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Resumen Las plantaciones forestales proveen múltiples beneficios económicos, sociales y ambientales pero su rendimiento puede verse amenazado por la aparición de plagas. Contar con métodos eficientes de monitoreo es de importancia para implementar mecanismos de control y seguimiento. En los últimos años los Vehículos Aéreos No Tripulados (VANTs) han posibilitado la adquisición de información de gran resolución espacio - temporal para el estudio de procesos ecológicos y forestales. Sus características únicas los convierten en potenciales herramientas de monitoreo sanitario en plantaciones forestales. A pesar de ello, en Argentina existen pocas experiencias documentadas sobre su aplicación en el monitoreo de plagas. En este trabajo se analizó el uso de un VANT como método de monitoreo y cuantificación del daño ocasionado por Sirex noctilio en forestaciones de coníferas. Particularmente se evaluó la capacidad de estimar los niveles de infestación y de generar productos cartográficos que contribuyan al análisis de la dinámica poblacional de la plaga. Las estimaciones logradas con el VANT fueron comparadas con los métodos de campo utilizados habitualmente en la región. Los resultados obtenidos han sido satisfactorios: el VANT permitió identificar a escala de árbol la sintomatología y cuantificar los niveles de daño. Las estimaciones mostraron una tendencia a subestimar en forma sesgada y con valores acep-tables. Asimismo, se obtuvieron productos espacialmente explícitos sobre la distribución de la plaga, permitiendo localizar pequeños focos o incluso individuos aislados sobre la superficie relevada. Los resultados de este trabajo sugieren que los VANTs pueden contribuir en generar mejores estrategias de manejo y control de plagas forestales en la región. Abstract Forest plantations provide a wide range of economic, social and environmental benefits in many parts of the world but their productivity could be affected by the presence of pests. Counting on efficient monitoring and surveying methods is important to help controlling and mitigating impacts caused by pathogens. Last years, Unmanned Air Vehicles (UAVs), commonly known as drones, have made it possible obtaining high space-time resolution information for studying ecological and forest processes. They have become potential tools for forest health studies due to their unique features. However, there is little knowledge about its performance concerning forest health monitoring in Argentina. This study analyzed the potential use of UAVs for forest health monitoring and damage estimation in coniferous plantation stands including Sirex noctilio. Particularly, the capacity for quantifying infestation levels and mapping distribution was tested. The UAVs estimations were compared to those obtained from traditional field survey methods used in this region. The results were satisfactory and promising. UAVs allowed to detect symptomatology at tree level and quantify infestation. Estimates showed a tendency to underestimate in a sly manner and with acceptable values, which could be statistically adjustable in the future. In addition, spatially explicit products were generated upon plague distribution which allowed for the detection of small infection spots and of isolated trees with visible symptoms. The results of this study suggest that UAVs may become key instruments for health surveying that contribute to efficient management and control of forest pests and diseases in Patagonia.

The breast cancer (BC) disease is characterized by a wide heterogeneity at both clinical and molecular level, showing distinct subtypes with different clinical outcomes. Thus, the choice of the therapeutic plan, such as the type of radiotherapy (RT) need to take into account this complexity. Indeed, the proton therapy (PT) shows a medical benefit compared to conventional X-ray RT, as regards the localized delivery of the radiation dose sparing health tissues, but few data regarding proton-induced molecular changes are currently available. The aim of this study was therefore to investigate the production of immunological molecules and gene expression profiles induced by proton irradiation on BC cell lines. Clonogenic survival assay, luminex assay and cDNA microarray gene expression analyses were performed both in the non-tumorigenic MCF10A cell line and in two tumorigenic MCF7 and MDA-MB-231 cell lines, following irradiation with 0.5, 2 and 9 Gy of clinical proton beams. We found that proton irradiation induced gene expression changes useful to define a cell line and dose-dependent gene signatures. The lack of molecular data in the literature can be filled by data here presented that could represent a useful tool to better understand the molecular mechanisms elicited by protons predicting the treatment outcome.

