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Present and future of metastatic colorectal cancer treatment: A review of new candidate targets

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World Journal of Gastroenterology 2017年第26期23卷 4675-4688页

作者： Giulia Martini Teresa Troiani Claudia Cardone Pietropaolo Vitiello Vincenzo Sforza Davide Ciardiello Stefania Napolitano Carminia Maria Della Corte floriana morgillo Antonio Raucci Antonio Cuomo Francesco Selvaggi Fortunato Ciardiello Erika Martinelli Department of Internal and Experimental Medicine“F.Magrassi e A.Lanzara” Institute of Medical OncologyUniversitàdegli studi della Campania Luigi Vanvitelli Department of Internal and Experimental Medicine Magrassi-LanzaraInstitute of RadiologyUniversitàdegli studi della Campania Luigi Vanvitelli Gastroenterology Unit Ospedale Umberto I Unit of Colorectal Surgery Department of MedicalSurgicalNeurologicalMetabolic and Ageing SciencesUniversità degli studi della Campania Luigi Vanvitelli

In the last two decades, great efforts have been made in the treatment of metastatic colorectal cancer(m CRC) due to the approval of new target agents for cytotoxic drugs. Unfortunately, a large percentage of patients present with metastasis at the time of diagnosis or relapse after a few months. The complex molecular heterogeneity of this disease is not completely understood; to date, there is a lack of predictive biomarkers that can be used to select subsets of patients who may respond to target drugs. Only the RAS-mutation status is used to predict resistance to anti-epidermal growth factor receptor agents in patients with m CRC. In this review, we describe approved targeted therapies for the management of metastatic m CRC and discuss new candidate targets on the horizon.

关键词： Novel biomarkers Monoclonal antibodies Resistance Mutation RAS Target therapy Metastatic colorectal cancer

Evaluation of the effective thermal conductivity of composite polymers by considering the filler size distribution law

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Journal of Zhejiang University-Science A(Applied Physics & Engineering) 2009年第5期10卷 704-709页

作者： Sorin HOLOTESCU floriana D. STOIAN Department of Thermal Machines Technology and Transportation "Politehnica" University of TimisoaraTimisoara RO-300222 Romania

We present an empirical model for the effective thermal conductivity (ETC) of a polymer composite that includes dependency on the filler size distribution-chosen as the Rosin-Rammler distribution. The ETC is determined based on certain hypotheses that connect the behavior of a real composite material A, to that of a model composite material B, filled with mono-dimensional filler. The application of these hypotheses to the Maxwell model for ETC is presented. The validation of the new model and its characteristic equation was carried out using experimental data from the reference. The comparison showed that by using the size distribution law a very good fit between the equation of the new model (the size distribution model for the ETC) and the reference experimental results is obtained, even for high volume fractions, up to about 50%.

关键词： Effective thermal conductivity (ETC) Filler size distribution Equivalent volume fraction Composite polymer

Manufacturing Outsourcing from China Luxury Companies Facing the Trade-Off between the Roi Increasing and the Risk of Brand Value Decreasing

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Manufacturing Outsourcing from China Luxury Companies Facing...

作者： Rosa morgillo 复旦大学

学位级别：硕士

如今,越来越多的奢侈品公司正在实施中国制造的外包生产策略,这些策略产生一个问题,即最终产品的买家对“中国制造”的国家品牌的感知方式。首先,我分析其背后的原因和奢侈品公司的外包选择的优势。其实由于金融和商业结构的原因,他们... 详细信息

