Avaliação Histológica e histomorfométrica do reparo ósseo em tíbias osteotomizadas de ratos (rattus novergicus albinus), submetidos a tratamento com ultrassom, frente à presença e ausência de carga

The response of bone metabolism is directly related to hormonal factors and mechanical stimuli that the bone is exposed. The ultrasonic energy on bone healing have been shown to be crucial for the stimulation and improvement in quality of newly formed tissue. The aim of this study was to analyze the action of low intensity ultrasound on bone healing of tibial osteotomy in rats subjected to tail suspension, through histological analysis and histomorphometry. Eighteen Rattus norvegicus albinos, Wistar, adults were divided into three groups, arranged as follows: G1 (n = 6), who remained free for a period of 15 days, G2 (n = 5), suspended by the tail for a period of 15 days and G3 (n = 7), suspended by the tail for a period of 36 days. In all three groups, both tibias were subjected to mono-cortical bone injury 4X2 mm in the medial region of the diaphysis, and the left limb was used as control and the right limb undergoing treatment with ultrasound (U.S.). The right tibia was treated with pulsed ultrasound at a frequency of 1.5 MHz, duty cycle 1:4, 30mW/cm2, for 12 sessions of 20 minutes each. Samples of tibia were subjected to histological analysis, blindly, with light microscopy and histomorphometric analysis by specific software Image-Pro 6.1. The average percentage of new bone formation were subjected to analysis of variance in subdivided parcels and multiple comparison test "Student-Newman-Keuls (SNK), with a significance level of 5%. The average values and standard deviations of the percentage of newly formed bone for the groups showed the least amount of bone repair G1t (13.62% ± 4.88%) - G1c (8.68% ± 4.16%) compared G2t groups (27.17% ± 11.36%) - G2c (10.10% ± 7.90%) and G3t (23.19% ± 5.61%) - G3c (15.74% ± 7 08%). However, the mean values and standard deviations of the percentage of newly formed bone repair in the tibia treated G2t and G3t were significantly higher when compared to the repair of tibia in the control group (G2c and G3c). Consequently, we conclude that ultrasound has helped to accelerate bone repair in both the presence and absence of cargo.

The Effectiveness of Psychological Interventions for the Treatment of Erectile Dysfunction: Systematic Review and Meta-Analysis, Including Comparisons to Sildenafil Treatment, Intracavernosal Injection, and Vacuum Devices

In contrast to the impressive advances in somatic research of erectile dysfunction (ED), scientific literature shows contradictory reports on the results of psychotherapy for the treatment of ED. Authors conducted a meta-analysis to evaluate the effectiveness of psychological interventions for the treatment of ED compared to oral drugs, local injection, vacuum devices, or other psychological intervention. Distinct sources of randomized controlled trials (RCTs) were searched: electronic databases (between 1966 and 2007), cross checking of references, and contact with scientific societies. For dichotomous outcomes the pooled relative risks were calculated and for continuous outcomes mean differences between interventions. Statistical heterogeneity was addressed. Eleven RCTs involving 398 men met the inclusion criteria. There is evidence that group therapy improves ED. Focused sex group therapy showed greater efficacy than control group. Men randomized to receive psychotherapy plus sildenafil showed significant improvement of ED and were less likely than those receiving only sildenafil to drop out. Regarding to the effectiveness of psychological interventions for the treatment of ED compared to local injection and vacuum devices no difference was found. Melnik T, Soares BGO, and Nasello AG. The effectiveness of psychological interventions for the treatment of erectile dysfunction: Systematic review and meta-analysis, including comparisons to sildenafil treatment, intracavernosal injection, and vacuum devices. J Sex Med 2008;5:2562-2574.