The S100 gene family is the largest subfamily of calcium binding proteins of EF-hand type, expressed in tissue and cell-specific manner. S100 proteins act as intracellular regulators and as extracellular signaling. Within cells, S100 have been involved in the regulation of proliferation, differentiation, apoptosis, energy metabolism, inflammation, migration and invasion via interactions with a variety of target proteins. Extracellular S100 proteins act in an autocrine and paracrine manner through the activation of surface receptors that regulate cell proliferation, differentiation, survival and migration. More recently, there is growing interest in the S100 proteins and their relationship with different cancers because of their involvement in a variety of biological events closely related to tumorigenesis and cancer progression1. However, the occurrence, the role and the possible coordination of this group of proteins in breast cancer is still poorly known. We previously describe a large-scale proteomic investigation performed on breast cancer patients for the screening of multiple forms of S100 proteins2,3. Our results have shown that the majority of S100 proteins are preferentially expressed in the tumor mass compared with the normal adjacent tissue and that some S100 protein members were ubiquitously expressed in almost all patients, while others appeared more sporadic among the same group of patients. More interestingly, patients which developed distant metastases showed a general tendency of higher S100 protein expression, compared to the disease-free group. Present study was aimed to assess the gene expression levels of the S100 protein family members utilizing a breast cancer dataset generated on Affymetrix microarrays technologies4. GOBO (Gene expression-based Outcome for Breast cancer Online) is a user-friendly online tool that allows, also, the identification of co-expressed genes and association with outcome in an 1881 breast cancer samples. Other important association with breast cancer outome was carried out by Kaplan Meir-plotter database5. Integrating results obtained by proteomic and trascriptomic analysis of S100 proteins highlight their important involvement in breast cancer progression, and support the idea that S100 proteins are important prognostic factors, related to survival period of tumor patients. However, the specific mechanisms by which S100 proteins affect progression of breast require further study.

The extracellular matrix (ECM) underlying epithelial tissues is involved in the maintenance of cell polarity and homeostasis. ECM is a dynamic structure under the regulated remodeling of its components. The major enzymes responsible of matrix degradation are the matrix metalloproteinases (MMPs), a well known family of zinc-dependent endopeptidases. Much attention has been focused on MMP-2 and MMP-9 because of their ability to degrade type IV collagen, a major constituent of basement membranes. A deregulated proteolysis of ECM molecules may cause the alteration of cell polarity and may contribute to the disruption of cell–cell and cell–ECM adhesions, promoting cancer progression. These alterations are responsible for a poor prognosis, and a positive correlation between the increase of MMPs and the degree of malignancy has also been observed FOR many tumor histotypes. To approach these issues on in vitro models, we performed a comparative study, between a couple of tumoral and non-tumoral mammary cell lines and a couple of thyroid cell lines derived respectively from a benign and malignant cancer. This experimental approach, based on scanning electron microscopy, on proteomic analysis and on gelatin zimography, highlighted a similar profiling of the two differential couples of cell lines: that is between malignant and non-malignant cells respectively, regardless of their histological origin. In particular, it was observed that the cell lines derived from aggressive cancers, when compared with their non-malignant counterpart, showed an increased secretion of MMPs, a cell shape highly pleomorphic and a higher expression of protein clusters potentially associated with invasion and metastasis. The analysis of the interactions between the expression of MMPs and of selected proteomic clusters have offered important indication on the complex network existing between neoplastic cells and their environment. The work was co-funded by the Italian 5x1000 to COBS.

The estabilishment of a dinamic crosstyalk between the malignant cells and several components of the ECM is a crucial step of the tumor progression. The aim of the present study was to improve the knowledge about the effects of ectopic decorin on the breast cancer cells, starting from our previous proteomic studies. The new proteomic evidences strenghteh the anti-oncogenic effects of decorin and hilight the attention on the decreased expression of the majority of the members of three protein classes closely related to the malignant phenotype: the metabolic enzymes, the S100 family and the cell motility proteins

