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INTRODUCTION: The following is a summary of the official guidelines of the Italian Association for the Study of the Pancreas regarding the medical, endoscopic and surgical management of acute pancreatitis. STATEMENTS: Clinical features together with elevation of the plasma concentrations of pancreatic enzymes are the cornerstones of diagnosis (recommendation A). Contrast-enhanced computed tomography (CT) provides good evidence for the presence of pancreatiti (recommendation C) and it should be carried out 48-72 h after the onset of symptoms in patients with predicted severe pancreatitis. Severity assessment is essential for the selection of the proper initial treatment in the management of acute pancreatitis (recommendation A) and should be done using the APACHE II score, serum C-reactive protein and CT assessment (recommendation C). The etiology of acute pancreatitis should be able to be determined in at least 80% of cases (recommendation B). An adequate volume of intravenous fluid should be administered promptly to correct the volume deficit and maintain basal fluid requirements (recommendation A); analgesia is crucial for the correct treatment of the disease (recommendation A). Enteral feeding is indicated in severe necrotizing pancreatitis and it is better than total parenteral nutrition (recommendation A). The use of prophylactic broad-spectrum antibiotics reduces infection rates in CT-proven necrotizing pancreatitis (recommendation A). Infected pancreatic necrosis in patients with clinical signs and symptoms of sepsis is an indication for intervention, including surgery and radiological drainage (recommendation B). CONCLUSIONS: The participants agreed to revise the guidelines every 3 years in order to re-evaluate each question on the management of acute pancreatitis patients according to the most recent literature.

In two experiments we assessed whether seeing objects automatically activates information regarding how to manipulate them. In Experiment 1 participants categorized photographs of objects that could be manipulated either with a power or a precision grip into artefacts or natural kinds. Target-objects were preceded by primes consisting of photographs of hands in grasping postures (precision or power grip). Experiment 2 involved a preliminary motor training phase in which each visual prime was associated with the actual motor action. In both experiments, natural kinds graspable with a power grip produced the fastest responses. In Experiment 2 we also found a congruency effect between the prime and the kind of grip required by the object (precision, power). Results suggest that visual stimuli automatically activate motor information. Specific motor programs are, however, activated only if motor training is performed before the categorization task. Implications of the results for the understanding of the organization of conceptual and motor information in the brain are discussed. © 2006 Elsevier Ireland Ltd. All rights reserved.

Vascular endothelial growth factor (VEGF) has been shown to play a major role in intraocular neovascularisation in ischaemic retinal diseases. The aim of this study was to evaluate the concentration of VEGF in vitreous, aqueous and epiretinal membranes of diabetic and non-diabetic patients, with other pathological conditions requiring surgical intervention. Higher VEGF concentration were found in samples from the eyes of diabetic patients versus other pathologies as well as in epiretinal membranes versus the other eye compartments in diabetic patients. However, high VEGF levels were also found in retinal detachment and proliferative vitreoretinopathy of non-diabetic patients. We concluded that VEGF is produced locally and plays a fundamental, but not specific, role in diabetic retinal neovascularisation and proliferation.

In four experiments we investigated whether the Simon effect consists of both facilitation and interference. In Experiment 1 subjects had to press one of two lateralized keys in response to one of two stimuli (a rectangle or a square). The stimuli were presented at fixation or to the right or left of it. The stimulus-response mappings could be corresponding (i.e., right key--rectangle or square on the right side), non-corresponding (i.e., right key--rectangle or square on the left side), or neutral (i.e., stimulus in the center). Results showed both facilitation and interference effects, but interference was three times greater than facilitation. To test whether the neutral position was favored by visual acuity, Experiments 2, 3 and 4 used slight different displays where visual acuity was the same at every stimulus position. Results indicated that the Simon effect is comprised of facilitation and interference components of the same magnitude. These findings were discussed with reference to dual-route models of the Simon effect.

An 82-year-old man underwent an endovascular procedure with a commercially available endovascular grail for an anastomotic juxtarenal abdominal aortic aneurysm. The anastomotic aneurysm, which showed no sign of infection, developed 4 years after implantation of an aortic end-to-end graft for an infrarenal aortic aneurysm. The aneurysm was diagnosed during routine ultrasonographic follow-up; there was no apparent infection of the graft. Aortography confirmed the diagnosis and also revealed a small pseudoaneurysm at The level of the distal aortic anastomosis. Endovascular surgery was performed in the operating room with the guidance of C-arm fluoroscopy and intravascular ultrasound. Two Vanguard(TM) Straight Endovascular Aortic Graft Cuffs (26 x 50 mm and 24 x 50 mml were implanted successfully excluding both the anastomotic juxtarenal aortic aneurysm and the distal pseudoaneurysm. The renal arteries were preserved and no early or late endoleaks were observed. The patient was discharged 2 days after the procedure. Sixteen months later, he was alive and well, with no endovascular leakage, no enlargement of the aortic aneurysms, and no sign of infection. In our opinion, this experience shows that commercially available endovascular grafts may be used successfully to treat anastomotic aortic aneurysms and pseudoaneurysms. An 82-year-old man underwent an endovascular procedure with a commercially available endovascular graft for an anastomotic juxtarenal abdominal aortic aneurysm. The anastomotic aneurysm, which showed no sign of infection, developed 4 years after implantation of an aortic end-to-end graft for an infrarenal aortic aneurysm. The aneurysm was diagnosed during routine ultrasonographic follow-up; there was no apparent infection of the graft. Aortography confirmed the diagnosis and also revealed a small pseudoaneurysm at the level of the distal aortic anastomosis. Endovascular surgery was performed in the operating room with the guidance of C-arm fluoroscopy and intravascular ultrasound. Two Vanguard™ Straight Endovascular Aortic Graft Cuffs (26 × 50 mm and 24 × 50 mm) were implanted, successfully excluding both the anastomotic juxtarenal aortic aneurysm and the distal pseudoaneurysm. The renal arteries were preserved and no early or late endoleaks were observed. The patient was discharged 2 days after the procedure. Sixteen months later, he was alive and well, with no endovascular leakage, no enlargement of the aortic aneurysms, and no sign of infection. In our opinion, this experience shows that commercially available endovascular grafts may be used successfully to treat anastomotic aortic aneurysms and pseudoaneurysms.

We investigated whether the Simon effect depends on the orienting of attention. In Experiment 1, participants were required to execute left-right discriminative responses to 2 patterns that were presented to the left or right of fixation. The 2 patterns were similar, and the discrimination was difficult. A letter at fixation signaled whether the current trial was a catch trial. The results showed a reversal of the Simon effect. That is, spatially noncorresponding responses were faster than spatially corresponding responses. In Experiment 2, the discrimination of the relevant stimulus attribute was easy. In Experiment 3, the discrimination of the relevant stimulus attribute was difficult, but the stimulus exposure time was long. In either experiment, the regular Simon effect was reinstated. In Experiment 4, the letter that signaled a catch trial appeared to the left or right of the imperative stimulus. The Simon effect occurred relative to the position of the letter.

We compared the performance of skilled drummers with that of nondrummers and nonmusicians in the Simon and spatial stimulus—response compatibility (SRC) tasks to investigate whether and to what extent spatial performance can be modified by motor behaviors acquired in real life. Drummers were chosen because, compared with other musicians and the general population, their efficient performance depends mainly on the processing of spatial information. Although the Simon effect was equivalent for the three groups, the spatial SRC effect was less pronounced in drummers. The advantage was present even when feet were used as responding effectors, suggesting a central locus of the effect. These results suggest that spatial stimulus—response translations are influenced by real-life motor training, with drummers’ training speeding up the intentional stimulus—response translations when stimulus and response locations are on opposite sides.