Titanium surface topography after brushing with fluoride and fluoride-free toothpaste simulating 10 years of use

Objectives: To conduct a controlled study contrasting titanium surface topography after procedures that simulated 10 years of brushing using toothpastes with or without fluoride. Methods: Commercially pure titanium (cp Ti) and Ti-6Al-4V disks (6 mm circle divide x 4 mm) were mirror-polished and treated according to 6 groups (n = 6) as a function of immersion (I) or brushing (B) using deionised water (W), fluoride-free toothpaste (T) and fluoride toothpaste (FT). Surface topography was evaluated at baseline (pretreatment) and post-treatment, using atomic force microscope in order to obtain three-dimensional images and mean roughness. Specimens submitted to immersion were submerged in the vehicles without brushing. For brushed specimens, procedures were conducted using a linear brushing machine with a soft-bristled toothbrush. Immersion and brushing were performed for 244 h. IFT and BFT samples were analysed under scanning electron microscope with Energy-Dispersive X-ray Spectroscopy (EDS). Pre and post-treatment values were compared using the paired Student T-test (alpha = .05). Intergroup comparisons were conducted using one-way ANOVA with Tukey post-test (alpha = .05). Results: cp Ti mean roughness (in nanometers) comparing pre and post-treatment were: IW, 2.29 +/- 0.55/2.33 +/- 0.17; IT, 2.24 +/- 0.46/2.02 +/- 0.38; IFT, 2.22 +/- 0.53/1.95 +/- 0.36; BW, 2.22 +/- 0.42/3.76 +/- 0.45; BT, 2.27 +/- 0.55/16.05 +/- 3.25; BFT, 2.27 +/- 0.51/22.39 +/- 5.07. Mean roughness (in nanometers) measured in Ti-6Al-4V disks (pre/post-treatment) were: IW, 1.79 +/- 0.25/2.01 +/- 0.25; IT, 1.61 +/- 0.13/1.74 +/- 0.19; IFT, 1.92 +/- 0.39/2.29 +/- 0.51; BW, 2.00 +/- 0.71/2.05 +/- 0.43; BT, 2.37 +/- 0.86/11.17 +/- 2.29; BFT, 1.83 +/- 0.50/15.73 +/- 1.78. No significant differences were seen after immersions (p > .05). Brushing increased the roughness of cp Ti and of Ti-6Al-4V (p < .01); cp Ti had topographic changes after BW, BT and BFT treatments whilst Ti-6Al-4V was significantly different only after BT and BTF. EDS has not detected fluoride or sodium ions on metal surfaces. Conclusions: Exposure to toothpastes (immersion) does not affect titanium per se; their use during brushing affects titanium topography and roughness. The associated effects of toothpaste abrasives and fluorides seem to increase roughness on titanium brushed surfaces. (C) 2012 Elsevier Ltd. All rights reserved.

Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis

Objective: Early treatment in sepsis may improve outcome. The aim of this study was to evaluate how the delay in starting resuscitation influences the severity of sepsis and the treatment needed to achieve hemodynamic stability. Design: Prospective, randomized, controlled experimental study. Setting: Experimental laboratory in a university hospital. Subjects: Thirty-two anesthetized and mechanically ventilated pigs. Interventions: Pigs were randomly assigned (n = 8 per group) to a nonseptic control group or one of three groups in which fecal peritonitis (peritoneal instillation of 2 g/kg autologous feces) was induced, and a 48-hr period of protocolized resuscitation started 6 (Delta T-6 hrs), 12 (Delta T-12 hrs), or 24 (Delta T-24 hrs) hrs later. The aim of this study was to evaluate the impact of delays in resuscitation on disease severity, need for resuscitation, and the development of sepsis-associated organ and mitochondrial dysfunction. Measurements and Main Results: Any delay in starting resuscitation was associated with progressive signs of hypovolemia and increased plasma levels of interleukin-6 and tumor necrosis factor-alpha prior to resuscitation. Delaying resuscitation increased cumulative net fluid balances (2.1 +/- 0.5 mL/kg/hr, 2.8 +/- 0.7 mL/kg/hr, and 3.2 +/- 1.5 mL/kg/hr, respectively, for groups.T-6 hrs, Delta T-12 hrs, and.T-24 hrs; p < .01) and norepinephrine requirements during the 48-hr resuscitation protocol (0.02 +/- 0.04 mu g/kg/min, 0.06 +/- 0.09 mu g/kg/min, and 0.13 +/- 0.15 mu g/kg/min; p = .059), decreased maximal brain mitochondrial complex II respiration (p = .048), and tended to increase mortality (p = .08). Muscle tissue adenosine triphosphate decreased in all groups (p < .01), with lowest values at the end in groups Delta T-12 hrs and.T-24 hrs. Conclusions: Increasing the delay between sepsis initiation and resuscitation increases disease severity, need for resuscitation, and sepsis-associated brain mitochondrial dysfunction. Our results support the concept of a critical window of opportunity in sepsis resuscitation. (Crit Care Med 2012; 40:2841-2849)