如今,越来越多的奢侈品公司正在实施中国制造的外包生产策略,这些策略产生一个问题,即最终产品的买家对“中国制造”的国家品牌的感知方式。首先,我分析其背后的原因和奢侈品公司的外包选择的优势。其实由于金融和商业结构的原因,他们不得不采用降低成本的策略,如产品的制造外包。在奢侈品行业,固定成本非常高,他们的供应链管理的最昂贵的部分是结尾部分(零售,市场营销,销售等)。产品制造外包给了奢侈品公司的机会,既降低成本,又要争取在生产管理上的灵活性。外包成功的关键是要在公司内部留住制造知识,并选择和控制供应商。这就是我们所谓的“豪华解决方案”。其次,我已经在奢侈品公司的全球供应链分析了中国制造业的作用,这是为了更好地理解为什么奢侈品公司大多选择中国作为其产品的“源头”而不是其他国家。中国制造系统的关键成功因素是：廉价的土地,劳动力和中国的潜在市场。根据2011年由美国劳工统计局公布的报告,在2008年,用美元来衡量,2008年中国制造业每小时劳动报酬成本大约为美国的4%,欧元区的3%。此外,实际上使中国区别于其他的“便宜”制造业国家的是产品质量和生产的灵活性,中国制造业企业有能力保证质量水平。奢侈品企业的工作,围绕品牌和品牌的顾客价值。事实上,我们已经看到,在世界上没有比奢侈品品牌更看重为客户创造价值这一目标,其目的就是被视为奢侈品、高档品牌。的确,品牌代表的奢侈品公司的投资组合中最重要的资产之一。事实上,奢侈品公司的供应链主要的活动就是为客户,从而为品牌创造价值,即品牌管理。这是因为品牌的理念,在客户的心目中存有故事,它是驱动利润的元素。奢侈品公司发展战略品牌,沟通和客户体验的共同目标是增加顾客资产。顾客资产是金融资产的序言：奢侈品牌的财务价值是来源于他们为客户,分销商,舆论领袖创造的头脑中和心中的资产。这些资产是品牌的知名度,独占性和优越性,价值利益和感情纽带。我们已经看到,影响客户权益的一个重要因素是该品牌原产的国家或地理位置1。国家品牌,利用某一特定国家的“遗产”,帮助企业建立消费者信心,刺激购买欲望。一个相当有趣的问题是关于品牌产品,一个品牌的产品“原产地认为国家”(即可以不同于“原产地认为国家”)。“设计的国家”或“组装的国家”与制造国类似,影响该国在国家产品线作为设计的具体位置的形象。因此今天的奢侈品公司在中国外包中,投入了大量旨在促进自己产品的“原产地感知国”(这可能不同于他们的产品在现实中的生产国国家)的沟通和零售策略。此外,由于缺乏全球性的,统一的立法或共识来规范什么事制造国,他们“支持”这种“误导”式的战略。在这样的背景下,奢侈品公司可以感觉更舒适,比过去更多地实施基于中国的产品制造外包生产,以削减成本。据“中国制造：2007年品牌研究报告”2(涉及700业务和营销专业人士的调查)证实,前三与中国制造的品牌/产品相关的属性是：价格便宜,良好的价值和年轻。此外,最后的三个属性,是：豪华,久负盛名,高品质。尽管这些结果,有三个因素,实际上减轻了“中国制造”的标签的挑战：首先最重要的是消费者并不坚持检查原产地标签。其次,这么多来自西方外包到中国制造公司,将生产转移到另一个国家的成本高,消费者在短期很少有其他选择。第三,消费者对产品品牌的信任可能减小对原产地的关注。这让我们得出结论,即使“中国制造”的标签不符合与奢侈品牌的产品,它可能只有有限的“负”品牌的认知效果。ABC的业务经验表明,即使奢侈品公司在中国开展产品制造外包,他们绝对保持强烈的对产品开发和设计导向(内部)。新品牌和沟通所起的作用,意味着人与奢侈品世界之间的关系由奢侈品牌与顾客的互动(而不是产品)定义,而产品的作用是只是“功能”性的。奢侈品牌,都能够通过提高他们的特权世界,从而“分散”客户对于产品生产地的关注,而更关心品牌的国籍。在任何情况下,产品制造策略应遵循和保持一致的品牌定位策略：这是在中国制造外包的奢侈品公司的金科玉律。事实上,根据ABC的经验,任何奢侈品牌实施战略要面对可取得型(驱动销量和品牌知名度)和排他性(即驱动品牌形象)之间的权衡,从中国制造外包是一种更好的可得性而非排他性策略。事实上,品牌和沟通战略被以某种方式利用,“隐藏操作细节”或“降低外包对品牌的影响”使今天民主化的奢侈品市场比未受污染的至高无上的奢侈品市场“更真”。例如,一些优质品牌,像阿玛尼,通过不同的定位,通过不同的营销组合战略和生产战略保护自己不进入第二或第三线品牌,即“大众高端品牌”。在ABC的案例下,投资组合中的品牌分为三个主要分支,根据自己的定位：豪华(为“真正的奢侈品”),高档和普通品牌;每个涉及在ABC组合的奢

