Government debts and credit markets in Renaissance Italy

At first sight a marked difference turns out among the Italian governments of early Renaissance: the means of financing their deficit. There are, on the one hand, communal cities and republics, raising money from citizens through the system of forced or voluntary loans; there are, on the other, princes and lords who exploit services of bankers and merchants. These two different systems of borrowing bring about significant financial and political aspects. In this paper I will examine the main features characterizing the two mechanisms of indebtedness and the implications concerning the emergence of a true financial market connected with state bonds.Public debts; Renaissance Italy; financial markets; financial institutions

Una fiera senza luogo. Was Bisenzone an offshore capital market in sixteenth-century Italy?

This paper discusses how Genoese bankers collected money at exchange fairs. This money was then lent to the King of Spain - through the asientos - from the mid-sixteenth to the early seventeenth centuries. Genoese bankers raised capital at the exchange fairs , which were typical short-term credit mechanism, where foreign bills of exchange were discounted over a three-month period. The Genoese funded long-term obligations by means of short term loans which meant they were able to enforce payment to the King and at the same time successfully manage the supply of finance from a large number of easily substitutable markets, located in different states. The Bisenzone fair of exchange was the forerunner to an efficient, widely integrated international capital market where Genoese pre-eminence was firmly established and which the Genoese kept firmly under their control. The success of the Bisenzone fairs of exchange directly challenges the theory which suggests that the laws against usury restrained the development of capital markets in early modern Italy.Financial markets, market integration, financial institutions

Frizzled receptor 6 marks rare, highly tumourigenic stem-like cells in mouse and human neuroblastomas

Copyright © 2011 Cantilena et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The article was made available through the Brunel Open Access Publishing Fund.Wnt signalling is an important component of vertebrate development, required for specification of the neural crest. Ten Wnt receptors [Frizzled receptor 1-10 (Fzd1-10)] have been identified so far, some of which are expressed in the developing nervous system and the neural crest. Here we show that expression of one such receptors, Fzd6, predicts poor survival in neuroblastoma patients and marks rare, HIF1/2 α-positive cells in tumour hypoxic areas. Fzd6 positive neuroblastoma cells form neurospheres with high efficiency, are resistant to doxorubicin killing and express high levels of mesenchymal markers such as Twist1 and Notch1. Expression of Fzd6 is required for the expression of genes of the noncanonical Wnt pathway and the spheres forming activity. When transplanted into immunodeficient mice, neuroblastoma cells expressing the Fzd6 marker grow more aggressively than their Fzd6 negative counterparts. We conclude that Fzd6 is a new surface marker of aggressive neuroblastoma cells with stem cell-like features.This work was sponsored by the Wellcome Trust, the RICC cancer fund, SPARKS, the Italian Association for Cancer Research, Regione Liguria and the Italian Ministry of Health

Roma Pride, identit\ue0 in parata: una etnografia al Circolo di Cultura Omosessuale Mario Mieli (Roma)

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Face mask use in the community and cutaneous reactions to them during the COVID-19 pandemic: results of a national survey in Italy.

To mitigate the outbreak of coronavirus disease 2019 pandemic, many countries have imposed the public use of face masks. We investigated attitudes and skin reactions in the Italian individuals wearing face masks during the pandemic. A cross-sectional survey on a random sample (N=1001) of the Italian adult population was conducted in May 2020 by the Italian Group for Epidemiological Research in Dermatology, and the Gallup International Association. Univariable and multivariable regression analysis were used to estimate the odds ratios and their 95% confidence intervals. Most individuals (72.5%) wore a mask, 56.5% used a surgical mask and 53.0% a disposable mask. One-third changed the mask at least once a day, two-thirds kept a distance of at least one meter from each other, 50% washed their hands before wearing a mask, and 17.6% adopted multiple hygienic behaviors. Twenty percent of individuals reported redness, swelling, itching or erosions in the skin area of mask contact; the risk of this reaction was associated with young age, the use of respirators and a history of pre-existing contact eczema, psoriasis or atopic dermatitis. Health educational programs may improve compliance with combined preventive measures and reduce skin reactions

Resistenza, adesione e frode fiscale nell'Europa della prima età moderna

The refusal to pay taxes and to fulfil tax obligations correctly has always characterised relations between taxpayers and fiscal authorities. The taxpayer’s fraudulent behaviour takes the form of misrepresentation or even the concealment of his income. The most common form of evasion is the declaration of a lower amount of income than that actually received or the claiming of an amount of exemptions and deductions beyond the legal level. But resistance to tax also manifests itself in other forms: by delaying payment, even by legal means, or even refusing to pay the amount due, to the point of violently opposing collection. This essay examines some forms of resistance to taxes in Europe between the 15th and 17th centuries, trying to highlight similarities and possible differences between various countries

