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Well established behavioral studies in Operations Management highlight that the Human’s behaviour deviates from the optimal solution, even in simplified operating conditions such as those represented by the famous Newsvendor problem. Built on the results of controlled human experiments, this study proposes a decision-making model that accounts for the heuristics of anchoring and adjustment. Two experimental conditions, differing in the provision of demand information to couple of decision makers, are used to generate data. The model estimated shows that anchoring and adjustment behaviour differs in the two conditions: demand information knowledge enables smoothing partially the pull to center effect.

Background The oncolytic virus (OV) Talimogene Laherparepvec (T-VEC) is a microorganism genetically modified (MOGM), since it is genetically engineered to no longer be capable of causing infection or of spreading in normal cells. Even if it was considered to have a minimal exposure risk, is there the need to take control measures? Purpose To implement the shared procedures, already created for appropriate management of OV, for T-VEC management, in CT for squamous-cell head-neck carcinoma (SCHN), between the pharmacy clinical studies ward and head-neck ward in our Oncology Institute, and to evaluate the risk of possible contamination at every step of operation conducted following the procedures. Material and methods The Internal Hospital Procedure of IMP Management, study protocol, national and European law for MOGM-type-2 (conteniment -level-2) management and revision of literature were examined. Each category of personnel involved, with their specific roles established, was documented and every step of the operation conducted. Results The activity levels (AL) (four) began from the Pharmacy-Clinical Studies Unit that documented every step of the product: Receipt and control. Storage (under 80°C) and use of individual protection devices (IPD). Guidelines for preparation, operation control, instruction operation and decontamination (sodium hypochlorite). Transport in specific box. The AL (one) of intersection between pharmacists and clinical research nurses of the head-neck carcinoma ward was product preparation. The operation was conducted separately from others in a specific vertical-flow biologic-safety-cabinet, always in double and documented (date, time, signature). The AL (one) for nurses was product administration. The operation was in a specific one-patient-room separated and before eventual concomitant therapy (pembrolizumab). The AL (one) for the Hygiene Unit was in the management of residual vials, medical devices and IPD. These actions permitted the separation of instruments used in previous steps and avoiding using the same autoclave available in the hospital for sterilisation. No exposure of personnel and patients or contamination of other IV products, including chemotherapy, was detected with this procedure. Conclusion Handling OV such as hazardous drugs in a coordinated method minimised the risk of exposure and therefore the risk of contamination. Furthermore, being aware in the future of the symptoms associated with infection due to virus will help in monitoring for possible exposure. No conflict of interest

The production systems are made up of technologies, organizational styles, management models and, above all, individuals. The human contribution in operations management is particularly critical because it has a significant effect on the outcomes and it is difficult to predict. The literature review shows that, even in simplified operating conditions, such as those represented by the famous problem of newsvendor and in conditions of complete information, the behavior of human managers deviates considerably from the optimal. The literature review also shows that, although the concept of bounded rationality is now well established, the modeling of human behavior is still incomplete, often limited to the verification of a single type of bias without considering their simultaneous presence. This study, based on the results obtained from controlled human experiments on newsvendor game, proposes a decision-making model that takes into account more than just one bias and is based on the heuristics of anchoring and adjustment. The model shows a promising capacity to reveal the individual's behavior.

// Floriana Morgillo 1 , Carminia Maria Della Corte 1 , Anna Diana 1 , Concetta di Mauro 2 , Vincenza Ciaramella 1 , Giusi Barra 3 , Valentina Belli 1 , Elisena Franzese 1 , Roberto Bianco 2 , Evaristo Maiello 4 , Ferdinando De Vita 1 , Fortunato Ciardiello 1 and Michele Orditura 1 1 Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Universita degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy 2 Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Universita degli Studi di Napoli “Federico II”, Napoli, Italy 3 Immunologia Clinica, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Universita degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy 4 IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy Correspondence to: Floriana Morgillo, email: florianamorgillo@yahoo.com , floriana.morgillo@unicampana.it Keywords: AKT, breast cancer, taselisib, ipatasertib, novel drugs Received: March 22, 2017 Accepted: July 26, 2017 Published: August 22, 2017 ABSTRACT Purpose: The Phosphatidylinositol 3-kinase (PI3Ks) pathway is commonly altereted in breast cancer patients, but its role is still unclear. Taselisib, a mutant PI3Kα selective inhibitor, and ipatasertib, an AKT inhibitor, are currently under investigation in clinical trials in combination with paclitaxel or hormonal therapies in breast cancer. The aim of this study was to evaluate if PI3K or AKT inhibition can prevent resistance to chemotherapy and potentiate its efficacy. Experimental design: The efficacy of combined treatment of ipatasertib and taselisib plus vinorelbine or paclitaxel or eribulin was evaluated in vitro on human breast cancer cells (with different expression profile of hormonal receptors, HER2, and of PI3Ka mutation) on cell survival by using MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium bromide) and colony forming assays on cell apoptosis by flow-cytometry analysis. We also investigated the effect of combined treatment on downstream intracellular signaling, by western blot analysis, and on metastatic properties, by migration assays. Finally, we analyzed changes in cell cytoskeleton by immunofluorescence. Results: A significant synergism of ipatasertib or taselisib plus anti-microtubule chemotherapy in terms of anti-proliferative, pro-apoptotic and anti-metastatic effect was observed. The combined treatment completely inhibited the activation of proteins downstream of PI3K and MAPK pathways and affected the expression of survivin. Combined treatments completely disorganized the cytoskeleton in human breast cancer cells, with contemporary delocalization of survivin from cytoplasm to nucleus, thus suggesting a potential mechanism for this combination. Conclusions: Targeting PI3K may enhance the efficacy of anti-microtubule drugs in human breast cancer cells.

