Prevention of recurrent respiratory tract infections: a literature review of the activity of the bacterial lysate Lantigen B.

OBJECTIVE: Lantigen B, a bacterial lysate, was developed in the 1960s and showed a prophylactic effect in patients with recurrent respiratory tract infections. The objective of this article is to review the literature to update the efficacy and safety profile of Lantigen B in preventing recurrent respiratory tract infections (RRTI). MATERIALS AND METHODS: Articles available from international data banks and producing company archives were used. Only clinical studies providing a control group were considered. The effects of Lantigen B on the number of infectious episodes or comparable parameters were analyzed. RESULTS: 22 randomized clinical trials on 4,571 patients published between 1963 and 2014, with different methodologic accuracy, consistently demonstrated that Lantigen B reduced RRTI vs. placebo (RR -0.47; 95% CI = -0.38 to -0.56). The RR always favored Lantigen B in all the other subsets analyzed in adults with RRTI (RR = -0.48; 95% CI = - 0.33 to -0.62) and children (RR = -0.490; 95% CI = - 0.36 to -0.61). Unfortunately, some studies performed in the past evaluated a small number of patients, and clinical procedures were not always performed according to the more recent good clinical practices. Despite these evident limitations of considered studies, the response frequency has remained almost unchanged since the first articles in the 1960s. CONCLUSIONS: These data confirm the efficacy of Lantigen B alone in the prophylaxis of acute respiratory infections in adults and children but also suggest that Lantigen B, used with novel therapeutic strategies, can further improve clinical outcomes.

Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect.

Proteasome inhibitors (PIs) represent the gold standard in the treatment of multiple myeloma. Among PIs, Bortezomib (BTZ) is frequently used as first line therapy, but peripheral neuropathy (PN), occurring approximately in 50% of patients, impairs their life, representing a dose-limiting toxicity. Carfilzomib (CFZ), a second-generation PI, induces a significantly less severe PN. We investigated possible BTZ and CFZ off-targets able to explain their different neurotoxicity profiles. In order to identify the possible PIs off-targets we used the SPILLO-PBSS software that performs a structure-based in silico screening on a proteome-wide scale. Among the top-ranked off-targets of BTZ identified by SPILLO-PBSS we focused on tubulin which, by contrast, did not turn out to be an off-target of CFZ. We tested the hypothesis that the direct interaction between BTZ and microtubules would inhibit the tubulin alfa GTPase activity, thus reducing the microtubule catastrophe and consequently furthering the microtubules polymerization. This hypothesis was validated in a cell-free model, since BTZ (but not CFZ) reduces the concentration of the free phosphate released during GTP hydrolysis. Moreover, NMR binding studies clearly demonstrated that BTZ, unlike CFZ, is able to interact with both tubulin dimers and polymerized form. Our data suggest that different BTZ and CFZ neurotoxicity profiles are independent from their proteasome inhibition, as demonstrated in adult mice dorsal root ganglia primary sensory neurons, and, first, we demonstrate, in a cell free model, that BTZ is able to directly bind and perturb microtubules.

First urinary tract infections in children: the role of the risk factors proposed by the Italian recommendations.

AIM: In 2009, the Italian society for paediatric nephrology suggested the need for cystography, following a first febrile urinary tract infection (UTI), only in children at high risk for dilating vesicoureteral reflux or in the event of a second infection. The aim of this study was to evaluate the adequacy of the risk factors proposed by the Italian guidelines. METHODS: Children aged 2-36 months, managed by 10 Italian hospitals between 2009 and 2013, with a first febrile UTI were retrospectively evaluated. RESULTS: Four hundred and fourteen children were included: 51% female, mean age eight months. Escherichia coli was responsible of 84% UTIs. 269 children (65%) presented at least one risk factor, thus were further investigated: 44% had a reflux. The presence of a pathogen other than E. coli significantly predicted high-grade reflux, both in the univariate (Odd Ratio 2.52, 95% Confidence Interval 1.32-4.81, p < 0.005) and multivariate analysis (OR 2.74, 95% CI: 1.39-5.41, p: 0.003). 26/145 children (18%) with no risk factors experienced a second UTI, which prompted the execution of cystography, showing a dilating reflux in 11. CONCLUSION: Among the risk factors proposed by the Italian guidelines, only the presence of a pathogen other than E. coli significantly predicted reflux. Cystography can be postponed in children with no risk factors.