ANALISI DI BIOMARCATORI GENETICI PER PREDIRE LA RISPOSTA IN PAZIENTI CON TUMORE AL RETTO E ALL'ESOFAGO TRATTATI CON CHEMIORADIOTERAPIA NEOADIUVANTE

Gastrointestinal (GI) tumors refers to malignant conditions afflicting esophagus, stomach, intestin, bladder, liver and pancreas. These kinds of neoplasms are considered overall the most lethal in the world. Gastrointestinal tumors represents 22% of total cancers and the major danger for world health with 12% of total annual deaths. In the last years, in Europe the high rate of GI tumors, evaluated more than 250.000 new cases and 140.000 deaths. Even though the incidence of GI tumors is decreasing in the western area of the world, these neoplasms actually remain a serious issue for worldwide public health. In particular in Asia and in some areas of South America, GI tumors are the most common cancers and represent the main cause of death. Although diagnosis improvements, many times GI tumors are identified too late due to unclear symptoms or uncertain screening method. In most cases, GI tumor patients are diagnosed at the late stage, therefore they loss the opportunity to take advantage of early clinical intervention and about 20-45% of them are surgically resected after tumor relapse or metastasis development. The aggressive character of GI tumors is related to an high number of anomalies among which oncogenes and telomerase activation, oncosuppressor genes inactivation and many anomalies in growth factors and receptors. In particular, rectal cancer is one of the most common tumor worldwide. Incidence and mortality rate change depending on geographic areas. In the United States, more than 130.000 new cases and more than 50.000 death every years are evaluated. In the European Union, rectal cancer represents more than 35% of total colorectal neoplasms; the incidence is 15-25/100.000 every year. Esophageal cancer is the sixth major cause of mortality correlated to the tumor and the eighth more common tumor type worldwide. In the world 450.000 individuals are afflicted by esophageal tumor and its incidence is increasing. Esophageal cancer represents the most common cause of cancer death in the world male population. The prognosis is moderately unfavourable with a 5 years survival rate varying between 15% to 26% according to the treatment type; best results can be obtained with an early diagnosis during the early stages. Surgical resection and radiotherapy represent the main curative treatments in early stages of both esophageal and rectal cancers but a considerable percentage of patients is classified as locally advanced tumor. In this group of patients, the tumor grows beyond rectal or esophageal epithelium or can invade surrounding organs and structures; in these cases surgery and radiotherapy are not sufficient leading to a major risk of locoregional recurrence and metastasis development. In the last years, surgical excision combined with neoadjuvant therapy are considered the gold standard treatment for locally advanced rectal and esophageal cancer. Effectively, more than half of patients treated with neo-adjuvant 5-Fluorouracil and/or cisplatin -based chemoradiotherapy (CRT) for locally advanced rectal and esophageal carcinomas has shown to be effective to downstage more than half preoperative treated patients. Other half patients is not able to be effective responders to chemotherapy. Up to date no variables are known to be strong predictive of response. Interindividual variations in DNA repair and metabolism of pyrimidine nucleotides, folates and cisplatin may be important mechanisms for resistance to radio and chemotherapy. Common gene polymorphisms in these pathways have been well described and their associations with anticancer-treatment outcome have been widely investigated using statitical linear models, with inconsitent results. Epistasis is the naturaly occurring interaction between genes at two or more loci so that the phenotype differes from what expected if the genes were expressed indipendently. Its a frequent phenomenon, that linear statistics cannot reveal and it shoud be considered in pharmacogenetic studies. The Multifactor Dimensionality Reduction (MDR) method was designed specifically to identify interactions among discrete variables that influence a binary outcome and is increasingly used in pharmacogenetics. This method classifies genotypes in “responders” or “non responders” in order to reduce the multidimensionality of data in only one dimension; so we can identify genetic combiantions confering disease prediction. The aim of the present study was to correlate some polymorphisms of genes involved in DNA repair systems, detoxification pathway and antitumoral drug mechanisms of action and methabolism with clinical outcome of concomitant chemoradiotherapy actually used as standard neoadjuvant for rectal and esophageal cancer patients. Furthermore, we want to evaluate the use of new approches to identify genotype-phenotype correlations. In this study, 70 patients with stage II and III rectal cancer were enrolled, 18 females and 52 males, mean age 62 years old. They were treated with 5 weeks of 300 mg/m2/die 5 fluorouracil protracted venous infusion concurrent to 56 Gy radiation followed by surgical resection. Responses at tumor level were directly evaluated on surgical specimens and scored according to TNM classification. Patients were considered as responders (if T0, complete response; if T1 or T2, partial response) or non responders (if T3 and T4). Genomic DNA was extracted from peripheral blood lymphocytes and ERCC1, XPD, XPA, XRCC1, XRCC3, UMPS, MTHFR677, MTHFR1298, TYMS 3'UTR and TYMS 5'VNTR genotypes were analyzed by PCR-RFLP and dHPLC. In particular, the following SNPs were analyzed: XRCC1 Arg399Gln (rs25487), MTHFR 677 C>T (rs1801133), MTHFR 1298 A>C (rs1801131),TYMS 3'UTR 1494del6 (rs34489327), TYMS 5'UTR 28bp (rs34743033), TYMS 5'UTR G/C (rs2853542), XPC Lys939Gln A>C (rs2228001), XPD (ERCC2) A>C (rs121913019), ERCC1 C>T (rs121913027), XRCC3 Thre241Met G>A (rs861539), UMPS T>C (rs10049380). Polymorphisms were selected according to genotipic frequencies of our population and considered only if