Synthesis and reactivity of cytotoxic platinum(II) complexes of bidentate oximes: a step towards the functionalization of bioactive complexes

Two new platinum(II) complexes bearing triphenylphosphine and bidentate oxime ligands [Pt(Cl)(PPh3){(κ2-N,O)-(1{C(R)=N(OH)-2(O)C10H6})}] (R = H, Me) were synthesized in good yields from trans-[PtCl(μ-Cl)(PPh3)]2. The structure of [Pt(Cl)(PPh3){(κ2-N,O)-(1{CH=N(OH)-2(O)C10H6})}] was determined by single-crystal X-ray diffraction. Both complexes showed good antiproliferative properties in vitro against HeLa, A2780, and A2780cis cancer cell lines. They reacted cleanly with alkylating agents in the presence of aqueous bases under phase-transfer catalysis conditions to afford the corresponding O-alkylation products [Pt(Cl)(PPh3){(κ2-N,O)-(1{HC=N(OR′)-2(O)C10H6})}] [R′ = CH2CH2Cl, CH2Ph, (CH2)4Br] in good yields

Redox proteomics of the inflammatory secretome identifies a common set of redoxins and other glutathionylated proteins released in inflammation, influenza virus infection and oxidative stress

Protein cysteines can form transient disulfides with glutathione (GSH), resulting in the production of glutathionylated proteins, and this process is regarded as a mechanism by which the redox state of the cell can regulate protein function. Most studies on redox regulation of immunity have focused on intracellular proteins. In this study we have used redox proteomics to identify those proteins released in glutathionylated form by macrophages stimulated with lipopolysaccharide (LPS) after pre-loading the cells with biotinylated GSH. Of the several proteins identified in the redox secretome, we have selected a number for validation. Proteomic analysis indicated that LPS stimulated the release of peroxiredoxin (PRDX) 1, PRDX2, vimentin (VIM), profilin1 (PFN1) and thioredoxin 1 (TXN1). For PRDX1 and TXN1, we were able to confirm that the released protein is glutathionylated. PRDX1, PRDX2 and TXN1 were also released by the human pulmonary epithelial cell line, A549, infected with influenza virus. The release of the proteins identified was inhibited by the anti-inflammatory glucocorticoid, dexamethasone (DEX), which also inhibited tumor necrosis factor (TNF)-α release, and by thiol antioxidants (N-butanoyl GSH derivative, GSH-C4, and N-acetylcysteine (NAC), which did not affect TNF-α production. The proteins identified could be useful as biomarkers of oxidative stress associated with inflammation, and further studies will be required to investigate if the extracellular forms of these proteins has immunoregulatory functions

A Community-Based Approach to Developing a Mobile Device for Measuring Ambient Air Exposure, Location, and Respiratory Health

In west Eugene (Oregon), community research indicates residents are disproportionately exposed to industrial air pollution and exhibit increased asthma incidence. In Carroll County (Ohio), recent increases in unconventional natural gas drilling sparked air quality concerns. These community concerns led to the development of a prototype mobile device to measure personal chemical exposure, location, and respiratory function. Working directly with the environmental justice (EJ) communities, the prototype was developed to (1) meet the needs of the community and; (2) evaluate the use in EJ communities. The prototype was evaluated in 3 community focus groups (n=25) to obtain feedback on the prototype and feasibility study design to evaluate the efficacy of the device to address community concerns. Focus groups were recorded and qualitatively analyzed with discrete feedback tabulated for further refinement. The prototype was improved by community feedback resulting in 8 alterations/additions to software and instructional materials. Overall, focus group participants were supportive of the device and believed it would be a useful environmental health tool. The use of focus groups ensured that community members were engaged in the research design and development of a novel environmental health tool. We found that community-based research strategies resulted in a refined device as well as relevant research questions, specific to the EJ community needs and concerns

Human malarial disease: a consequence of inflammatory cytokine release

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease

Outcomes of an integrated cognitive behaviour therapy (CBT) treatment program for co-occurring depression and substance misuse in young people

Background: There are high rates of co-occurring depression among young people with substance use disorders. While there is preliminary evidence for the effectiveness of integrated cognitive behaviour therapy (CBT) in combination with antidepressants among alcohol and substance dependent adolescents and adults with co-existing depression, no studies have examined the effectiveness of integrated CBT interventions in the absence of pharmacotherapy. The aim of the current study was to determine the outcomes of an integrated CBT intervention for co-occurring depression and substance misuse in young people presenting to a mental health setting. Methods: Sixty young people (aged 15 to 25), with a DSM-IV diagnosis of Major Depressive Disorder and concurrent substance misuse (at least weekly use in the past month) or disorder were recruited from a public youth mental health service in Melbourne, Australia. Participants received 10 sessions of individual integrated CBT treatment delivered with case management over a 20-week period. Results: The intervention was associated with significant improvements in depression, anxiety, substance use, coping skills, depressive and substance use cognitions and functioning at mid- (10\ua0weeks) and post- (20\ua0weeks) treatment. These changes were maintained at 6\ua0months follow-up (44\ua0weeks). Conclusions: These results provide preliminary evidence for the effectiveness of the integrated CBT intervention in young people with co-occurring depression and substance misuse. Further studies using randomised controlled designs are required to determine its efficacy

Conversazione con tre urbanisti italiani

E' un testo sul modo di intendere visioni e scenari, restituito sotto forma di conversazione con l'autore del libro, un'occasione per riprendere e sviluppare argomenti sui quali ho scritto ripetutamente (le altre due conversazioni dell'autore Pidalà sono con Alberto Magnaghi e Pier Carlo Palermo)

Myelodysplasia as assessed by multiparameter flow cytometry refines prognostic stratification provided by genotypic risk in systemic mastocytosis

Systemic mastocytosis (SM) is characterized by extreme heterogeneity of manifestations and prognosis. Several disease-related biomarkers, including clinical, hematological and molecular variables, have been correlated with prognosis. Although relevant, the mutation profile closely reflects the WHO classification that has per se prognostic value. High-risk mutations (HRM) are largely confined to advanced forms, and thus fail in providing information regarding progression and outcome in the not-advanced variants. In this work, we studied hematopoietic cells by multi-parameter flow cytometry (MFC) in order to highlight dysplastic traits that might provide insights into outcome. A score previously validated for myelodysplastic syndromes, with high reproducibility in standard diagnostics, was used. The application of an MFC score to a cohort of 71 SM cases, concurrently genotyped for configuring a HRM category, resulted in the identification of two separate patients' categories (MFC+ and MFC-) characterized by significantly different clinical and laboratory features at presentation. The extent of dysplasia by MFC tended to parallel WHO-category and genotype-related stratification. MFC+ patients had shorter survival compared to MFC- ones, for whom the incidence of progression and/or death was virtually null. Of note, MFC score remained prognostically informative in unadvanced subsets. Furthermore, the integration of MFC and HRM was an independent predictor for outcome, also overcoming WHO-categories in multivariate analysis for EFS. Our results support the use of MFC analysis in the evaluation of patients with SM, alone and in combination with HRM, for refinement of prognosis assessment