关键词：奢侈品制造外包品牌价值国家价值制造地标志

Anion-induced N-doping of naphthalenediimide polymer semiconductor in organic thin-film transistors

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npj Flexible Electronics 2018年第1期2卷 90-96页

作者： Yang Han Zhuping Fei Yen-Hung Lin Jaime Martin floriana Tuna Thomas DAnthopoulos Martin Heeney Dept.Chemistry and Centre for Plastic Electronics Imperial College LondonExhibition RdLondon SW72AZUK Dept.Physics and Centre for Plastic Electronics Imperial College LondonExhibition RdLondon SW72AZUK Dept.of Materials Imperial College LondonExhibition RdLondon SW72AZUK School of Chemistry and Photon Science Institute University of ManchesterOxford RdManchester M139PLUK Division of Physical Sciences and Engineering King Abdullah University of Science and TechnologyThuwal 23955-6900Saudi Arabia

Molecular doping is an important strategy to improve the charge transport properties of organic semiconductors in various electronic *** to p-type dopants,the development of n-type dopants is especially challenging due to poor dopant stability against atmospheric *** this article,we report the n-doping of the milestone naphthalenediimide-based conjugated polymer P(NDI2OD-T2)in organic thin film transistor devices by soluble anion *** addition of the dopants resulted in the formation of stable radical anions in thin films,as confirmed by EPR *** tuning the dopant concentration via simple solution mixing,the transistor parameters could be readily *** the contact resistance between the electrodes and the semiconducting polymer could be significantly reduced,which resulted in the transistor behaviour approaching the desirable gate voltage-independent *** hysteresis was also observed,thanks to the trap filling by the *** optimal doping concentrations the channel on-current was increased several fold whilst the on/off ratio was simultaneously increased by around one order of *** doping with soluble organic salts appears to be a promising route to improve the charge transport properties of n-type organic semiconductors.

关键词： dopant tuning doping

Role of concomitant therapy for Helicobacter pylori eradication: A technical note

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World Journal of Gastroenterology 2016年第38期22卷 8638-8640页

作者： Giuseppe Losurdo floriana Giorgio Andrea Iannone Mariabeatrice Principi Michele Barone Alfredo Di Leo Enzo Ierardi Section of Gastroenterology Department of Emergency and Organ TransplantationUniversity of Bari

We read with interest the recent meta-analysis by Lin et al who evaluated the effectiveness of concomitant regimen for Helicobacter pylori(H. pylori) in Chinese regions. They found that 7-d concomitant regimen is undoubtedly superior to 7-d triple therapy(91.2% vs 77.9%, P < 0.0001). However, it is a common belief that a triple therapy lasting 7 d should be definitively removed from the clinical practice for its ineffectiveness. Only its prolongation to 14 d may give satisfactory success rate. Thus, the assessment of an old and outdated treatment versus a more recent and successful one does not seem to bring novel and useful information. Moreover, a 7-d duration has not been ascertained for concomitant regimen, as main guidelines recommend a 10-d schedule for this scheme. Therefore, only studies comparing 10-d concomitant versus 14-d triple seem to be appropriate according to current Guidelines and would clarify which regimen is the most suitable worldwide. Additionally, in this metaanalysis concomitant and sequential therapy showed similar performances, despite it is common opinion that sequential is more prone than concomitant therapy to fail when metronidazole resistance occurs, and China is characterized by high rate of resistance to this antibiotic. None of the included studies evaluated a priori antibiotic resistances, and the lack of this detail hampers the unveiling of this apparent contradiction. In conclusion, the lack of the evaluation of the quality of included trials as well as their high heterogeneity constitute a burdensome limit to draw solid conclusions in this meta-analysis. On the bases of these considerations and the low number of examined trials, we believe that further studies and the knowledge of antibiotic resistances will support with high quality evidence which is the best regimen and its optimal duration.

关键词： Helicobacter pylori Eradication Sequential Concomitant Triple therapy Antibiotic resistances

Noninvasive molecular analysis of Helicobacter pylori : Is it time for tailored first-line therapy?

