Highlights of New Strategies to Increase the Efficacy of Transition Metal Complexes for Cancer Treatments

Although important progress has been made, cancer still remains a complex disease to treat. Serious side effects, the insurgence of resistance and poor selectivity are some of the problems associated with the classical metal-based anti-cancer therapies currently in clinical use. New treatment approaches are still needed to increase cancer patient survival without cancer recurrence. Herein, we reviewed two promising-at least in our opinion-new strategies to increase the efficacy of transition metal-based complexes. First, we considered the possibility of assembling two biologically active fragments containing different metal centres into the same molecule, thus obtaining a heterobimetallic complex. A critical comparison with the monometallic counterparts was done. The reviewed literature has been divided into two groups: the case of platinum; the case of gold. Secondly, the conjugation of metal-based complexes to a targeting moiety was discussed. Particularly, we highlighted some interesting examples of compounds targeting cancer cell organelles according to a third-order targeting approach, and complexes targeting the whole cancer cell, according to a second-order targeting strategy

DNA-directed immobilization of horseradish peroxidase onto porous SiO2 optical transducers.

Multifunctional porous Si nanostructure is designed to optically monitor enzymatic activity of horseradish peroxidase. First, an oxidized PSi optical nanostructure, a Fabry-Pérot thin film, is synthesized and is used as the optical transducer element. Immobilization of the enzyme onto the nanostructure is performed through DNA-directed immobilization. Preliminary studies demonstrate high enzymatic activity levels of the immobilized horseradish peroxidase, while maintaining its specificity. The catalytic activity of the enzymes immobilized within the porous nanostructure is monitored in real time by reflective interferometric Fourier transform spectroscopy. We show that we can easily regenerate the surface for consecutive biosensing analysis by mild dehybridization conditions

Mechanistic Evaluations of the Effects of Auranofin Triethylphosphine Replacement with a Trimethylphosphite Moiety

Auranofin, a gold(I)-basedcomplex, is under clinicaltrials forapplication as an anticancer agent for the treatment of nonsmall-celllung cancer and ovarian cancer. In the past years, different derivativeshave been developed, modifying gold linear ligands in the search fornew gold complexes endowed with a better pharmacological profile.Recently, a panel of four gold(I) complexes, inspired by the clinicallyestablished compound auranofin, was reported by our research group.As described, all compounds possess an [Au{P(OMe)(3)}](+) cationic moiety, in which the triethylphosphine of the parentcompound auranofin was replaced with an oxygen-rich trimethylphosphiteligand. The gold(I) linear coordination geometry was complementedby Cl-, Br-, I-, and the auranofin-like thioglucose tetraacetate ligand. As previouslyreported, despite their close similarity to auranofin, the panel compoundsexhibited some peculiar and distinctive features, such as lower log P values which can induce relevant differences in the overallpharmacokinetic profiles. To get better insight into the P-Austrength and stability, an extensive study was carried out for relevantbiological models, including three different vasopressin peptide analoguesand cysteine, using P-31 NMR and LC-ESI-MS. A DFT computationalstudy was also carried out for a better understanding of the theoreticalfundamentals of the disclosed differences with regard to triethylphosphineparent compounds.Acombined experimental and theoretical approach has beenused in order to assess how the structural modifications on the phosphineligand of auranofin impact the chemical features of the resultingderivatives. These structural modifications were able to stronglyaffect the -Au-P- bond strength until obtainingan inverted order of ligand exchangeability with respect to the AFbehavior, impacting the overall biological mode of action

ultrasound mediated synthesis of ecofriendly zinc chalcogenates in on water conditions

Nucleophilic Selenium is a convenient strategy for the functionalization of organic substrates having electrophilic character. Among all the methods developed for their preparation, the reduction of the corresponding diselenides represents the most versatile procedure. Using these protocols selenolates were usually prepared in situ using atom expensive reducing agents such as NaBH4, LiAlH4, or metals (Na, Li) or metal hydride (NaH). We recently reported that zinc can be efficiently used to reduce Se-halogen bond affording bench stable regents such as PhSeZnCl that showed a strong rate acceleration in "on water" conditions for a number of reactions: alkyl, aryl, vinyl and acyl substitutions, ring-opening reactions of epoxides and aziridines and Michael type addition. We report now the use of Ultrasound irradiation for the oxidative insertion of zinc into Se-Se bond and the formation of the nucleophilic reagent PhSeZnSePh as a green strategy to avoid the use of useless halogen and increase the atom economy of the selenenylating species

