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Osteosarcoma is the most common malignant bone tumor in children and young adults. The identification of proteins which exhibit different subcellular localization in low- versus high-risk osteosarcoma can be instrumental to obtain prognostic information and to develop innovative therapeutic strategies. Beside the well-characterized membrane and cytoplasmic localization of Src protein, this study evaluated the prognostic relevance of its so-far unknown nuclear compartmentalization. We analyzed the subcellular distribution of total and activated (pY418) Src in a tissue microarray including 60 osteosarcoma samples. Immunohistochemical analyses revealed a variable pattern of Src expression and localization, ranging from negative to high-stained nuclei combined with a substantial cytoplasmic staining for total and activated forms. The analysis of Kaplan-Meier survival curves in relationship to the diverse permutations of cytoplasmic and nuclear staining suggested a correlation between Src subcellular localization and the overall survival (OS) of osteosarcoma patients. In order to explain this different subcellular localization, normal osteoblasts and three osteosarcoma cell lines were used to investigate the molecular mechanism. Once confirmed a variable Src localization also in these cell lines, we demonstrated a correlation between the N-myristoyltransferase enzymes expression and activity and the Src nuclear content. In conclusion, these results described a so-far unknown Src nuclear localization in osteosarcoma cells, suggesting that the combined detection of nuclear and cytoplasmic Src levels can be used as a prognostic marker for osteosarcoma patient survival. A correlation between the N-myristoyltransferase enzymes and the Src subcellular localization was described as well.

Antimicrobial peptides are promising alternative to traditional antibiotics and antitumor drugs for the battle against new antibiotic resistant bacteria strains and cancer maladies. The study of their structural and dynamics properties at physiological conditions can help to understand their stability, delivery mechanisms, and activity in the human body. In this article, we have used molecular dynamics simulations to study the effects of solvent environment, temperature, ions concentration, and peptide concentration on the structural properties of the antimicrobial hybrid peptide Cecropin A–Magainin 2. In TFE/water mixtures, the structure of the peptide retained α-helix contents and an average hinge angle in close agreement with the experimental NMR and CD measurements reported in literature. Compared to the TFE/water mixture, the peptide simulated at the same ionic concentration lost most of its α-helix structure. The increase of peptide concentration at both 300 and 310 K resulted in the peptide aggregation. The peptides in the complex retained the initial N-ter α-helix segment during all the simulation. The α-helix stabilization is further enhanced in the high salt concentration simulations. The peptide aggregation was not observed in TFE/water mixture simulations and, the peptide aggregate, obtained from the water simulation, simulated in the same conditions did dissolve within few tens of nanoseconds. The results of this study provide insights at molecular level on the structural and dynamics properties of the CA-MA peptide at physiological and membrane mimic conditions that can help to better understand its delivery and interaction with biological interfaces. © 2014 Wiley Periodicals, Inc. Biopolymers 103: 1–14, 2015

In the framework of a hybrid particle-field simulation technique where self-consistent field (SCF) theory and molecular dynamics (MD) are combined, specific coarse-grained (CG) models for Pluronic block copolymers are developed. In particular, the behavior of the model in the correct reproduction of micellar and non-micellar phases has been tested for Pluronic L62 and L64. At different temperature and polymer contents of the water-polymer mixture, the proposed model is able to correctly describe the different morphologies that are experimentally found. The proposed CG models, still very close to atomistic ones, allow the reconstruction of full atomistic structures by applying suitable reverse mapping techniques. This opens the way to all atom description of these systems. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

An efficient method to align low-molecular-mass molecules by enclosing them as isolated guests of the nanoporous host δ phase of syndiotactic polystyrene oriented films, is presented. This new method is compared with the classic method consisting in the absorption of low- molecular-mass molecules as a solute of amorphous phases of highly oriented semicrystalline polymeric films. It is shown that this new molecular alignment method provides a powerful tool to study in detail several features (spectroscopic properties, molecular motions) of relevant molecules, by separating with unprecedented selectivity their anisotropic spectral responses. The reported results refer to infrared and solid-state- 2 H-NMR spectra.

