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1.  Sporadic Isolation of Sabin-Like Polioviruses and High-Level Detection of Non-Polio Enteroviruses during Sewage Surveillance in Seven Italian Cities, after Several Years of Inactivated Poliovirus Vaccination 
Applied and Environmental Microbiology  2014;80(15):4491-4501.
Sewage surveillance in seven Italian cities between 2005 and 2008, after the introduction of inactivated poliovirus vaccination (IPV) in 2002, showed rare polioviruses, none that were wild-type or circulating vaccine-derived poliovirus (cVDPV), and many other enteroviruses among 1,392 samples analyzed. Two of five polioviruses (PV) detected were Sabin-like PV2 and three PV3, based on enzyme-linked immunosorbent assay (ELISA) and PCR results. Neurovirulence-related mutations were found in the 5′ noncoding region (5′NCR) of all strains and, for a PV2, also in VP1 region 143 (Ile > Thr). Intertypic recombination in the 3D region was detected in a second PV2 (Sabin 2/Sabin 1) and a PV3 (Sabin 3/Sabin 2). The low mutation rate in VP1 for all PVs suggests limited interhuman virus passages, consistent with efficient polio immunization in Italy. Nonetheless, these findings highlight the risk of wild or Sabin poliovirus reintroduction from abroad. Non-polio enteroviruses (NPEVs) were detected, 448 of which were coxsackievirus B (CVB) and 294 of which were echoviruses (Echo). Fifty-six NPEVs failing serological typing were characterized by sequencing the VP1 region (nucleotides [nt] 2628 to 2976). A total of 448 CVB and 294 Echo strains were identified; among those strains, CVB2, CVB5, and Echo 11 predominated. Environmental CVB5 and CVB2 strains from this study showed high sequence identity with GenBank global strains. The high similarity between environmental NPEVs and clinical strains from the same areas of Italy and the same periods indicates that environmental strains reflect the viruses circulating in the population and highlights the potential risk of inefficient wastewater treatments. This study confirmed that sewage surveillance can be more sensitive than acute flaccid paralysis (AFP) surveillance in monitoring silent poliovirus circulation in the population as well as the suitability of molecular approaches to enterovirus typing.
doi:10.1128/AEM.00108-14
PMCID: PMC4148784  PMID: 24814793
2.  Complete pathological regression of hepatocellular carcinoma with portal vein thrombosis treated with sorafenib 
Sorafenib is a molecular-targeted therapy used in palliative treatment of advanced hepatocellular carcinoma (HCC) in Child-Pugh A patients. We describe the case of a patient who presented with a large HCC in the left liver associated with portal vein thrombosis (PVT). After 9 months of sorafenib treatment, reassessment showed that the tumors had decreased in size with recanalization of the portal vein. A lateral left hepatectomy was performed and pathology showed complete necrosis of the tumor. Sorafenib can downstage HCC in patients with cirrhosis allowing further surgical resection.
doi:10.1186/1477-7819-11-171
PMCID: PMC3735470  PMID: 23914915
Hepatocellular carcinoma; Sorafenib; Liver resection
3.  A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination 
The Journal of Cell Biology  2014;206(2):307-328.
RAB5A and RAB4 promote breast tumor cell dissemination by controlling the trafficking of proteins necessary for localized invadosome formation.
The mechanisms by which tumor cells metastasize and the role of endocytic proteins in this process are not well understood. We report that overexpression of the GTPase RAB5A, a master regulator of endocytosis, is predictive of aggressive behavior and metastatic ability in human breast cancers. RAB5A is necessary and sufficient to promote local invasion and distant dissemination of various mammary and nonmammary tumor cell lines, and this prometastatic behavior is associated with increased intratumoral cell motility. Specifically, RAB5A is necessary for the formation of invadosomes, membrane protrusions specialized in extracellular matrix (ECM) degradation. RAB5A promotes RAB4- and RABENOSYN-5–dependent endo/exocytic cycles (EECs) of critical cargos (membrane-type 1 matrix metalloprotease [MT1-MMP] and β3 integrin) required for invadosome formation in response to motogenic stimuli. This trafficking circuitry is necessary for spatially localized hepatocyte growth factor (HGF)/MET signaling that drives invasive, proteolysis-dependent chemotaxis in vitro and for conversion of ductal carcinoma in situ to invasive ductal carcinoma in vivo. Thus, RAB5A/RAB4 EECs promote tumor dissemination by controlling a proteolytic, mesenchymal invasive program.
doi:10.1083/jcb.201403127
PMCID: PMC4107781  PMID: 25049275
4.  Fast demographic traits promote high diversification rates of Amazonian trees 
Ecology Letters  2014;17(5):527-536.