Defective endoplasmic reticulum-mitochondria contacts and bioenergetics in SEPN1-related myopathy

: SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired

Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

<p>Abstract</p> <p>Background</p> <p>During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions.</p> <p>Methods</p> <p>Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations.</p> <p>Results</p> <p>We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001.</p> <p>Conclusion</p> <p>Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On the other hand, we obtained detailed breast cancer survival functions that will be used for modeling the effect of screening and adjuvant treatments in Catalonia.</p

A well-tempered density functional theory of electrons in molecules

Reporting extensions of a recently developed approach to density functional theory with correct long-range be-havior (Phys. Rev. Lett. 94, 043002 (2005)). The central quantities are a splitting functional gamma[n] and a complementary exchange-correlation functional. We give a practical method for determining the value of \gamma in molecules, assuming an approximation for XC energy is given. The resulting theory shows good ability to reproduce the ionization potentials for various molecules. However it is not of sufficient accuracy for forming a satisfactory framework for studying molecular properties. A somewhat different approach is then adopted, which depends on a density-independent \gamma and an additional parameter w eliminating part of the local exchange functional. The values of these two parameters are obtained by best-fitting to experimental atomization energies and bond-lengths of the molecules in the G2(1) database. The optimized values are gamma=0.5 a_0^{-1} and w=0.1 . We then examine the performance of this slightly semi-empirical functional for a variety of molecular properties, comparing to related works and to experiment. We show that this approach can be used for describing in a satisfactory manner a broad range of molecular properties, be they static or dynamic. Most satisfactory is the ability to describe valence, Rydberg and inter-molecular charge-transfer excitations

Genetic diversity and local connectivity in the mediterranean red gorgonian coral after mass mortality events

Estimating the patterns of connectivity in marine taxa with planktonic dispersive stages is a challenging but crucial task because of its conservation implications. The red gorgonian Paramuricea clavata is a habitat forming species, characterized by short larval dispersal and high reproductive output, but low recruitment. In the recent past, the species was impacted by mass mortality events caused by increased water temperatures in summer. In the present study, we used 9 microsatellites to investigate the genetic structure and connectivity in the highly threatened populations from the Ligurian Sea (NW Mediterranean). No evidence for a recent bottleneck neither decreased genetic diversity in sites impacted by mass mortality events were found. Significant IBD pattern and high global F-ST confirmed low larval dispersal capability in the red gorgonian. The maximum dispersal distance was estimated at 20-60 km. Larval exchange between sites separated by hundreds of meters and between different depths was detected at each site, supporting the hypothesis that deeper subpopulations unaffected by surface warming peaks may provide larvae for shallower ones, enabling recovery after climatically induced mortality events

Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register

Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations

THE ‘‘NORMALITY’’ OF ‘‘SECOND GENERATIONS’’ IN ITALY AND THE IMPORTANCE OF LEGAL STATUS: A SELF-REPORT DELINQUENCY STUDY

This paper is a critical analysis of the relation between immigration and crime/criminalisation in Italy, with particular reference to \u201csecond-generation\u201d immigrants enrolled in the eighth grade of a sample of junior high schools in Bologna (Italy). The paper investigates whether \u2013 after allowing for differences in sex, social class, and other relevant variables \u2013 significant differences in self-reported deviance would emerge between second-generation immigrants and Italians. The research draws on three major criminological theories about deviant behavior: social control theory, labeling approach, and culture conflict theory. The study has been conducted as a self-report survey of a sample of 335 students enrolled in the 8th grade of 4 junior high schools in the metropolitan area of Bologna (Italy). Respondents were administered a questionnaire in the classroom, and asked to answer questions focusing on socio-biographical factors, socio-economic conditions, value-orientation, and self-reported deviant behaviors. Regression analysis was conducted on the data, and an interpretative model was developed based on the findings. The research offers no evidence of a higher frequency or seriousness of self-reported deviance among young \u201csecond-generation\u201d immigrants compared to Italians. The findings suggest that \u2013 both for Italian and immigrant respondents \u2013 self-reported deviant behaviors appear to be strongly correlated with cultural/generational conflict, the perception of stigma, and weak family bonds. The paper offers an original contribution to scholarly research about migration and crime/criminalisation. More specifically, it supports those criminological studies which deny any role of migration or national origin in the etiology of criminal behaviors