Objectives: Melanoma cells take advantage of impaired ability to undergo programmed cell death in response to different external stimuli and chemotherapeutic drugs; this makes prevention of tumour progression very difficult. The aim of this study was to demonstrate whether 3-O-methylfunicone (OMF), a metabolite of Penicillium pinophilum, has the ability to arrest cell population growth and to induce apoptosis in A375P (parental) and A375M (metastasis derivatived) melanoma cell lines. Materials and methods: Cell proliferation and apoptosis were analysed by flow cytometry, DNA fragmentation, caspase-3 and caspase-9 activation, and PARP-1 cleavage. Results: We demonstrated that OMF affected cell proliferation in a time- and dose-dependent manner, reaching the best effect at concentration of 80 g/ml for 24 h. Flow cytometry revealed that OMF caused significant G2 phase arrest, which was associated with marked decrease in cyclin B1/p34cdc2 complex and p21 induction. OMF also induced marked decrease of survivin expression. Reduced levels of apoptosis were evident after silencing p21 expression in both cell lines. Finally, the effect exercised by OMF on hTERT and TEP-1 gene expression confirmed the ability of this molecule to interfere with replicative ability of cells. Conclusions: The results reported here seem to suggest that OMF as a promising molecule to include in strategies for treatment of melanoma. © 2009 Blackwell Publishing Ltd.

In this study we investigated in a Simon-like task whether task-irrelevant spatial information, delivered by centrally presented patterns, interfered with response selection in the same way as laterally presented stimuli. Second, we asked whether such interference was equal for different kinds of stimuli. Participants were required to respond to the colour of two framed squares, two arrows, or two schematic eyes by pressing one of two lateralized response keys. The results consistently show that the Simon effect occurs independently of the nature of the stimulus, as classically reported for lateralized stimuli. Response times were influenced by the direction and frame-relative position of the stimuli, being faster for responses corresponding to the direction indicated by the stimuli than for noncorresponding responses regardless of stimulus types. Contrary to findings with lateralized nondirectional stimuli, such an effect increased with increasing RTs indicating that for centrally presented patterns the extraction of spatial information is time consuming. Spatial location has been demonstrated to be automatically coded with a large variety of stimuli, even in situations in which it is irrelevant to the task to be performed (e.g., Tsal & Lavie, 1993). The effects of irrelevant spatial codes emerge very clearly in the Simon task in which participants are presented with two different lateralized patterns (i.e., placed in the periphery of the visual field) and are required to press the right-side key in response to one pattern, and the left-side key in response to the other (Simon & Rudell, 1967; see Hommel & Prinz, 1997; Lu & Proctor, 1995, for reviews). Even though participants are clearly instructed to select the response exclusively on the basis of the relevant nonspatial stimulus dimension, irrelevant information concerning stimulus location is processed. As a consequence, faster responses are made when the position of the stimulus and the position of the response key are located on the same side (right-right or left-left; i.e., corresponding S-R pairings) compared to when they are positioned differently (stimulus on the right side and response on the left side, or vice versa; i.e., noncorresponding S-R pairings). Recent studies seem to suggest that stimulus position is not the only dimension capable of automatically activating a response spatial code that influences performance. For instance, central arrows have been shown to influence both voluntary (e.g., Posner, 1980) and automatic (e.g., Danziger, Kingston, & Ward, 2001; Eimer, 1997; Hommel, Pratt, Colzato, & Godijn, 2001; Ristic, Friesen, & Kingstone, 2002; Tipples, 2002) orienting of visual attention. Furthermore, it seems well established that centrally presented arrows (i.e., presented at central fixation) can produce the Simon effect (e.g., Masaki, Takasawa, & Yamazaki, 2000). This result is not surprising since arrows are commonly used to convey spatial information and have therefore acquired a directional meaning. Gaze direction is another stimulus shown to deliver spatial information (e.g., Ansorge, 2003b; Zorzi, Mapelli, Rusconi, & Umilta, 2003; Langton & Bruce, 2000). However, not only does it provide the observer with directional spatial information, but it can communicate different types of crucial information such as the focus of attention, interest, emotions, and intentions of others (e.g., Baron-Cohen & Cross, 1994; Emery, 2000). Eye direction is also capable of automatically and reflexively triggering the orienting behaviour of the observer (e.g., Driver et al., 1999; Friesen & Kingstone, 1998; Friesen, Ristic, & Kingstone, 2004; Langton & Bruce, 1999). All this makes gaze direction biologically relevant for survival and the eyes a key social cue for understanding the mind of others (Baron-Cohen, 1995). Recently, Zorzi et al. (2003) showed that the direction of eye-like stimuli elicits a specific spatial code, independent from the stimulus spatial position, which can influence lateralized manual responses. …

Recent evidence assigns integrins and metalloproteinases (MMPs) an important role in regulating tumor cell progression. Here, we demonstrate that 3-O-methylfunicone (OMF), a secondary metabolite produced by Penicillium pinophilum, affects cell proliferation and motility of breast cancer MCF-7 cells, downregulating avb5 integrin, and inhibiting MMP-9 secretion. This effect was absent when the non-tumoral MCF-10 cell line was used. Inhibition of cell motility was also associated to modifications in cell shape and in the distribution of tubulin fibers of OMF-treated MCF- 7 cells. In addition, a possible effect on survivin and hTERT was also investigated. We found that OMF strongly inhibits survivin and hTERT gene expression. The results of this study indicate that OMF-induced inhibition of cell motility may be mediated through the modulation of avb5 integrin and MMP-9secretion. In addition, the inhibition of typical markers of tumor progression such as hTERT and survivin in MCF-7 and their inactivity towards MCF10 provide strong evidence for a potential use of OMF in anticancer therapy Recent evidence assigns integrins and metalloproteinases (MMPs) an important role in regulating tumor cell progression. Here, we demonstrate that 3-O-methylfunicone (OMF), a secondary metabolite produced by Penicillium pinophilum, affects cell proliferation and motility of breast cancer MCF-7 cells, downregulating αvβ5 integrin, and inhibiting MMP-9 secretion. This effect was absent when the non-tumoral MCF-10 cell line was used. Inhibition of cell motility was also associated to modifications in cell shape and in the distribution of tubulin fibers of OMF-treated MCF-7 cells. In addition, a possible effect on survivin and hTERT was also investigated. We found that OMF strongly inhibits survivin and hTERT gene expression. The results of this study indicate that OMF-induced inhibition of cell motility may be mediated through the modulation of αvβ5 integrin and MMP-9 secretion. In addition, the inhibition of typical markers of tumor progression such as hTERT and survivin in MCF-7 and their inactivity towards MCF10 provide strong evidence for a potential use of OMF in anticancer therapy. © 2007 Wiley-Liss, Inc.

Oesophageal neoplasm; Oligometastasis; Radiosurgery Neoplàsia esofàgica; Oligometàstasi; Radiocirurgia Neoplasia esofágica; Oligometástasis; Radiocirugía Background Consensus about the definition and treatment of oligometastatic oesophagogastric cancer is lacking. Objective To assess the definition and treatment of oligometastatic oesophagogastric cancer across multidisciplinary tumour boards (MDTs) in Europe. Material and methods European expert centers (n = 49) were requested to discuss 15 real-life cases in their MDT with at least a medical, surgical, and radiation oncologist present. The cases varied in terms of location and number of metastases, histology, timing of detection (i.e. synchronous versus metachronous), primary tumour treatment status, and response to systemic therapy. The primary outcome was the agreement in the definition of oligometastatic disease at diagnosis and after systemic therapy. The secondary outcome was the agreement in treatment strategies. Treatment strategies for oligometastatic disease were categorised into upfront local treatment (i.e. metastasectomy or stereotactic radiotherapy), systemic therapy followed by restaging to consider local treatment or systemic therapy alone. The agreement across MDTs was scored to be either absent/poor (

3‐O‐Methylfunicone (OMF) is a secondary metabolite produced by the soil fungus Penicillium pinophilum which has cytostatic properties. The aim of this study was to investigate the mechanisms by which such properties are exerted, with special reference to any anti‐proliferative and apoptotic potential, on HeLa cells. OMF treatment caused about 44% inhibition of cell growth after 24 h, and modifications in the tubulin fibre organization. In addition, a significant increase in p21 mRNA expression and a decrease in cyclin D1 and Cdk4 mRNA expression resulted at the same time. Apoptosis induction was demonstrated by the annexin V assay, cytofluorimetric analysis of the DNA content of the sub‐G(1) fraction and DNA laddering. Taken together, our data showed that the compound inhibits proliferation of HeLa cells by several mechanisms, such as disruption of tubulin fibres, cell cycle arrest and apoptosis induction. The capacity of the compound to affect the cell cycle and to modulate apoptosis is indicative of a potential for the development of a new agent for cancer chemotherapy.

