Ruthenium(III) complexes entrapped in liposomes with enhanced cytotoxic and anti-metastatic properties

Metal-based anticancer drugs are pivotal in the fight against cancer pathologies. Since 1978 cis-platin was licensed for medical treatment of a wide number of tumor pathologies(1). However its chemiotherapic use is strongly limited by many and severe side effects and acquired tumor resistance. Since these limitations could be overcome by other metal complexes, in the last thirty years ruthenium compounds have been tested showing a remarkable antitumoral and antimetastatic activity associated with a lower toxicity. A hexacoordinate Ru(III) complex (NAMI-A) is currently undergoing advanced clinical evaluation (2). All data indicate that NAMI-A acts as a pro-drug, but the integrity of ruthenium complexes is essential to store the cytotoxic activity. In this scenario the condition of administration of ruthenium drugs are crucial to exploit their anticancer activity (3). In the last years innovative strategies have been produced to vehicle ruthenium ions in tumor cells like aggregates. This study aims to incorporate the ruthenium complexes in the inner aqueous compartment of liposomes and to test biological properties of two NAMI-A like pyridine derivatives. Specifically, we have investigated the pyridine derivatives of the sodium-compensated analogue of NAMI-A, Na[trans-RuCl4(pyridine)(DMSO)] (NAMI-Pyr) and Na[trans-RuCl4(Pytri)(DMSO)] (NAMI-Pytri). In thelatter complex the pyridine ligand is functionalized with a sugar moiety so as to increase biocompatibility and the ability to cross the cell membrane. The stability of the complexes was studied and compared in solution at different pH following UV-VIS spectra. Lipid formulations based on Egg PC were prepared adding Cholesterol, DSPE-PEG2000 joining molar ratio 57/38 /5% w/w respectively in MeOH/CHCl3 (50/50 v/v) mixture and hydrated with 0.9% w/w of NaCl. This composition was selected to reproduce analog supramolecular aggregates in clinical use to vehicle doxorubicin (Doxil). Ruthenium complexes were loaded into liposomes using the passive equilibration loading method. Full drug containing liposomes were structurally characterized by dynamic light scattering (DLS) measurements. Data indicate the formation of stable aggregates with size and shape in the right range for in vivo applications. The amount of encapsulated ruthenium complexes was quantified by means of ICP-AES. Stability and drug release properties of ruthenium containing liposomes were confirmed in buffer. The growth inhibitory effects of both liposomal and free complexes drug were tested on prostate cancer cells (PC3). Preliminary results show high cytotoxic effect of ruthenium complexes delivered by supramolecular aggregates with respect to free complexes drug

Reverse engineering of mandible and prosthetic framework: Effect of titanium implants in conjunction with titanium milled full arch bridge prostheses on the biomechanics of the mandible.

This study aimed at investigating the effects of titanium implants and different configurations of full-arch prostheses on the biomechanics of edentulous mandibles. Reverse engineered, composite, anisotropic, edentulous mandibles made of a poly(methylmethacrylate) core and a glass fibre reinforced outer shell were rapid prototyped and instrumented with strain gauges. Brånemark implants RP platforms in conjunction with titanium Procera one-piece or two-piece bridges were used to simulate oral rehabilitations. A lateral load through the gonion regions was used to test the biomechanical effects of the rehabilitations. In addition, strains due to misfit of the one-piece titanium bridge were compared to those produced by one-piece cast gold bridges. Milled titanium bridges had a better fit than cast gold bridges. The stress distribution in mandibular bone rehabilitated with a one-piece bridge was more perturbed than that observed with a two-piece bridge. In particular the former induced a stress concentration and stress shielding in the molar and symphysis regions, while for the latter design these stresses were strongly reduced. In conclusion, prosthetic frameworks changed the biomechanics of the mandible as a result of both their design and manufacturing technology

The Role of BRAP-2 in Caenorhabditis Elegans DNA Damage Induced Germline Apoptosis Development and Germline Health