In vitro analysis of the influence of surface treatment of dental implants on primary stability

Surface treatment interferes with the primary stability of dental implants because it promotes a chemical and micromorphological change on the surface and thus stimulates osseointegration. This study aimed to evaluate the effects of different surface treatments on primary stability by analyzing insertion torque (IT) and pullout force (PF). Eight samples of implants with different surface treatments (TS - external hexagon with acid surface treatment; and MS - external hexagon, machined surface), all 3.75 mm in diameter x 11.5 mm in length, were inserted into segments of artificial bones. The IT of each sample was measured by an electronic torquemeter, and then the pullout test was done with a universal testing machine. The results were subjected to ANOVA (p < 0.05), followed by Tukey's test (p < 0.05). The IT results showed no statistically significant difference, since the sizes of the implants used were very similar, and the bone used was not highly resistant. The PF values (N) were, respectively, TS = 403.75 +/- 189.80 and MS = 276.38 +/- 110.05. The implants were shown to be different in terms of the variables of maximum force (F = 4.401, p = 0.0120), elasticity in maximum flexion (F = 3.672, p = 0.024), and relative stiffness (F = 4.60, p = 0.01). In this study, external hexagonal implants with acid surface treatment showed the highest values of pullout strength and better stability, which provide greater indication for their use.

Increased levels of Porphyromonas gingivalis are associated with ischemic and hemorrhagic cerebrovascular disease in humans: an in vivo study

Objective: This study investigated the role of periodontal disease in the development of stroke or cerebral infarction in patients by evaluating the clinical periodontal conditions and the subgingival levels of periodontopathogens. Material and Methods: Twenty patients with ischemic (I-CVA) or hemorrhagic (H-CVA) cerebrovascular episodes (test group) and 60 systemically healthy patients (control group) were evaluated for: probing depth, clinical attachment level, bleeding on probing and plaque index. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were both identified and quantified in subgingival plaque samples by conventional and real-time PCR, respectively. Results: The test group showed a significant increase in each of the following parameters: pocket depth, clinical attachment loss, bleeding on probing, plaque index and number of missing teeth when compared to control values (p<0.05, unpaired t-test). Likewise, the test group had increased numbers of sites that were contaminated with P. gingivalis (60%x10%; p<0.001; chi-squared test) and displayed greater prevalence of periodontal disease, with an odds ratio of 48.06 (95% CI: 5.96-387.72; p<0.001). Notably, a positive correlation between probing depth and the levels of P. gingivalis in ischemic stroke was found (r=0.60; p=0.03; Spearman's rank correlation coefficient test). A. actinomycetemcomitans DNA was not detected in any of the groups by conventional or real-time PCR. Conclusions: Stroke patients had deeper pockets, more severe attachment loss, increased bleeding on probing, increased plaque indexes, and in their pockets harbored increased levels of P. gingivalis. These findings suggest that periodontal disease is a risk factor for the development of cerebral hemorrhage or infarction. Early treatment of periodontitis may counteract the development of cerebrovascular episodes.

Multiple Tooth Agenesis in Non-syndromic Patient: a rare case report

Dental agenesis is a term referred to the absence of one or more teeth. However, oligodontia is a severe type of tooth agenesis involving six or more congenitally missing teeth, excluding the third molars. Oligodontia has a low prevalence and is a very rare condition. The aim was to show this case report of a 13-year-old female patient who presented oligodontia with absence of eight permanent teeth and condylar atrophy on left side. The patient had no history of any syndrome or systemic disease according to the anamnesis. Is very important to know oligodontia features to perform a carefully treatment plan.