To program proper reactions, athletes must anticipate opponents’ actions on the basis of previous visuomotor experience. In particular, such abilities seem to rely on processing others’ intentions to act. We adopted a new approach based on an attentional spatial compatibility paradigm to investigate how elite volleyball players elaborate both spatial and motor information at upper-limb posture presentation. Forty-two participants (18 volleyball players and 17 nonathlete controls assigned to Experiments 1 a and b, and eight basketball players assigned to Experiment 2) were tested to study their ability to process the intentions to act conveyed by hands and extract motor primitives (i.e., significant components of body movements). Analysis looked for a spatial compatibility effect between direction of the spike action (correspondence factor) and response side for both palm and back of the hand (view factor). We demonstrated that volleyball players encoded spatial sport-related indices from bodily information and showed preparatory motor activation according to the direction of the implied spike actions for the palm view (Experiment 1, hand simulating a cross-court spike, p = 0.013, and a down-the-line spike, p = 0.026) but both nonathlete controls (Experiment 1, both p &lt, 0.05) and other sports athletes (basketball players, Experiment 2, p = 0.34, only cross-court spike) did not. Results confirm that elite players’ supremacy lies in the predictive abilities of coding elementary motor primitives for their sport discipline.

The Simon effect refers to the fact that, even though stimulus position is task-irrelevant, responses to a task-relevant stimulus dimension are faster and more accurate when the stimulus and response spatially correspond than when they do not. Although the Simon effect is a very robust phenomenon, it is modulated by practice or transfer from previous tasks. Practice refers to the modulation of the Simon effect as a function of number of trials. Transfer refers to the modulation of the Simon effect as a function of preceding tasks. The aim of the present study is to disentangle the role of practice and transfer in modulating the Simon effect and to investigate whether such modulation can be extended to a different response modality. Three experiments were conducted, which included three sessions: the Baseline session, the Inducer session and the Diagnostic session. The task performed in the Baseline and the Diagnostic sessions were comprised of location-irrelevant trials (i.e., they were Simon tasks). The task performed in the Inducer session required performing location-relevant trials (i.e., it was a spatial compatibility task with a compatible or an incompatible stimulus–response mapping). In the first and third experiments, participants were required to respond manually in all sessions. In the second experiment, the task performed in the Inducer session required manual response, while in the Baseline and Diagnostic sessions the tasks required ocular response. Results showed a reduced-Diagnostic Simon effect after both compatible and incompatible mapping in the Inducer session, regardless of whether response modality was the same or different. These results support the notion that the practice effect prevails over the transfer effect.

Objectives During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, dramatic endothelial cell damage with pulmonary microvascular thrombosis have been was hypothesized to occur. The aim was to assess whether pulmonary vascular thrombosis (PVT) is due to recurrent thromboembolism from peripheral deep vein thrombosis or to local inflammatory endothelial damage, with a superimposed thrombotic late complication. Design Observational study. Setting Medical and intensive care unit wards of a teaching hospital. Participants The authors report a subset of patients included in a prospective institutional study (CovidBiob study) with clinical suspicion of pulmonary vascular thromboembolism. Interventions Computed tomography pulmonary angiography and evaluation of laboratory markers and coagulation profile. Measurements and Main Results Twenty-eight of 55 (50.9%) patients showed PVT, with a median time interval from symptom onset of 17.5 days. Simultaneous multiple PVTs were identified in 22 patients, with bilateral involvement in 16, mostly affecting segmental/subsegmental pulmonary artery branches (67.8% and 96.4%). Patients with PVT had significantly higher ground glass opacity areas (31.7% [22.9-41] v 17.8% [10.8-22.1], p < 0.001) compared with those without PVT. Remarkably, in all 28 patients, ground glass opacities areas and PVT had an almost perfect spatial overlap. D-dimer level at hospital admission was predictive of PVT. Conclusions The findings identified a specific radiologic pattern of coronavirus disease 2019 (COVID-19) pneumonia with a unique spatial distribution of PVT overlapping areas of ground-glass opacities. These findings supported the hypothesis of a pathogenetic relationship between COVID-19 lung inflammation and PVT and challenged the previous definition of pulmonary embolism associated with COVID-19 pneumonia., Graphical abstract Computed Tomography Pulmonary Angiography (CTPA) imaging demonstrating, in three different clinical scenarios, eventual filling defects in branches of the pulmonary arteries (white arrows) and their spatial distribution according to the corresponding ventilation maps (white asterisks indicate normal lung parenchyma). In (a) [non COVID-19 pneumonia] and (c) [non COVID-19 ARDS] filling defects are electively found in the branches of the pulmonary arteries accountable for the vascularization of healthy lung segments. On the contrary, in (b) [COVID-19 pneumonia] there is an almost perfect topographical overlap between filling defects distribution and pneumonia extent.Image, graphical abstract

In the present study, we examined the pupillary response of White participants who were asked to tell the truth or lie to White or Black partners. Research on cues to deception has assumed that lying is more cognitively demanding that truth telling. In line with this assumption, previous studies have shown that lying is associated with greater pupil dilation, a behavioral cue that typically manifests itself under conditions of stress or cognitive effort. In accordance with these results, we predicted greater pupil dilation when lying than when telling the truth. Furthermore, pupil dilation was expected to be greater when responding to White than Black partners. Finally, we hypothesized that pupil dilation would be greater when lying to White than Black partners. Participants were instructed to answer a set of questions, half truthfully and half deceptively. They were led to believe that White vs. Black partners (one male and one female) would ask the questions via computer connection. Indeed, we used feminine and masculine synthetic voices. Pupil dilation was assessed with a remote eye-tracking system. Results provided support for the first two hypotheses. However, the predicted interaction between race of partners and truth status of message (lying vs. telling the truth) was nonsignificant. Our findings highlight the importance of considering race in the study of truthful and deceptive communications.

Number processing induces spatial attention shifts to the left or right side for small or large numbers, respectively. This spatial-numerical association (SNA) extends to mental calculation, such that subtractions and additions induce left or right biases, respectively. However, the time course of activating SNAs during mental calculation is unclear. Here, we addressed this issue by measuring visual position discrimination during auditory calculation. Thirty-four healthy adults listened in each trial to five successive elements of arithmetic facts (first operand, operator, second operand, equal and result) and verbally classified their correctness. After each element (except for the result), a fixation dot moved equally often to either the left or right side and participants pressed left or right buttons to discriminate its movement direction (four times per trial). First and second operand magnitude (small/large), operation (addition/subtraction), result correctness (right/wrong) and movement direction (left/right) were balanced across 128 trials. Manual reaction times of dot movement discriminations were considered in relation to previous arithmetic elements. We found no evidence of early attentional shifts after first operand and operator presentation. Discrimination performance was modulated consistent with SNAs after the second operand, suggesting that attentional shifts occur once there is access to all elements necessary to complete an arithmetic operation. Such late-occurring attention shifts may reflect a combination of multiple element-specific biases and confirm their functional role in mental calculation.