S100 gene family is the largest subfamily of calcium binding proteins, expressed in tissue and cell-specific manner. Within cells, S100 have been involved in the regulation of proliferation, differentiation, apoptosis, energy metabolism, inflammation, migration and invasion. Extracellular S100 proteins act in an autocrine and paracrine manner and regulate cell proliferation, differentiation, survival and migration. S100 proteins play important roles in the development and progression of tumors due to their multifunctional roles. However, the occurrence, the role and the possible coordination of this group of proteins in breast cancer is still poorly known. We previously describe a large-scale proteomic investigation performed on breast cancer patients for the screening of multiple forms of S100 proteins1,2. Our results have shown that the majority of S100 proteins are preferentially expressed in the tumor mass compared with the normal adjacent tissue and that some S100 protein members were ubiquitously expressed in almost all patients, while others appeared more sporadic among the same group of patients. More interestingly, patients which developed distant metastases showed a general tendency of higher S100 protein expression, compared to the disease-free group. Present study was aimed to assess the gene expression levels of the S100 protein family members utilizing a breast cancer dataset generated on Affymetrix microarrays technologies3. GOBO (Gene expression-based Outcome for Breast cancer Online) is a user-friendly online tool that allows, also, the identification of co-expressed genes and association with outcome in an 1881 breast cancer samples. Other important association with breast cancer outome was carried out by Kaplan Meir-plotter database4. Integrating results obtained by proteomic and trascriptomic analysis of S100 proteins highlight their important involvement in breast cancer progression. Future studies are needed to disclose molecular mechanisms and signaling pathways that define the multiple and specific roles of S100 proteins in breast cancer.

During the Space Telescope and Optical Reverberation Mapping Project observations of NGC 5548, the continuum and emission-line variability became decorrelated during the second half of the six-month-long observing campaign. Here we present Swift and Chandra X-ray spectra of NGC 5548 obtained as part of the campaign. The Swift spectra show that excess flux (relative to a power-law continuum) in the soft X-ray band appears before the start of the anomalous emission-line behavior, peaks during the period of the anomaly, and then declines. This is a model-independent result suggesting that the soft excess is related to the anomaly. We divide the Swift data into on- and off-anomaly spectra to characterize the soft excess via spectral fitting. The cause of the spectral differences is likely due to a change in the intrinsic spectrum rather than to variable obscuration or partial covering. The Chandra spectra have lower signal-to-noise ratios, but are consistent with the Swift data. Our preferred model of the soft excess is emission from an optically thick, warm Comptonizing corona, the effective optical depth of which increases during the anomaly. This model simultaneously explains all three observations: the UV emission-line flux decrease, the soft-excess increase, and the emission-line anomaly.

This study is the second of a series of seven, and\ud belongs to the second Italian systematic replication of\ud findings from two previous series (Widdowson 2012a,\ud 2012b, 2012c, 2013; Benelli, 2016a, 2016b, 2016c) that\ud investigated the effectiveness of a manualised\ud transactional analysis treatment for depression through\ud Hermeneutic Single-Case Efficacy Design. The therapist\ud was a white Italian woman with 10 years of clinical\ud experience and the client, Caterina, was a 28-year old\ud white Italian woman who attended 16 sessions of\ud transactional analysis psychotherapy. Caterina satisfied\ud DSM-5 criteria for major depressive disorder with\ud generalized anxiety disorder. The conclusion of the\ud judges was that this was an outstanding good-outcome\ud case: the depressive symptoms showed an early clinical\ud and reliable improvement, maintained till the 6 months\ud follow-up, accompanied by reductions in anxiety\ud symptoms, global distress and severity of personal\ud problems. Adherence to the manualised treatment for\ud depression appears good to excellent. In this case study,\ud transactional analysis treatment for depression has\ud proven its efficacy in treating major depressive disorder\ud in comorbidity with anxiety disorder.