Glycosylated simple phenolic profiling of food tannins using high resolution mass spectrometry (Q-Orbitrap).

Tannins are polyphenolic compounds extensively present in plants and used by food industry as processing aids. Due to the heterogeneity of plant sources, actions involved in food processing and tannin commercial costs can be different. In the last years different approaches aimed at correctly identifying the tannin botanical origin have been developed, in order to satisfy the industry's request to verify product labels. This work aimed to define the glycosidic simple phenolic profile of a large selection of monovarietal commercial tannins of different origin, using a high-resolution untargeted approach. Using accurate mass, isotopic pattern and MS/MS fragmentation, 167 precursors, 89 as monoglycosylated and 78 as diglycosylated derivatives were tentatively identified in tannins, validating the untargeted approach with 3 custom-synthesized glycosidic precursors. Almost all tannin botanical varieties were shown to be characterised by a specific glycosylated phenolic profile, providing possible tools for tannin classification in the case of glycosylphenol standard availability.

Non-targeted glycosidic profiling of international wines using neutral loss-high resolution mass spectrometry.

Many metabolites naturally occur as glycosides, since sugar moieties can be crucial for their biological activity and increase their water solubility. In the plant kingdom they may occur as glycosides or sugar esters, depending on precursor chemical structure, and in wine they have traditionally attracted attention due to their organoleptic properties, such as astringency and bitterness, and because they affect the colour and aroma of wines. A new approach directed at detailed description of glycosides in a large selection of monovarietal wines (8 samples each of Pinot Blanc, Muller Thurgau, Riesling, Traminer, Merlot, Pinot Noir and Cabernet Sauvignon) was developed by combining high performance liquid chromatography with high resolution tandem mass spectrometry. Analytical separation was performed on an Accucore™ Polar Premium LC column, while mass analysis was performed in negative ion mode with an non-targeted screening approach, using a Full MS/AIF/NL dd-MS2 experiment at a resolving power of 140,000 FWHM. Over 280 glycoside-like compounds were detected, of which 133 (including low-molecular weight phenols, flavonoids and monoterpenols) were tentatively identified in the form of pentose (6), deoxyhexose (17), hexose (73), hexose-pentose (16), hexose-deoxyhexose (7), dihexose (5) and hexose ester (9) derivatives. It was not possible to univocally define the corresponding chemical structure for the remaining 149 glycosides. Non-parametric statistical analysis showed it was possible to well characterise the glycosylated profile of all red and Traminer wines, while the identified glycosides were almost entirely lacking in Pinot Blanc, Riesling and Muller Thurgau wines. Also Tukey's Honestly Significant Difference test (p < 0.05) and Principal Component Analysis confirmed that it was possible to almost entirely distinguish the selected red wines from each other according to their glycosylated profile.

Estimating terrestrial gross primary productivity in water limited ecosystems across Africa using the Southampton Carbon Flux (SCARF) model.

The amount of carbon uptake by vegetation is an important component to understand the functioning of ecosystem processes and their response/feedback to climate. Recently, a new diagnostic model called the Southampton Carbon Flux (SCARF) Model driven by remote sensing data was developed to predict terrestrial gross primary productivity (GPP) and successfully applied in temperate regions. The model is based on the concept of quantum yield of plants and improves on the previous diagnostic models by (i) using the fraction of photosynthetic active radiation absorbed by the photosynthetic pigment (FAPARps) and (ii) using direct quantum yield by classifying the vegetation into C3 or C4 classes. In this paper, we calibrated and applied the model to evaluate GPP across various ecosystems in Africa. The performance of the model was evaluated using data from seven eddy covariance flux tower sites. Overall, the modelled GPP values showed good correlation (R>0.59, p<0.0001) with estimated flux tower GPP at most sites (except at a tropical rainforest site, R=0.38, p=0.02) in terms of their seasonality and absolute values. Mean daily GPP across the investigated period varied significantly across sites depending on the vegetation types from a minimum of 0.44gCm-2day-1 at the semi-arid and sub-humid savanna grassland sites to a maximum of 9.86gCm-2day-1 at the woodland and tropical rain forest sites. Generally, strong correlation is observed in savanna woodlands and grasslands where vegetation follows a prescribed seasonal cycle as determined by changes in canopy chlorophyll content and leaf area index. Finally, the mean annual GPP value for Africa predicted by the model was 35.25PgCyr-1. The good performance of the SCARF model in water-limited ecosystems across Africa extends its potential for global application.