Purpose: Leakage of the gastric remnant after laparoscopic sleeve gastrectomy (LSG) represents an unpredictable, dreadful occurrence. Our aim was to assess whether routine postoperative CT scan is an effective tool for early prediction of leakage after LSG. Materials and Methods: From a prospectively acquired database, all consecutive patients who underwent LSG between January 2015 and December 2018 were identified; within this database, all patients who were evaluated with at least one contrast-enhanced CT scan within 48h from surgery were enrolled in this retrospective study. The selected CT findings included twisting of the gastric remnant, perigastric air bubbles, and hematoma; the antral segment proximal from the pylorus to the first staple firing was also analyzed in terms of distance (StP, stapler to pylorus distance) and linearity (LI, linearity index). Results: After exclusions, 250 patients were included; 10 patients suffered from gastric leakage. Patients with perigastric hematoma and/or twisting of the distal part of the gastric remnant on routine postoperative CT scan were found to be more likely to develop leakage after LSG (p= 0.005 and p< 0.001, respectively). The mean StP was 45 ± 19.1mm; the mean LI was 1.54 ± 0.4. Patients with subsequent development of leakage had significantly lower StP (26.7 ± 12.5mm vs. 45.9 ± 18.9mm; p= 0.001) and LI values (1.16 ± 0.11 vs. 1.55 ± 0.39; p= 0.002). Conclusion: Routine postoperative CT scan after LSG permits early stratification of leakage risk, thus providing an actual aid for patients’ management.

Previous research has shown an effect of handle-response correspondence on key-press responses when participants judged the upright or inverted orientation of photographed one-handled graspable objects. In three experiments, we explored whether this effect still holds for symmetric graspable objects that are usually grasped by two hands (i.e. two-handled objects; e.g. shears). In Experiments 1 and 2, participants were required to perform a between-hand response in order to categorize cooking or amusement objects appearing as grasped from either an allocentric (Experiment 1) or an egocentric perspective (Experiment 2). In Experiment 3, they were required to perform a within-hand response to categorize the same stimuli appearing as grasped from an egocentric perspective. Across all three experiments, results showed that categorization was more difficult when the objects were displayed as grasped on the opposite side than the response rather than on the same side. We discuss the implications of these results for theories of action potentiation and spatial coding and suggest that different mechanisms may be recruited depending on the required action (i.e. response mode).

Summary Background Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. Methods This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18–75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m 2 , nab-paclitaxel 150 mg/m 2 , and gemcitabine 800 mg/m 2 on days 1 and 15 and oral capecitabine 1250 mg/m 2 on days 1–28 every 4 weeks), or nab-paclitaxel and gemcitabine alone (nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 on days 1, 8, and 15 every 4 weeks). The primary endpoint was the proportion of patients who were progression-free at 6 months, analysed in the intention-to-treat population. Data cutoff was on March 31, 2018. The safety population included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01730222, and is now closed. Findings Between April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58–86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31–63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group. Interpretation Despite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma. Funding Celgene.

Boosted by the general aim of exploiting the biotechnological potential of the microbial component of biodiversity, research on the secondary metabolite production of endophytic fungi has remarkably increased in the past few decades. Novel compounds and bioactivities have resulted from this work, which has stimulated a more thorough consideration of various natural ecosystems as conducive contexts for the discovery of new drugs. Thriving at the frontier between land and sea, mangrove forests represent one of the most valuable areas in this respect. The present paper offers a review of the research on the characterization and biological activities of secondary metabolites from manglicolous strains of species belonging to the genus Talaromyces. Aspects concerning the opportunity for a more reliable identification of this biological material in the light of recent taxonomic revisions are also discussed.

In microbial cultures the production of secondary metabolites is affected by experimental conditions, and the discovery of novel compounds is often prevented by the re-isolation of known metabolites. To limit this, it is possible to cultivate microorganisms by simulating naturally occurring interactions, where microbes co-exist in complex communities. In this work, co-culturing experiments of the biocontrol agent Trichoderma harzianum M10 and the endophyte Talaromyces pinophilus F36CF have been performed to elicit the expression of genes which are not transcribed in standard laboratory assays. Metabolomic analysis revealed that the co-culture induced the accumulation of siderophores for both fungi, while production of M10 harzianic and iso-harzianic acids was not affected by F36CF. Conversely, metabolites of the latter strain, 3-O-methylfunicone and herquline B, were less abundant when M10 was present. A novel compound, hereby named harziaphilic acid, was isolated from fungal co-cultures, and fully characterized. Moreover, harzianic and harziaphilic acids did not affect viability of colorectal cancer and healthy colonic epithelial cells, but selectively reduced cancer cell proliferation. Our results demonstrated that the co-cultivation of plant beneficial fungi may represent an effective strategy to modulate the production of bioactive metabolites and possibly identify novel compounds.

Patients with borderline (BL) or locally advanced (LA) pancreatic adenocarcinoma are usually treated with primary chemotherapy (CT), followed by resection when feasible. Scanty data are available about the criteria to candidate patients to resection after CT.Between 2002 and 2016 overall 223 patients diagnosed with BL or LA pancreatic adenocarcinoma were primarily treated with Gemcitabine combination (4-drugs or nab-paclitaxel-gemcitabine) for 3-6 months followed by surgery and/or chemoradiation. Resection was carried out when radical resection could be predicted by imaging studies and intraoperative findings. The prognostic value of both pre-treatment factors and treatment response was retrospectively evaluated, searching for criteria that could improve the selection of patients for surgery.Median survival (MS) for the whole population was 18.3 months. Surgical resection was carried out in 61 patients; MS in resected patients was significantly longer (30.0 months) as compared with 162 non-resected patients (16.5 months) (P 0.00001). According to response criteria, 48% had a radiological partial response, 47% a stable disease and 5% a disease progression); CA19.9 response (reduction 50%) was obtained in 77.8% of patients. Among resected patients, neither pre-treatment factors, including BL/LA distinction, nor radiological response, were able to prognosticate survival differences. Survival of resected patients having no CA19.9 response was significantly lower as compared with responders (MS 15.0 versus 31.5 months, P = 0.04), and was similar to non-responders patients that did not undergo resection (MS 10.9 months, P= 0.25). Multivariate analysis carried out on the overall population, showed that Karnofsky performance status, T3-T4 status, resection and CA19.9 response were independent prognostic factors, while radiological response, BL/LA distinction and baseline CA19.9 had not significant influence on survival.CA19.9 response may allow a better selection of patients who will benefit from resection after primary CT for BL or LA pancreatic adenocarcinoma.

Background New therapies are needed for pancreatic cancer. Objective To determine the feasibility and safety of a new endoscopic treatment. Secondary endpoints were to determine effects on tumor growth measured with CT scan and to find the overall survival. Design A cohort study of patients with local progression of advanced pancreatic adenocarcinoma after neoadjuvant therapy. The cryotherm probe (CTP), a flexible bipolar device that combines radiofrequency with cryogenic cooling, was used under EUS guidance. Setting San Raffaele Hospital, Milan, Italy; University Medical Center, Hamburg-Eppendorf, Germany. Patients A total of 22 patients (male/female 11/11; mean age 61.9 years) were enrolled from September 2009 to May 2011. Intervention Radiofrequency heating: 18 W; pressure for cooling: 650 psi (Pounds per Square Inch); application time: depending on tumor size. Main Outcome Measurements Feasibility was evaluated during the procedure. A clinical and radiologic follow-up was planned. Results The CTP was successfully applied in 16 patients (72.8%); in 6 it was not possible because of stiffness of the GI wall and of the tumor. Amylase arose in 3 of 16 patients; none had clinical signs of pancreatitis. Late complications arose in 4 cases: 3 were mostly related to tumor progression. Median postablation survival time was 6 months. A CT scan was performed in all patients, but only in 6 of 16 was it possible to clearly define the tumor margins after ablation. In these patients, the tumor appeared smaller compared with the initial mass (P = .07). Limitations Small sample of patients, difficulty of objectifying the size of the ablated zone by CT scan. Conclusion EUS-guided CTP ablation is feasible and safe. Further investigations are needed to demonstrate progression-free survival and local control.