Background:Cetuximab is the only targeted agent approved for the treatment of head and neck squamous cell carcinomas (HNSCC), but low response rates and disease progression are frequently reported. As the phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways have an important role in the pathogenesis of HNSCC, we investigated their involvement in cetuximab resistance.Methods:Different human squamous cancer cell lines sensitive or resistant to cetuximab were tested for the dual PI3K/mTOR inhibitor PF-05212384 (PKI-587), alone and in combination, both in vitro and in vivo.Results:Treatment with PKI-587 enhances sensitivity to cetuximab in vitro, even in the condition of epidermal growth factor receptor (EGFR) resistance. The combination of the two drugs inhibits cells survival, impairs the activation of signalling pathways and induces apoptosis. Interestingly, although significant inhibition of proliferation is observed in all cell lines treated with PKI-587 in combination with cetuximab, activation of apoptosis is evident in sensitive but not in resistant cell lines, in which autophagy is pre-eminent. In nude mice xenografted with resistant Kyse30 cells, the combined treatment significantly reduces tumour growth and prolongs mice survival.Conclusions:Phosphoinositide 3-kinase/mammalian target of rapamycin inhibition has an important role in the rescue of cetuximab resistance. Different mechanisms of cell death are induced by combined treatment depending on basal anti-EGFR responsiveness. © 2014 Cancer Research UK.

Aim: Triple-negative breast cancer (TNBC) is a group of tumors that do not express HER2, estrogen and progesterone receptors. Due to reduced response to conventional antitumor therapies and poor prognosis, new targeted agents are needed for such aggressive sub-type of breast cancer. Multiple lines of evidence support the idea that deregulation of Hedgehog (Hh) signaling has a role in the pathogenesis of breast cancer, in part through the promotion of epithelial-stromal interactions. Therefore, the inhibition of the Hh pathway has been proposed as an interesting therapeutic approach Methods: The main objective of this study is to investigate the role of Hh signaling pathway in TNBC. To this aim, we used a panel of human breast cancer cell lines, including five cancer cells lines positive for ER, PR and HER2 expression (nTNBC) and five Triple Negative Breast Cancer cell lines (TNBC). The effects induced by the Smo-inhibitor NVP-LDE225 on proliferation, angiogenesis and signal transduction of breast cancer cells were investigated Results: GLI1, one of the major transcription factors induced by Hh signaling activation, is more expressed in TNBC than in nTNBC cell lines. Consistently, NVP-LDE225 treatment induced a more pronounced inhibitory effect on TNBC, in terms of tumor growth: while nTNBC cells display an IC50 of∼5mM, TNBC cell lines are more sensitive, with an average IC50 of∼2mM. In addition, Hh inhibition caused a robust impairment of TNBC cells invasion capabilities. These effects are coupled with a strong inhibition of VEGFA production by both tumor and stromal cells (human fibroblasts and HUVECs). Accordingly, NVP-LDE225 treatment interfered with HUVEC capillary tube formation, an effect even more evident than that observed with bevacizumab, the only targeted agent approved to date for TNBC patients Conclusions: Our results suggest that Hh has a specific role in breast epithelial-stromal interactions by regulation of angiogenesis. An orthotopic in vivo experiment in nude mice xenografted with TNBC cells, testing the combination of NVP-LDE225 with bevacizumab, is ongoing Disclosure: All authors have declared no conflicts of interest.

Different approaches are being developed to improve the differentiation of Leishmania genus using biochemical and molecular methods. In this study, 11 independent polymorphic microsatellites were used for the typing of strains of L. infantum isolated in Sicily. Polymerase chain reaction was employed to amplify the microsatellites contained in 12 DNA regions selected from among more investigated loci. A total of 51 isolates of L. infantum from dogs were tested by using the same locus panel. The products were successively analysed using an automatic sequence detector (ABI PRISM 3130 AB), to discover relevant microsatellite polymorphisms. It was possible to discriminate between MON-1 and non-MON-1 groups. Moreover, the method permitted to distinguish various genotypes of L. infantum isolates within each zymodema. Model- and distance-based analyses of the data set showed comparable results. The frequency of heterozygosity in the alleles analysed varied extremely between the different groups of isolates. As the method exhibits a high level of discrimination, it is suitable for characterization of closely related strains in epidemiological studies.

