Effect of cisplatin and c-myb antisense phosphorothioate oligodeoxynucleotides combination on a human colon carcinoma cell line in vitro and in vivo

We investigated the effect of c-myb antisense phosphorothioate oligodeoxynucleotides [(S)ODNs] and cisplatin (CDDP) combination on the human colon carcinoma cell line LoVo Dx both in vitro and in nude mice bearing LoVo Dx solid tumour. We show that antisense (S)ODN treatment decreases c-myb mRNA and protein expression, induces growth arrest in the G1 phase of the cell cycle, and inhibits cell proliferation. In vivo treatment with c-myb antisense (S)ODNs results in a reduction in tumour growth. A greater inhibition of cell proliferation in vitro and a higher increase of tumour growth inhibition and growth delay in vivo were obtained with the combination of (S)ODNs and CDDP than when the two agents were administered separately. This comparative study, using the same tumour cell line in vitro and in vivo, suggests that c-myb antisense (S)ODNs might be useful in the therapy of colon cancer in combination with antineoplastic drugs.     

Deep Resequencing of 9 Candidate Genes Identifies a Role for ARAP1 and IGF2BP2 in Modulating Insulin Secretion Adjusted for Insulin Resistance in Obese Southern Europeans

Type 2 diabetes is characterized by impairment in insulin secretion, with an established genetic contribution. We aimed to evaluate common and low-frequency (1–5%) variants in nine genes strongly associated with insulin secretion by targeted sequencing in subjects selected from the extremes of insulin release measured by the disposition index. Collapsing data by gene and/or function, the association between disposition index and nonsense variants were significant, also after adjustment for confounding factors (OR = 0.25, 95% CI = 0.11–0.59, p = 0.001). Evaluating variants individually, three novel variants in ARAP1, IGF2BP2 and GCK, out of eight reaching significance singularly, remained associated after adjustment. Constructing a genetic risk model combining the effects of the three variants, only carriers of the ARAP1 and IGF2BP2 variants were significantly associated with a reduced probability to be in the lower, worst, extreme of insulin secretion (OR = 0.223, 95% CI = 0.105–0.473, p < 0.001). Observing a high number of normal glucose tolerance between carriers, a regression posthoc analysis was performed. Carriers of genetic risk model variants had higher probability to be normoglycemic, also after adjustment (OR = 2.411, 95% CI = 1.136–5.116, p = 0.022). Thus, in our southern European cohort, nonsense variants in all nine candidate genes showed association with better insulin secretion adjusted for insulin resistance, and we established the role of ARAP1 and IGF2BP2 in modulating insulin secretion.     

A unified mathematical programming formulation of strain driven and interior point algorithms for shakedown and limit analysis

A mathematical programming formulation of strain‐driven path‐following strategies to perform shakedown and limit analysis for perfectly elastoplastic materials in an FEM context is presented. From the optimization point of view, standard arc‐length strain‐driven elastoplastic analyses, recently extended to shakedown, are identified as particular decomposition strategies used to solve a proximal point algorithm applied to the static shakedown theorem that is then solved by means of a convergent sequence of safe states. The mathematical programming approach allows: a direct comparison with other non‐linear programming methods, simpler convergence proofs and duality to be exploited. Owing to the unified approach in terms of total stresses, the strain‐driven algorithms become more effective and less non‐linear with respect to a self‐equilibrated stress formulation and easier to implement in the existing codes performing elastoplastic analysis. The elastic domain is represented avoiding any linearization of the yield function so improving both the accuracy and the performance. Better results are obtained using two different finite elements, one with a good behavior in the elastic range and the other suitable for performing elastoplastic analysis. The proposed formulation is compared with a specialized implementation of the primal–dual interior point method suitable to solve the problems at hand. Copyright © 2011 John Wiley & Sons, Ltd.     

Comparative in vitro and in vivo study of a nitroxyl derivative of 5-fluorouracil (magnizil) on human gastrointestinal tumors

AIMS AND BACKGROUND: There is much interest in nitroxyl derivatives of cytotoxic agents. We evaluated the potential activity of magnizil, a derivative of 5-fluorouracil, on human gastrointestinal tumors in 3 different in vitro and in vivo experimental models. METHODS: The activities of magnizil and 5-fluorouracil were comparatively determined in vitro on the HT29 cell line by a clonogenic assay and on tumor clinical specimens by an antimetabolic assay. The activity of both the drugs against human tumors was also assessed in mice with the subrenal capsule assay. RESULTS: A similar cytotoxic activity was found for magnizil and 5-fluorouracil on the HT29 cell line. As regards human tumors, a lower activity was observed for the nitroxyl derivative than for 5-fluorouracil, with response rates of 25% and 50%, respectively, at comparable concentrations. Moreover, among the tumors transplanted in the subrenal capsule of mice, two were sensitive to magnizil and 3 to 5-fluorouracil. CONCLUSIONS: Even though experimental results on human tumors indicate a somewhat lower activity for magnizil than the parent compound, its low toxicity and the possibility to clinically use high doses suggest the opportunity to further investigate the potential of this new anticancer agent on larger series of colorectal cancers in experimental systems.     

