Clinical pharmacokinetics of theophylline during co-treatment with ticarcillin plus clavulanic acid in patients suffering from acute exacerbation of chronic bronchitis

The results in 185 patients with coronary artery disease undergoing implantation of an automatic implantable cardioverter defibrillator (AICD) were reviewed with regard to the operative technique applied and problems observed. In 123 patients (group I) only AICD implantation was performed. Ninety patients were operated through sternotomy or thoracotomy while in 33 patients an endovenous/subcutaneous technique was used. Sixty-two patients (group II) underwent simultaneous coronary artery bypass grafting (CABG) and AICD implantation by median sternotomy. Perioperative mortality was 2.4% in group I with one fatality in the subgroup of endevenous/AICD placements and 11.3% in group II (p < 0.01). Overall infectious complications were low with 2 removals in group I and 1 in group II; however, no infections were observed after endovenous system implantation. It is concluded that the operative mortality rate of a combined approach is significantly higher, when compared to isolated AICD placement. However, the greater risk of the former cohort is mainly due to the impaired ventricular performance. Further investigations will have to prove whether a two-step approach using the endovenous technique in patients with a need for AICD and CABG will reduce the operative mortality.     

Self‐Immobilizing Precatalysts: Norbornene‐Bridged Zirconium ansa‐Metallocenes

We report here the synthesis of new tethered biscyclopentadienyl and bisindenyl zirconocenes, bearing one unsaturation on the interannular bridge, and their use as self‐immobilizing catalysts. They proved to be active catalysts towards ethylene polymerization in solution, with activities comparable to those displayed by commercial rac‐Et(Ind)₂ZrCl₂. When tested as self‐polymerization catalysts under suitable experimental conditions, they gave colored precipitates that, once reactivated with MAO, were significantly active in ethylene polymerization, although lower than those of the corresponding catalytic systems in solution. The molecular weights of the produced polymers were similar to those obtained with the same catalysts in solution, but their distribution resulted to be broader, with values typical of heterogeneous catalytic systems. From ¹³C NMR studies we had the first spectroscopic evidence of the actual incorporation of a metallocene of this type into a polymeric chain.     

Fermentative stress adaptation of hybrids within the Saccharomyces sensu stricto complex

Along the fermentation process yeasts are affected by a succession of stress conditions that affect their viability and fermentation efficiency. Among the stress conditions the most relevant are high sugar concentration and low pH in musts, temperature and, as fermentation progresses, ethanol accumulation. Nowadays, due to the demanding nature of modern winemaking practices and sophisticated wine markets, there is an ever-growing search for particular wine yeast strains possessing a wide range of optimized, improved or novel enological characteristics. Traditionally, the species S. cerevisiae and S. bayanus within the Saccharomyces sensu stricto species are considered some of the most important yeast species involved in fermentation processes. However, in the last years, hybrid strains between the species S. cerevisiae, S. bayanus and S. kudriavzevii have been described as yeasts conducting the alcoholic fermentations and some of them are commercially available. Our results indicate that yeasts in the Saccharomyces sensu stricto complex were not affected by low pH or high glucose content in the media; however temperature and ethanol concentration variables appreciably affected their growth. The strains pertaining to S. cerevisiae were able to tolerate high temperature stress, whereas strains within S. bayanus and S. kudriavzevii were better adapted to growth at lower temperatures. Regarding to alcohol tolerance, S. cerevisiae is tolerating alcohol better than S. bayanus or S. kudriavzevii. Surprisingly, the natural hybrids between these species have adapted to growth under ethanol and temperature stress by inheriting competitive traits from one or another parental species. These results open new perspectives in the construction of new hybrid strains with biotechnological interest, as the characteristics of the parents may result in interesting combinations in the hybrids.     

Peptides from water buffalo cheese whey induced senescence cell death via ceramide secretion in human colon adenocarcinoma cell line

Scope: Milk proteins are a source of bioactive peptides. Recent studies have indicated that protein‐derived peptides released in buffalo cheese acid whey exert a cytomodulatory effect in human epithelial colon cancer (CaCo2) cells. The aim of the present study was to explain the molecular mechanism involved in the response of CaCo2 cells to oxidative stress in the presence of peptide fractions of buffalo cheese whey, purified and characterized by mass spectrometry. Methods and results: We demonstrated that treatment of CaCo2 treated with H₂O₂ (H‐CaCo2) cells with a partially purified peptide sub‐fraction (f3) from buffalo cheese acid whey induced a reduction of mitochondrial superoxide anion with subsequent decrease in heat shock protein 70 and 90 expression. Moreover, we observed a 5‐fold decrease in cyclin A expression and cell cycle arrest in G1/G0 phases. These responses were associated with increased activity of alkaline phosphatase and beta‐galactosidase, markers of differentiation and senescence respectively. Conclusions: The structural characterization of the active peptide fraction and the elucidation of the effects induced by its treatment on H‐CaCo2 cells in vitro demonstrated an activity of this peptide sub‐fraction in the modulation of cell cycle, thus suggesting potential application for the development of nutraceuticals as well as health‐promoting functional foods.     