In spite of its acknowledged relevance, the impact of managerial and organizational aspects on hospital wards’ efficiency has been so far overlooked by the literature. In order to explore this issue, this paper presents a model of the relations between the decision making process of a hospital ward and its technical efficiency. In order to test the model, a two-step approach has been adopted. In the first step the technical efficiency of wards belonging to a large Italian Hospital Enterprise has been calculated using DEA. In the second step, efficiency scores have been regressed on a set of variables capturing managerial goals and actions internal to the ward, as well as re-organizations imposed by the hospital central management. Responses to a questionnaire administered to the heads of ward were used to build the independent variables. Results show that both decisions internal to the ward and exogenous re-organizations affect the ward’s efficiency, and suggest that these variables are more significant in explaining efficiency than environmental ones.

Eight reproductive boars were divided into three groups and inoculated with Toxoplasma gondii [GI (n=3) 1.5x10(4) oocysts strain P; GII (n=3) 1.0x10(6) tachyzoites strain RH; and GIII (n=2) non-inoculated control]. Clinical, hematological, parasitemia and serological tests and studies of the parasite in the semen through bioassay and PCR, and in reproductive organs (Bioassay and immunohistochemical analyses) were conducted to evaluate the toxoplasmic infection. Blood and semen were collected on day -2, -1, 1, 3, 5, 7, 9, 11, 14 and weekly up to 84 days post-inoculation (DPI). No clinical or hematimetric alteration was observed in the boars. Parasitemia was detected in one boar inoculated with oocysts at the 7th DPI and in another boar infected with tachyzoites (GII) at the 3rd and 49th DPI. Serological tests revealed antibodies against T. gondii in animals inoculated with oocysts or tachyzoites at the 7th DPI with dilutions of 1:256 and 1:64, which reached peaks of 1:4096 at day 11 and 9, respectively. The bioassays revealed the presence of the parasite in semen samples of a boar inoculated with oocysts (GI) at 3, 49 and 56 DPI and from two boars infected with tachyzoites (GII), one animal at 5 and two animals at 49 days DPI. Mice inoculated with semen from the control group (GIII) remained serologically negative. PCR analysis showed T. gondii DNA in the semen of Boar 1 and Boar 3 inoculated with tachyzoites and oocysts, respectively. The immuno-histochemical tests showed T. gondii in the reproductive organs of Boar 1 and Boar 2, inoculated with tachyzoites and oocysts, respectively. These findings suggest the possible occurrence of venereal transmission of T. gondii in swine.Oito reprodutores suínos foram divididos em três grupos e inoculados com Toxoplasma gondii [GI (n=3) 1.5x10(4) oocistos cepa P; GII (n=3) 1.0x10(6) taquizoítos cepa RH, e GIII (n=2) controle, não inoculados]. Exames clínicos, hematológicos, de parasitemia e sorológicos foram realizados para avaliar a infecção toxoplásmica. Pesquisa do parasito no sêmen, por meio do bioensaio e pela técnica da PCR, e em órgãos do sistema reprodutor (bioensaio e imunohistoquímica) foi realizada. Sangue e sêmen foram colhidos nos dias -2, -1, 1, 3, 5, 7, 9, 11, 14, e semanalmente até o 84º dia pós-infecção (DPI). Nenhuma alteração clínica ou hematimétrica foi observadda nos animais. Parasitemia foi detectada em um animal inoculado com oocistos no 7º DPI e em outro inoculado com taquizoítos (GII) nos 3º e 49º DPI. A sorologia revelou a presença de anticorpos contra T. gondii nos animais inoculados com oocistos ou taquizoítos no 7º DPI com títulos de 1:256 e 1:64, que atingiram picos de 1:4096 nos dias 11 e 9, respectivamente. O bioensaio revelou a presença do parasita em amostras seminais de um animal inoculado com oocistos (GI) nos 3º, 49º e 56º DPI, e de dois animais infectados com taquizoítos (GII), um deles no 5º DPI e os dois ao 49º DPI. Pela PCR, o DNA de T. gondii foi detectado no sêmen dos Suínos 1 e 3 inoculados com taquizoítos e oocistos, respectivamente. A imunohistoquímica revelou T. gondii em órgão do aparelho reprodutor dos Suínos 1 e 2, inoculados com taquizoítos e oocistos, respectivamente. Esses achados sugerem a possibilidade da ocorrência da transmissão venérea do T. gondii em suínos.