Purpose We report the off-label study aimed at investigating the use of temozolomide (TMZ) as single agent in relapsed or resistant pediatric solid tumors. The drug was administered at the dose of 215 mg/m2/day × 5 days or 180 mg/m2/day × 5 days in patients with prior craniospinal irradiation (CSI) or autologous bone marrow transplantation (ABMT). Patients and Methods Fifty two patients, median age 127.6 months, with resistant or relapsed solid tumors were enrolled. Tumor types were: neuroblastoma (NB; n = 17), medulloblastoma (MB; 8), brain stem glioma (BSG; 8), extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor (EOES; 4), Ewing's sarcoma (ES; 4), anaplastic astrocytoma (AA; 3), rhabdomyosarcoma (RMS; 2), ependymoma (EP; 2), cerebral primitive neuroectodermal tumor (cPNET; 2), hepatocarcinoma (HC; 1), and osteosarcoma (OS; 1). All patients were pre-treated. Two outpatient courses were administered, with a median of 4.8 courses/pt. Results Objective response-rate (CR + PR + MR) in our series was 13.4% (1.9% CR, 3.8% PR, and 7.7% MR), SD occurred in 38.4% of patients and 48% had PD. The median survival was 7.8 months (range 1–37) and median time to progression was 3.4 months (range 1–20); these data were significantly correlated with histology and previous nitrosureas administration in multivariate analysis. Haematological toxicity grade 3–4 (mainly thrombocytopenia) was observed in 21.4% of administered courses, nausea was reported in 3.1% and respiratory distress in 0.7%. Conclusion Oral TMZ was well tolerated in children with resistant or relapsed solid tumors and showed activity in NB and CNS tumours refractory to standard chemotherapy. © 2005 Wiley-Liss, Inc.

A new analytical form for bond and angle potentials suitable for obtaining mesoscale effective force fields from target distributions is reported. Applications to realistic coarse-grained models of atactic polystyrene and polyamide-6,6 are described. The potential optimization procedure, despite its simplicity, allows the accurate reproduction of the target atomistic distributions. The procedure has been validated for both bond and angle potentials. Nonbonded numerical potentials have been optimized by pressure-corrected iterative Boltzmann inversion. Thus, the proposed coarse-graining strategy consists of hybrid analytical and numerical contributions to the mesoscale polymer force field. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 871–885, 2005

Children affected by advanced neuroblastoma have a discouraging prognosis, but intensive induction chemotherapy may increase the complete response rate. The combination of ifosfamide, carboplatin and etoposide (ICE) was used for the first time as front-line regimen in patients with stage 4 neuroblastoma over the age of 1 y. Similarly, second-line treatment for children with relapsed neuroblastoma, particularly after high-dose chemotherapy, has been unsatisfactory. The combination of topotecan and cyclophosphamide was studied in resistant or relapsed solid tumors. Furthermore, there is a need for effective palliative treatment in patients failing therapy. Temozolomide, a new dacarbazine analog with optimal oral bioavailability, is being used in an ongoing phase II study as an alternative to oral etoposide. Seventeen patients with stage 4 neuroblastoma have entered the ICE study; 15/16 (94%) major responses after induction were observed and 6/16 (37%) evaluable patients are disease free after a median of 51 mo. Twenty-one patients with relapsed/refractory disease (of whom 13 neuroblastomas) entered the topotecan/cyclophosphamide study: 7/21 (33%) patients responded. Forty-one patients entered the temozolomide study (of whom 16 had neuroblastomas): stable disease and symptom relief were obtained in 15/30 (50%) evaluable patients. Intensive induction with ICE resulted in a faster response with high response rate; a larger study with longer follow-up is needed to confirm a survival advantage. Second-line treatment was effective in obtaining remissions, some of them long lasting. Third-line treatment did not elicit measurable responses in neuroblastoma, but achieved prolonged freedom from disease progression and excellent palliation in several patients.