Scientific reports 6, 21706 (2016). doi:10.1038/srep21706, Published by Nature Publishing Group, London

Background: Nab-paclitaxel-gemcitabine combination significantly improved overall survival over gemcitabine in metastatic pancreatic adenocarcinoma. A phase 1b trial was performed (ClinicalTrials.gov number, NCT01730222) to determine the recommended phase 2 dose (RP2D) of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine at fixed dose (800, 30, and 1250 mg m(-2) every 2 weeks, respectively; PAXG regimen). Methods: Nab-paclitaxel doses were escalated from 100 (level one) to 125 (level two) and 150 mg m(-2) (level three) every 2 weeks in cohorts of 3-6 patients with pathologically confirmed unresectable or borderline resectable pancreatic adenocarcinoma. Results: Between Dec 2012 and Apr 2014, 24 patients were enroled (3 at level one, 5 at level two, 16 at level three) and received 117 cycles of PAXG. No dose-limiting toxicity occurred and level three was the RP2D. At this dose, nab-paclitaxel dose-intensity was 91%. Worse per patient grade 3/4 toxicity were neutropenia 25/31%; fatigue 19%; anaemia and hand-foot syndrome 12%, nausea 6%, and febrile neutropenia 6%. A partial response (PR) was observed in 16 (67%) and stable disease (SD) in 8 patients (33%). Among 21 patients with a baseline positive positron emission tomography (PET) scan, a complete metabolic response was observed in 9 (43%), PR in 10 (48%), SD in 2. CA19-9 decreased by >= 49% in all the 19 patients with elevated basal value. Six patients were resected after chemotherapy. Progression-free survival at 6 months (PFS-6) was 96%. Conclusions: The RP2D of nab-paclitaxel in the PAXG regimen was 150 mg m(-2) every 2 weeks. The preliminary results are promising and warrant further exploration. ZB 0 Z8 0 ZR 0 ZS 0

Background The aim of this study was to prospectively compare the diagnostic performance of magnetic resonance imaging (MRI), multidetector computed tomography (MDCT) and endoscopic ultrasonography (EUS) in the preoperative locoregional staging of gastric cancer. Methods This study had Institutional Review Board approval, and informed consent was obtained from all patients. Fifty-two patients with biopsy-proven gastric cancer underwent preoperative 1.5-T MRI, 64-channel MDCT and EUS. All images were analysed blind, and the results were compared with histopathological findings according to the seventh edition of the TNM classification. After the population had been divided on the basis of the local invasion (T1-3 vs T4a-b) and nodal involvement (N0 vs N+), sensitivity, specificity, positive and negative predictive value, and accuracy were calculated and diagnostic performance measures were assessed using the McNemar test. Results For T staging, EUS showed higher sensitivity (94 %) than MDCT and MRI (65 and 76 %; p = 0.02 and p = 0.08). MDCT and MRI had significantly higher specificity (91 and 89 %) than EUS (60 %) (p = 0.0009 and p = 0.003). Adding MRI to MDCT or EUS did not result in significant differences for sensitivity. For N staging, EUS showed higher sensitivity (92 %) than MRI and MDCT (69 and 73 %; p = 0.01 and p = 0.02). MDCT showed better specificity (81 %) than EUS and MRI (58 and 73 %; p = 0.03 and p = 0.15). Conclusions Our prospective study confirmed the leading role of EUS and MDCT in the staging of gastric cancer and did not prove, at present, the value of the clinical use of MRI.

There is evidence suggesting that viewing hands triggers automatic access to the Body Structural Description, a visual-spatial representation of human body parts configuration. Hands, however, have a special representational status within the brain because of their significance for action and cognition. We tested whether feet, less important in gestural and object-directed action, would similarly show automatic access to the Body Structural Description. Positive evidence of that would be finding a Sidedness effect (Ottoboni et al. J Exp Psychol Hum Percept Perform 31:778–789, 2005), a Simon-like paradigm previously used to study automatic hand recognition. This effect demonstrates that processing hands generates spatial codes corresponding to the side of the body on which the hand would be located within the Body Structural Description map. Feet were shown with toes pointing upwards (Experiment 1), without any connection to the ankle and the leg (Experiment 2) and with toes pointing downwards (Experiment 3). Results revealed a Sidedness effect in both Experiments 1 and 3: spatial compatibility occurred according to the side of the body that each foot would assume within the Body Structural Description. In Experiment 2, as already found in stimuli similarly featured, no effect emerged, due to the lack of the necessary anatomical links connecting the foot to a body. Results suggest that body parts with variable degrees of significance for action and cognition can access automatically the Body Structural Description hence reinforcing the hypothesis of its pure visuo-spatial nature.

A variety of studies have shown action- and object-related visuo-motor priming in behavioural tasks. The peculiarity of this study lies in using a hand-cued line bisection task to explore the main properties of the motor effects evoked by action and object processing. In five experiments it is shown that flanking a line (thin vs. thick line) with images of hands (biological vs. non-biological hand) representing different actions (power vs. precision grip) biases performance towards the action more compatible with the object (power grip - thick line, precision grip - thin line). This effect is larger for the precision grip than for the power grip suggesting a functional rather than manipulative activation. In addition, the effect is larger for the biological than for the non-biological hand. We suggest that this paradigm could be potentially useful for neuropsychological studies as well as for addressing unsolved issues of embodied theories of cognition.

Background: At the time of upfront treatment failure, over half of the patients with advanced pancreatic cancer are candidates for further treatment. Methods: Patients with metastatic gemcitabine-resistant pancreatic cancer were treated with mitomycin 8 mg/m2 on day 1, ifosfamide 2,500 mg/m2 and mesna 3,000 mg/m2 on days 1–3 every 28 days until progressive disease. A positive responder was defined as a patient who was progression free at 6 months from trial enrolment. According to the Fleming design, a sample size of 34 patients was estimated assuming p0 = 0.05 and p1 = 0.20. Results: Between May 2006 and December 2007, 21 patients (median age 56 years; median Karnofsky performance score 80) were enrolled. One patient died before receiving any treatment. Eighteen patients interrupted chemotherapy due to progressive disease (n = 15), toxicity (n = 2) or refusal (n = 1). Grade >2 toxicity consisted of neutropenia in 80% of patients, thrombocytopenia and fatigue in 20% and anemia in 10%. Only 1 patient was progression free at 6 months (5%). One patient had a partial response (5%) and 2 patients had stable disease (10%). Median survival was 3.7 months. Conclusion: Based on the poor outcome observed and on the high level of grade 3–4 toxicity, the trial was prematurely stopped and the mitomycin and ifosfamide regimen was considered insufficiently active in gemcitabine-pretreated advanced pancreatic cancer.

Objective Celiac artery compression syndrome (CACS) is an unusual condition caused by abnormally low insertion of the median fibrous arcuate ligament and muscular diaphragmatic fiber resulting in luminal narrowing of the celiac trunk. Surgical treatment is the release of the extrinsic compression by division of the median arcuate ligament overlying the celiac axis and skeletonization of the aorta and celiac trunk. The laparoscopic approach has been recently reported for single cases. Percutaneous transluminal angioplasty (PTA) and stenting of the CA alone, before or after the surgical relief of external compression to the celiac axis, has also been used. We report our 7-year experience with the laparoscopic management of CACS caused by the median arcuate ligament. Methods Between July 2001 and May 2008, 16 patients (5 men; mean age, 52 years) were treated. Diagnosis was made by duplex ultrasound scan and angiogram (computed tomography [CT] or magnetic resonance). The mean body mass index of the patients was 21.2 kg/m 2 . One patient underwent laparoscopic surgery after failure of PTA and stenting of the CA, and two patients after a stenting attempt failed. Results All procedural steps were laparoscopically completed, and the celiac trunk was skeletonized. The laparoscopic procedures lasted a mean of 90 minutes. Two cases were converted to open surgery for bleeding at the end of the operation when high energies were used. The postoperative course was uneventful. Mean postoperative hospital stay was 3 days. On follow-up, 14 patients remained asymptomatic, with postoperative CT angiogram showing no residual stenosis of the celiac trunk. One patient had restenosis and underwent aortoceliac artery bypass grafting after 3 months. Another patient had PTA and stenting 2 months after laparoscopic operation. All patients reported complete resolution of symptoms at a mean follow-up of 28.3 months. Conclusions The laparoscopic approach to CACS appears to be feasible, safe, and successful, if performed by experienced laparoscopic surgeons. PTA and stenting resulted in a valid complementary procedure only when performed after the release of the extrinsic compression on the CA. Additional patients with longer follow-up are needed.