The Amazon rain forest sustains the world's highest tree diversity, but it remains unclear why some clades of trees are hyperdiverse, whereas others are not. Using dated phylogenies, estimates of current species richness and trait and demographic data from a large network of forest plots, we show that fast demographic traits – short turnover times – are associated with high diversification rates across 51 clades of canopy trees. This relationship is robust to assuming that diversification rates are either constant or decline over time, and occurs in a wide range of Neotropical tree lineages. This finding reveals the crucial role of intrinsic, ecological variation among clades for understanding the origin of the remarkable diversity of Amazonian trees and forests.
doi:10.1111/ele.12252
PMCID: PMC4285998  PMID: 24589190
Diversity; generation time; traits; tropical forest; turnover
5.  Tetrahydroisoquinolinone-based Steroidomimetic and Chimeric Microtubule Disruptors 
ChemMedChem  2013;9(1):10.1002/cmdc.201300261.
A SAR translation strategy was used for the discovery of tetrahydroisoquinoline (THIQ)-based steroidomimetic and chimeric microtubule disruptors based upon a steroidal starting point. A steroid A,B-ring-mimicking THIQ core was connected to methoxy aryl D-ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g. 20c GI50 2.1 μM). Optimisation and control experiments demonstrate the complementary SAR of this series and the steroid derivatives that inspired its design. Linkage of the THIQ-based A,B-mimic with the trimethoxy aryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (to GI50 40 nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 20z relative to a benchmark steroidal bis-sulfamate in an in vivo model of multiple myeloma.
doi:10.1002/cmdc.201300261
PMCID: PMC3877212  PMID: 24124095
tetrahydroisoquinolines; microtubule disruptors; tubulin assembly; colchicine binding
6.  Cigarette Smoking, Desire to Quit, and Tobacco-Related Counseling among Adult Health Center Patients 
American journal of public health  2015;105(1):180-188.
Background
Federally supported health centers provide primary care services for over 20 million medically underserved patients across the U.S. Health centers are well-positioned to identify patients who smoke and ensure receipt of needed cessation counseling or treatment.
Purpose
Determine the prevalence of current cigarette smoking, desire to quit, and receipt of tobacco-related counseling among a national sample of adult health center patients; identify sociodemographic and health-related factors associated with these measures.
Methods
Data came from the 2009 Health Center Patient Survey and the 2009 National Health Interview Survey. The analytic sample included 3,949 adult health center patients and 27,731 U.S. adults.
Results
Findings showed that 31% of adult health center patients were current smokers, compared with 21% of U.S. adults in general. Among currently smoking health center patients, 83% reported a desire to quit and 68% reported receiving tobacco counseling. In multivariable models, patients had higher odds of wanting to quit if they showed signs of severe mental illness (OR=3.26, 95% CI: 1.19–8.97) and lower odds if they had health insurance (OR=0.43, 95% CI: 0.22–0.86). Patients had higher odds of receiving counseling if they had two or more chronic conditions (OR=2.05, 95% CI: 1.11–3.78) and lower odds if they were Hispanic (OR=0.57-0.34-0.96).
Conclusions
The prevalence of cigarette smoking is substantially higher among health center patients than the U.S. in general. However, most smokers seen in health centers desire to quit smoking. Continued efforts are warranted to reduce tobacco use in this vulnerable segment of the population.
doi:10.2105/AJPH.2013.301691
PMCID: PMC4163128  PMID: 24625147
7.  Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis 
The Journal of Clinical Investigation  2014;124(10):4577-4589.