minor variant frequency was at least 10% in the Caucasian population. Genotypes were correlated with tumor outcomes to CRT considering both complete (T0 vs T1-4) and major (T0-2 vs T3-4) responses. About the second set of samples, 124 mid/low locally advanced esophageal GEJ tumors patients (T2-T4 with or without positive lymph nodes) and treated with neoadjuvant CRT were enrolled. All patients received weekly docetaxel (35 mg/m2) and cisplatin (25mg/m2), protracted venous infusion of fluorouracil (150 mg/m2/die) and concomitant radiotherapy (50 Gy). Radical surgery was performed 6-8 weeks after treatment was completed. DNA was extracted from peripheral leukocytes using a commercial kit (Wizard Genomic, Promega). Polymorphisms in genes of the DNA repair systems (XPA-rs1800975, XPC-rs2228000, XPC-rs2228001, XPD-rs13181, XRCC1-rs25487, XRCC3-rs861539, ERCC1-rs11615), drug pathways (MTHFR-rs1801133, TYMS-rs34743033, UMPS-rs1801019) and detoxification (MDR1-rs2032582, GSTP1-rs11338272) were characterized through RLFP-PCR and dHPLC analysis. Tumor responses were directly evaluated on surgical specimes and organized according to TNM classification. Pathological complete response (CR) was defined as the absence of residual tumor (ypT0N0); near pathological complete response (nCR) was defined as the presence of microfoci of cancer cells at the primary site with negative lymph nodes; the remaining patients were classified as non responders (NR). Responders were defined as patients having CR or nCR. Cancer specific survival (CSS) was defined as the time between diagnosis and death from cancer; relapse-free survival (RFS) was defined as the time between initiation of therapy and the first evidence of disease recurrence. Survival curves were computed with the Kaplan-Meyer method and compared using the log rank test. Statistical analysis were performed using chi square test, logistic regression and Multifactor Dimensionality Reduction method. Patients responded to CRT at tumor level as follows: pT0 (patients without tumor) in 25.7% , pT1-2 (patients with an important tumor reduction) in 34.3% and pT3-4 (patients without tumor reduction) in 40%. So less than half of patients demostrated to have any response from CRT, according to the literature. All genotype data were correlated to pathological response. Chi square tests showed no significant correlation between genotipization and local patological respose. Also logistic regression was performed and no associations between genotype, sex, age and pathological response were revealed. On the contrary, using the MDR method, we showed a significant correlation between the combination of XRCC1/MTHFR677 genetic variants and major response (p=0,0009) that was correcly predicted in 77.8% of patients. About the esophageal cancer set of patients, univariate analysis showed that MTHFR 677TT, MDR1 2677GT, GSTP1 114CC, XPC 499CC and XPC 939AC+CC genotypes were associated to shorter RFS with a p value ≤0.1 and were defined as high risk variants. A model including these five polymorphisms discriminated three numerically similar subgroups, carriers of 0-2 (n= 48), 3 (n= 38) or 4-5 (n= 36) high risk genotypes, for which 5-year RFS was 67.1%, 50.0% and 20.9% (p= 0.0002) and 5-year CSS was 71.1%, 55.8% and 25.8% (p=0.0003), respectively. When the 5-SNP panel was combined with histology, the analysis split patients in two main subsets with 5-year RFS rates ranging from 61% to75% and 22% to 36%. In particular, 5-year RFS was different in the subset with 3 high risk polymorphisms according to histology: 61% in squamous and 36% in adenocarcinoma patients (p=0.06). Globally, two class risk could be obtained with 5 years RFS and CSS rates of 65% vs 27% (HR 3.0, 95% CI 2.0-6.0, p<0.0001) and 69% vs 31% (HR 2.9, 95% CI 1.8-5.7, p<0.0001), respectively. In the end, the combination of pathological response with the 5-SNP panel allowed the allocation of the whole series in two major informative risk classes: high (47.5% of patients, including all NRs and nCRs with 3-5 unfavourable genotypes) or low risk (52.5% of patients, including all CRs and nCRs with 0-2 unfavourable genotypes) class. The two final groups had statistically different outcomes: 5-year PFS rates were 79.4% vs 17.7% (HR 6.71, 95% CI : 3.98-12.0, p<0.0001) and 5-year CSS rates were 79.3% vs 26.3% (HR 6.25, 95% CI : 3.6-11.5, p<0.0001). The internal validation procedure by MDR confirmed our models as good predictors. Finally, important to underline, before establishing the SNPs panel, all the single polymorphisms were evaluated and associated to pathological response, both in rectal and in esophageal cancer patients through univariate analysis. XPC Lys939Gln SNP was significantly associated with pathological response: pts carrying wild genotype presented complete or major response in 84.1% of cases, compared to 52.6% and 40% in heterozygotes and Gln homozygotes, respectively (p=0.0006). No association was found with the other SNPs. In contrast with these findings, in the set of rectal patients, as above mentioned, univariate analysis revealed any statistically significant association between pathological response and SNPs, not even with XPC Lys939Gln, predicting pathological response in esophageal neoplasms; in this sample set it was not related to a significant reduction of tumor mass in rectal cancers (p=0.37). In conclusion our data demonstrated the role of a panel of 4 genes/5 SNPs in predicting PFS and CSS in patients receiving the same intensive neoadjuvant chemoradiation protocol. Polymorphisms of XPC, MDR1, GSTP1 and MTHFR deserve further evaluation in order to guide therapeutic decisions in this setting of patients. Another important aspect of these results is the predictive value in pathological response only in esophageal and not in rectal cancer patients. Furthermore, our findings suggest that epistasis should be considered when analysing pharmacogenetic associations. The Multifactor Dimensionality Reduction is an easy and valid method to detect genetic combinations that can identify patients with a high probability of tumor response when chemoradiotherapy for colonrectal cancer is indicated