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World Journal of Gastroenterology 2017年第14期23卷 2453-2458页

作者： Enzo Ierardi floriana Giorgio Andrea Iannone Giuseppe Losurdo Mariabeatrice Principi Michele Barone Antonio Pisani Alfredo Di Leo Gastroenterology Section Department of Emergency and Organ Transplantation University of Bari

The main problem of Helicobacter pylori(H. pylori) infection management is linked to antibiotic resistances. This phenomenon has grown in the last decade, inducing a dramatic decline in conventional regimen effectiveness. The causes of resistance are point mutations in bacterial DNA, which interfere with antibiotic mechanism of action, especially clarithromycin and levofloxacin. Therefore, international guidelines have recently discouraged their use in areas with a relevant resistance percentage, suggesting first-line schedules with expected high eradication rates, i.e., bismuth containing or non-bismuth quadruple therapies. These regimens require the daily assumption of a large number of tablets. Consequently, a complete adherence is expected only in subjects who may be motivated by the presence of major disorders. However, an incomplete adherence to antibiotic therapies may lead to resistance onset, since sub-inhibitory concentrations could stimulate the selection of resistant mutants. Of note, a recent meta-analysis suggests that susceptibility tests may be more useful for the choice of first than second-line or rescue treatment. Additionally, susceptibility guided therapy has been demonstrated to be highly effective and superior to empiric treatments by both meta-analyses and recent clinical studies. Conventional susceptibility test is represented by culture and antibiogram. However, the method is not available everywhere mainly for methodology-related factors and fails to detect hetero-resistances. Polymerase chain reaction(PCR)-based, culture-free techniques on gastric biopsy samples are accurate in finding even minimal traces of genotypic resistant strains and hetero-resistant status by the identification of specific point mutations. The need for an invasive endoscopic procedure has been the most important limit to their spread. A further step has, moreover, been the detection of point mutations in bacterial DNA fecal samples. Few studies on clarithromycin su

关键词： Helicobacter pylori Antibiotic resistance Noninvasive molecular test Tailored therapy Stool

Exploring the Usefulness of Extensible Business Reporting Language （XBRL） for Reporting Intellectual Capital （IC）： Evidence From Italian Preparers

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Journal of Modern Accounting and Auditing 2014年第5期10卷 537-550页

作者： Marco Papa floriana Luisi University ofBari Aldo Moro Bari Italy

Intellectual capital disclosure （ICD） has experienced a substantial increase in recent decades and many frameworks and guidelines have been issued to provide directions with regard to what constitutes ＂good＂ ICD. Companies can use Extensible Business Reporting Language （XBRL） to ＂build＂ their own intellectual capital （IC） reports. This digital format has both technical and operating characteristics suitable for reporting non-financial information. This paper reports the findings of a survey of the views of 37 Italian preparers on the scope, the taxonomy, and the assurance of IC reporting via XBRL. It was found that respondents favor the adoption of an IC reporting framework and the standardization of IC indicators. Preferences reveal uncertainty about the level of flexibility for tagging IC information, while supporting the main benefits of XBRL and indicating a marked inclination for tagged information certified by an independent audit. Overall, despite a low awareness of XBRL, the importance placed on standardization of IC information and on the usefulness of the comparability and the speed attribute of XBRL supports the appealing features of this language for developing IC reporting.

关键词： Extensible Business Reporting Language (XBRL) digital reporting intellectual capital disclosure (ICD) business reporting

Silymarin,boswellic acid and curcumin enriched dietetic formulation reduces the growth of inherited intestinal polyps in an animal model

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World Journal of Gastroenterology 2020年第14期26卷 1601-1612页

作者： Bruna Girardi Maria Pricci floriana Giorgio Mariano Piazzolla Andrea Iannone Giuseppe Losurdo Mariabeatrice Principi Michele Barone Enzo Ierardi Alfredo Di Leo THD SpA Correggio 42015Italy Gastroenterology Section Department of Emergency and Organ TransplantationUniversity of BariBari 70124Italy