Controlling the overwhelming inflammatory reaction associated with polymicrobial sepsis remains a prevalent clinical challenge with few treatment options. In septic peritonitis, blood neutrophils and monocytes are rapidly recruited into the peritoneal cavity to control infection, but the role of resident sentinel cells during the early phase of infection is less clear. In particular, the influence of mast cells on other tissue-resident cells remains poorly understood. Here, we developed a mouse model that allows both visualization and conditional ablation of mast cells and basophils to investigate the role of mast cells in severe septic peritonitis. Specific depletion of mast cells led to increased survival rates in mice with acute sepsis. Furthermore, we determined that mast cells impair the phagocytic action of resident macrophages, thereby allowing local and systemic bacterial proliferation. Mast cells did not influence local recruitment of neutrophils and monocytes or the release of inflammatory cytokines. Phagocytosis inhibition by mast cells involved their ability to release prestored IL-4 within 15 minutes after bacterial encounter, and treatment with an IL-4–neutralizing antibody prevented this inhibitory effect and improved survival of septic mice. Our study uncovers a local crosstalk between mast cells and macrophages during the early phase of sepsis development that aggravates the outcome of severe bacterial infection.
doi:10.1172/JCI75212
PMCID: PMC4191002  PMID: 25180604
8.  Dynamically controlling the emission of single excitons in photonic crystal cavities 
Nature Communications  2014;5:5786.
Single excitons in semiconductor microcavities represent a solid state and scalable platform for cavity quantum electrodynamics, potentially enabling an interface between flying (photon) and static (exciton) quantum bits in future quantum networks. While both single-photon emission and the strong coupling regime have been demonstrated, further progress has been hampered by the inability to control the coherent evolution of the cavity quantum electrodynamics system in real time, as needed to produce and harness charge–photon entanglement. Here using the ultrafast electrical tuning of the exciton energy in a photonic crystal diode, we demonstrate the dynamic control of the coupling of a single exciton to a photonic crystal cavity mode on a sub-nanosecond timescale, faster than the natural lifetime of the exciton. This opens the way to the control of single-photon waveforms, as needed for quantum interfaces, and to the real-time control of solid-state cavity quantum electrodynamics systems.
Controlling the coherent evolution of cavity quantum electrodynamics systems is key for future quantum networks. Here Pagliano et al. demonstrate dynamic control of the coupling of a single exciton to a photonic micro-resonator using electrical tuning of the exciton energy in a photonic crystal cavity diode.
doi:10.1038/ncomms6786
PMCID: PMC4275591  PMID: 25503405
9.  Familial 1q22 microduplication associated with psychiatric disorders, intellectual disability and late-onset autoimmune inflammatory response 
Molecular Cytogenetics  2014;7(1):90.
Background
Despite the extensive use of chromosomal microarray technologies in patients with neurodevelopmental disorders has permitted the identification of an increasing number of causative submicroscopic rearrangements throughout the genome, constitutional duplications involving chromosome 1q22 have seldom been described in those patients.
Results
We report on a pedigree with seven affected members showing varying degrees of behavioural and emotional disturbances including general anxiety disorder, mood disorders, and intellectual disability. Two adult female patients also showed late onset autoimmune inflammatory responses characterized by alopecia, skin ulcers secondary to inflammatory vasculitis, interstitial lung disease, and Raynaud’s phenomenon. Array-CGH analysis identified in the affected individuals a 290 Kb microduplication in the chromosome 1q22. The rearrangement involves eleven known genes and is not present in the databases of polymorphic copy number variants.
Conclusions
The rearrangement segregates with the neurological clinical features observed in our patients, suggesting that dosage imbalance of one or more genes in this genomic region may lead to the observed phenotype. The association between the microduplication and the inflammatory disease is much less evident. Additional reported patients carrying similar microduplications are needed to clarify this aspect.
doi:10.1186/s13039-014-0090-7
PMCID: PMC4276019  PMID: 25540671
CBCL dysregulation syndrome; 1q22; LMNA; SEMA4A; LAMTOR2; Intellectual disability; CNV; Duplication; Inflammatory disease
10.  Reversal of IgM deficiency following a gluten-free diet in seronegative celiac disease 
World Journal of Gastroenterology : WJG  2014;20(46):17686-17689.
Selective IgM deficiency (sIGMD) is very rare; it may be associated with celiac disease (CD). We present the case of an 18-year-old man with sIGMD masking seronegative CD. Symptoms included abdominal pain, diarrhea and weight loss. Laboratory tests showed reduced IgM, DQ2-HLA and negative anti-transglutaminase. Villous atrophy and diffuse immature lymphocytes were observed at histology. Tissue transglutaminase mRNA mucosal levels showed a 6-fold increase. The patient was treated with a gluten-free diet (GFD) and six months later the symptoms had disappeared, the villous architecture was restored and mucosal tissue transglutaminase mRNA was comparable to that of healthy subjects. After 1 year of GFD, a complete restoration of normal IgM values was observed and duodenal biopsy showed a reduction of immature lymphocytes and normal appearance of mature immune cells.
doi:10.3748/wjg.v20.i46.17686
PMCID: PMC4265634  PMID: 25516687
Selective IgM deficiency; Seronegative celiac disease; Tissue transglutaminase; Gluten-free diet
11.  Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study 
British Journal of Cancer  2013;109(12):3057-3066.