OBJECTIVE To evaluate 10 years of experience, and thus define the occurrence and causes, of neurogenic lower urinary tract dysfunction in children with pelvic neoplasms treated by surgery. PATIENTS AND METHODS From 1991 to 2000, 33 children were operated by the same surgeons for pelvic neoplasms; 11 were analysed, comprising four each with sacrococcygeal teratoma (ST) and ganglioneuroma, and one each with yolk sac tumour (YST), neuroblastoma and myofibroblastic bladder sarcoma (MBS). The other patients were not assessed because eight had died or were in severe progression, three were treated by bladder substitution and the others were lost to follow-up or refused a urological evaluation. All 11 children were evaluated at ≥ 6 months after surgery with a questionnaire about bowel and voiding habits, a neurological and orthopaedic assessment, a noninvasive urodynamic study, renal ultrasonography and spinal and pelvic magnetic resonance imaging (MRI). All patients with signs of bladder dysfunction were evaluated by a pressure-flow study. The results were analysed for surgical approach and anatomical involvement, i.e. group A, extensive surgery for complete tumour excision in the sacral area (ST and YST); group B, surgery for tumour resection in the paraspinal ganglia area (neuroblastoma and ganglioneuroma); and group C, bladder tumour with partial bladder resection (MBS). RESULTS Eight patients had signs or symptoms related to bladder sphincter dysfunction. One child refused the invasive urodynamic evaluation, leaving seven for analysis (two each ST and ganglioneuroma, one each YST, neuroblastoma and MBS). The urodynamic findings were normal in three children. On spinal and pelvic MRI a presacral lipoma with syringomyelia was discovered in one child with ST. Eight children had bladder dysfunction and two had no neurogenic damage (which was only in sacral tumours); in one child it was related to an upper motor neurone lesion from spinal dysraphism and in the other to a lower motor neurone lesion from surgical injury to the splanchnic nerves. Patients operated for paraspinal tumours had more bladder dysfunction but no signs of neurogenic damage, as did the patient with partial bladder resection. However in Group B, there may have been a transient or incomplete nerve injury in one patient. CONCLUSIONS Deficits of parasympathetic, sympathetic and somatic innervation of the bladder and the urethra may occur in children after surgery for pelvic neoplasms, related to minor or major surgical trauma. In ST, a tethered cord may be associated with mixed neurogenic damage. Knowledge of bladder dysfunction in anorectal malformations, spinal dysraphism, etc. and the clinical protocol used in these patients also seemed to be useful for understanding the development of voiding dysfunction in patients with neoplasm.

This paper reports the assignment of the 13 C NMR resonances of the S ββ and S αγ methylenes observed in the spectra of copolymers of propylene with trace amounts of enriched ethylene-1- 13 C. The assignment is achieved by comparing the chemical shifts calculated by an empirical method (at the CH 2 stereochemical pseudohexad level), with the experimental spectra of regioregular copolymers with different stereochemical structure. The implications of the observed S ββ and S αγ resonances on the stereochemical polymerization mechanisms are also discussed.

Theoretical studies relative to propene primary insertion for polymerization catalysts based on Brookharttype Ni(II) and biscyclopentadienyl Ti(IV) complexes are reported. On the basis of geometrical considerations relative to calculated transition states, a unified mechanism for like (isospecific) and unlike (syndiospecific) chain-end stereocontrol for primary propene polymerizations, which can be considered as a sub-case of the more general mechanism of the chiral orientation of the growing chain, is suggested. As usual, the selection between monomer enantiofaces would be determined by the conformation relative to the Mt-C bond (negative or positive values of θ 1 ), which for these catalysts would be determined by the configuration of the tertiary carbon bond of the growing chain being closest to the metal, but would also be critically depending on the conformation of the first C-C bond of the chain. In particular, chain-end stereocontrolled polymerization catalysts imposing that the first tertiary H atom would point toward the metal (θ 2H 0°) or toward the monomer (θ 2H 100°) would lead to preference for isospecific and syndiospecific propagation, respectively.

A systematic ab initio investigation of the complexes benzene/halogen molecules is presented. For the whole halogen series, the T-shaped geometry is clearly favored relative to the sandwich geometry. This preference is rationalized in terms of the electrostatic fields generated by the interacting molcules. Higher binding energies have been calculated on going from /F2 to /I2 molecular complexes.

Background Pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) may rarely occur in visceral tissues, and little is known about their clinical history. The present study retrospectively analyzed a group of patients prospectively registered in Italian pediatric protocols conducted between 1979 and 2004. Methods Inclusion criteria for the study were as follows: a pathological diagnosis of “adult-type NRSTS,” arising at visceral sites (lung-pleurae, liver, kidney, and mesentery-bowel); age under 18 years; no previous treatment except for primary surgery; available clinical data; and written consent. Results Thirty cases with visceral NRSTS were collected and analyzed. Sites of origin were as follows: mesentery-bowel in 12 cases, lung-pleurae in 11, liver in 5, and kidney in 2. According to the Intergroup Rhabdomyosarcoma Study (IRS) surgical grouping system, patients were classified as follows: nine IRS group I, three group II, 12 group III, and six group IV. Patients were treated with a multimodal approach including surgery, radiotherapy, and/or chemotherapy, according to their characteristics. For the series as a whole, the 5-year event-free and overall survival rates were 33.3% and 40.0%, respectively. The IRS group (reflecting the feasibility of initial complete resection) emerged as the main prognostic factor. Survival rates also correlated with tumor size and local invasiveness, histological subtype, and tumor sites (the worst outcome was seen for tumors arising in the lung and pleurae). Conclusions This study confirmed that visceral NRSTS are aggressive tumors carrying a worse prognosis than pediatric NRSTS arising in soft tissues of the extremities. Local treatment remains the main challenge for these tumors.