BACKGROUND Some substances of plant origin have been reported to exert an effect in reducing intestinal neoplasm development,especially in animal *** polyposis coli multiple intestinal neoplasia-ApcMin/+is the most studied murine model of genetic intestinal *** To assess whether an enriched nutritional formulation(silymarin,boswellic acid and curcumin)with proven“in vitro”and“in vivo”anti-carcinogenetic properties may prevent inherited intestinal cancer in animal *** Forty adenomatous polyposis coli multiple intestinal neoplasia-ApcMin/+mice were used for the study of cancer *** were divided into two groups:20 assumed standard and 20 enriched *** the 110th d animals were *** each group,four subgroups received intraperitoneal bromodeoxyuridine injection at different times(24,48,72 and 96 h before the sacrifice)in order to assess epithelial ***,we evaluated the following parameters:Intestinal polypoid lesion number and size on autoptic tissue,dysplasia and neoplasia areas by histological examination of the whole small intestine,inflammation by histology and cytokine mRNA expression by real-time polymerase chain reaction,bromodeoxyuridine and TUNEL immunofluorescence for epithelial turnover and apoptosis,***,we performed western blotting analysis for the expression of estrogen alpha and beta receptors,cyclin D1 and cleaved caspase 3 in normal and polypoid *** Compared to standard,enriched diet reduced the total number(203 vs 416)and the mean±SD/animal(12.6±5.0 vs 26.0±8.8;P<0.001)of polypoid *** enriched diet group a reduction in polyp size was observed(P<0.001).Histological inflammation and pro-inflammatory cytokine expression were similar in both *** of low-grade dysplasia(P<0.001)and intestinal carcinoma(IC;P<0.001)were significantly decreased in enriched diet *** was observed in 100%in standard and 85%in enriched formulation assumin

关键词： Intestinal cancer Familial adenomatous polyposis Chemopreventive diet Apc^Min/+mice Boswellia Curcumin

The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13

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Cellular & Molecular Immunology 2021年第6期18卷 1512-1527页

作者： floriana Mulas Xu Wang Shanshan Song Gopala Nishanth Wenjing Yi Anna Brunn Pia-Katharina Larsen Berend Isermann Ulrich Kalinke Antonio Barragan Michael Naumann Martina Deckert Dirk Schlüter Institute of Medical Microbiology and Hospital Hygiene Otto-von-Guericke University Magdeburg39120MagdeburgGermany Institute of Medical Microbiology and Hospital Epidemiology Hannover Medical School30625HannoverGermany Chemical Biology Research Center School of Pharmaceutical SciencesWenzhou Medical University325035WenzhouChina Department of Neuropathology Faculty of Medicine and University Hospital CologneUniversity of Cologne50931CologneGermany Institute for Experimental Infection Research TWINCORE Centre for Experimental and Clinical Infection Researcha joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research30625HannoverGermany Institute for Clinical Chemistry and Pathobiochemistry Otto-von-Guericke University Magdeburg39120MagdeburgGermany Cluster of Excellence-Resolving Infection Susceptibility(RESIST) Hannover Medical School30625HannoverGermany Department of Molecular Biosciences Stockholm University10691StockholmSweden Institute for Experimental Internal Medicine Otto-von-Guericke University Magdeburg39120MagdeburgGermany

Dendritic cells(DCs)are indispensable for defense against pathogens but may also contribute to *** of DCs upon the sensing of pathogens by Toll-like receptors(TLRs)is largely mediated by pattern recognition receptor/nuclear factor-κB(NF-κB)signaling and depends on the appropriate ubiquitination of the respective signaling ***,the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely ***,we reveal that the deubiquitinase OTU domain,ubiquitin aldehyde binding 1(OTUB1)is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide *** of DCs with the TLR11/12 ligand *** profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-κB activation in OTUB1-competent cells,resulting in elevated interleukin-6(IL-6),IL-12,and tumor necrosis factor(TNF)production,which was also observed upon the specific stimulation of TLR2,TLR3,TLR7,and ***,OTUB1 promoted NF-κB activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13,resulting in increased K63-linked ubiquitination of IRAK1(IL-1 receptor-associated kinase 1)and TRAF6(TNF receptor-associated factor 6).Consequently,DC-specific deletion of OTUB1 impaired the production of cytokines,in particular IL-12,by DCs over the first 2 days of *** infection,resulting in the diminished production of protective interferon-γ(IFN-γ)by natural killer cells,impaired control of parasite replication,and,finally,death from chronic ***,all of which could be prevented by low-dose IL-12 treatment in the first 3 days of *** contrast,impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced ***,these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.

关键词： OTUB1 dendritic cell signal transduction ubiquitination innate immunity