Background:
Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking.
Methods:
Expression of HER2, β-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated.
Results:
We obtained samples from 63 SBA patients (tumour stages: I–II: 30% III: 35% IV: 32% locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of β-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9–72.2). For all patients, in univariate analysis, stages I–II (P<0.001), WHO PS 0–1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS. In multivariate analysis, disease stage (P=0.01) and WHO PS 0–1 (P=0.001) independently predicted longer OS. For stage IV patients, median OS was 20.5 months (95% CI: 14.6; 36.6 months). In multivariate analysis, WHO PS 0–1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS.
Conclusion:
This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high frequencies of KRAS mutations. The seemingly higher frequency of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA patients. A dMMR phenotype was significantly associated with a non-metastatic tumour (P=0.02). A trend for a good prognosis and a duodenum or jejunum primary site was associated with dMMR.
doi:10.1038/bjc.2013.677
PMCID: PMC3859950  PMID: 24196786
rare tumour; carcinogenesis; KRAS; prognostic factor; microsatellite instability; small intestine adenocarcinoma
12.  Are all species necessary to reveal ecologically important patterns? 
Ecology and Evolution  2014;4(24):4626-4636.
While studying ecological patterns at large scales, ecologists are often unable to identify all collections, forcing them to either omit these unidentified records entirely, without knowing the effect of this, or pursue very costly and time-consuming efforts for identifying them. These “indets” may be of critical importance, but as yet, their impact on the reliability of ecological analyses is poorly known. We investigated the consequence of omitting the unidentified records and provide an explanation for the results. We used three large-scale independent datasets, (Guyana/ Suriname, French Guiana, Ecuador) each consisting of records having been identified to a valid species name (identified morpho-species – IMS) and a number of unidentified records (unidentified morpho-species – UMS). A subset was created for each dataset containing only the IMS, which was compared with the complete dataset containing all morpho-species (AMS: = IMS + UMS) for the following analyses: species diversity (Fisher's alpha), similarity of species composition, Mantel test and ordination (NMDS). In addition, we also simulated an even larger number of unidentified records for all three datasets and analyzed the agreement between similarities again with these simulated datasets. For all analyses, results were extremely similar when using the complete datasets or the truncated subsets. IMS predicted ≥91% of the variation in AMS in all tests/analyses. Even when simulating a larger fraction of UMS, IMS predicted the results for AMS rather well. Using only IMS also out-performed using higher taxon data (genus-level identification) for similarity analyses. Finding a high congruence for all analyses when using IMS rather than AMS suggests that patterns of similarity and composition are very robust. In other words, having a large number of unidentified species in a dataset may not affect our conclusions as much as is often thought.
doi:10.1002/ece3.1246
PMCID: PMC4278815  PMID: 25558357
Beta-diversity; Fisher's alpha; indets; large-scale ecological patterns; Mantel test; morpho-species; nonmetric multidimensional scaling; similarity of species composition; spatial turnover
13.  DEPDC1B Coordinates De-adhesion Events and Cell-Cycle Progression at Mitosis 
Developmental Cell  2014;31(4):420-433.
Summary
Cells entering mitosis become rounded, lose attachment to the substrate, and increase their cortical rigidity. Pivotal to these events is the dismantling of focal adhesions (FAs). How mitotic reshaping is linked to commitment to divide is unclear. Here, we show that DEPDC1B, a protein that accumulates in G2, coordinates de-adhesion events and cell-cycle progression at mitosis. DEPDC1B functions as an inhibitor of a RhoA-based signaling complex, which assembles on the FA-associated protein tyrosine phosphatase, receptor type, F (PTPRF) and mediates the integrity of FAs. By competing with RhoA for the interaction with PTPRF, DEPDC1B promotes the dismantling of FAs, which is necessary for the morphological changes preceding mitosis. The circuitry is relevant in whole organisms, as shown by the control exerted by the DEPDC1B/RhoA/PTPRF axis on mitotic dynamics during zebrafish development. Our results uncover an adhesion-dependent signaling mechanism that coordinates adhesion events with the control of cell-cycle progression.