Evaluation of the Profile and Mechanism of Neurotoxicity of Water-Soluble [Cu(P)4]PF6 and [Au(P)4]PF6 (P = thp or PTA) Anticancer Complexes.

[Cu(thp)4]PF6, [Cu(PTA)4]PF6, [Au(thp)4]PF6 and [Au(PTA)4]PF6 are phosphane (thp = tris(hydroxymethyl)phosphane; PTA = 1,3,5-triaza-7-phosphaadamantane) copper(I) and gold(I) water-soluble complexes characterized by high anticancer activity in a wide range of solid tumors, often able to overcome drug resistance of platinum-based compounds. For these reasons, they have been proposed as a valid alternative to platinum-based chemotherapeutic drugs (e.g., cisplatin and oxaliplatin). In vitro experiments performed on organotypic cultures of dorsal root ganglia (DRG) from 15-day-old rat embryos revealed that copper-based compounds were not neurotoxic even at concentrations higher than the IC50 obtained in human cancer cells while [Au(PTA)4]PF6 was neurotoxic at lower concentration than IC50 in cancer cell lines. The ability of these compounds to hinder the proteasome machinery in DRG neurons was tested by fluorimetric assay showing that the non-neurotoxic copper-based complexes do not inhibit proteasome activity in DRG primary neuron cultures. On the contrary, the neurotoxic complex [Au(PTA)4]PF6, induced a significant inhibition of proteasome activity even at concentrations lower than the IC50 in cancer cells. The proteasome inhibition induced by [Au(PTA)4]PF6 was associated with a significant increase in α-tubulin polymerization that was not observed following the treatment with copper-based compounds. Uptake experiments performed by atomic absorption spectrometry showed that both copper-based complexes and [Au(PTA)4]PF6 are internalized in neuron cultures. In vitro and in vivo preliminary data confirmed copper-based complexes as the most promising compounds, not only for their anticancer activity but also concerning the peripheral neurotoxicity profile.

Free and glycosylated simple phenol profiling in Apulian Italian wines.

Free simple phenols have a significant role in defining the sensory and nutritional characteristics of wines, affecting the organoleptic profile and having positive effects on health, but glycosidically bound phenols can also be hydrolysed during the winemaking process, releasing the corresponding volatile compounds and making a possible contribution to the final sensory profile. In this work, application of on-line SPE liquid chromatography-high resolution mass spectrometry, operating in negative polarity with heated electrospray, allowed to detect over eighty free and glycosylated simple phenols in Primitivo di Manduria and Negroamaro wines. Sixty-one phenols, four of which phenolic glucosidic precursors, were quantified as having quantification limits ranging from 0.001 to 0.1µgmL(-1), calibration R(2) of 0.99 for over 92% of compounds, and precision (R.S.D.%) always lower than 12%. Twenty-four simple phenolic precursors were tentatively identified as hexoside, pentoside and hexoside-hexoside derivatives, on the basis of accurate mass, isotopic pattern and MS/MS fragmentation.

Identification and quantification of 56 targeted phenols in wines, spirits, and vinegars by online solid-phase extraction - ultrahigh-performance liquid chromatography - quadrupole-orbitrap mass spectrometry.

Phenolic compounds seriously affect the sensory and nutritional qualities of food products, both through the positive contribution of wood transfer in barrel-aged products and as off-flavours. A new targeted analytical approach combining on-line solid-phase extraction (SPE) clean-up to reduce matrix interference and rapid chromatographic detection performed with ultrahigh-performance liquid chromatography coupled with quadrupole/high-resolution mass spectrometry (Q-Orbitrap), was developed for the quantification of 56 simple phenols. Considering the advantages of using on-line SPE and a resolving power of 140,000, the proposed method was applied to define phenolic content in red (N=8) and white (8) wines, spirits (8), common (8) and balsamic (8) vinegars. The final method was linear from the limits of quantification (0.0001-0.001µgmL(-1)) up to 10µgmL(-1) with R(2) of at least 0.99. Recovery, used to define method accuracy, ranged from 80 to 120% for 89% of compounds. The method was suitable for analytical requirements in the tested matrices being able to analyse 46 phenols in red wines, 41 phenols in white wines and in spirits, 42 phenols in common vinegars and 44 phenols in balsamic vinegars.