The aim of this study was to assess the maximum tolerated dose (MTD) of an intensified PEFG regimen administered every 14 days to patients with Stage III or metastatic pancreatic adenocarcinoma. Twenty-nine patients received fixed doses of both epirubicin (30 mg/m(2)) and 5-fluorouracil (200 mg/m(2)/day on Days 1-14) and of escalating doses of cisplatin and gemcitabine. The MTD was cisplatin 30 mg/m(2) and gemcitabine 800 mg/m(2). With respect to classical PEFG, intensified regimen potentially improved the dose-intensity of both cisplatin and epirubicin by 50 percent and of gemcitabine by 33 percent, reduced Grade 3-4 haematological toxicity and the number of outpatient accesses.

Limited information on salvage treatment in patients affected by pancreatic cancer is available. At failure, about half of the patients present good performance status ( PS) and are candidate for further treatment. Patients > 18 years, PS >= 50, with metastatic pancreatic adenocarcinoma previously treated with gemcitabine- containing chemotherapy, and progression- free survival ( PFS) < 12 months received a combination of raltitrexed ( 3 mgm (-2)) and oxaliplatin ( 130 mgm (-2)) every 3 weeks until progression, toxicity, or a maximum of six cycles. A total of 41 patients received 137 cycles of chemotherapy. Dose intensity for both drugs was 92% of the intended dose. Main grade 42 toxicity was: neutropenia in five patients ( 12%), thrombocytopenia, liver and vomiting in three ( 7%), fatigue in two ( 5%). In total, 10 patients ( 24%) yielded a partial response, 11 a stable disease. Progression- free survival at 6 months was 14.6%. Median survival was 5.2 months. Survival was significantly longer in patients with previous PFS 46 months and in patients without pancreatic localisation. A clinically relevant improvement of quality of life was observed in numerous domains. Raltitrexed oxaliplatin regimen may constitute a treatment opportunity in gemcitabine- resistant metastatic pancreatic cancer. Previous PFS interval may allow the identification of patients who are more likely to benefit from salvage treatment.

Myrtucommulones are acylphloroglucinol compounds reported from myrtle (Myrtus communis) and a few more plant species belonging in the Myrtaceae that have recently attracted the attention of pharmacologists for their anti-oxidant, anti-inflammatory and anti-tumor properties. An endophytic strain of Neofusicoccum australe recovered from a myrtle branch was selected based on the bioactivity of its culture extracts, and found to produce myrtucommulones A and D. A mixture of these compounds induced anti-proliferative effects on the human prostatic cancer cell lines DU145 and PC3, with a IC₅₀ of respectively 4.64 and 3.11 mg/l. Along the lines of recent evidences of the ability by endophytic fungi to produce bioactive compounds originally extracted from their host plants, this is the first report of myrtucommulones as secondary metabolites of an endophytic fungal strain. The availability of a microbial strain to be cultured in vitro may provide access to more substantial amounts of these products for further investigations in view of their possible pharmaceutical use.

In a series of five experiments we investigated whether observers could focus attention on a restricted visual area that was demarcated by Kanizsa-like subjective contours, and whether this effect also occurred in the case of overlapping figures. The task was a simple reaction time to a luminance increment and the basic finding was that reaction time was faster when the imperative stimulus fell inside the focus of attention than when it fell outside. The first two experiments showed that the extent of the attentional focus could be adapted to a region that was demarcated by subjective contours, thus extending the results of previous studies that used regions demarcated by real contours. The last three experiments showed that, regardless of the type of margins, focusing was more efficient for the figure that was perceived as lying in front in a pair of overlapping figures.

A variety of studies showed that participants are facilitated when responding to graspable objects, while it has not been fully investigated what happens during interactions with graspable objects that are potentially dangerous. The present study focuses on the mechanisms underlying the processing of dangerous objects. In two experiments, we adopted a paradigm that has never been employed in this context, a bisection task. The line was flanked by objects belonging to different categories. We explored the sensitivity to the distinction between neutral and dangerous objects, by measuring whether the performance was biased toward a specific object category. In Experiment 1 both teenagers and adults bisected lines flanked by dangerous and neutral graspable objects, and they misperceived the line midpoint toward the neutral graspable object or, stated differently, on the opposite side of the dangerous graspable object. In Experiment 2 adults bisected lines flanked by dangerous and neutral objects matched on graspability (both graspable and ungraspable, Experiment 2a), or by graspable and ungraspable objects matched on dangerousness (both neutral and dangerous, Experiment 2b). Results confirmed the finding of Experiment 1, but also indicated that participants misperceived the line midpoint toward the ungraspable object when it was presented, being it dangerous or not. This evidence demonstrated sensitivity to object dangerousness maintained across lifespan. The emergence of aversive affordances evoked by dangerous graspable objects strenghtens the importance to consider graspability in the investigation of dangerous objects. Possible neural mechanisms involved in the processing of dangerous graspable objects are discussed.

We investigated whether and how comprehending sentences that describe a social context influences our motor behaviour. Our stimuli were sentences that referred to objects having different connotations (e.g., attractive/ugly vs. smooth/prickly) and that could be directed towards the self or towards “another person” target (e.g., “The object is ugly/smooth. Bring it to you/Give it to another person”). Participants judged whether each sentence was sensible or non-sensible by moving the mouse towards or away from their body. Mouse movements were analysed according to behavioral and kinematics parameters. In order to enhance the social meaning of the linguistic stimuli, participants performed the task either individually (Individual condition) or in a social setting, in co-presence with the experimenter. The experimenter could either act as a mere observer (Social condition) or as a confederate, interacting with participants in an off-line modality at the end of task execution (Joint condition). Results indicated that the different roles taken by the experimenter affected motor behaviour and are discussed within an embodied approach to language processing and joint actions.

Several studies suggest that numerical and spatial representations are intrinsically linked. Recent findings demonstrate that also motor actions interact with number magnitude processing, showing a motor-to-semantic effect. The current study assesses whether calculation processes can be modulated by motions performed with the whole body. Participants were required to make additions or subtractions while performing (on-line condition) or after having experienced (off-line condition) an ascending or descending motion through a passive (i.e., taking the elevator) or an active (i.e., taking the stairs) mode. Results show a congruency effect between the type of calculation and the direction of the motion depending on: a) the off-line or on-line condition, b) the passive or active mode and c) the real or imagined task. Implications of the results for an embodied and grounded perspective view will be discussed.