Graphical Abstract
Highlights
•DEPDC1B is a cell-cycle gene involved in the transition from G2 phase to mitosis•Persistent adhesion at G2 phase delays CycB/CDK1 activation and G2/M transition•DEPDC1B controls RhoA/ROCK-dependent adhesion dynamics at G2 phase•DEPDC1B inhibits RhoA activation by displacing it from the PTPRF/GEF-H1 complex
During mitosis, cells become rounded and lose attachment to the substrate. Marchesi et al. show that DEPDC1B, a cell-cycle-regulated protein, binds to the focal-adhesion-associated receptor PTPRF, thus inhibiting RhoA activation and leading to dismantling of focal adhesions upon mitotic entry. DEPDC1B thus links mitotic progression to de-adhesion.
doi:10.1016/j.devcel.2014.09.009
PMCID: PMC4250264  PMID: 25458010
14.  Post-operative endophthalmitis caused by Acremonium falciforme with orbital and extra-orbital involvement following combined cataract and glaucoma surgery: a case report 
Introduction
In this report, we describe an unusual case of post-operative Acremonium falciforme endophthalmitis with orbital and extra-orbital involvement following combined cataract and glaucoma surgery.
Case presentation
A 68-year-old Caucasian man with glaucoma presented with endophthalmitis characterized by pain, redness and impaired vision in the left eye fifteen days after combined cataract and filtering surgery. He subsequently underwent a pars plana vitrectomy, with vitreous sampling, silicone oil placement and intra-vitreal injection of antibiotics, but only after a second vitrectomy we identified Acremonium falciforme as the causative agent for the endophthalmitis. An antifungal systemic and topical therapy was started, but meanwhile the infection extended to orbital and peri-orbital tissues. Following these procedures, even if the eye went slowly in phthisis, we were able to limit the further extension and circumscribe the orbital and extra-orbital involvement.
Conclusion
To our knowledge, this report is the first describe Acremonium falciforme endophthalmitis with orbital and extra-orbital involvement, following anterior segment combined surgery. Ophthalmologists and physicians should be aware of the extension risk of a fungal panophthalmitis, but also to potentially serious side effects related to systemic therapy.
doi:10.1186/1752-1947-8-373
PMCID: PMC4275749  PMID: 25406374
Cataract surgery; Fungal endophthalmitis; Orbital involvement
15.  Bevacizumab maintenance in metastatic colorectal cancer: How long? 
The management of patients with non-progressive metastatic colorectal cancer after six months of treatment has not yet been codified. The most relevant concerns are the effectiveness of maintenance vs discontinuation, and the tolerability of prolonged treatment. Here we report the case of a 72-year-old man affected by colorectal cancer with lung metastases who achieved a complete response after receiving capecitabine, oxaliplatin and bevacizumab for six months, and bevacizumab alone for six months. Bevacizumab was continued as maintenance regimen for more than three years. It was discontinued because of an arthroplasty. Fifty-eight months after beginning first-line treatment, the patient remains free from relapse. Adverse effects were minimal and easily controlled.
doi:10.12998/wjcc.v2.i11.717
PMCID: PMC4233413  PMID: 25405197
Metastatic colorectal cancer; Bevacizumab; Maintenance
16.  Behavioral and physiological responses to fruit availability of spider monkeys ranging in a small forest fragment 
American Journal of Primatology  2014;76(11):1049-1061.
Numerous animal species currently experience habitat loss and fragmentation. This might result in behavioral and dietary adjustments, especially because fruit availability is frequently reduced in fragments. Food scarcity can result in elevated physiological stress levels, and chronic stress often has detrimental effects on individuals. Some animal species exhibit a high degree of fission–fusion dynamics, and theory predicts that these species reduce intragroup feeding competition by modifying their subgroup size according to resource availability. Until now, however, there have been few studies on how species with such fission–fission dynamics adjust their grouping patterns and social behavior in small fragments or on how food availability influences their stress levels. We collected data on fruit availability, feeding behavior, stress hormone levels (measured through fecal glucocorticoid metabolites (FGCM)), subgroup size, and aggression for two groups of brown spider monkeys (Ateles hybridus) in a small forest fragment in Colombia and examined whether fruit availability influences these variables. Contrary to our predictions, spider monkeys ranged in smaller subgroups, had higher FGCM levels and higher aggression rates when fruit availability was high compared to when it was low. The atypical grouping pattern of the study groups seems to be less effective at mitigating contest competition over food resources than more typical fission–fusion patterns. Overall, our findings illustrate that the relationship between resource availability, grouping patterns, aggression rates, and stress levels can be more complex than assumed thus far. Additional studies are needed to investigate the long-term consequences on the health and persistence of spider monkeys in fragmented habitats.