Effective Critical Infrastructure Protection and Resilience (CIP-R) depends on numerous stakeholders collaborating at different institutional and operational levels and exchanging information by means of a variety of channels. In this regard regional programmes or partnerships, have emerged as one of the key strategies to deal with CIP-R and Emergency Management (EM) issues effectively. Previous research has set the theoretical base of Public-Private Partnerships (PPP) and claimed their high potential for enhancing CIP-R that is vastly unexploited due to challenges in their establishment and management. It is now necessary to move forward to studying practical side of these programmes. MIRACLE (Multi-level Alignment of Regional Approaches to CI Resilience by Learning from Experience) is a research project funded by EC – DG HOME that aims at supporting regional CIP-R strategies in order to improve exiting capacities of the EU Member States to prevent, prepare and protect people against security related risks. This study presents a review of existing Good Practices (GPs), i.e. tools, technologies, activities and processes that are able to support: i) Establishment and management of regional PPPs for CIP-R; ii) Achievement of their main objectives and specific goals. The collected GPs are used to improve resilience levels in different phases of EM. GPs have been identified through an online survey, institutional websites, insights from professionals, available reports, documents and scientific literature. Finally, through engagement of international experts, professionals and researchers the GPs have been evaluated along three main parameters: implementation effort, transferability potential, type and relevance of expected benefits.

Background The EGFR tyrosine kinase inhibitors gefitinib and erlotinib are first-line therapy for NSCLCs harbouring EGFR-activating mutations. The intrinsic and acquired resistance to these agents is a relevant clinical issue. Although Src tyrosine kinase has been involved in such resistance in preclinical models, clinical development of these agents has been so far limited. Methods We used a panel of human NSCLC cell lines: PC9 and HCC827 (EGFR-activating mutation; highly sensitive to erlotinib), Calu3 (EGFR/Ras wild-type, wt; moderately sensitive), Calu3-ER (with acquired resistance), H1299 and A549 (Ras mutant; resistant), H1975 (EGFR T790M mutant; resistant). In these models, we tested three different Src inhibitors (saracatinib, dasatinib, and bosutinib), both in vitro and in vivo. Findings NSCLC cell lines showed different activation of EGFR-dependent and Src-dependent pathways and variable sensitivity to Src inhibitors. A kinase assay demonstrated that all the compounds are able to directly inhibit EGFR tyrosine kinase variants. In cell lysates only saracatinib and bosutinib efficiently reduced EGFR activation, while dasatinib was the more effective agent in inhibiting Src tyrosine kinase. Consistently, in EGFR-activating mutant, erlotinib sensitive cells, saracatinib and bosutinib showed anti-proliferative effects related to simultaneous EGFR/Src inhibition. In EGFR wt/Ras mutant cells Src inhibition by dasatinib interfered with cell proliferation and signal transduction. Since Src inhibitors had only moderate effects as single agents we tested the combination of saracatinib with EGFR inhibitors (erlotinib or cetuximab) in EGFR-addicted cells, and of dasatanib with MEK inhibitors (selumetinib) in Ras mutant, erlotinib resistant models. These combinations were effective both in vitro and in nude mice, inhibiting tumour growth, prolonging mice survival, and interfering with signal transduction. Importantly, the combination of saracatanib and cetuximab was effective also in the erlotinib resistant, EGFR T790M mutant model. Interpretation Src inhibitors may act with different mechanisms in NSCLC cell lines, depending on EGFR/Ras mutational profile. Integration of anti-Src agents with EGFR or MEK inhibitors could represent effective therapeutic options for different cohorts of NSCLC patients.

Background: Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth. Methods: We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo. To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib - a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC. Results: NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays. Conclusions: Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients.

Aim Triple-negative breast cancer (TNBC) is a group of tumors that do not express HER2, estrogen and progesterone receptors. Due to reduced response to conventional antitumor therapies and poor prognosis, new targeted agents are needed for such aggressive sub-type of breast cancer. Multiple lines of evidence support the idea that deregulation of Hedgehog (Hh) signaling has a role in the pathogenesis of breast cancer, in part through the promotion of epithelial-stromal interactions. Therefore, the inhibition of the Hh pathway has been proposed as an interesting therapeutic approach Methods The main objective of this study is to investigate the role of Hh signaling pathway in TNBC. To this aim, we used a panel of human breast cancer cell lines, including five cancer cells lines positive for ER, PR and HER2 expression (nTNBC) and five Triple Negative Breast Cancer cell lines (TNBC). The effects induced by the Smo-inhibitor NVP-LDE225 on proliferation, angiogenesis and signal transduction of breast cancer cells were investigated Results GLI1, one of the major transcription factors induced by Hh signaling activation, is more expressed in TNBC than in nTNBC cell lines. Consistently, NVP-LDE225 treatment induced a more pronounced inhibitory effect on TNBC, in terms of tumor growth: while nTNBC cells display an IC50 of∼5mM, TNBC cell lines are more sensitive, with an average IC50 of∼2mM. In addition, Hh inhibition caused a robust impairment of TNBC cells invasion capabilities. These effects are coupled with a strong inhibition of VEGFA production by both tumor and stromal cells (human fibroblasts and HUVECs). Accordingly, NVP-LDE225 treatment interfered with HUVEC capillary tube formation, an effect even more evident than that observed with bevacizumab, the only targeted agent approved to date for TNBC patients Conclusions Our results suggest that Hh has a specific role in breast epithelial-stromal interactions by regulation of angiogenesis. An orthotopic in vivo experiment in nude mice xenografted with TNBC cells, testing the combination of NVP-LDE225 with bevacizumab, is ongoing Disclosure All authors have declared no conflicts of interest.