A bayesian network meta-analysis on comparisons of enamel matrix derivatives, guided tissue regeneration and their combination therapies

Aims: Guided tissue regeneration (GTR) and enamel matrix derivatives (EMD) are two popular regenerative treatments for periodontal infrabony lesions. Both have been used in conjunction with other regenerative materials. We conducted a Bayesian network meta-analysis of randomized controlled trials on treatment effects of GTR, EMD and their combination therapies. Material and Methods: A systematic literature search was conducted using the Medline, EMBASE, LILACS and CENTRAL databases up to and including June 2011. Treatment outcomes were changes in probing pocket depth (PPD), clinical attachment level (CAL) and infrabony defect depth. Different types of bone grafts were treated as one group and so were barrier membranes. Results: A total of 53 studies were included in this review, and we found small differences between regenerative therapies which were non-significant statistically and clinically. GTR and GTR-related combination therapies achieved greater PPD reduction than EMD and EMD-related combination therapies. Combination therapies achieved slightly greater CAL gain than the use of EMD or GTR alone. GTR with BG achieved greatest defect fill. Conclusion: Combination therapies performed better than single therapies, but the additional benefits were small. Bayesian network meta-analysis is a promising technique to compare multiple treatments. Further analysis of methodological characteristics will be required prior to clinical recommendations.

Pain and quality of life in patients undergoing radiotherapy for spinal metastatic disease treatment

Abstract Background Radiotherapy is an important tool in the control of pain in patients with spinal metastatic disease. We aimed to evaluate pain and of quality of life of patients with spinal metastatic disease undergoing radiotherapy with supportive treatment. Methods The study enrolled 30 patients. From January 2008 to January 2010, patients selection included those treated with a 20 Gy tumour dose in five fractions. Patients completed the visual analogue scale for pain assessment and the SF-36 questionnaire for quality of life assessment. Results The most frequent primary sites were breast, multiple myeloma, prostate and lymphoma. It was found that 14 spinal metastatic disease patients (46.66%) had restricted involvement of three or fewer vertebrae, while 16 patients (53.33%) had cases involving more than three vertebrae. The data from the visual analogue scale evaluation of pain showed that the average initial score was 5.7 points, the value 30 days after the end of radiotherapy was 4.60 points and the average value 6 months after treatment was 4.25 points. Notably, this final value was 25.43% lower than the value from the initial analysis. With regard to the quality of life evaluation, only the values for the functional capability and social aspects categories of the questionnaire showed significant improvement. Conclusion Radiotherapy with supportive treatment appears to be an important tool for the treatment of pain in patients with spinal metastatic disease.

Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1

Surgical approaches to pancreatic endocrine tumors associated with multiple endocrine neoplasia type 1 may differ greatly from those applied to sporadic pancreatic endocrine tumors. Presurgical diagnosis of multiple endocrine neoplasia type 1 is therefore crucial to plan a proper intervention. Of note, hyperparathyroidism/multiple endocrine neoplasia type 1 should be surgically treated before pancreatic endocrine tumors/multiple endocrine neoplasia type 1 resection, apart from insulinoma. Non-functioning pancreatic endocrine tumors/multiple endocrine neoplasia type 1 >1 cm have a high risk of malignancy and should be treated by a pancreatic resection associated with lymphadenectomy. The vast majority of patients with gastrinoma/multiple endocrine neoplasia type 1 present with tumor lesions at the duodenum, so the surgery of choice is subtotal or total pancreatoduodenectomy followed by regional lymphadenectomy. The usual surgical treatment for insulinoma/multiple endocrine neoplasia type 1 is distal pancreatectomy up to the mesenteric vein with or without spleen preservation, associated with enucleation of tumor lesions in the pancreatic head. Surgical procedures for glucagonomas, somatostatinomas, and vipomas/ multiple endocrine neoplasia type 1 are similar to those applied to sporadic pancreatic endocrine tumors. Some of these surgical strategies for pancreatic endocrine tumors/multiple endocrine neoplasia type 1 still remain controversial as to their proper extension and timing. Furthermore, surgical resection of single hepatic metastasis secondary to pancreatic endocrine tumors/multiple endocrine neoplasia type 1 may be curative and even in multiple liver metastases surgical resection is possible. Hepatic trans-arterial chemo-embolization is usually associated with surgical resection. Liver transplantation may be needed for select cases. Finally, pre-surgical clinical and genetic diagnosis of multiple endocrine neoplasia type 1 syndrome and localization of multiple endocrine neoplasia type 1related tumors are crucial for determining the best surgical strategies in each individual case with pancreatic endocrine tumors.