doi:10.1002/ajp.22292
PMCID: PMC4229060  PMID: 24820229
habitat fragmentation; glucocorticoid metabolites; fission–fusion dynamics; spider monkeys; aggression
17.  Detection of Rare G3P[19] Group A Rotavirus in Human Patient, Italy 
Emerging Infectious Diseases  2014;20(11):1906-1910.
Infection with a rare G3P[19] rotavirus A strain was identified in an immunosuppressed patient in Italy. The strain showed a P[19] viral protein 4 gene and a complete AU-1–like genomic constellation. Phylogenetic analyses showed high nucleotide identity between this strain and G3P[19] rotavirus A strains from Asia, indicating possible reassortment events.
doi:10.3201/2011.131699
PMCID: PMC4214293  PMID: 25340712
group A rotavirus; diarrhea; gene; evolution; sequence; G3P[19]; human; adult; Italy; viruses; rotavirus
18.  In human retinoblastoma Y79 cells okadaic acid–parthenolide co-treatment induces synergistic apoptotic effects, with PTEN as a key player 
Cancer Biology & Therapy  2013;14(10):922-931.
Retinoblastoma is the most common intraocular malignancy of childhood. In developing countries, treatment is limited, long-term survival rates are low and current chemotherapy causes significant morbidity to pediatric patients and significantly limits dosing. Therefore there is an urgent need to identify new therapeutic strategies to improve the clinical outcome of patients with retinoblastoma. Here, we investigated the effects of two natural compounds okadaic acid (OKA) and parthenolide (PN) on human retinoblastoma Y79 cells. For the first time we showed that OKA/PN combination at subtoxic doses induces potent synergistic apoptotic effects accompanied by lowering in p-Akt levels, increasing in the stabilized forms of p53 and potent decrease in pS166-Mdm2. We also showed the key involvement of PTEN which, after OKA/PN treatment, potently increased before p53, thus suggesting that p53 activation was under PTEN action. Moreover, after PTEN-knockdown p-Akt/ pS166Mdm2 increased over basal levels and p53 significantly lowered, while OKA/PN treatment failed both to lower p-Akt and pS166-Mdm2 and to increase p53 below/over their basal levels respectively. OKA/PN treatment potently increased ROS levels whereas decreased those of GSH. Reducing cellular GSH by l-butathionine-[S,R]-sulfoximine treatment significantly anticipated the cytotoxic effect exerted by OKA/PN. Furthermore, the effects of OKA/PN treatment on both GSH content and cell viability were less pronounced in PTEN silenced cells than in control cells. The results provide strong suggestion for combining a treatment approach that targets the PTEN/Akt/Mdm2/p53 pathway.
doi:10.4161/cbt.25944
PMCID: PMC3926889  PMID: 23938948
retinoblastoma; Y79 cells; synergistic apoptotic effects; oxidative stress; natural drugs; PTEN/Akt/Mdm2/p53 pathway; parthenolide; okadaic acid
19.  Quantitative proteomic analysis of signalosome dynamics in primary T cells identifies the CD6 surface receptor as a Lat-independent TCR signaling hub 
Nature immunology  2014;15(4):384-392.
T cell antigen receptor (TCR)-mediated T cell activation requires the interaction of dozens of proteins. We used quantitative mass spectrometry and activated primary CD4+ T cells from mice in which a tag for affinity purification was knocked into several genes to determine the composition and dynamics of multiprotein complexes forming around the kinase Zap70 and the adaptors Lat and SLP-76. Most of the 112 high confidence time-resolved protein interactions we observed were novel. The CD6 surface receptor was found capable of initiating its own signaling pathway by recruiting SLP-76 and Vav1, irrespective of the presence of Lat. Our findings provide a more complete model of TCR signaling in which CD6 constitutes a signaling hub contributing to TCR signal diversification.
doi:10.1038/ni.2843
PMCID: PMC4037560  PMID: 24584089
20.  Low Molecular Weight Hyaluronan-Pulsed Human Dendritic Cells Showed Increased Migration Capacity and Induced Resistance to Tumor Chemoattraction 
PLoS ONE  2014;9(9):e107944.