To the Editor: Chronic granulomatous disease (CGD) is a rare genetic disease caused by defects in genes encoding the subunits of the nicotinamide adenine dinucleotide phosphate oxidase complex.1 Accordingly, patients with CGD are affected by life-threatening bacterial and fungal infections, as well as extensive tissue granuloma formation. Most frequently, CGD is caused by mutations in the X-chromosomal CYBB gene, which encodes for the gp91phox subunit.2 X-chromosome–linked CGD (X-CGD) generally produces a severe phenotype, with a mortality rate of 3% to 5% per year despite state-of-the-art prophylaxis and intensive multimodal treatment.3 Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with X-CGD with excellent survival thanks to recent improvements in HSCT protocols.4 The treatment of patients without an HLA-matched donor and active infections/inflammatory complications remains challenging and requires novel approaches.5 Recently, pioglitazone, a peroxisome proliferator–activated receptor gamma agonist approved for type 2 diabetes, was reported in this journal to induce mitochondrial (mt) reactive oxygen species (ROS) production in mice with X-CGD. Restored phagocytes demonstrated significantly enhanced killing of Staphylococcus aureus in vitro and in vivo.6 We report, for the first time, the use of pioglitazone as a novel therapeutic approach in a 5-month-old boy with X-CGD experiencing multiple severe infections. At 1 month of life, the patient developed a cutaneous abscess, fever, and respiratory distress requiring artificial ventilation in pediatric intensive care unit. During the hospitalization, he developed 3 septic shocks, secondary to a peritonsillar abscess, Candida albicans, and Staphylococcus epidermidis dissemination, respectively. Thoracic computed tomography scan showed multiple pulmonary abscesses (Fig 1, A). Because of the susceptibility to severe infections with organ damage and failure to thrive, he was investigated for a potential congenital immunodeficiency. Dihydrorhodamine (DHR) fluorescence showed impaired response in his peripheral blood and a mutation of the CYBB gene was identified (c.483+1G>T). This mutation, in literature, is associated with a X-linked CGD form with undetectable level of gp91phox protein.7 Fig 1 Chest computed tomography scan before (A) and after (B) pioglitazone treatment. Fig 1, A, Large left pulmonary consolidation involving the inferior lobe and, partly, the dorsal and lingular segments of the superior lobe, with multiple internal air bronchograms: ... Because of the underlying general conditions of the patient with persistent pulmonary distress requiring protracted noninvasive ventilation, severe delay in neuromuscular development, and failure to thrive, HSCT was postponed despite availability of an HLA-identical sibling. Encouraged by the innovative findings on the effect of pioglitazone on ROS production and consequent protection from infection in vitro in human cells and in vivo in an animal model,6 we sought to investigate, for the first time to our knowledge in children, the potential beneficial effect of oral pioglitazone. After parent informed consent for off-label use, pioglitazone was administered at a starting dose of 1 mg/kg and given the absence of adverse effects was progressively increased up to 3 mg/kg (15 mg/daily). After 10 days of pioglitazone at target dose (3 mg/kg), the DHR test showed a percentage of granulocytes with increased DHR fluorescence (bright fluorescent cells = 12.90%; value before treatment 0.06%; Fig 2, A and B), albeit at a lower mean fluorescence intensity than normal donor cells. This effect was maintained in the following weeks until withdrawal (day+30), although at a lower level (day+17, 7.55%; day+25, 4.86%). Moreover, an overall shift in DHR of the whole population of patient's granulocytes was noted after pioglitazone treatment (for details, see Table E1 in this article's Online Repository at www.jacionline.org). Fig 2 DHR fluorescence after stimulation with the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), before and after pioglitazone treatment for the patient (PT) and a healthy donor (HD). DHR analysis was performed on granulocytes by Phagoburts ... These findings paralleled well with clinical, radiological, and blood parameters. The patient experienced a progressive improvement in general clinical condition, respiratory parameters, and function with stable oxygen saturation under neurally adjusted ventilatory assist-noninvasive ventilation. Lung computed tomography scan performed on the day of pioglitazone withdrawal showed clear improvement (Fig 1, B). White blood cell (WBC) counts, as well as neutrophil counts, progressively decreased to normal levels (WBC, 13.9 × 109/L, and neutrophil, 8.2 × 109/L before pioglitazone; WBC, 6.8 × 109/L, and neutrophil, 2 × 109/L at pioglitazone withdrawal, respectively). C-Reactive protein level decreased from 24.4 mg/L to 13.1 mg/L before and after pioglitazone, respectively. The clinical and radiologic amelioration allowed for HSCT; pioglitazone was withdrawn and after 1 week, conditioning regimen based on treosulfan/fludarabine/Thiotepa was administered to the patient.8 Graft versus host disease prophylaxis was conducted through administration of cyclosporin-A and short-term methotrexate. Neutrophil and platelet engraftment took place at day+17 and +32, respectively. The patient did not develop signs of graft versus host disease. He is currently at day+150 after HSCT in good clinical condition with donor chimerism above 90% on CD14+, CD15+, and CD3+ cells in peripheral blood. He does not require any respiratory support, he has a satisfactory oral food intake with weight gain, and he shows neuromuscular development improvement. Although observed in a single child, pioglitazone might have played a role in the protection of the patient from further infections and in the improvement of his pulmonary situation, by reducing the inflammatory status and by partial restoration of host defense through induction of mtROS production in his granulocytes. This is also supported by the fact that concomitant medications were not increased, but rather reduced in intensity during pioglitazone treatment (for details, see Table E2 in this article's Online Repository at www.jacionline.org). Moreover, corticosteroids were never administered to the patient, neither before nor during pioglitazone treatment. Moreover, the patient did not develop any adverse effects related to pioglitazone administration, confirming the safety of this therapeutic approach. Considering data in female carriers, patients with HSCT, and improvement after gene therapy,7, 9 we speculate that even an enhancement in DHR fluorescence in a relatively small population of leukocytes might be the expression of a protective ROS production. Accordingly, Fernandez-Boyanapalli et al6 suggest that the mechanism responsible for peroxisome proliferator–activated receptor gamma agonist effect in mice with CGD is related to increased ROS production by mitochondria in a subpopulation of neutrophils, monocytes, and inflammatory macrophages. It remains to be determined which population is targeted by pioglitazone in vivo. Presently our observations cannot provide information regarding long-term effects on mtROS production, but suggest that pioglitazone might be used as bridge treatment for these fragile chronic patients. Fernandez-Boyanapalli et al's findings and our experience on the use of pioglitazone provide relevant insights into the treatment of this rare disease especially for those patients without a prompt suitable matched donor or for whom the critical disease conditions force to postpone HSCT. Further studies conducted through well-designed clinical trials are warranted to investigate the drug's precise mechanism of action, as well as to define the role of pioglitazone in the therapeutic armamentarium of patients with X-CGD.

Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti-vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine-specific T cells exceeds the clinical responses observed. Here, we evaluate immunological and clinical responses in 23 MAGE-A3+ melanoma patients treated with autologous lymphocytes genetically engineered to express the tumor antigen MAGE-A3 and the viral gene product thymidine kinase of the herpes simplex virus (HSV-TK). HSV-TK was used as safety system in case of adverse events and as tracer antigen to monitor the immune competence of treated patients. The increase of anti-TK and anti-MAGE-A3 T-cells after vaccination was observed in 90 and 27% of patients, respectively. Among 19 patients with measurable disease, we observed a disease control rate of 26.3%, with one objective clinical response, and four durable, stable diseases. Three patients out of five with no evidence of disease (NED) at the time of vaccination remained NED after 73+, 70+ and 50+ months. Notably, we report that only patients experiencing MAGE-A3-specific immune responses showed a clinical benefit. Additionally, we report that responder and non-responder patients activate and expand T cells against the tracer antigen TK in a similar way, suggesting that local rather than systemic immune suppression might be involved in limiting clinically relevant antitumor immune responses. OI bregni, marco/0000-0002-3789-1199

An important challenge of embodied theories is to explain the comprehension of abstract sentences. The aim of the present study was to scrutinize the role of the motor cortex in this process. We developed a new paradigm to study the abstract-concrete dimension by combining concrete (i.e., action-related) and abstract (i.e., non-action-related) verbs with nouns of graspable and non-graspable objects. Using these verb-noun combinations we performed a Transcranial Magnetic Stimulation (TMS) on the left primary motor cortex while participants performed a sentence sensibility task. Single-TMS pulses were delivered 250ms after verb or noun presentation in each of four combinations of abstract and concrete verbs and nouns. To evaluate cortico-spinal excitability we registered the electromyographic activity of the right first dorsal interosseous muscle. As to verb-noun integration, analysis of motor evoked potentials (MEPs) after TMS pulse during noun presentation revealed greater peak-to-peak amplitude in phrases containing abstract rather than concrete verbs. Response times were also collected and showed that compatible (Concrete-Concrete and Abstract-Abstract) combinations were processed faster than mixed ones; moreover in combinations containing concrete verbs, participants were faster when the pulse was delivered on the first word (verb) than on the second one (noun). Results support previous findings showing early activation of hand-related areas after concrete verbs processing. The prolonged or delayed activation of the same areas by abstract verbs will be discussed in the framework of recent embodied theories based on multiple types of representation, particularly theories emphasizing the role of different acquisition mechanisms for concrete and abstract words (Borghi and Cimatti, 2009,2012).

Two experiments investigated whether the triadic interaction between objects, ourselves and other persons modulates motor system activation during language comprehension. Participants were faced with sentences formed by a descriptive part referring to a positive or negative emotively connoted object and an action part composed of an imperative verb implying a motion toward the self or toward other persons (e.g., “The object is attractive/ugly. Bring it toward you/Give it to another person/Give it to a friend”). Participants judged whether each sentence was sensible or not by moving the mouse toward or away from their body. Findings showed that the simulation of a social context influenced both (1) the motor system and (2) the coding of stimulus valence. Implications of the results for theories of embodied and social cognition are discussed.