To gain further insights into the immunopharmacological mode of action of the immunosuppressant antibiotic deoxyspergualin (DSP), its effects were evaluated in murine lethal endo- and exotoxemia. These are two cytokine-mediated macrophage and T cell dependent immunoinflammatory conditions that can be induced in D-Galactosamine (D-Gal) presensitized mice by the injections with either LPS or SEB, respectively. The results show that prophylactic treatment with DSP (2.5 or 5 mg/kg bd.wt. 48, 24 and 2 h prior to challenge) neither improved the rate of survival, nor influenced the massive increase in the blood levels of tumor necrosis factor-alpha which followed the challenge with LPS or SEB. In sharp contrast, these clinical and seroimmunological events were both markedly counteracted by prophylactic treatment with sodium fusidate, another immunosuppressive agent used as control.

Controlled human experiments are adopted in this paper to investigate the impact of supply uncertainty on buyers' inventory management. The experiments aim at assessing the impact of one specific source of supply chain uncertainty, namely stochastic lead times, on inventory holdings and the extent of the bullwhip effect. Three experimental treatments are run within the framework of the beer game manipulating variability in demand and in lead times. Results confirm that the bullwhip effect arises in all experimental treatments and that the variance of orders is higher under stochastic lead times. Analysis of players' behaviour in the course of the game suggests that players react to higher uncertainty by holding fewer inventories, a behaviour consistent with the predictions of some psychological models of choice under ambiguity.

We describe how to build statistically-based flexible models of the 3D structure of variable objects, given a training set of uncalibrated images. We assume that for each example object there are two labelled images taken from different viewpoints. From each image pair a 3D structure can be reconstructed, up to either an affine or projective transformation, depending on which camera model is used. The reconstructions are aligned by choosing the transformations which minimise the distances between matched points across the training set. A statistical analysis results in an estimate of the mean structure of the training examples and a compact parameterised model of the variability in shape across the training set. Experiments have been performed using pinhole and affine camera models. Results are presented for both synthetic data and real images.

Technological and natural disasters occurred in Europe during last decades showed an increased vulnerability of our society to different risks. Authorities and civil protection need instruments which allow having a better understanding of the variety of risks over a territory and help them in managing the resources and planning the emergency. However, many difficulties arise in comparing hazards, vulnerabilities and risks among them. The existing risk mapping in European countries often allows a simplified comparison of risks by means of potential damages but does not permit any qualitative assessment of multi‐risk situations. The aim of this project carried out for the Piedmont Region (Italy) is the development of a decision support system based on a multi‐risk approach which can overcome difficulties in the overall risk assessment over a territory. To define multi‐risk maps, a multi‐risk perspective and stakeholder's perceptions were integrated to a classical risk assessment frame. The specific purpose ...

The negative correlations of fat and protein concentrations and milk yield, existing in all ruminants dairy species (Oftedal, 1984; Mepham, 1987), reflect a deep mechanism regulating the respective kinetics of secretion of carrier (mainly lactose which is the major responsible for the water drawn to the milk) and of fat and protein. Whereas the correlation coefficients are low (from –0.2 to – 0.4), fat and protein daily yield and milk production are positively and strongly linked (r = 0.8÷0.9). It means that more productive animals have higher fat and protein yield, but their milk has lower concentration of these components. The aim of this work is to investigate the relationships between milk, fat and protein yield in all main ruminant dairy species by using a simple mathematical model.