Cancer metastasis is the result of a series of deregulated biological phenomena, including alterations of cell-cell and cell-matrix interactions and of other microenvironmental conditions such as the oxygen tissue supply. Hypoxia is a well-known driver of aggressive cancer phenotypes, indeed tumors with poor prognosis have higher proportions of anoxic and hypoxic areas1. The consequences of tumour hypoxia can be local or even systemic towards distant organs, and it can evoke diversified responses: whereas low oxygen concentration in tissue environments. (pO2

During an intensive Hubble Space Telescope (HST) Cosmic Origins Spectrograph (COS) UV monitoring campaign of the Seyfert~1 galaxy NGC 5548 performed from 2014 February to July, the normally highly correlated far-UV continuum and broad emission-line variations decorrelated for ~60 to 70 days, starting ~75 days after the first HST/COS observation. Following this anomalous state, the flux and variability of the broad emission lines returned to a more normal state. This transient behavior, characterised by significant deficits in flux and equivalent width of the strong broad UV emission lines, is the first of its kind to be unambiguously identified in an active galactic nucleus reverberation mapping campaign. The largest corresponding emission-line flux deficits occurred for the high-ionization collisionally excited lines, C IV and Si IV(+O IV]), and also He II(+O III]), while the anomaly in Ly-alpha was substantially smaller. This pattern of behavior indicates a depletion in the flux of photons with E_{\rm ph} > 54 eV, relative to those near 13.6 eV. We suggest two plausible mechanisms for the observed behavior: (i) temporary obscuration of the ionizing continuum incident upon BLR clouds by a moving veil of material lying between the inner accretion disk and inner BLR, perhaps resulting from an episodic ejection of material from the disk, or (ii) a temporary change in the intrinsic ionizing continuum spectral energy distribution resulting in a deficit of ionizing photons with energies > 54 eV, possibly due to a transient restructuring of the Comptonizing atmosphere above the disk. Current evidence appears to favor the latter explanation., 12 pages, 2 figures, accepted for publication in ApJ, Friday 25th March 2016. A movie of the anomalous emission-line behavior can be found in the ancilliary documents

Immune tolerance induction (ITI) is effective in approximately 70% of haemophilia patients with inhibitors. Poor prognostic factors are age >6 years, ITI started >1 year from inhibitor development, inhibitor peaks >200 BU, inhibitor titre >10 BU when ITI is started and previously failed ITI. The objective of this study was to identify the effectiveness in ITI of a high purity von Willebrand factor/factor VIII (VWF/FVIII) complex concentrate in inhibitor patients at high risk of failure. Patients with severe or moderate haemophilia A and high responding inhibitors who had at least one poor prognostic factor for ITI failure were prospectively followed-up. Success was defined by undetectable inhibitor, recovery and half life >66% of expected values. ITI dose regimens were chosen by each haemophilia centre. Seventeen haemophiliacs (16 severe, one moderate), aged 4-54 years (median 23) were followed-up for 6-71 months. Poor prognostic factors were delayed-onset ITI (n = 16), age >6 years (n = 16), previously failed ITI (n = 4), inhibitor peak >200 BU (n = 2) and inhibitor >10 BU when ITI was started (n = 4). Complete success was obtained in nine patients (53%) after 4-30 months of treatment (median 24), including two of four patients who had previously failed ITI. Seven patients achieved a partial success, with sustained low inhibitor titres (median 1.5 BU, range 1.1-2.8) but abnormal recovery and/or half-life, while the remaining patient withdrew ITI after 12 months when the inhibitor titer was still 70 BU. These findings suggest that high purity VWF/FVIII complex concentrates are effective in ITI, even in patients at high risk of failure.

BACKGROUND: The Human Epidermal Growth Factor Receptor 2 (HER-2), overexpressed in 25-30% of breast carcinomas (BC), is the therapeutic target for trastuzumab, a recombinant humanized monoclonal antibody. The initial response to trastuzumab is often followed by drug-insensitivity within one year. Several hypotheses have been raised to explain this event, but the mechanisms behind the responses to trastuzumab are still unclear. Aim: To study the effects of short and prolonged trastuzumab treatment on the proteomic profiles of HER-2-overexpressing SKBR-3 BC cells. MATERIALS AND METHODS: Cells were treated with trastuzumab to obtain sensitive and resistant clones. The drug effects were evaluated at the phenotypical and proteomic levels. RESULTS: In the trastuzumab-resistant cells the expression of a large amount of proteins, initially affected by treatment, reverted to levels of the untreated cells. CONCLUSION: The results obtained so far illustrate for the first time a large-scale differential protein expression between trastuzumab-treated and untreated cells, and between trastuzumab-sensitive and resistant cells. We believe that the results obtained will help to increase the knowledge of the molecular effects of trastuzumab and will be useful to better-understand the drug resistance mechanisms.

