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Copyright of Der MKG-Chirurg is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Deregulation of the transforming acidic coiled-coil protein 3 (TACC3), an important factor in the centrosome-microtubule system, has been linked to a variety of human cancer types. We have recently reported on the oncogenic potential of TACC3; however, the molecular mechanisms by which TACC3 mediates oncogenic function remain to be elucidated. In this study, we show that high levels of TACC3 lead to the accumulation of DNA double-strand breaks (DSBs) and disrupt the normal cellular response to DNA damage, at least in part, by negatively regulating the expression of ataxia telangiectasia mutated (ATM) and the subsequent DNA damage response (DDR) signaling cascade. Cells expressing high levels of TACC3 display defective checkpoints and DSB-mediated homologous recombination (HR) and non-homologous end joining (NHEJ) repair systems, leading to genomic instability. Importantly, high levels of TACC3 confer cellular sensitization to radiation and poly(ADP-ribose) polymerase (PARP) inhibition. Overall, our findings provide critical information regarding the mechanisms by which TACC3 contributes to genomic instability, potentially leading to cancer development, and suggest a novel prognostic, diagnostic and therapeutic strategy for the treatment of cancer types expressing high levels of TACC3. [ABSTRACT FROM AUTHOR]

Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Inter-α-trypsin inhibitors (ITIs) are protease inhibitors stabilizing the extracellular matrix. ITIs consist of one light (bikunin) and two heavy chains (ITIHs). We have recently characterized ITIH5, a novel member of the ITIH gene family, and showed that its messenger RNA is lost in a high proportion of breast tumours. In the present study, an ITIH5-specific polyclonal antibody was generated, validated with western blot and used for immunohistochemical analysis on a tissue microarray; ITIH5 was strongly expressed in epithelial cells of normal breast (n=11/15), while it was lost or strongly reduced in 42% (92/217) of invasive breast cancers. ITIH5 expression in invasive carcinomas was associated with positive expression of oestrogen receptor (P=0.008) and histological grade (P=0.024). Correlation of ITIH5 expression with clinical outcome revealed that patients with primary tumours retaining abundant ITIH5 expression had longer recurrence-free survival (RFS; P=0.037) and overall survival (OS; P=0.044), compared to those with reduced expression (mean RFS: 102 vs 78 months; mean OS: 120 vs 105 months). Methylation-specific PCR analysis frequently showed strong methylation of the ITIH5 promoter in primary breast tumours (41%, n=109) and breast cancer cell lines (n=6). Methylation was significantly associated with mRNA loss (P<0.001; n=39), and ITIH5 expression was induced after treatment of tumour cell lines with the demethylating agent 5-aza-2′-deoxycytidine. Moreover, ITIH5 promoter methylation was significantly associated with reduced OS (P=0.008). The cellular function of ITIH5 was evaluated by forced expression of a full-length ITIH5 complementary DNA in the breast cancer cell line MDA-MB-231, which does not endogenously express ITIH5. ITIH5-expressing clones showed a 40% reduced proliferation rate compared to mock-transfected cells. Overall, these data show that promoter methylation-mediated loss of ITIH5 expression is associated with unfavourable outcome in breast cancer patients, and thus ITIH5 could be used as a prognostic marker, although this marker is not multivariate independent due to its close association with ER expression. Our data indicate that ITIH5 is a candidate class II tumour suppressor gene and could be involved in tumour progression, invasion and metastasis, as its absence is associated with increased proliferation rates and a prognostic value indicating poor clinical outcome.Oncogene (2008) 27, 865–876; doi:10.1038/sj.onc.1210669; published online 23 July 2007 [ABSTRACT FROM AUTHOR]

The new type of phosphoniminoxy free radicals was generated electrochemically or by chemical oxidation of oximes. It was established the strong difference of ESR parameters for isomeric Z and E forms of the radicals. The spin distribution and its correlation with electronic and spatial characteristics of molecules as well as with intramolecular interactions are discussed. [ABSTRACT FROM AUTHOR]

The effects of a series of novel phosphonates on the kinetics of mineral development in an ionophore-primed 7:2:1 phosphatidylcholine (PC): dicetylphosphate (DCP): cholesterol (Chol) liposomal model system are reported. When present at 2.5 micromol/liter or 25 micromol/liter concentrations in the solution surrounding the liposomes, the investigated phosphonates did not significantly delay the initial formation of hydroxyapatite-like calcium phosphate salts (HAP) within the liposomes or the penetration of HAP crystals through the enclosing membranes. However, the phosphonates variably retarded the subsequent growth and proliferation of the HAP crystals once they became directly exposed to the phosphonate-containing solution. The effectiveness of phosphonates in inhibiting extraliposomal precipitation strongly depended on their structure. The inhibitory action on active surface growth sites of released intraliposomal crystals was found to be the most effective if the phosphonate molecule contained two phosphonic groups linked to the same C atom. At a phosphonate concentration of 25 micromol/liter, the following general order of effectiveness was established: geminal bisphosphonate >/= geminal tetrakisphosphonate > bisacylphosphonates > monoacylphosphonate > bisalkylphosphonate. Within the bisacylphosphonate family, the highest inhibitory action was observed when four or five -CH2- groups separated the ketophosphonic groups. [ABSTRACT FROM AUTHOR]

The occurrence of a high-field signal in theP FT NMR-spectrum of the reaction mixture of nitrones ( 1 or 2) and 2-cyanomethyl-4,5-dimethyl-2-oxo-1,3,2-dioxyphospholane ( 7), is interpreted in terms of a pentacoordinated phosphorus intermediate. [ABSTRACT FROM AUTHOR]

Collaborative research partnerships are necessary to answer key questions in global mental health, to share expertise, access funding and influence policy. However, partnerships between low- and middle-income countries (LMIC) and high-income countries have often been inequitable with the provision of technical knowledge flowing unilaterally from high to lower income countries. We present the experience of the Programme for Improving Mental Health Care (PRIME), a LMIC-led partnership which provides research evidence for the development, implementation and scaling up of integrated district mental healthcare plans in Ethiopia, India, Nepal, South Africa and Uganda. We use Tuckman's first four stages of forming, storming, norming and performing to reflect on the history, formation and challenges of the PRIME Consortium. We show how this resulted in successful partnerships in relation to management, research, research uptake and capacity building and reflect on the key lessons for future partnerships., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest.