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Systems pharmacology modeling in neuroscience: Prediction and outcome of PF-04995274, a 5-HT4 partial agonist, in a clinical scopolamine impairment trial

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Advances in Alzheimer's Disease 2013年第3期2卷 83-98页

作者： Timothy Nicholas Sridhar Duvvuri Claire Leurent David Raunig Tracey Rapp Phil Iredale Carolyn Rowinski Robert Carr Patrick Roberts athan spiros Hugo Geerts ICON North Wales USA In Silico Biosciences Lexington USA Pfizer Global Research and Development Groton USA

Background: 5-HT4receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer’s disease (AD). A systems pharmacology approach was adopted to evaluate the potential of the 5-HT4 modulation in providing beneficialeffects on cognition in AD. Methods: A serotonergic synaptic cleft model was developed by integrating serotonin firing, release, synaptic half-life, drug/tracer properties (affinity and agonism) as inputs and5-HT4 activity as output. The serotonergic model was calibrated using bothinvivo data on free 5-HT levels in preclinical models and human imaging data. The model was further expanded to other neurontransmitter systems and incorporated into a computer-based cortical network model which implemented the physiology of 12 different membrane CNS targets. A biophysically realistic, multi-compartment model of 80 pyramidal cells and 40 interneurons was further calibrated usingdata reported for working memory tasks in healthyhumans and schizophrenia patients. Model output was the duration of the network firing activity in response to an external stimulus. Alzheimer’s disease (AD) pathology, in particular synapse and neuronal cell loss in addition to cholinergic deficits, was calibrated to align with the natural clinical disease progression. The model was used to provide insights into the effect of 5-HT4 activation on working memory and to prospectively simulate the response of PF- 04995274, a 5-HT4partial agonist, in a scopolamine-reversal trial in healthy human subjects. Results: The model output suggested a beneficial effect of 5-HT4 agonism on working memory. The model also projected no effect or an exacerbation of scopolamine impairment for low in- trinsic activity 5-HT4agonists, which was supported by the subsequent human trial outcome. The clinical prediction of the disease model strongly suggests that 5-HT4 agonists with high intrinsic activity may have a beneficial effect on cognition in AD

关键词： Systems Pharmacology 5-HT4 Receptor Partial Agonist Scopolamine-Reversal

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Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity,to curtail dependence on host tissue:molecular mode

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Cancer Biology & Medicine 2017年第3期14卷 254-270页

作者： spiros A.Vlahopoulos The First Department of Pediatrics University of AthensHoremeio Research LaboratoryAthens 11527Greece

The role of the transcription factor NF-κB in shaping the cancer microenvironment is becoming increasingly clear. Inflammation alters the activity of enzymes that modulate NF-κB function, and causes extensive changes in genomic chromatin that ultimately drastically alter cell-specific gene expression. NF-κB regulates the expression of cytokines and adhesion factors that control interactions among adjacent cells. As such, NF-κB fine tunes tissue cellular composition, as well as tissues' interactions with the immune system. Therefore, NF-κB changes the cell response to hormones and to contact with neighboring cells. Activating NF-κB confers transcriptional and phenotypic plasticity to a cell and thereby enables profound local changes in tissue function and composition. Research suggests that the regulation of NF-κB target genes is specifically altered in cancer. Such alterations occur not only due to mutations of NF-κB regulatory proteins, but also because of changes in the activity of specific proteostatic modules and metabolic pathways. This article describes the molecular mode of NF-κB regulation with a few characteristic examples of target genes.

关键词： Cytokine mucin chemokine IL-8/CXCL8 MUC1 NF-κB IL-6 TNFα

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Selection criteria for liver resection in patients with hepatocellular carcinoma and chronic liver disease

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World Journal of Gastroenterology 2008年第22期14卷 3452-3460页

作者： spiros G Delis Christos Dervenis 1st Surgical Clinic Liver Surgical Unit Kostantopouleio-Agia Olga HospitalAthens 14233 Greece

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with an annual occurrence of one million new cases. An etiologic association between HBV infection and the development of HCC has been established with a relative risk 200-fold greater than in non-infected individuals. Hepatitis C virus is also proving an important predisposing factor for this malignancy with an incidence rate of 7% at 5 years and 14% at 10 years. The prognosis depends on tumor stage and degree of liver function, which affect the tolerance to invasive treatments. Although surgical resection is generally accepted as the treatment of choice for HCC, new treatment strategies, such as local ablative therapies, transarterial embolization and liver transplantation, have been developed nowadays. With increasing detection of small HCCs from screening programs for cirrhotic patients, it is foreseen that locoregional therapy will play an important role in the near future.

关键词： Hepatocellular carcinoma Hepatoma Resection Ablation Transplantation ICG clearance Remnant liver volume Milan criteria MELD score

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Current role of bloodless liver resection

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World Journal of Gastroenterology 2007年第6期13卷 826-829页

作者： spiros G Delis Juan Madariaga A Bakoyiannis Ch Dervenis Liver Surgical Unit A Surgical Clinic Agia Olga Hospital Athens Greece Department of Surgery Division of Transplantation & Liver Surgery University Of Miami School of Medicine Miami Florida United States

Liver resections are demanding operations which can have life threatening complications although they are performed by experienced liver surgeons. Recently new technologies are applied in the field of liver surgery, having one goal: safer and easier liver operations. The aim of this article is to address the issue of bloodless liver resection using radiofrequency energy. Radionics, Cool-tipTM System and Tissue Link are some of the devices which are using radiofrequency energy. All information included in this article, refers to these devices in which we have personal experience in our unit of liver surgery. These devices take advantage of its unique combination of radiofrequency current and internal electrode cooling to perform sealing of the small vessels and biliary radicals. Dissection is also feasible with the cool-tip probe. For the purposes of this study patient sex, age, type of disease and type of surgical procedure in association with the duration of parenchymal transection, blood loss, length of hospital stay, morbidity and mortality were analyzed. Cool-tip RF device may provide a unique, simple and rather safe method of bloodless liver resections if used properly. It is indicated mostly in cirrhotic patients with challenging hepatectomies (segment Ⅷ, central resections). The total operative time is eliminated and the average blood loss is significantly decreased. It is important to note that this technique should not be applied near the hilum or the vena cava to avoid damage of these structures.

关键词： Bloodless liver resection Radiofrequency Cool-tip Tissue link Hepatectomy

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Colonic gas explosion during therapeutic colonoscopy with electrocautery

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World Journal of Gastroenterology 2007年第40期13卷 5295-5298页

作者： spiros D Ladas George Karamanolis Emmanuel Ben-Soussan Hepatogastroenterology Unit 2~(nd) Department of Internal Medicine-PropaedeuticMedical SchoolAthens University"Attikon"University General HospitalAthensGreece Clinique de I'Alma 166 rue de I'université 750007ParisFrance

Therapeutic colonoscopy with electrocautery is widely used around the world. Adequate colonic cleansing is considered a crucial factor for the safety of this procedure. Colonic gas explosion, although rare, is one of the most frightening iatrogenic complications during colonoscopy with electrocautery. This complication is the result of an accumulation of colonic gases to explosive concentrations, but may be prevented by meticulous bowel preparation. The purpose *** review is to discuss the indications and the types of bowel preparations for therapeutic colonoscopy, and to contribute recommendations for the adequate bowel preparation for colonoscopy with electrocautery.

关键词： Colonic gas explosion Electrocautery Therapeutic polypectomy Argon plasma coagulation Polypectomy

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Arsenic speciation in fish from Greek coastal areas

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Journal of Environmental Sciences 2017年第6期29卷 300-312页

作者： Ioanna Kalantzi Kyriaki Mylona Katerina Sofoulaki Manolis Tsapakis spiros A.Pergantis Institute of Oceanography Hellenic Centre for Marine Science(HCMR)PO Box 2214Heraklion 71003CreteGreece Environmental Chemical Processes Laboratory Department of ChemistryUniuersity of CreteHeraklion 71003CreteGreece

Arsenic speciation analysis was conducted on fish samples （sardine and anchovy） collected from six areas along the Greek coastline, i.e. Artemisium Straits, Thermaikos Gulf, Amvrakikos Gulf, Strymonian Gulf, Thracian Sea, and Elefsina Gulf. Total arsenic levels ranging from 11.8 to 62.6 mg As/kg dry weight were determined. Arsenobetaine, a non-toxic form of arsenic, was found to be the main arsenic species, present at 8.6 to 58.8 mg As/kg dry weight, accounting for 67--95% of the total arsenic. Also detected in all fish samples was dimethylarsinic acid, although at considerably lower concentrations, ranging from 0.072-3.956 mg As/kg dry weight. Monomethylarsonic acid was detected at low levels in all anchovy samples, and only in sardines from one area. Finally, inorganic arsenic in the form of arsenate was detected only in fish at one area, indicating the possible effect of an environmental parameter on its presence at detectable amounts. Statistical analysis revealed the environmental variables, such as salinity, total organic carbon and nitrogen, ammonium, phosphate, total phosphorus, dissolved oxygen and pressure index, are potentially correlated to As species concentrations. Furthermore, based on factor analysis, the biological parameters, such as fish weight, lipids, protein and ash content, that are correlated to As species concentrations of fish were also identified. The interrelationship of arsenobetaine and dimethylarsinic acid concentrations within each fish species was evaluated.

关键词： Arsenic speciationArsenobetaineDimethylarsinic acidArsenateFishEnvironmental and biologicalparameters

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Biogenic amines in fresh fish and fishery products and emerging control

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Aquaculture and Fisheries 2023年第4期8卷 431-450页

作者： Abimannan Arulkumar spiros Paramithiotis Sadayan Paramasivam Department of Oceanography and Coastal Area Studies School of Marine SciencesAlagappa UniversityScience CampusKaraikudi630003Tamil NaduIndia Department of Biotechnology Achariya Arts and Science CollegeAffiliated to Pondicherry UniversityVillianurPuducherry605110India Department of Food Science and Human Nutrition Agricultural University of AthensIera Odos 75GR-11855AthensGreece

Occurrence of biogenic amines in fresh fish and fishery products constitute a significant safety *** of histamine is identified as the causative agent of several food poisoning incidences on an annual *** addition,cadaverine,putrescine and tyramine have been recognized as potentiators of histamine *** of biogenic amines in fresh fish and fishery products has been mainly attributed to growth of bacteria possessing amino acid decarboxylase activity,which is facilitated by lack of hygienic conditions and strict temperature control during their *** this end,the effectiveness of traditional and modern approaches to control biogenic amine accumulation has been in the epicenter of intensive *** aim of the present review article is to update and integrate current knowledge regarding the biogenic amine content of fresh fish and fishery products as well as the capacity of traditional and emerging control strategies.

关键词： Fresh fish Cephalopods Crustaceans Shellfish Histamine

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Alignment calibration and performance study of the STAR PXL detector

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Nuclear Science and Techniques 2017年第2期28卷 61-69页

作者： Long Ma Xin Dong Hao Qiu spiros Margetis Yu-Gang Ma Shanghai Institute of Applied Physics Chinese Academy of Sciences Shanghai 201800 China University of Chinese Academy of Sciences Beijing 100049China Nuclear Science Division Lawrence Berkeley National Laboratory Berkeley CA 94720 USA Purdue University West Lafayette IN 47907 USA Kent State University Kent OH 44242 USA ShanghaiTech University Shanghai 200031 China

We report in this paper the alignment calibration of the STAR pixel detector(PXL) prototype for the RHIC2013 run and performance study of the full PXL detector installed and commissioned in the RHIC 2014 run. PXL detector is the innermost two silicon layers of the STAR heavy flavor tracker aiming at high-precision reconstruction of secondary decay vertex of heavy flavor particles. To achieve the physics goals, the calibration work was done on the detector with high precision. A histogram-based method was successfully applied for the alignment calibration, and the detector efficiency after alignment was studied using both p t p collision data and cosmic ray data.

关键词： Alignment calibration Heavy flavor tracker STAR

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Rare cystic liver lesions: A diagnostic and managing challenge

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World Journal of Gastroenterology 2013年第43期19卷 7603-7619页

作者： Andreas Bakoyiannis spiros Delis Charina Triantopoulou Christos Dervenis First Surgical Department-HPB Surgical Unit Konstantopouleion Agia Olga General Hospital14233 AthensGreece Radiology Department Konstantopouleion Agia Olga General Hospital14233 AthensGreece

Cystic formations within the liver are a frequent finding among *** the common cystic lesions,like simple liver cysts,rare cystic liver lesions like cystadenocarcinoma should also be considered in the differential *** knowledge of each entity’s nature and course are key elements to successful *** search in PubMed,Cochrane Database,and international published literature regarding rare cystic liver lesions was carried *** our research are included not only primary rare lesions like cystadenoma,hydatid cyst,and polycystic liver disease,but also secondary ones like metastasis from gastrointestinal stromal tumors ***-to date knowledge regarding diagnosis and management of rare cystic liver lesions is provided.A diagnostic and therapeutic algorithm is also *** need for a multidisciplinary approach by a team including radiologists and surgeons familiar with liver cystic entities,diagnostic tools,and treatment modalities is *** with cystic liver lesions must be carefully evaluated by a multidisciplinary team,in order to receive the most appropriate treatment,since many cystic liver lesions have a malignant potential and evolution.

关键词： Liver cyst Cystic tumor Hepatic lesion Gastrointestinal stromal tumors Metastases Cystadenoma Cystadenocarcinoma Hydatid cyst Polycystic liver disease Caroli Echinococcus

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Two cameras detect more lesions in the small-bowel than one

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World Journal of Gastroenterology 2011年第11期17卷 1462-1467页

作者： Konstantinos Triantafyllou Ioannis S Papanikolaou Kostis Papaxoinis spiros D Ladas Hepatogastroenterology Unit 2nd Department of Internal Medicine-PropaedeuticAttikon University General HospitalMedical SchoolAthens University12464 AthensGreece 1st Department of Internal Medicine-Propaedeutic Laiko General HospitalMedical SchoolAthens University11527 AthensGreece

AIM:To explore the feasibility of dual camera capsule (DCC)small-bowel(SB)imaging and to examine if two cameras complement each other to detect more SB ***:Forty-one eligible,consecutive patients underwent DCC SB *** experienced investigators examined the videos and compared the total number of detected lesions to the number of lesions detected by each camera *** tolerability was assessed using a ***:One patient was *** cameras detected 68 positive findings(POS)in 20(50%)*** of them were detected by the"yellow"camera,48 by the"green"and 28 by both cameras;44%(n=22)of the"yellow"camera’s POS were not detected by the"green"camera and 42%(n=20)of the"green" camera’s POS were not detected by the"yellow"*** two cases,only one camera detected significant *** participants had 216 findings of unknown significance(FUS).The"yellow","green"and both cameras detected 171,161,and 116 FUS,respectively;32%(n=55)of the"yellow"camera’s FUS were not detected by the"green"camera and 28%(n=45)of the"green"camera’s FUS were not detected by the "yellow"*** were no complications related to the examination,and 97.6%of the patients would repeat the examination,if ***:DCC SB examination is feasible and well *** two cameras complement each other to detect more SB lesions.

关键词： Small-bowel capsule endoscopy Dual camera capsule endoscope Feasibility Lesion detection Diagnostic yield

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