Effect of multiple sources of disturbance on rocky benthic assemblages in some localities of Salento, Apulia

The first part of my work consisted in samplings conduced in nine different localities of the salento peninsula and Apulia (Italy): Costa Merlata (BR), Punta Penne (BR), Santa Cesarea terme (LE), Santa Caterina (LE), Torre Inserraglio (LE), Torre Guaceto (BR), Porto Cesareo (LE), Otranto (LE), Isole Tremiti (FG). I collected data of species percentage covering from the infralittoral rocky zone, using squares of 50x50 cm. We considered 3 sites for location and 10 replicates for each site, which has been taken randomly. Then I took other data about the same places, collected in some years, and I combined them together, to do a spatial analysis. So I started from a data set of 1896 samples but I decided not to consider time as a factor because I have reason to think that in this period of time anthropogenic stressors and their effects (if present), didn’t change considerably. The response variable I’ve analysed is the covering percentage of an amount of 243 species (subsequently merged into 32 functional groups), including seaweeds, invertebrates, sediment and rock. 2 After the sampling, I have been spent a period of two months at the Hopkins Marine Station of Stanford University, in Monterey (California,USA), at Fiorenza Micheli's laboratory. I've been carried out statistical analysis on my data set, using the software PRIMER 6. My explorative analysis starts with a nMDS in PRIMER 6, considering the original data matrix without, for the moment, the effect of stressors. What comes out is a good separation between localities and it confirms the result of ANOSIM analysis conduced on the original data matrix. What is possible to ensure is that there is not a separation led by a geographic pattern, but there should be something else that leads the differences. Is clear the presence of at least three groups: one composed by Porto cesareo, Torre Guaceto and Isole tremiti (the only marine protected areas considered in this work); another one by Otranto, and the last one by the rest of little, impacted localities. Inside the localities that include MPA(Marine Protected Areas), is also possible to observe a sort of grouping between protected and controlled areas. What comes out from SIMPER analysis is that the most of the species involved in leading differences between populations are not rare species, like: Cystoseira spp., Mytilus sp. and ECR. Moreover I assigned discrete values (0,1,2) of each stressor to all the sites I considered, in relation to the intensity with which the anthropogenic factor affect the localities. 3 Then I tried to estabilish if there were some significant interactions between stressors: by using Spearman rank correlation and Spearman tables of significance, and taking into account 17 grades of freedom, the outcome shows some significant stressors interactions. Then I built a nMDS considering the stressors as response variable. The result was positive: localities are well separeted by stressors. Consequently I related the matrix with 'localities and species' with the 'localities and stressors' one. Stressors combination explains with a good significance level the variability inside my populations. I tried with all the possible data transformations (none, square root, fourth root, log (X+1), P/A), but the fourth root seemed to be the best one, with the highest level of significativity, meaning that also rare species can influence the result. The challenge will be to characterize better which kind of stressors (including also natural ones), act on the ecosystem; and give them a quantitative and more accurate values, trying to understand how they interact (in an additive or non-additive way).