Hybrid Self-Assembling Nanoparticles Encapsulating Zoledronic Acid: A Strategy for Fostering Their Clinical Use

Self-assembling nanoparticles (SANPs) promise an effective delivery of bisphosphonates or microRNAs in the treatment of glioblastoma (GBM) and are obtained through the sequential mixing of four components immediately before use. The self-assembling approach facilitates technology transfer, but the complexity of the SANP preparation protocol raises significant concerns in the clinical setting due to the high risk of human errors during the procedure. In this work, it was hypothesized that the SANP preparation protocol could be simplified by using freeze-dried formulations. An in-depth thermodynamic study was conducted on solutions of different cryoprotectants, namely sucrose, mannitol and trehalose, to test their ability to stabilize the produced SANPs. In addition, the ability of SANPs to deliver drugs after lyophilization was assessed on selected formulations encapsulating zoledronic acid in vitro in the T98G GBM cell line and in vivo in an orthotopic mouse model. Results showed that, after lyophilization optimization, freeze-dried SANPs encapsulating zoledronic acid could retain their delivery ability, showing a significant inhibition of T98G cell growth both in vitro and in vivo. Overall, these results suggest that freeze-drying may help boost the industrial development of SANPs for the delivery of drugs to the brain.     

Do social sciences and humanities behave like life and hard sciences?

Scientometrics - The quantitative evaluation of Social Science and Humanities (SSH) and the investigation of the existing similarities between SSH and Life and Hard Sciences (LHS) represent the...     

A YAP camera 40×40 mm2 with fast readoutelectronics

Previous papers have already demonstrated the suitability for single-photon emission computed tomography (SPECT) tracers biodistribution studies on small animals, of a miniature gamma camera composed by a YAP:Ce scintillating array 4×4×1 cm³ coupled to a 3-in Hamamatsu crossed-wire anode position sensitive photomultiplier (PSPMT). Some modifications have been applied to the imaging system readout in order to adapt its utilization for specific purposes (i.e. SPECT radiopharmaceutical testing) and to reduce construction costs so that a larger scale production may be feasible. In particular, the system introduced here is based on a resistive chain readout and an integrated acquisition electronics. The intrinsic performance of this new version has been analyzed and compared to the previous system, which had a single-wire readout. Results showed that the basic characteristics of the imaging system remain substantially unchanged in this simplified version, while a faster count rate is achieved. A test on a biological sample performed with the YAP camera both in single-wire and in resistive chain readout modality is also presented, which shows the system high performance in comparison to the Auger camera     

Aromatic Core Extension in the Series of N‐Cyclic Bay‐Substituted Perylene G‐Quadruplex Ligands: Increased Telomere Damage,Antitumor Activity,and Strong Selectivity for Neoplastic over Healthy Cells

Based on previous work on both perylene and coronene derivatives as G‐quadruplex binders, a novel chimeric compound was designed: N,N′‐bis[2‐(1‐piperidino)‐ethyl]‐1‐(1‐piperidinyl)‐6‐[2‐(1‐piperidino)‐ethyl]‐benzo[ghi]perylene‐3,4:9,10‐tetracarboxylic diimide (EMICORON), having one piperidinyl group bound to the perylene bay area (positions 1, 12 and 6, 7 of the aromatic core), sufficient to guarantee good selectivity, and an extended aromatic core able to increase the stacking interactions with the terminal tetrad of the G‐quadruplex. The obtained “chimera” molecule, EMICORON, rapidly triggers extensive DNA damage of telomeres, associated with the delocalization of telomeric protein protection of telomeres 1 (POT1), and efficiently limits the growth of both telomerase‐positive and ‐negative tumor cells. Notably, the biological effects of EMICORON are more potent than those of the previously described perylene derivative (PPL3C), and more interestingly, EMICORON appears to be detrimental to transformed and tumor cells, while normal fibroblasts expressing telomerase remain unaffected. These results identify a new promising G‐quadruplex ligand, structurally and biologically similar on one side to coronene and on the other side to a bay‐monosubstituted perylene, that warrants further studies.     

Neurovascular considerations in surgery of glomus tumors with intracranial extensions

Paragangliomas of the skull base, by virtue of their location, locally infiltrative behavior, and vascular nature, are difficult tumors to resect. Surgical removal is especially complicated when intracranial extensions are encountered. Our experience with a one-stage resection of intracranial extensions of glomus tumors in 20 patients is presented. These 20 patients had a total of 29 paragangliomas: 23 glomus jugulare or tympanicum tumors, 5 carotid body tumors, and 1 pterygopalatine lesion. Ten patients had intradural extension; the other 10 had intracranial extradural tumors. The primary complicating treatment factor was the loss of surgical planes in 6 patients with prior surgery and or radiotherapy. The presence of multiple paragangliomas (20%) and catecholamine secretion by the tumors (15%) complicated surgical treatment as well. Surgical morbidity was primarily related to deficits of lower cranial nerves (50%).