Managing chronic myeloid leukaemia in the elderly with intermittent imatinib treatment.

The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ⩾65 years in optimal and stable response with ⩾2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35-59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response.

Bortezomib-induced peripheral neurotoxicity in human multiple myeloma-bearing mice.

The proteasome inhibitor bortezomib is an antineoplastic drug mainly used for the treatment of multiple myeloma (MM). Despite its effectiveness, bortezomib clinical use is often limited by the onset of peripheral neuropathy (BiPN). To better understand the mechanisms of BiPN several rat and mice models have been proposed, but no studies in MM-bearing animals allowing to test the antitumor activity of the selected schedules and the role of MM by itself in peripheral nervous system damage have been reported to date. Here, we carried out a study using immunodeficient C.B-17/Prkdcscid (SCID) mice injected with RPMI8266 human MM cells and treated with bortezomib 1 mg/kg once a week for five weeks. Animals were assessed with neurophysiological, behavioral and pathological methods and tumor volume measurement was performed along the study. At the end of the study BiPN was evident in bortezomib-treated animals, and this neurotoxic effect was evident using a schedule able to effectively prevent tumor growth. However, neurophysiological and pathological evidence of MM induced peripheral nervous system damage was also reported. This model based on MM-bearing animals is more reliable in the reproduction of the clinical setting and it is, therefore, more suitable than the previously reported models of BiPN to study its pathogenesis. Moreover, it represents an optimal model to test the efficacy of neuroprotective agents and at the same time their non-interference with bortezomib antineoplastic activity.

Synergistic anti-tumor activity and inhibition of angiogenesis by cotargeting of oncogenic and death receptor pathways in human melanoma.

Improving treatment of advanced melanoma may require the development of effective strategies to overcome resistance to different anti-tumor agents and to counteract relevant pro-tumoral mechanisms in the microenvironment. Here we provide preclinical evidence that these goals can be achieved in most melanomas, by co-targeting of oncogenic and death receptor pathways, and independently of their BRAF, NRAS, p53 and PTEN status. In 49 melanoma cell lines, we found independent susceptibility profiles for response to the MEK1/2 inhibitor AZD6244, the PI3K/mTOR inhibitor BEZ235 and the death receptor ligand TRAIL, supporting the rationale for their association. Drug interaction analysis indicated that a strong synergistic anti-tumor activity could be achieved by the three agents and the AZD6244-TRAIL association on 20/21 melanomas, including cell lines resistant to the inhibitors or to TRAIL. Mechanistically, synergy was explained by enhanced induction of caspase-dependent apoptosis, mitochondrial depolarization and modulation of key regulators of extrinsic and intrinsic cell death pathways, including c-FLIP, BIM, BAX, clusterin, Mcl-1 and several IAP family members. Moreover, silencing experiments confirmed the central role of Apollon downmodulation in promoting the apoptotic response of melanoma cells to the combinatorial treatments. In SCID mice, the AZD6244-TRAIL association induced significant growth inhibition of a tumor resistant to TRAIL and poorly responsive to AZD6244, with no detectable adverse events on body weight and tissue histology. Reduction in tumor volume was associated not only with promotion of tumor apoptosis but also with suppression of the pro-angiogenic molecules HIF1α, VEGFα, IL-8 and TGFß1 and with inhibition of tumor angiogenesis. These results suggest that synergistic co-targeting of oncogenic and death receptor pathways can not only overcome melanoma resistance to different anti-tumor agents in vitro but can also promote pro-apoptotic effects and inhibition of tumor angiogenesis in vivo.

Identification of new flavonols in hybrid grapes by combined liquid chromatography-mass spectrometry approaches.

