffuse TH was seen in all NB-PD, NB-D, GNB and GN, but 9/15 NB-UD and a nodule in GNBn didn't express TH (n=55/65). PCC/PG expressed diffuse Phox2b (n=23/23) and diffuse TH except for one tumor (n=22/23). In composite rhabdomyosarcoma, TH was expressed only in neuroblastic cells and Phox2b was diffusely positive in neuroblastic cells and focally in rhabdomyosarcoma. All other tumors were negative for Phox2b (n=0/44). Conclusion Phox2b was a specific and sensitive marker for pNT and PCC/PG, especially useful for identifying NB-UD often lacked TH. Our study also presented a composite rhabdomyosarcoma/neuroblastoma of neural-crest origin. This article is protected by copyright. All rights reserved.

Sinusoidal obstructive syndrome prophylaxis with recombinant human soluble thrombomodulin is feasible in gemtuzumab ozogamicin-treated patients undergoing allogeneic hematopoietic cell transplantation

A 9-year-old girl was referred to our hospital because of facial palsy. Both physical and blood examination revealed hepatosplenomegaly and leukocytosis, respectively. A bone marrow examination demonstrated marked hypercellularity involving myeloblasts and lymphoblasts. Based on these results, we suspected mixed phenotype acute leukemia. However, her leukemic blasts expressed B-cell antigens, and a chromosomal analysis of her bone marrow cells revealed the following karyotype: 46, XX, t (9;22) (q34;q11.2). All her neutrophils were positive for the breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 fusion protein. Based on these findings, she was diagnosed with a lymphoblastic crisis of chronic myelogenous leukemia (CML). Combined chemotherapy, involving imatinib, resulted in complete molecular remission. She received cord blood transplant (CBT) during the first complete remission; she is alive and has not suffered a relapse since two years after the CBT. The sudden onset of a blastic crisis in pediatric CML is rare, and it may be difficult to distinguish such cases from de novo Ph-positive leukemia. For diagnostic purposes, it is essential to consider a patient's clinical course and blood test results.

Wiskott–Aldrich syndrome is a rare X-linked recessive disease resulting from variations in the WAS gene. Wiskott–Aldrich syndrome is sometimes difficult to differentiate from immune thrombocytopenic purpura. A 2-month-old boy was admitted to our hospital for purpura and thrombocytopenia. His mean platelet volume was reported to be normal. Treatment with intravenous immunoglobulins failed to improve the patient’s platelet count. Subsequently, an acute cytomegalovirus infection was confirmed by serological testing and antigenemia. The patient was diagnosed with immune thrombocytopenic purpura secondary to a cytomegalovirus infection. However, based on the patient’s clinical course and the refractoriness of his condition, Wiskott–Aldrich syndrome was strongly suspected. Through direct sequencing of the genomic DNA of the Wiskott–Aldrich syndrome protein (WASP) gene, we identified a novel missense mutation in exon 3 of the patient’s WASP gene (c. 343 C>T, p. H115T), and the patient was diagnosed with Wiskott–Aldrich syndrome at 3 months after onset. Children with Wiskott–Aldrich syndrome are often initially diagnosed with immune thrombocytopenic purpura, which can lead to inappropriate treatment and delays to life-saving definitive therapy. Our findings imply that Wiskott–Aldrich syndrome should be considered as a differential diagnosis in cases of refractory immune thrombocytopenic purpura combined with a cytomegalovirus infection.

Hepatic SOS is a potentially life-threatening complication of conditioning for allogeneic HSCT. rTM is a new drug for treating DIC. We report our experience of the use of rTM as a prophylaxis against SOS in high-risk pediatric patients that underwent HSCT. We evaluated the cases of 19 pediatric hematology and oncology patients who underwent HSCT at our institution between 2007 and 2016. The patients who received HSCT after 2012 (n = 8) were treated with rTM as a prophylaxis against SOS together with UDCA and LMWH, whereas the others (n = 11) were only treated with UDCA and LMWH. Although SOS occurred by post-HSCT day 35 in 3 (27%) patients in the control group, SOS was not seen in the rTM group. Two of the former three patients suffered severe SOS, and one died of the condition. The mean peak level of PAI-1 (a marker of endothelial damage) was significantly lower in the rTM group. rTM appears to be a safe prophylaxis for SOS. The present findings suggest that prophylactic rTM after HSCT might help to prevent SOS.