Modulation of hypoxia-inducible factors as a therapeutic target for multiple myeloma

Hypoxia-inducible factor-1 alpha (HIF-1α) plays a critical role in survival and is associated with poor prognosis in solid tumors. The role of HIF-1α in multiple myeloma is not completely known. In the present study, we explored the effect of EZN2968, an locked nucleic acid antisense oligonucleotide against HIF-1α, as a molecular target in MM. A panel of MM cell lines and primary samples from MM patients were cultured in vitro in the presence of EZN2968 . Under normoxia culture condition, HIF-1α mRNA and protein expression was detectable in all MM cell lines and in CD138+ cells from newly diagnosed MM patients samples. Significant up-regulation of HIF-1α protein expression was observed after incubation with IL6 or IGF-I, confirming that HIF-1α can be further induced by biological stimuli. EZN2968 efficiently induces a selective and stable down-modulation of HIF-1α and decreased the secretion of VEGF released by MM cell. Treatment with EZN2968 gave rise to a progressive accumulation of cells in the S and subG0 phase. The analysis of p21, a cyclin-dependent kinase inhibitors controlling cell cycle check point, shows upregulation of protein levels. These results suggest that HIF-1α inhibition is sufficient for cell cycle arrest in normoxia, and for inducing an apoptotic pathways.. In the presence of bone marrow microenvironment, HIF-1α inhibition blocks MAPK kinase pathway and secretion of pro-surviaval cytokines ( IL6,VEGF,IL8) In this study we provide evidence that HIF-1α, even in the absence of hypoxia signal, is expressed in MM plasma cells and further inducible by bone marrow milieu stimuli; moreover its inhibition is sufficient to induce a permanent cell cycle arrest. Our data support the hypothesis that HIF-1α inhibition may suppress tumor growth by preventing proliferation of plasma cells through p21 activation and blocking pro-survival stimuli from bone marrow microenvironment.

The impact of polymorphisms in P-gp, DNA repair and folic acid metabolism genes in newly diagnosed multiple myeloma patients treated with thalidomide plus dexamethasone, with or without bortezomib

The principle aim of this study was to investigate biological predictors of response and resistance to multiple myeloma treatment. Two hypothesis had been proposed as responsible of responsiveness: SNPs in DNA repair and Folate pathway, and P-gp dependent efflux. As a first objective, panel of SNPs in DNA repair and Folate pathway genes, were analyzed. It was a retrospective study in a group of 454, previously untreated, MM patients enrolled in a randomized phase III open-label study. Results show that some SNPs in Folate pathway are correlated with response to MM treatment. MTR genotype was associated with favorable response in the overall population of MM patients. However, this relation, disappear after adjustment for treatment response. When poor responder includes very good partial response, partial response and stable/progressive disease MTFHR rs1801131 genotype was associated with poor response to therapy. This relation - unlike in MTR – was still significant after adjustment for treatment response. Identification of this genetic variant in MM patients could be used as an independent prognostic factor for therapeutic outcome in the clinical practice. In the second objective, basic disposition characteristics of bortezomib was investigated. We demonstrated that bortezomib is a P-gp substrate in a bi-directional transport study. We obtain apparent permeability rate values that together with solubility values can have a crucial implication in better understanding of bortezomib pharmacokinetics with respect to the importance of membrane transporters. Subsequently, in view of the importance of P-gp for bortezomib responsiveness a panel of SNPs in ABCB1 gene - coding for P-gp - were analyzed. In particular we analyzed five SNPs, none of them however correlated with treatment responsiveness. However, we found a significant association between ABCB1 variants and cytogenetic abnormalities. In particular, deletion of chromosome 17 and t(4;14) translocation were present in patients harboring rs60023214 and rs2038502 variants respectively.