The DNA damage response protects the genome by executing processes that prevent the disruption of normal cell physiology and the inheritance of mutations. BRCA1 is an essential tumor suppressor gene that facilitates DNA repair, transcription and plays a more complex role in apoptosis. A novel BRCA1 binding protein known as BRAP2/IMP has been characterized as a RAS effector with ubiquitin ligase activity and as a cytoplasmic retention protein. BRAP2 is conserved in C. elegans, and is known as BRAP-2. Previously, we have shown that BRAP-2 is a negative regulator of SKN-1/Nrf2 dependent detoxification gene expression. In addition, brap-2 deletion mutants experience BRC-1 (BRCA1 ortholog) dependent larval arrest when exposed to oxidative stress. BRC-1 function in DNA repair is conserved in the germline, where a loss of brc-1 increases apoptosis. Due to the conservation of BRC-1 function in C. elegans and the genetic link between BRC-1 and BRAP-2 upon oxidative stress, in this study we examined the role of BRAP-2 in DNA damage induced germline apoptosis, C. elegans development and germline health. We found that brap-2 mutants display a reduction in DNA damage induced germline apoptosis and that apoptosis induced by loss of BRC-1 requires BRAP-2. We also found that a loss of PMK-1, SKN-1 and AKT-1 in brap-2 mutants increases apoptosis, indicating that a loss of BRAP-2 limits DNA damage induced germline apoptosis and promotes cell survival through regulation of the PMK-1 activated SKN-1 oxidative stress response pathway and Insulin/Insulin-like growth factor signaling. In addition, brap-2 mutants display defects in development, survival, brood size and germline morphology. Taken together, this suggests that BRAP-2 is required to promote DNA damage induced germline apoptosis by regulating pro-cell survival pathways and that BRAP-2 is required for proper C. elegans growth, development and germline health

An Interview with Giancarlo Casale

This is an interview with Prof. Giancarlo Casale, an Ottoman historian, in which he discusses the challenges of historical and archival research, presenting also his last book, "Prisoner of the Infidels: The Memoir of an Ottoman Muslim in Seventeenth-Century Europe" (2021, University of California Press)

Sugar-Incorporated N-Heterocyclic-Carbene-Containing Gold(I) Complexes: Synthesis, Characterization, and Cytotoxic Evaluation

A series of neutral and cationic gold(I) complexes bearing a glucopyranoside-incorporated N-heterocyclic carbene (NHC) ligand are synthetized and structurally characterized. Different secondary ligands (chlorido, phosphane, or sugar–NHC) are employed to tune the properties of the complexes. The antiproliferative effects of the compounds are evaluated against PC-3 prostate cancer cells and a panel of human tumor cell lines. The activities of the phosphane complexes are comparable to that observed for cisplatin. The combined results provide further insights into the biological behavior of NHC–gold complexes

TP53 gene polymorphisms at codons 11, 72, and 248 and association with endometriosis in a Brazilian population

We evaluated the association between TP53 gene polymorphisms and endometriosis in Brazilian women. Genomic DNA was extracted from swabs of buccal cells collected from hospital patients. TP53 gene polymorphisms were investigated at three codons: TP53*11 Glu/Gln or Lys (GAG->CAG or AAG), TP53*72 Arg/Pro (CCG->CCC), and TP53*248 Arg/Thr (CGG->TCG) using the polymerase chain reaction-restriction fragment length polymorphism method. TP53*11 presented the following genotypic distribution: the control group was 98.28% homozygous wild-type (Glu) and 1.72% homozygous variant (Gln/Lys), and the heterozygous genotype was not identified. the genotypic distribution in the endometriosis group was 96% homozygous wild-type (Glu) and 4% heterozygous (Glu-Gln/Lys); the homozygous variant genotype was not identified (P = 0.02). TP53*72 showed the following genotypic distribution: the control group was 29.75% homozygous wild-type (Arg), 47.11% heterozygous (Arg-Pro), and 23.14% homozygous variant (Pro). the genotypic distribution in the endometriosis group was 16.15% homozygous wildtype (Arg), 51.54% heterozygous (Arg-Pro), and 32.31% homozygous variant (Pro) (odds ratio = 2.26; 95% confidence interval = 1.19-4.03; P = 0.02). Only one patient had the homozygous TP53*248 genotype (Arg-Trp/Gln); all other patients were homozygous wild-type in both the control and endometriosis groups (P = 0.51; NS). We found that TP53*72 polymorphism may be associated with susceptibility to endometriosis; the presence of at least 1 polymorphic allele increased the chance of disease development by 2.26-fold. Hence, this genetic variant is a potential candidate marker for endometriosis.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Escola Paulista Med, Dept Ginecol, Lab Ginecol Mol & Prote, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Ginecol, Lab Ginecol Mol & Prote, São Paulo, BrazilFAPESP: 09/53000-2Web of Scienc