In patients with essential arterial hypertension (EAH) the left heart ventricular hypertrophy (LVH) causes structural and functional alterations of the coronary vessels that can alter the coronary blood flow reserve. The aim of this study is to evaluate in hypertensive patients with or without LVH versus normotensive subjects, the blood flow and the coronary vasodilatation capability and the coronary blood flow reserve in basal conditions and during dipiridamole i.v. infusion.Eighty patients have been selected by ECG, echo color Doppler, transesophageal echocardiography: 50 were hypertensive patients with and without LVH, from mild to moderate to severe and 30 were normotensive subjects. The enrolled patients underwent a first transesophageal echocardiography, before and during infusion of 0.86 mg/kg of dipiridamole in growing doses, 0.56 in four minutes followed after three minutes by 0.30 mg/kg. The observation lasted 18 months, and no patients left the study.The coronary resistances in hypertensive patients were significintally reduced during dipiridamole infusion, maintaining their level higher compared to the normal controls. The reduced coronary vasodilatation capability in hypertensive subjects could be due to an increase of the basal vessel tone and/or a reduced compliance of the coronary resistances. The coronary blood flow reserve is significantly reduced in all hypertensive studied, included those without LVH. It is suggested that this is secondary to increase of the coronary blood flow and tone.In conclusion essential arterial hypertension is the cause of early anatomical and functional coronary alterations leading hypertensive subjects to risk for coronary events before LVH.

Aim: The EGFR TKIs gefitinib and erlotinib are the first-line therapy for NSCLCs harboring EGFR-activating mutations. The intrinsic resistance to these agents and the onset of acquired resistance in the responders is a relevant clinical issue and the aim of this work is to test the efficacy of three different Src inhibitors in these models of resistance. Methods: We used a panel of human NSCLC cell lines with different EGFR/Ras mutational profile and erlotinib sensitivity: PC9 and HCC827 (EGFR-activating mutation, highly sensitive), Calu3 (EGFR/Ras wt; moderately sensitive), Calu3-ER (with acquired resistance), H1299 and A549 (Ras mutant; resistant), H1975 (EGFR T790M mutant; resistant). In these models, we tested three different Src inhibitors (saracatinib, dasatinib and bosutinib), both in vitro and in vivo Results: NSCLC cell lines showed different activation of EGFR- and Src-dependent pathways and variable sensitivity to Src inhibitors. A kinase assay demonstrated that all the compounds are able to directly inhibit not only Src, but also EGFR TK variants. However, in cell lysates only saracatinib and bosutinib efficiently reduced EGFR activation, while dasatinib was the more effective agent in inhibiting Src TK. In EGFR-activating mutant, erlotinib sensitive cells, saracatinib and bosutinib showed anti-proliferative effects related to simultaneous EGFR/Src inhibition. In EGFR wt/Ras mutant cells Src inhibition by dasatinib interfered with cell proliferation and signal transduction. Since Src inhibitors had only moderate effects as single agents, both in vitro and in vivo, we tested the combination of saracatinib with EGFR inhibitors (erlotinib or cetuximab) in EGFR-addicted cells, and of dasatanib with MEK inhibitors (selumetinib) in Ras mutant, erlotinib resistant models. These combinations were effective both in vitro and in vivo, inhibiting tumor growth, prolonging mice survival and interfering with signal transduction. Importantly, the combination of saracatanib and cetuximab was effective also in the erlotinib resistant, EGFR T790M mutant model. Conclusions: Src inhibitors may act with different mechanisms in NSCLC cell lines, depending on EGFR/Ras mutational profile. Integration of anti-Src agents with EGFR or MEK inhibitors could represent effective therapeutic options for different cohorts of NSCLC patients. Disclosure: All authors have declared no conflicts of interest.

Background Imatinib (Gleevec) is a protein kinase inhibitor initially registered in Italy as an orphan drug for the treatment of chronic myeloid leukaemia (CML) and gastro-intestinal stromal tumours (GIST): its use in clinical practice began in 2004 with a cost to the public per pack of 3,313.47 € (2,007.67 € ex -factory). The dosage varies from 400–800 mg/day and must be continued chronically until disease progression (DP) or until side effects appear. Purpose To examine the level of spending on imatinib in the National Cancer Institute of Milan (INT) compared with consumption in Italy. Materials and methods We interrogated the national reports on the use of drugs in Italy (OsMed) published by the AIFA requesting a report on consumption (extracted from the flow of File F for active drug) by number of treated patients and by department (SC Haematology and SC Sarcomas), in order to proceed to the comparison. Results Analysis of the data revealed that in the course of 5 years (2008–12) the expenditure at the national level went from 144,700,000 € to 122,478,260 € (period Jan–Sept 2012), peaking at 173,300,000 in 2011 €. In INT the figures were 2,419,605 € in 2008 to 2,881,185 € in 2012, peaking at nearly 3 million euro in 2011. The decrease since 2011 is considered to be linked to two factors: some patients showed resistance to the treatment, so they switched to use a second line treatment with sunitinib; some local health authorities have intervened in the supply of the drug to their patients. Conclusions In the period under consideration, INT expenditure was about 6% of the entire national expenditure, about 11.6% of the expenditure of the BPE. According to the latest epidemiological data, a slight increase is expected in new diagnoses with a consequent increase in spending both nationally and in individual structures. Will the NHS manage to ensure the continuity of care for life, with an average cost for each treatment of about 80 €/day? Is it necessary to wait for 2016 for the generic drug or should we turn to the Indian market, where the average cost is about 9 €/day? No conflict of interest.