Boron determination in biological samples - Intercomparison of three analytical methods to assist development of a treatment protocol for neoplastic diseases of the liver with Boron Neutron Capture Therapy

Die Bor-Neuroneneinfang-Therapie (engl.: Boron Neutron Capture Therapy, BNCT) ist eine indirekte Strahlentherapie, welche durch die gezielte Freisetzung von dicht ionisierender Strahlung Tumorzellen zerstört. Die freigesetzten Ionen sind Spaltfragmente einer Kernreaktion, bei welcher das Isotop 10B ein niederenergetisches (thermisches) Neutron einfängt. Das 10B wird durch ein spezielles Borpräparat in den Tumorzellen angereichert, welches selbst nicht radioaktiv ist. rnAn der Johannes Gutenberg-Universität Mainz wurde die Forschung für die Anwendung eines klinischen Behandlungsprotokolls durch zwei Heilversuche bei Patienten mit kolorektalen Lebermetastasen an der Universität Pavia, Italien, angeregt, bei denen die Leber außerhalb des Körpers in einem Forschungsreaktor bestrahlt wurde. Als erster Schritt wurde in Kooperation verschiedener universitärer Institute eine klinische Studie zur Bestimmung klinisch relevanter Parameter wie der Borverteilung in verschiedenen Geweben und dem pharmakokinetischen Aufnahmeverhalten des Borpräparates initiiert.rnDie Borkonzentration in den Gewebeproben wurde hinsichtlich ihrer räumlichen Verteilung in verschiedenen Zellarealen bestimmt, um mehr über das Aufnahmeverhalten der Zellen für das BPA im Hinblick auf ihre biologischen Charakteristika zu erfahren. Die Borbestimung wurde per Quantitative Neutron Capture Radiography, Prompt Gamma Activation Analysis und Inductively Coupled Plasma Mass Spectroscopy parallel zur histologischen Analyse des Gewebes durchgeführt. Es war möglich zu zeigen, dass in Proben aus Tumorgewebe und aus tumorfreiem Gewebe mit unterschiedlichen morphologischen Eigenschaften eine sehr heterogene Borverteilung vorliegt. Die Ergebnisse der Blutproben werden für die Erstellung eines pharmakokinetischen Modells verwendet und sind in Übereinstimmung mit existierenden pharmakokinetische Modellen. Zusätzlich wurden die Methoden zur Borbestimmung über speziell hergestellte Referenzstandards untereinander verglichen. Dabei wurde eine gute Übereinstimmung der Ergebnisse festgestellt, ferner wurde für alle biologischen Proben Standardanalyseprotokolle erstellt.rnDie bisher erhaltenen Ergebnisse der klinischen Studie sind vielversprechend, lassen aber noch keine endgültigen Schlussfolgerungen hinsichtlich der Wirksamkeit von BNCT für maligne Lebererkrankungen zu. rn

Study of PI3K/Akt signaling pathway as potential molecular target for T-cell acute lymphoblastic leukemia (T-ALL) treatment: pan-inhibition of PI3K catalitic isoforms as better therapeutic approach

Class I phosphatidylinositol 3-kinases (PI3Ks) are heterodimeric lipid kinases consisting of a regulatory subunit and one of four catalytic subunits (p110α, p110β, p110γ or p110δ). p110γ/p110δ PI3Ks are highly enriched in leukocytes. In general, PI3Ks regulate a variety of cellular processes including cell proliferation, survival and metabolism, by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). Their activity is tightly regulated by the phosphatase and tensin homolog (PTEN) lipid phosphatase. PI3Ks are widely implicated in human cancers, and in particular are upregulated in T-cell acute lymphoblastic leukemia (T-ALL), mainly due to loss of PTEN function. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. At present different compounds which target single or multiple PI3K isoforms have entered clinical trials. In the present research, it has been analyzed the therapeutic potential of the pan-PI3K inhibitor BKM120, an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T-lymphoblasts. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. BKM120 efficacy was confirmed in in vivo studies to a subcutaneous xenotransplant model of human T-ALL. Because it is still unclear which agents among isoform-specific or pan inhibitors can achieve the greater efficacy, further analyses have been conducted to investigate the effects of PI3K inhibition, in order to elucidate the mechanisms responsible for the proliferative impairment of T-ALL. Overall, these results indicated that BKM120 may be an efficient treatment for T-ALLs that have aberrant up-regulation of the PI3K signaling pathway and strongly support clinical application of pan-class I PI3K rather than single-isoform inhibitors in T-ALL treatment.