We have shown that ex vivo pre-conditioning of bone marrow-derived dendritic cells (DC) with low molecular weight hyaluronan (LMW HA) induces antitumor immunity against colorectal carcinoma (CRC) in mice. In the present study we investigated the effects of LMW HA priming on human-tumor-pulsed monocytes-derived dendritic cells (DC/TL) obtained from healthy donors and patients with CRC. LMW HA treatment resulted in an improved maturation state of DC/TL and an enhanced mixed leucocyte reaction activity in vivo. Importantly, pre-conditioning of DC/TL with LMW HA increased their ability to migrate and reduced their attraction to human tumor derived supernatants. These effects were associated with increased CCR7 expression levels in DC. Indeed, a significant increase in migratory response toward CCL21 was observed in LMW HA primed tumor-pulsed monocyte-derived dendritic cells (DC/TL/LMW HA) when compared to LWM HA untreated cells (DC/TL). Moreover, LMW HA priming modulated other mechanisms implicated in DC migration toward lymph nodes such as the metalloproteinase activity. Furthermore, it also resulted in a significant reduction in DC migratory capacity toward tumor supernatant and IL8 in vitro. Consistently, LMW HA dramatically enhanced in vivo DC recruitment to tumor-regional lymph nodes and reduced DC migration toward tumor tissue. This study shows that LMW HA –a poorly immunogenic molecule- represents a promising candidate to improve human DC maturation protocols in the context of DC-based vaccines development, due to its ability to enhance their immunogenic properties as well as their migratory capacity toward lymph nodes instead of tumors.
doi:10.1371/journal.pone.0107944
PMCID: PMC4169605  PMID: 25238610
21.  Computational evaluation of the thrombogenic potential of a hollow-fiber oxygenator with integrated heat exchanger during extracorporeal circulation 
The onset of thromboembolic phenomena in blood oxygenators, even in the presence of adequate anticoagulant strategies, is a relevant concern during extracorporeal circulation (ECC). For this reason, the evaluation of the thrombogenic potential associated with extracorporeal membrane oxygenators should play a critical role into the preclinical design process of these devices. This study extends the use of computational fluid dynamics simulations to guide the hemodynamic design optimization of oxygenators and evaluate their thrombogenic potential during ECC. The computational analysis accounted for both macro- (i.e., vortex formation) and micro-scale (i.e., flow-induced platelet activation) phenomena affecting the performances of a hollow-fiber membrane oxygenator with integrated heat exchanger. A multiscale Lagrangian approach was adopted to infer the trajectory and loading history experienced by platelet-like particles in the entire device and in a repetitive subunit of the fiber bundles. The loading history was incorporated into a damage accumulation model in order to estimate the platelet activation state (PAS) associated with repeated passes of the blood within the device. Our results highlighted the presence of blood stagnation areas in the inlet section that significantly increased the platelet activation levels in particles remaining trapped in this region. The order of magnitude of PAS in the device was the same as the one calculated for the components of the ECC tubing system, chosen as a term of comparison for their extensive diffusion. Interpolating the mean PAS values with respect to the number of passes, we obtained a straightforward prediction of the thrombogenic potential as a function of the duration of ECC.
doi:10.1007/s10237-012-0445-0
PMCID: PMC4163497  PMID: 23053595
Computational fluid dynamics; Multiscale analysis; Extracorporeal circulation; Platelet activation; Thrombogenic potential
22.  Petrological and seismic precursors of the paroxysmal phase of the last Vesuvius eruption on March 1944 
Scientific Reports  2014;4:6297.