The objective of this study is to evaluate the oxidative stress status in patients affected by Alzheimer's disease, considering the role played by the free radicals in the progression and determination of this disease.We have studied 13 patients aged between 65 and 84 years and diagnosed with Alzheimer's disease on the basis of Brain CT scan or MRI results, PTEA (uditive mapped slow potential waves), EEG analysis, evaluation questionnaire (MMSE, ADAS), free radicals levels.This study proved the presence of an oxidative stress status in all patients studied, showing an interaction between the disease and oxidative status. A reduction of the free radicals levels after therapy with determinable anti radicals has also been observed.The existence between Alzheimer's disease and oxidative stress has already been demonstrated. This study is a contribution to this orientation. Further studies are suggested on the preventive effects, but particularly to demonstrate if the use of antioxidants may be able to decrease or stop the evolution of this disease.

In the various sectors of animal science there has been little exploration of the theoretical mathematical aspects of data analysis and modelling. The dominant statistical methods used for the analysis of experimental data are rarely valuable for developing a deeper understanding of the problem. In addition they do not take account of the evolution over time of those variables of major interest to be studied. Only recently have more sophisticated methods of mathematical modelling begun to be used. Nonetheless attention tends to be focused exclusively on empirical models. Mathematical models with greater explanatory power, in particular those which use differential equations, are as yet little used. This work develops a mathematical approach to a problem that is of great interest in animal science: the development over time of milk production in economically important ruminant species.

The effects of three lipid peroxidation end-products, 4-hydroxynonenal (HNE), 2-nonenal (NE) and nonanal, on phosphoinositide-specific phospholipase C (PL-C) activity were studied in HL-60 cells. Enzymatic activity was determined by measuring the amounts of inositol-P3 (Ins-P3) produced by the cells incubated at 37 degrees C in the presence of the various compounds. HNE was shown to activate PL-C at concentrations of between 10(-8) and 10(-6) M; 10(-9) and 10(-8) M of NE also strongly stimulated PL-C. In contrast, nonanal failed to modify enzymatic activity. The concentrations of HNE and NE active on PL-C showed good correspondence with those that have been reported to be chemotactic towards rat neutrophils. The pretreatment of cells with 1 microM pertussis toxin completely prevented the increase of Ins-P3 production induced by HNE and NE. Maximal PL-C stimulation was produced by 10 nM NE; the degree of inositol-P3 production induced by the simultaneous addition of an equimolar dose of HNE was not significantly different from the activity value induced by NE alone, suggesting a possible competition between the two compounds. The data indicate that both HNE and NE share a common mechanism of action which, as with other better-known chemoattractants, involves PL-C activation through a G regulatory protein.

Myelodysplastic syndromes (MDS) are diseases typical of the adult age, characterized by a clonal alteration of the totipotent staminal cell which causes an inefficient hemopoiesis, reduction of bone marrow cell number, increased bone marrow cell destruction, dysplasia of at least two of the three hemopoietic cell lines and by the tendency to evolve towards acute myeloid leukemia (AML). In patients with MSD, particularly in the advanced primary form, single or multiple chromosomal abnormalities can be found frequently, which may show up and/or modify themselves in any moment of the disease (multistep pathogenetic hypothesis) and whose severity influences significantly the prognosis of MSD patients. In November 1998, a 22 year old female patient (C. C.) was admitted to the Department of Internal medicine of the Garibaldi Hospital, Catania for anemia of unknown origin. The normalities of the hematochemical tests and of other instrumental examinations, induces to perform an osteo-medullary biopsy which revealed the presence of a typical MSD, refractory anemia with excess of blasts type. This disease in its primary form is rare in youth and has a high tendency to evolve in AML. The good clinical conditions of the patient, the absence of chromosomal abnormalities, the normal levels of HbF, the short time interval of the initial diagnosis induced to proceed to bone marrow transplantation, that, as shown by the data reported in the international literature, may give her a good quoad vitam prognosis.

Histiocytic Necrotising Lymphadenitis by Kikuchi-Fujimoto (NHL) is a rare disease of unknown etiopathogenesis, characterized by cervical lymphadenomegaly, fever and asthenia. It has a good prognosis with a complete functional recovery of the affected lymph nodes. In 1998 a 28 year-old patient (A. G.) was admitted in the Department of Internal Medicine, Garibaldi Hospital, Catania for fever, asthenia and cervical lymphadenopathy. Hemato-chemical tests performed during hospitalization showed only relative leukopenia and a significant increase of ESR. An initial cervical lymph node biopsy made the diagnosis of Hodgkin's lymphoma. However, the favourable clinical course and the normalization of the previous altered hematochemical tests, induced to perform a second lymph node biopsy which led to diagnosis of NHL. The patient was given antibiotics and anti-inflammatory drugs for ten days with a complete healing which persisted at a twelve-month follow-up. The conclusion is drawn that NHL of unknown etiopathogenesis and with a good prognosis is more frequent than what revealed by the data in the literature because of its insidious and aspecific clinical presentation.