SummaryThe benefits of prophylaxis of haemophilia A patients regarding joint health and quality-of-life are well established. However, adherence to an up to every-other-day infusion regimen is a barrier to widespread adoption of prophylaxis. BAY 79–4980 is an investigational drug consisting of rFVIII-FS (sucrose-formulated recombinant FVIII) reconstituted with liposome solvent. Previous clinical studies showed extended protection from bleeding after a single injection of BAY 79–4980 (13.3 ± 6.2 days) compared with rFVIII-FS (7.2 ± 1.7 days). The effect of once-a-week prophylaxis with BAY 79–4980 (35 IU/kg) compared with three times-per-week rFVIII-FS (25 IU/kg) in previously treated, severe haemophilia A patients was evaluated in a 52-week, double-blind, two-arm, randomised, controlled study. The primary and secondary endpoints were protection from total bleeds and joint bleeds, respectively. Short- and long-term safety and tolerability of BAY 79–4980 including effects on lipid levels were assessed. A total of 139 and 131 subjects were evaluable for safety and efficacy analyses, respectively. A large difference in efficacy between treatment groups was observed with 72.1% (49/68) in the rFVIII-FS control group demonstrating

influences emanating from the tissue microenvironment, such as cell-cell and cell-matrix interactions and other local pathophysiologic conditions as hypoxia. However the hypoxic effect may be different according to the cell conditions. For example, the low concentration of tissue oxygen (pO2

During the Space Telescope and Optical Reverberation Mapping Project (STORM) observations of NGC 5548, the continuum and emission-line variability became de-correlated during the second half of the 6-month long observing campaign. Here we present Swift and Chandra X-ray spectra of NGC 5548 obtained as a part of the campaign. The Swift spectra show that excess flux (relative to a power-law continuum) in the soft X-ray band appears before the start of the anomalous emission-line behavior, peaks during the period of the anomaly, and then declines. This is a model-independent result suggesting that the soft excess is related to the anomaly. We divide the Swift data into on- and off-anomaly spectra to characterize the soft excess via spectral fitting. The cause of the spectral differences is likely due to a change in the intrinsic spectrum rather than being due to variable obscuration or partial covering. The Chandra spectra have lower signal-to-noise ratios, but are consistent with Swift data. Our preferred model of the soft excess is emission from an optically thick, warm Comptonizing corona, the effective optical depth of which increases during the anomaly. This model simultaneously explains all the three observations: the UV emission line flux decrease, the soft-excess increase, and the emission line anomaly., ApJ in press. Replaced with the accepted version

International audience; Therapeutic plasma exchange (PE) is the accepted therapy for thrombotic thrombocytopenic purpura (TTP). Because not all patients achieve remission, other treatment modalities have been used in addition to PE, but no randomized clinical trial evaluated their efficacy. The aim of this multicentric study was to compare the effectiveness of standard- versus high-dose methylprednisolone as an adjunctive treatment to PE in the acute phase of TTP. Sixty patients with idiopathic TTP were randomized to receive methylprednisolone 1 mg/kg/die intravenous or 10 mg/kg/die for 3 days, thereafter, 2.5 mg/kg/die in addition to PE. Both dosages of steroids were well tolerated. At the end of induction therapy (day 23), the percentage of patients failing to achieve complete remission was significantly higher in the standard dose (16 of 30) than in the high-dose group (seven of 30). Also, the number of cases without a good response at day 9 and the number of deaths were higher in the standard-dose arm, but the differences did not reach the statistical significance. Results of present study indicate that the association of PE with high-dose instead of standard-dose steroids reduces the percentage of TTP patients that fail to achieve complete remission.