Neuroblastomas with a high mitosis-karyorrhexis index (High-MKI) are often associated with MYCN amplification, MYCN protein overexpression and adverse clinical outcome. However, the prognostic effect of MYC-family protein expression on these neuroblastomas is less understood, especially when MYCN is not amplified. To address this, MYCN and MYC protein expression in High-MKI cases (120 MYCN amplified and 121 non-MYCN amplified) was examined by immunohistochemistry. The majority (101) of MYCN-amplified High-MKI tumors were MYCN(+), leaving one MYC(+), 2 both(+), and 16 both(-)/(+/-), whereas non-MYCN-amplified cases appeared heterogeneous, including 7 MYCN(+), 36 MYC(+), 3 both(+), and 75 both(-)/(+/-) tumors. These MYC-family proteins(+), or MYC-family driven tumors, were most likely to have prominent nucleolar (PN) formation (indicative of augmented rRNA synthesis). High-MKI neuroblastoma patients showed a poor survival irrespective of MYCN amplification. However, patients with MYC-family driven High-MKI neuroblastomas had significantly lower survival than those with non-MYC-family driven tumors. MYCN(+), MYC-family protein(+), PN(+), and clinical stage independently predicted poor survival. Specific inhibition of hyperactive rRNA synthesis and protein translation was shown to be an effective way to suppress MYC/MYCN protein expression and neuroblastoma growth. Together, MYC-family protein overexpression and PN formation should be included in new neuroblastoma risk stratification and considered for potential therapeutic targets.

Clarifying material–cell interactions after eliminating various effects including cell–cell interactions is a very important issue in tissue and cell engineering. We investigated several cellular behaviors dynamically after growing cells individually one by one to eliminate cell–cell contact by direct observation using the quartz crystal microbalance with dissipation (QCM-D) and microscopy. The initial cellular behaviors of several cells (adsorption, attachment and spreading of L929 mouse fibroblasts) on the gold electrode of the QCM-D were classified into three regions according to the slope of the Df plots: I, cell adsorption and desorption; II, attachment and spreading; and III, secretion of microexudates. When the number of cells increased which leads to increase of cell–cell distance, region III disappeared and the slope of the Df plots in region II became steeper. The behavior related to the variation in the number of attached cells was indicated by the adhesion strength between the cells and the gold electrode. Furthermore, the slope of the Df plots was not shown on the (poly(2-methacryloyloxyethyl phosphorylcholine)– co –2-(methacryloyloxy)ethylthiol)-modified gold electrode and almost all of the cells were not attached to the polymer surface. The initial cell attachment behavior, especially the strength of cell adhesion to the material surface, was evaluated quantitatively by determining the slope of the Df plots using the QCM-D system.

To functionalize polyurethane, a novel synthetic reaction of diol compounds derived from methacrylates with various functional groups was investigated. The methacrylates were reacted with α-thioglycerol via a Michael-type addition to obtain the corresponding diol compounds under mild conditions. In this reaction, diisopropylamine was a much better catalyst than triethylamine. The conversion was dependent on the functional group in the methacrylate. The fluoroalkyl group in 2,2,2-trifluoroethyl methacrylate was better than the alkyl group in butyl methacrylate. No reaction was observed in the case of styrene. Using these diol compounds, polyurethanes were prepared by polyaddition with 4,4-diphenylmethane diisocyanate. When the polyurethanes were casted on the substrate, the functional groups influenced surface hydrophilicity and protein adsorption resistance property of the polyurethane significantly. In particular, phosphorylcholine group was the best to reduced protein adsorption. Based on these findings, the variety of these diol compounds synthesized from methacrylates has the potential for use in the production of novel polyurethanes.

Summary The functionality of nanocolloids used in biomedical applications are subject to strong interference arising from significant interactions with biological components such as proteins and cells. Among the known examples of surface treatment of nanocolloids, the construction of an artificial cell membrane structure based on phospholipid polymers has proven effective in preventing the occurrence of biological reactions at the surface. Furthermore, certain bioactive molecules can be immobilized on the surface of the phospholipid polymer platform to generate bioaffinity for other biomolecules. This review describes preparation and characterization of integrated functional nanocolloids covered by artificial cell membrane structures and their performance in biomedical applications.