Recent findings have indicated the association between APC-resistance and cerebrovascular disease. These reports prompted us to investigate whether resistance to APC could be found in patients suffering from stroke.Therefore, we studied APC-resistance in 50 young adults (or =45 yrs) with a history of ischemic stroke. Eleven out of fifty cerebrovascular subjects showed APC-resistance, while 2 had PC deficiency and 3 PS deficiency. No deficiencies in the anticoagulant protein AT III and in fibrinolytic proteins were found. The family history demonstrated a distribution of APC-resistance compatible with dominant autosomal inheritance. The plasma concentration of prothrombin fragment 1+2 (F1+2), which is a marker of hypercoagulable states, was also measured in patients and family members of resistant subjects (n = 38).DNA analysis showed factor V R506Q mutation (Leiden mutation) in 11 patients and their relatives with poor response to activated protein C detected by APTT tests. Of 11 investigated subjects with APC-resistance, 9 were heterozygotes and 2, with the lowest APC-ratio values, were homozygotes for factor V mutation. Among 38 relatives, 22 showed a poor response to APC and according to the APC-ratio values, 18 were heterozygotes and 4 homozygotes for FV Leiden mutation. The mutation, in heterozygous form, was also found in 2% of our normal population (n = 100). The plasma concentration of F1+2 was significantly higher both in 11 individuals carrying the FV:Q506 mutation and in 39 patients without APC-resistance compared to that found in the control group. However, the patients with FV:Q506 mutation showed the highest values in F1+2. In the studied family members F1+2 plasma levels were within normal values.Our findings indicate a possible involvement of APC-resistance in the pathogenesis of cerebral thrombosis in young adults and agree with the hypothesis that individuals with APC-resistance have an imbalance between pro-and anti-coagulant forces leading to increased thrombin generation and a hypercoagulable state.

Recent findings have indicated the association between activated protein C (APC)-resistance and cerebrovascular disease. These reports prompted us to investigate whether resistance to APC could be found in patients suffering from transient ischaemic attacks or stroke. Therefore, we studied APC-resistance in 14 young adults belonging to three different families with a history of transient ischemic attacks (TIAs) and stroke. Nine out of fourteen subjects showed APC-resistance but no deficiencies in the anticoagulant proteins AT III, PC and PS. The family history demonstrated a distribution of APC-resistance compatible with dominant autosomal inheritance. A rapid screening method to detect factor V R506Q (Leiden) mutation without sequencing or restriction enzyme digestion has been set-up after biochemical analyses. DNA analysis showed a guanine to adenine transition at nucleotide 1,691 in patients and their relatives with poor response to activated protein C detected by APTT tests. Of 14 investigated subjects and their family members, 5 were normals, 6 were heterozygotes and 3 were homozygotes for factor V mutation. The mutation, in heterozygous form, was also found in 1.3% of our normal population (n = 75). Our findings indicate a possible involvement of APC-resistance in the pathogenesis of arterial thrombosis in young adults.

Objects of the same class often exhibit variation in shape. This shape variation has previously been modelled by means of point distribution models (PDMs) in which there is a linear relationship between a set of shape parameters and the positions of points on the shape. Here we present a new form of PDM, which uses a multilayer perceptron (MLP) to carry out nonlinear principal component analysis. We demonstrate that MLP-PDMs can model the shape variability in classes of object for which the linear model fails. We describe the use of MLP-PDMs in image search and present quantitative results for a practical application (face recognition), demonstrating the ability to locate image structures accurately starting from a very poor initial approximation to their pose and shape. © 1996 IEEE.

The aim of this study was to investigate the role of natural cascade inhibitors in Juvenile Transient Ischemic Attacks. Fifty patients with anterior or posterior brain attacks were studied. One hundred healthy subjects matched for sex and age were randomly assigned to a control group. All had a physical examination and radiologic work-up. Computerized tomography showed no ischaemia either with or without contrast medium. Digital angiography of epiaortic and intracerebral vessels was unremarkable patients non controls ever had war-farin therapy. Antithrombin III, protein C and plasminogen were determined by functional methods. Protein S was assayed by a functional clotting method based on prolonged PT. The activated protein C resistance test was performed and a poor response to activated protein C was verified in patients. Our findings show protein S, protein C and antithrombin III type I deficiency with a functional activity70% compared to controls. Eight of fifty patients (16%) had low protein S levels, 5 (10%) had low protein C, 2 (4%) had low antithrombin III and 1 (2%) plasminogen deficiency. A significant (p0.01) difference in activated protein C ratio was seen for controls and patients. These results suggest that screening for natural anticoagulants in young people suffering from transient ischemic attacks could be beneficial and should be encouraged.