Local-to-Global Principles for the Hitting Sequence of a Rotor Walk

In rotor walk on a finite directed graph, the exits from each vertex follow a prescribed periodic sequence. Here we consider the case of rotor walk where a particle starts from a designated source vertex and continues until it hits a designated target set, at which point the walk is restarted from the source. We show that the sequence of successively hit targets, which is easily seen to be eventually periodic, is in fact periodic. We show moreover that reversing the periodic patterns of all rotor sequences causes the periodic pattern of the hitting sequence to be reversed as well. The proofs involve a new notion of equivalence of rotor configurations, and an extension of rotor walk incorporating time-reversed particles.Massachusetts Institute of Technology. Undergraduate Research Opportunities ProgramNational Science Foundation (U.S.) (Grant 0644877)National Science Foundation (U.S.) (Grant 1001905)National Science Foundation (U.S.) (Postdoctoral Research Fellowship)National Science Foundation (U.S.). Research Experience for Undergraduates (Program

Desapropriação e função social da propriedade: o declínio das reformas de base, da Constituição de 46 à “Lei do Retrofit” em São Paulo: Expropriation and social function of property: the decline of the basic reforms, from the '46 Constitution to the "Retrofit Law" in São Paulo

Sob o ponto de vista de uma certa dogmática jurídica, a desapropriação não seria um problema de grande relevância. No processo judicial obrigatório para o sacrifício da propriedade, a contestação é limitada ao valor da desapropriação ou a vício processual (art. 20 do Dec.-Lei 3.365/41), sendo ademais proibida a discussão sobre a titularidade da propriedade (art. 34 Dec.-Lei 3.365/41). A desapropriação seria algo relacionado a obras e melhoramentos urbanos, algo localizado e absolutamente necessário ao interesse público