Progesterone receptor gene polymorphism (PROGINS) in women with pelvic endometriosis

OBJECTIVE: the aim of the present study was to verify whether there is a correlation between the prevalence of the polymorphism in the progesterone receptor gene named PROGINS and pelvic endometriosis at different stages. METHODS: a case-control study carried out from November 2003 to May 2004. The genotypes of 104 women were analyzed 66 women had had surgically confirmed endometriosis (26 women at stages I-II and 40 at stages III-IV), and 38 were healthy women. The 306-base pair Alu insertion polymorphism in the intron G of the progesterone receptor gene was detected by polymerase chain reaction and analyzed on 2% agarose gel stained with ethidium bromide. ANOVA analysis was performed in order to make comparisons between among the studied groups. RESULTS: the groups of women with endometriosis stages I-II (EndoI group) and stages III-IV (EndoII group) showed statistically significant increased incidence of PROGINS polymorphic allele as compared with the control group: 27% in the EndoI group, 38% in EndoII and 18% in the control group (p < 0.001. In the analyses, a high frequency of the PROGINS insertion was observed in women with endometriosis as compared to healthy women, disregarding the clinical stage of the disease (p = 0.0385). CONCLUSION: there is a significant statistical association between the PROGINS polymorphism and pelvic endometriosis.OBJETIVO: o objetivo do estudo foi verificar a prevalência do polimorfismo denominado PROGINS no gene do receptor de progesterona entre mulheres com endometriose em seus diferentes estádios. MÉTODOS: estudo caso-controle desenvolvido entre novembro de 2003 e maio de 2004. Foram analisados os genótipos de 104 mulheres, das quais 66 com endometriose comprovada por videolaparoscopia (26 mulheres nos estádios I-II e 40 nos estádios III-IV) e 38 saudáveis. A inserção Alu de 306 pares de base no intron G do gene do receptor de progesterona denominada PROGINS foi detectada por meio de reação em cadeia da polimerase e analisada em gel de agarose 2% corado com brometo de etídio. Para análise estatística foi utilizado o teste ANOVA paramétrico. RESULTADOS: as amostras pertencentes aos grupos endometriose estádios I-II (grupo EndoI) e estádios III-IV (grupo EndoII) tiveram significativo aumento na incidência do alelo polimórfico do receptor de progesterona em relação ao grupo controle: 27% no grupo EndoI, 38% no EndoII e apenas 18% no grupo controle (p < 0,001). A prevalência da inserção, quando comparamos mulheres com endometriose, independente do estádio, com as do grupo controle, foi estatisticamente superior no grupo das doentes (p = 0,0385). CONCLUSÃO: há associação estatisticamente significante entre o polimorfismo PROGINS e a endometriose pélvica.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de GinecologiaUNIFESP, EPM, Depto. de GinecologiaSciEL

Gallotta, Aldo

Questa voce enciclopedica ricostruisce la carriera accademica e le pubblicazioni scientifiche del prof. Aldo Gallotta, insigne turcologo italiano

In una lingua che non è la mia: memoria, scrittura e separazione

This article explores the use of a foreign language in Ottoman women’s autobiographical writing that first appeared between the end of the 19th century and the beginning of the 20th century. By analyzing the texts of these authors writing about the self outside of their “mother tongue”, this article addresses the issue of language – in this case English – as a negotiated space for one’s own multiple identities, both with local and Western audiences. In particular, it examines to what extent the choice, however conscious, of using a foreign language engenders an identity break, a separation of the author from the world in which her memories were originally produced. Furthermore, this article seeks to determine the traumas that could motivate or arise from this choice

Emotion, Diplomacy and Gift Exchanging Practices in the Ottoman Context

In recent years, an increasing number of studies on diplomatic gifts in the Ottoman context have emphasised, through different approaches, the central role played by gifts in the performance of diplomatic interactions. The articles by Hedda Reindl-Kiel, Michał Wasiucionek and Rosita D'Amora that make up this thematic section, Emotion, Diplomacy and Gift Exchanging Practices in the Ottoman Context, take a step in a new direction by posing challenging questions regarding the emotional implications of the processes of exchanging gifts in the framework of Ottoman diplomatic encounters