Grape flavonols are involved in the phenomenon of copigmentation in red wines. These compounds are characterised by nutraceutical properties, have antioxidant activity and are studied for chemotaxonomy of grapes. In general, hybrid grapes are characterised by presence of polyphenols often qualitatively and quantitatively different from Vitis vinifera varieties. In this work, flavonols of 34 hybrid grape varieties (22 red and 12 white) produced by crossing of V. vinifera, Vitis riparia, Vitis labrusca, Vitis lincecumii and Vitis rupestris species, were studied. Compounds were characterised by combining different liquid chromatography/mass spectrometry (LC/MS) methods: precursor-ion and neutral-loss multiple-reaction-monitoring (MRM), and high-resolution mass spectrometry. Twenty-four glycoside flavonols were identified, including 4 quercetin, 5 myricetin, 4 kaempferol, 3 isorhamnetin, 2 laricitrin, 3 syringetin and 3 dihydroflavonol derivatives; myricetin hexoside-glucuronide, myricetin O-di-hexoside, syringetin O-di-hexoside, isorhamnetin rutinoside and kaempferol rutinoside were found in grape for the first time. Statistical analysis (PCA and cluster analysis) divided the samples in four groups on the basis of their flavonol profiles.

Combating the rise of antibiotic resistance in children.

Antibiotics are a cornerstone to treat bacterial infections and children received more frequently these drugs than any other class of medication. However, the improper and excessive use of antibiotics in the past decades has increased the emergence of resistant bacterial strains. Moreover, the lack of specific pediatric clinical trials on antibiotics led to a scarcity of high-evidence-level knowledge. The problem of the increase in antibiotic resistance should be known by all medical figures and probably by all members of the society, and a plan for an efficient strategy to improve antibiotic use in the entire world is highly needed. This review summarizes how antibiotics are mainly used in pediatrics and highlights the main problems related to the increase of antimicrobial-resistant bacterial strains, suggesting possible methods for reducing this increase. An excellent instrument to contain the emergence of antimicrobial resistance appeared the antibiotic stewardship program, that should be proposed and actualized in all contests in which antibiotics use is a common practice. Targeting the existing antibiotics with specific updated guidelines is also an essential measure to avoid antibiotics misuse. Moreover, educational on-line tools and their diffusions are useful strategies to diffuse knowledge on when and how to use antibiotics.

LH, progesterone, and TSH can stimulate aldosterone in vitro: a study on normal adrenal cortex and aldosterone producing adenoma.

Endocrine factors different from ACTH or angiotensin II can stimulate aldosterone secretion and have a role in the pathophysiology of hyperaldosteronism. Aldosterone may increase in luteotropic/progestogenic and in hypothyroid states; LH and, occasionally, TSH receptors have been detected in normal adrenal cortex and aldosterone-producing adenoma. The aim of the study was to compare adrenal contents of LH and TSH receptors between normal cortex and aldosterone-producing adenoma and to evaluate the ability of LH, its product progesterone, and TSH to stimulate aldosterone secretion in vitro from primary adrenocortical cells. Surgical aldosterone-producing adenoma fragments from 19 patients and adrenal cortex fragments from 10 kidney donors were used for Western blotting and cell cultures. LH (n=26), TSH (n=19) and progesterone (n=8) receptor proteins were investigated; LH receptor-mRNA was also tested in 8 samples. Aldosterone responses in vitro to LH, progesterone, and TSH stimulation were assayed. LH and TSH receptors were more expressed in adenoma than normal cortex (p<0.01, p<0.05, respectively); progesterone receptor was observed in 6/8 samples. Aldosterone increased after in vitro stimulation with LH (5/12 adenoma, 1/7 normal cells), progesterone (4/5 adenoma, 5/6 normal cells), and TSH (3/5 adenoma and 3/5 normal cells). LH and TSH receptors were more expressed in aldosterone producing adenoma than normal adrenal cortex. LH, progesterone, and TSH can stimulate aldosterone in vitro. Similar mechanisms could participate in vivo in the aldosterone increase in lutheotropic, progestogenic, or hypothyroid states and may exist in both normal adrenal cortex and adenoma in responsive individuals.

Evaluation of an aSi-EPID with flattening filter free beams: applicability to the GLAaS algorithm for portal dosimetry and first experience for pretreatment QA of RapidArc.