Abrupt transitions in style and intensity are common during volcanic eruptions, with an immediate impact on the surrounding territory and its population. Defining the factors trigger such sudden shifts in the eruptive behavior as well as developing methods to predict such changes during volcanic crises are crucial goals in volcanology. In our research, the combined investigation of both petrological and seismic indicators has been applied for the first time to a Vesuvius eruption, that of March 1944 that caused the present dormant state of the volcano. Our results contribute to elucidate the evolution of the conduit dynamics that generated a drastic increase in the Volcanic Explosivity Index, associated to the ejection of huge amount of volcanic ash. Remarkably, our study shows that the main paroxysm was announced by robust changes in petrology consistent with seismology, thus suggesting that the development of monitoring methods to assess the nature of ejected juvenile material combined with conventional geophysical techniques can represent a powerful tool for forecasting the evolution of an eruption towards violent behavior. This in turn is a major goal in volcanology because this evidence can help decision-makers to implement an efficient safety strategy during the emergency (scale and pace of evacuation).
doi:10.1038/srep06297
PMCID: PMC4158333  PMID: 25199537
23.  Hydrophobic Substituents of the Phenylmethylsulfamide Moiety Can Be Used for the Development of New Selective Carbonic Anhydrase Inhibitors 
BioMed Research International  2014;2014:523210.
A new series of compounds containing a sulfamide moiety as zinc-binding group (ZBG) has been synthesized and tested for determining inhibitory properties against four human carbonic anhydrase (hCA) isoforms, namely, CAs I, II, IX, and XII. The X-ray structure of the cytosolic dominant isoform hCA II in complex with the best inhibitor of the series has also been determined providing further insights into sulfamide binding mechanism and confirming that such zinc-binding group, if opportunely derivatized, can be usefully exploited for obtaining new potent and selective CAIs. The analysis of the structure also suggests that for drug design purposes the but-2-yn-1-yloxy moiety tail emerges as a very interesting substituent of the phenylmethylsulfamide moiety due to its capability to establish strong van der Waals interactions with a hydrophobic cleft on the hCA II surface, delimited by residues Phe131, Val135, Pro202, and Leu204. Indeed, the complementarity of this tail with the cleft suggests that different substituents could be used to discriminate between isoforms having clefts with different sizes.
doi:10.1155/2014/523210
PMCID: PMC4167230  PMID: 25258712
24.  Multiplex Real-Time PCR for Detecting and Typing Clostridium botulinum Group III Organisms and Their Mosaic Variants 
Botulism is a neuroparalytic disease that can occur in all warm-blooded animals, birds, and fishes. The disease in animals is mainly caused by toxins produced by Clostridium botulinum strains belonging to group III, although outbreaks due to toxins produced by group I and II organisms have been recognized. Group III strains are capable of producing botulinum toxins of type C, D, and C/D and D/C mosaic variants. Definitive diagnosis of animal botulism is made by combining clinical findings with laboratory investigations. Detection of toxins in clinical specimens and feed is the gold standard for laboratory diagnosis. Since toxins may be degraded by organisms contained in the gastrointestinal tract or may be present at levels below the detection limit, the recovery of C. botulinum from sick animal specimens is consistent for laboratory confirmation. In this article we report the development and in-house validation of a new multiplex real-time PCR for detecting and typing the neurotoxin genes found in C. botulinum group III organisms. Validation procedures have been carried out according to ISO 16140, using strains and samples recovered from cases of animal botulism in Italy and France.
doi:10.1089/bsp.2012.0084
PMCID: PMC3752518  PMID: 23971808
25.  Using the electronic health record to connect primary care patients to evidence-based telephonic tobacco quitline services: a closed-loop demonstration project 
ABSTRACT
Few smokers receive evidence-based tobacco treatment during healthcare visits. Electronic health records (EHRs) present an opportunity to efficiently identify and refer smokers to state tobacco quitlines. The purpose of this case study is to develop and evaluate a secure, closed-loop EHR referral system linking patients visiting healthcare clinics with a state tobacco quitline. A regional health system, EHR vendor, tobacco cessation telephone quitline vendor, and university research center collaborated to modify a health system’s EHR to create an eReferral system. Modifications included the following: clinic workflow adjustments, EHR prompts, and return of treatment delivery information from the quitline to the patient’s EHR. A markedly higher percentage of adult tobacco users were referred to the quitline using eReferral than using the previous paper fax referral (14 vs. 0.3 %). The eReferral system increased the referral of tobacco users to quitline treatment. This case study suggests the feasibility and effectiveness of a secure, closed-loop EHR-based eReferral system.
doi:10.1007/s13142-014-0259-y
PMCID: PMC4167898  PMID: 25264471
Electronic health record; Tobacco cessation; Telephonic tobacco quitline; Workflow; Healthcare system

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