New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies

The Amyloid Precursor Protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) in Alzheimer’s disease (AD). However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y₆₈₂ mutation in the ₆₈₂YENPTY₆₈₇ domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS) on hippocampal tissue extracts of three month-old mice incubated with either the ₆₈₂YENPTY₆₈₇ peptide, its mutated form, ₆₈₂GENPTY₆₈₇ or its phosphorylated form, ₆₈₂pYENPTY₆₈₇. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc) and its Adaptor Protein 2 (AP-2). Overall our results consolidate and refine the importance of Y₆₈₂ in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies.     

α–ω Alkenyl-bis-S-Guanidine Thiourea Dihydrobromide Affects HeLa Cell Growth Hampering Tubulin Polymerization

Cancer is going to be the first cause of mortality worldwide in the 21th century. It is considered a multifactorial disease that results from the combined influence of many genetic aberrations, leading to abnormal cell proliferation. As microtubules are strongly implicated in cellular growth, they represent an important target for cancer treatment. The well-known microtubule-targeting agents (MTAs) including paclitaxel, colchicine and vinca alkaloids are commonly used in the treatment of various cancers. However, adverse effects and drug resistance are major limitations in their clinical use. To find new candidates able to induce microtubule alteration with reduced toxic effects or drug resistance, we studied a small new series of derivatives that present imidazolinic, guanidinic, thioureidic and hydrazinic groups ( 1 – 9 ). All the compounds were tested for their antitumor activity against a panel of six tumoral cell models. In particular, compound 8 (nonane-1,9-diyl-bis-S-amidinothiourea dihydrobromide) showed the lowest IC₅₀ value against HeLa cells, together with a low cytotoxicity for normal cells. This compound was able to induce the apoptotic mitochondrial pathway and inhibited tubulin polymerization with a similar efficacy to vinblastine and nocodazole. Taken together, these promising biological properties make compound 8 useful for the development of novel therapeutic approaches in cancer treatment.     

A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors

Multiple sclerosis is a complex, multifactorial, dysimmune disease prevalent in women. Its etiopathogenesis is extremely intricate, since each risk factor behaves as a variable that is interconnected with others. In order to understand these interactions, sex must be considered as a determining element, either in a protective or pathological sense, and not as one of many variables. In particular, sex seems to highly influence immune response at chromosomal, epigenetic, and hormonal levels. Environmental and genetic risk factors cannot be considered without sex, since sex-based immunological differences deeply affect disease onset, course, and prognosis. Understanding the mechanisms underlying sex-based differences is necessary in order to develop a more effective and personalized therapeutic approach.     

Reduced Gonadotrophin Receptor Expression Is Associated with a More Aggressive Ovarian Cancer Phenotype

Follicle-stimulating hormone (FSH) and luteinising hormone (LH) play important roles in regulating cell growth and proliferation in the ovary. However, few studies have explored the expression of FSH and LH receptors (FSHR and LHCGR) in ovarian cancer, and their functional roles in cancer progression remain inconclusive. This study investigated the potential impact of both mRNA (FSHR, LHCGR) and protein (FSHR, LHCGR) expression on ovarian cancer progression using publicly available online databases, qRT-PCR (high grade serous ovarian cancers, HGSOC, n = 29 and benign ovarian tumors, n = 17) and immunohistochemistry (HGSOC, n = 144). In addition, we investigated the effect of FSHR and LHCGR siRNA knockdown on the pro-metastatic behavior of serous ovarian cancer cells in vitro. High FSHR or high LHCGR expression in patients with all subtypes of high-grade ovarian cancer was significantly associated with longer progression-free survival (PFS) and overall survival (OS). High FSHR protein expression was associated with increased PFS (p = 0.050) and OS (p = 0.025). HGSOC patients with both high FSHR and high LHCGR protein levels had the best survival outcome, whilst both low FSHR and low LHCGR expression was associated with poorest survival (p = 0.019). Knockdown of FSHR significantly increased the invasion of serous ovarian cancer cells (OVCAR3 and COV362) in vitro. LHCGR knockdown also promoted invasion of COV362 cells. This study highlights that lower FSHR and LHCGR expression is associated with a more aggressive epithelial ovarian cancer phenotype and promotes pro-metastatic behaviour.