von Willebrand disease (VWD) is the most common hereditary bleeding disorder affecting both males and females. It arises from quantitative or qualitative defects of von Willebrand factor (VWF) and causes bleeding of mucous membranes and soft tissues. The aim of treatment is to correct the dual defect of haemostasis caused by the abnormal/reduced VWF and the concomitant deficiency of factor VIII (FVIII).This document contains evidence-based recommendations for the management of VWD compiled by AICE (the Italian Association of Haemophilia Centres). All the evidence supporting these recommendations are based on non-randomised comparative studies or case series, because randomised controlled clinical trials or meta-analyses are not available for this disease.Desmopressin (DDAVP) is the treatment of choice for patients with type 1 VWD with FVIII and VWF levels of 10 U/dL or more, while VWF/FVIII concentrates are indicated for those who are unresponsive or insufficiently responsive to DDAVP (severe type 1, type 2 and 3 VWD). VWF concentrates devoid of FVIII, not yet licensed in Italy, may be considered for short-term prophylaxis in elective surgery or for long-term secondary prophylaxis.

National haemophilia registries are powerful instruments to support health care and research. A national registry was established in Italy by the Ministry of Health until 1999. Since 2003 the Italian Association of Haemophilia Centres (AICE) started a new programme aiming at building up the Italian Registry of Haemophilia and Allied Disorders. The AICE identified an expert panel to steer the registry. A computer software to assist patient management was developed and all the AICE-affiliated haemophilia treatment centres (HTC) were prompted to adopt it. Twice a year a predefined set of anonymized data is centralized and merged into a national database. Duplicated entries are managed through a confidentiality sparing mechanism. The database covers sociodemographic, clinical, laboratory and treatment data. A subset of data are shared with the Ministry of Health (Istituto Superiore di Sanita,ISS).Overall, data were collected six times by 43 of 49 HTC; 41 centres updated their patients' records up to December 2006. The database contains 6632 unique records, 442 of them referring to dead patients. Database growth and missing data clearance showed a constantly positive trend over time. The database has collected records of the following alive patients - haemophilia A: 1364 severe, 398 moderate and 935 mild; haemophilia B: 231 severe, 138 moderate and 204 mild; von Willebrand's disease: 1208 type 1, 346 type 2 and 96 type 3. Inhibitor patients were 296 (of which 194 high responders and 65 low responders).The Italian registry run by AICE adds to the list of the available national haemophilia registries and is intended to establish treatment guidelines and foster research projects in Italy.

Intracranial haemorrhage (ICH) is the most serious bleeding symptom in haemophiliacs, resulting in high rates of mortality and disabling sequelae. The Association of Italian Haemophilia Centres carried out a retrospective survey (1987-2008) of ICH occurring in haemophiliacs with the goals to establish: (i) incidence, location of bleeding, death rate and disabling sequels; (ii) risk factors for ICH; and (iii) treatment used during the acute phase of ICH and for recurrence prevention. A total of 112 ICH episodes had occurred in 88 patients (78 haemophilia A, 10 haemophilia B), 24 of whom experienced recurrences. The cumulative hazard of ICH for the whole cohort over the entire follow-up period was 26.7 per 1000 patients, and the annualized rate of ICH was 2.50 events per 1000 patients (95% CI 1.90-3.31). The risk of ICH was higher in the youngest children (24.4 per 1000, 95% CI 12.7-47.0 in the first year of age and 14.9, 95% CI 7.1-31.4 in the second year of age) and then progressively rose again after the age of 40. Univariate, bivariate (age-adjusted) and multivariate analysis investigating the effects of patient characteristics on ICH occurrence showed that haemophilia severity and inhibitor status were strongly associated with ICH [severe vs. mild, HR 3.96 (2.39-6.57); inhibitor vs. non-inhibitor 2.52 (1.46-4.35)]. HCV infection was also associated with the risk of ICH [HR 1.83 (1.25-2.69)]. Therapeutic suggestions based upon our experience to control ICH recurrence are provided.