Gaze direction and facial expressions are critical components of face processing and have been shown to influence attention deployment. We investigated whether gaze direction (direct vs. averted) combined with a neutral or angry expression modulates the deployment of attentional resources over time. In a rapid serial visual presentation (RSVP) paradigm participants had to decide the gender of a neutral or an angry target face with direct or averted gaze (T1) and then to judge the orientation of a target picture of a landscape (T2), following the face at different time intervals. Results showed no attentional blink effect (i.e., no deterioration in T2 accuracy) when T1 was an angry face with direct gaze, whereas it was present for angry faces with averted gaze or neutral faces with either averted or direct gaze. These findings are consistent with appraisal theories and are discussed against the background of automatic processing of threat stimuli.

Malignant pleural mesothelioma is a fatal malignancy linked to asbestos exposure. The main challenge for mesothelioma treatment is to go beyond the drug resistance, in particular against cisplatin (CDDP), one of the most used chemotherapeutic drug. 3-O-methylfunicone (OMF) is a metabolite produced by the fungus Penicillium pinophilum; its antiproliferative properties have been previously studied in vitro. Particularly, OMF is able to inhibit mesothelioma cell motility. To improve the effects of CDDP by-passing the resistance of mesothelioma cells to this drug, in the present study we investigated the combined treatment of OMF with CDDP respectively in an established mesothelioma cell line (NCI) and primary mesothelioma cells (Mest). As compared to the effect of single treatments, the combination of OMF and CDDP resulted in a stronger inhibition of NCI and Mest cell proliferation. OMF combination with CDDP was also able to affect the migratory ability of NCI and Mest cells by down-regulating αv and β5 expression and reducing metalloproteinase 2 (MMP-2) production. In addition, this association was effective in modulating VEGF gene expression. This finding highlights the possibility to use OMF and CDDP together to regulate angiogenesis and tumour progression in mesothelioma.

Two experiments, one on school-aged children and one on adults, explored the mechanisms underlying responses to an image prime (hand vs. control object) followed by graspable objects that were, in certain cases, dangerous. Participants were presented with different primes (a male, a female and a robotic grasping-hand; a male and a female static-hand; a control stimulus) and objects representing two risk levels (neutral and dangerous). The task required that a natural/artifact categorization task be performed by pressing different keys. In both adults and children graspable objects activated a facilitating motor response, while dangerous objects evoked aversive affordances, generating an interference-effect. Both children and adults were sensitive to the distinction between biological and non-biological hands, however detailed resonant mechanisms related to the hand-prime gender emerged only in adults. Implications for how the concept of “dangerous object” develops and the relationship between resonant mechanisms and perception of danger are discussed.

Facial emotions and emotional body postures can easily grab attention in social communication. In the context of faces, gaze has been shown as an important cue for orienting attention, but less is known for other important body parts such as hands. In the present study we investigated whether hands may orient attention due to the emotional features they convey. By implying motion in static photographs of hands, we aimed at furnishing observers with information about the intention to act and at testing if this interacted with the hand automatic coding. In this study, we compared neutral and frontal hands to emotionally threatening hands, rotated along their radial-ulnar axes in a Sidedness task (a Simon-like task based on automatic access to body representation). Results showed a Sidedness effect for both the palm and the back views with either neutral and emotional hands. More important, no difference was found between the two views for neutral hands, but it emerged in the case of the emotional hands: faster reaction times were found for the palm than the back view. The difference was ascribed to palm views' "offensive" pose: a source of threat that might have raised participants' arousal. This hypothesis was also supported by conscious evaluations of the dimensions of valence (pleasant-unpleasant) and arousal. Results are discussed in light of emotional feature coding.

Purpose PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6). Methods Chemo-naive patients with stage III or metastatic PA received P (30 mg/m(2) day 1 and 15), G (800 mg/m(2) day 1 and 15), and capecitabine (1,250 mg/m(2)/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m(2) day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m(2) day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, alpha = 0.05 and beta = 0.10; the study was to enroll 52 patients per arm. Results Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS > 70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%. Conclusions The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens. PURPOSE: PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6). METHODS: Chemo-naive patients with stage III or metastatic PA received P (30 mg/m(2) day 1 and 15), G (800 mg/m(2) day 1 and 15), and capecitabine (1,250 mg/m(2)/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m(2) day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m(2) day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, α = 0.05 and β = 0.10; the study was to enroll 52 patients per arm. RESULTS: Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS >70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%. CONCLUSIONS: The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens.

BACKGROUND: Biliary tract adenocarcinoma (BTA) is an uncommon tumor with a poor prognosis and no standard, systemic chemotherapy. The combined cisplatin, epirubicin, 5-fluorouracil, and gemcitabine (PEFG) regimen is an effective, upfront treatment for advanced pancreatic cancer. In this study, the authors assessed the activity and safety of this combination regimen in patients with advanced BTA. METHODS: PEFG (cisplatin 40 mg/m2 and epirubicin 40 mg/m2 on Day 1; gemcitabine 600 mg/m2 on Days 1 and 8; and 5-fluorouracil [FU] 200 mg/m2 daily as a continuous infusion) was administered to chemotherapy-naive patients who had a cytologic or histologic diagnosis of locally advanced or metastatic BTA, aged ≤75 years, and a performance status (PS) >60 either until they had evidence progressive disease or for a maximum of 6 months. Tumor size was assessed every 2 months during treatment. RESULTS: Between May 1999 and December 2005, 37 patients (62% metastatic) who had a median age of 62 years and a median PS of 90 received the PEFG regimen at the authors' institution. Primary tumor sites were the intrahepatic bile duct in 10 patients (27%), the extrahepatic bile duct in 8 patients (22%), the gallbladder in 12 patients (32%), and the ampulla of Vater in 7 patients (19%). A partial response was observed in 16 patients (43%), and stable disease was observed in 12 patients (32%). The median overall survival (OS) was 12.1 months, and the 1-year OS rate was 52%. The median progression-free survival (PFS) was 7.9 months, and the 6-month PFS rate was 67%. The main grade 3/4 toxicity was neutropenia in 18% of cycles followed by thrombocytopenia in 9% of cycles, nausea/vomiting in 5% of cycles, and febrile neutropenia, fatigue, anemia, and stomatitis in 2% of cycles. CONCLUSIONS: The current results demonstrated that PEFG was an active regimen with a manageable toxicity profile for patients with advanced BTA. Cancer 2010. © 2010 American Cancer Society.

Categorization studies have focused on the importance of a variety of perceptual properties (shape, size, weight). The present study explored whether the softness or hardness of an object might influence the way we categorize and consider category members. Of additional interest was whether information on consistence is automatically activated and whether it is modulated by the kind of task and of response modality. Three experiments demonstrated that information on consistence is automatically activated, and it helps us to distinguish between artefacts and natural objects. Interestingly, the results are in agreement with the simulation hypothesis; namely, when we consider artefacts, we simulate using them and information on their consistence is activated; this simulation is modulated by the task. The way we differently process artefacts and natural objects across the experiments confirms the simulation hypothesis and our sensitivity to the response modality.

In the present study two separate stimulus–response compatibility effects (functional affordance and Simon-like effects) were investigated with centrally presented pictures of an object tool (a torch) characterized by a structural separation between the graspable portion and the goal-directed portion. In Experiment 1, participants were required to decide whether the torch was red or blue, while in Experiment 2 they were required to decide whether the torch was upright or inverted. Our results showed that with the same stimulus two types of compatibility effect emerged: one based on the direction signalled by the goal-directed portion of the tool (a Simon-like effect as observed in Experiment 1), and the other based on the actions associated with an object (a functional affordance effect as observed in Experiment 2). Both effects emerged independently of the person's intention to act on the stimulus, but depended on the stimulus properties that were processed in order to perform the task.