PURPOSE: To demonstrate the feasibility of portal dosimetry with an amorphous silicon mega voltage imager for flattening filter free (FFF) photon beams by means of the GLAaS methodology and to validate it for pretreatment quality assurance of volumetric modulated arc therapy (RapidArc). METHODS: The GLAaS algorithm, developed for flattened beams, was applied to FFF beams of nominal energy of 6 and 10 MV generated by a Varian TrueBeam (TB). The amorphous silicon electronic portal imager [named mega voltage imager (MVI) on TB] was used to generate integrated images that were converted into matrices of absorbed dose to water. To enable GLAaS use under the increased dose-per-pulse and dose-rate conditions of the FFF beams, new operational source-detector-distance (SDD) was identified to solve detector saturation issues. Empirical corrections were defined to account for the shape of the profiles of the FFF beams to expand the original methodology of beam profile and arm backscattering correction. GLAaS for FFF beams was validated on pretreatment verification of RapidArc plans for three different TB linacs. In addition, the first pretreatment results from clinical experience on 74 arcs were reported in terms of γ analysis. RESULTS: MVI saturates at 100 cm SDD for FFF beams but this can be avoided if images are acquired at 150 cm for all nominal dose rates of FFF beams. Rotational stability of the gantry-imager system was tested and resulted in a minimal apparent imager displacement during rotation of 0.2 ± 0.2 mm at SDD = 150 cm. The accuracy of this approach was tested with three different Varian TrueBeam linacs from different institutes. Data were stratified per energy and machine and showed no dependence with beam quality and MLC model. The results from clinical pretreatment quality assurance, provided a gamma agreement index (GAI) in the field area for six and ten FFF beams of (99.8 ± 0.3)% and (99.5 ± 0.6)% with distance to agreement and dose difference criteria set to 3 mm/3% with 2 mm/2% thresholds, GAI resulted (95.7.0 ± 2.3)% and (97.2 ± 2.1)%. CONCLUSIONS: The GLAaS methodology, introduced in clinical practice for conventional flattened photon beams for machine, IMRT, and RapidArc quality assurance, was successfully adapted for FFF beams of Varian TrueBeam Linac. The detector saturation effects could be eliminated if the portal images acquired at 150 cm for all nominal dose rates of FFF beams.

Dosimetric evaluation of photon dose calculation under jaw and MLC shielding.

PURPOSE: The accuracy of photon dose calculation algorithms in out-of-field regions is often neglected, despite its importance for organs at risk and peripheral dose evaluation. The present work has assessed this for the anisotropic analytical algorithm (AAA) and the Acuros-XB algorithms implemented in the Eclipse treatment planning system. Specifically, the regions shielded by the jaw, or the MLC, or both MLC and jaw for flattened and unflattened beams have been studied. METHODS: The accuracy in out-of-field dose under different conditions was studied for two different algorithms. Measured depth doses out of the field, for different field sizes and various distances from the beam edge were compared with the corresponding AAA and Acuros-XB calculations in water. Four volumetric modulated arc therapy plans (in the RapidArc form) were optimized in a water equivalent phantom, PTW Octavius, to obtain a region always shielded by the MLC (or MLC and jaw) during the delivery. Doses to different points located in the shielded region and in a target-like structure were measured with an ion chamber, and results were compared with the AAA and Acuros-XB calculations. Photon beams of 6 and 10 MV, flattened and unflattened were used for the tests. RESULTS: Good agreement between calculated and measured depth doses was found using both algorithms for all points measured at depth greater than 3 cm. The mean dose differences (± 1SD) were -8% ± 16%, -3% ± 15%, -16% ± 18%, and -9% ± 16% for measurements vs AAA calculations and -10% ± 14%, -5% ± 12%, -19% ± 17%, and -13% ± 14% for Acuros-XB, for 6X, 6 flattening-filter free (FFF), 10X, and 10FFF beams, respectively. The same figures for dose differences relative to the open beam central axis dose were: -0.1% ± 0.3%, 0.0% ± 0.4%, -0.3% ± 0.3%, and -0.1% ± 0.3% for AAA and -0.2% ± 0.4%, -0.1% ± 0.4%, -0.5% ± 0.5%, and -0.3% ± 0.4% for Acuros-XB. Buildup dose was overestimated with AAA, while Acuros-XB gave results more consistent with measurements. From RapidArc plan analysis the average difference between calculation and measurement in the shielded region was -0.3% ± 0.4% and -2.5% ± 1.2% for AAA and Acuros-XB, respectively, relative to the mean target dose value (1.6% ± 2.3%, -12.7% ± 4.0% if relative to each local value). These values were compared with the corresponding differences in the target structure: -0.7% ± 2.3% for AAA, and -0.5% ± 2.3% for Acuros-XB. CONCLUSIONS: The two algorithms analyzed showed encouraging results in predicting out-of-field region dose for clinical use.