For preparing a "highly lubricated biointerface", which has both excellent lubricity and biocompatibility, we investigated the factors responsible for resistance to friction during polymer grafting. We prepared poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), poly(2-hydroxyethyl methacrylate) (PHEMA), and poly(methyl methacrylate) (PMMA) brush layers with high graft density and well-controlled thickness using atom transfer radical polymerization (ATRP). We measured the water absorptivity in the polymer brush layers and the viscoelasticity of the polymer-hydrated layers using a quartz crystal microbalance with dissipation monitoring (QCM-D) measurements. The PMPC brush layer had the highest water absorptivity, while the PMPC-hydrated layer had the highest fluidity. The friction properties of the polymer brush layers were determined in air, water, and toluene by atomic force microscopy (AFM). The friction on each polymer brush decreased only when a good solvent was chosen for each polymer. In conclusion, the brush layer possessing high water absorptivity and fluidity in water contributes to reduce friction. PMPC grafting is an effective and promising method for obtaining highly lubricated biointerfaces.

The effect of water-soluble phospholipid polymer conjugated to a protein on conformational change during heat-quenched stress was investigated in this study. Well-defined pyridine disulfide end-functional poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) was synthesized by well controlled atom transfer radical polymerization method. Synthesized PMPC was the site specifically conjugated to a protein, and the effect on conformational change during heat-quenched stress was estimated by circular dichroism and fluorescence study. As a result, a single phospholipid polymer chain conjugated to a protein give a great effect on conformational preservation in both secondary and tertiary structures even after the heat-quenched process. Moreover, even the conformational recovery which gave the completely reversible conformational preservation was observed in circular dichroism study. The resulting protein activity was also confirmed, and no significant decline was induced by heat-quenched stress.

We investigated the morphological effect of phase-separated block copolymer surfaces composed of poly(2-methacryloyloxyethyl phosphorylcholine (MPC)) (PMPC) and poly(dimethylsiloxane) (PDMS) on protein adsorption and cell adhesion behavior. We observed three different types of phase-separated surface morphologies by TEM and AFM. The elemental composition of phosphorus on the surface increases with the PMPC composition. Furthermore, the polymer surface formed by a block copolymer-containing a higher MPC unit composition shows a slightly lower static water contact angle. This result indicates that the elemental surface ratio of the surface depends on the MPC composition in the block copolymer. Protein adsorption tests revealed that only hydrophobic PDMS domains showed selective protein adsorption. Cell adhesion tests revealed that the number of adhered cells increased with increasing hydrophobic PDMS domain size of block copolymers in serum-containing media. In contrast, no cells adhered onto block copolymer surfaces in serum-free media, whereas a large amount of adhered cells were observed on the hydrophobic PDMS surface. This result indicates that segregated hydrophobic domains on a biocompatible PMPC surface strongly affect serum protein adsorption, thereby promoting considerable cell adhesion, although the surface is hydrophilic. Thus, both the composition of MPC units and the segregated hydrophobic surface morphology are important considerations in biomaterial surface design.

To obtain novel biodegradable sirolimus-releasing polymer films that could release nanovehicles incorporating sirolimus, polyester, a water-soluble amphiphilic phospholipid polymer, and sirolimus were blended. The sirolimus-releasing polymer films were characterized by scanning electron microscopy and differential scanning calorimetry. Nanovehicles were formed with the phospholipid polymer chains and could be released from the sirolimus-releasing polymer films. The hydrodynamic diameter of the nanovehicles in phosphate-buffered saline was smaller than 20 nm. The nanovehicles substantially enhanced the carrier-mediated delivery of sirolimus and attenuated its degradation product. This study demonstrates that the delivery of sirolimus was enhanced by nanovehicles released from sirolimus-eluting materials.

Surface modifications of nanoparticles with phospholipid polymers composed of 2 -methacryloyloxyethyl phosphorylcholine (MPC), are summarized. The MPC can be available for various polymerization methods such as conventional radical polymerization and living radical polymerization, and easily copolymerized with other vinyl compounds. The MPC polymers have been widely used as biocompatible coating and stabilizer for nanoparticles even when they are under biological environment. Additionally, for immobilization of biomolecules, such as antibody and enzyme, the MPC polymers having active ester group are applicable. These MPC polymers coated on the nanoparticles immobilize protein under mild condition and the protein maintained bioactivity well. Moreover, introduction of functional inorganic nanocrystals inside of the nanoparticles is effective to obtain good imaging tool for specific cells. The potential of molecular integration on nanoparticles based on MPC polymer chemistry will be expanded nanobiosensing, nanoimaging and nanodiagnostic system.