The effect of Photon Activation Therapy on cisplatin pre-treated human tumour cell lines: comparison with conventional X-ray irradiation.

Cisplatin is an antineoplastic drug widely used for the treatment of several solid tumours. However, the side effects related to cisplatin-based anticancer therapy often outweigh the benefits. Therefore, the identification of new anticancer strategies able to offer a better toxicity profile while maintaining the same level of efficacy as platinum-based treatments would be highly desirable. We assessed the efficacy of synchrotron radiation in triggering the Auger effect in human A549 non-small cell lung cancer and IGROV-1 ovarian cancer cells pre-treated with cisplatin. Cisplatin was chosen as the carrier of platinum atoms in the cells because of its alkylating-like activity and the irradiation was done with monochromatic beams above and below the platinum K-shell edge (78.39 keV). On cisplatin-treated cells, at concentrations allowing 80 percent of cell survival with respect to controls, no differences were observed in cell viability when they were irradiated either above or below the K-shell edge of platinum, suggesting that cisplatin toxicity can mask the enhancement of cell death induced by the irradiation. At lower cisplatin concentrations allowing 95-90 percent of cell survival, an enhancement in cellular death with respect to conventional irradiation conditions was clearly observed in all cancer types when cells were irradiated with beams either above or below the platinum K-shell edge. Our results lend additional support to the suggestion that the Photon Activation Therapy in combination with cisplatin treatment should be further explored in relevant in vivo models of glioma and non-glioma cancer models.

Functionalized mesoporous silica nanoparticles: a possible strategy to target cancer cells reducing peripheral nervous system uptake.

Mesoporous silica materials (MSM) have been proposed as promising tools for cell specific drug delivery or fluorescent cell tracking. In cancer therapy there is an urgent need to develop a cancer cell specific drug carrier able to limit the non-specific uptake of the drug by normal cells thereby reducing serious side effects. Chemotherapy induced peripheral neurotoxicity (CIPN) is one of the most clinically relevant side effects linked to the use of several antineoplastic drugs. In this study we showed that the uptake of MSM (synthesized using a PEG surfactant-based interfacial synthesis procedure), functionalised with folic acid (MSM-FOL) after 1, 6 and 24 hours is very limited in neuronal-like cellular systems such as differentiated SH-SY5Y human neuroblastoma cells and rat embryonic dorsal root ganglia sensory neurons. By contrast, the nanoparticles are highly internalized in A549 and IGROV-1 cancer cells. The 6 hour-treatment of A549 and IGROV-1 cells with nanoparticles loaded with the antineoplastic drug cisplatin (CP) induced significant cytotoxicity with respect to CP alone. These results were observed treating IGROV-1 cells with 25 and 50 µg/ml nanoparticles doses (corresponding respectively to CP 6.25 and 12.5 µM) and treating A549 with 50 µg/ml.Our results demonstrated a selective uptake of functionalized MSM suggesting them as promising tools for targeted antineoplastic therapy. Further studies will be necessary in order to confirm if this approach may be useful in reducing neurotocity of anticancer drugs.

New insights into mechanisms of cardioprotection mediated by thyroid hormones.

Heart failure represents the final common outcome in cardiovascular diseases. Despite significant therapeutic advances, morbidity and mortality of heart failure remain unacceptably high. Heart failure is preceded and sustained by a process of structural remodeling of the entire cardiac tissue architecture. Prevention or limitation of cardiac remodeling in the early stages of the process is a crucial step in order to ameliorate patient prognosis. Acquisition of novel pathophysiological mechanisms of cardiac remodeling is therefore required to develop more efficacious therapeutic strategies. Among all neuroendocrine systems, thyroid hormone seems to play a major homeostatic role in cardiovascular system. In these years, accumulating evidence shows that the "low triiodothyronine" syndrome is a strong prognostic, independent predictor of death in patients affected by both acute and chronic heart disease. In experimental models of cardiac hypertrophy or myocardial infarction, alterations in the thyroid hormone signaling, concerning cardiac mitochondrion, cardiac interstitium, and vasculature, have been suggested to be related to heart dysfunction. The aim of this brief paper is to highlight new developments in understanding the cardioprotective role of thyroid hormone in reverting regulatory networks involved in adverse cardiac remodeling. Furthermore, new recent advances on the role of specific miRNAs in thyroid hormone regulation at mitochondrion and interstitial level are also discussed.