A potential role for lamellar insulin-like growth factor-1 receptor in the pathogenesis of hyperinsulinaemic laminitis

The reason why a sustained high concentration of insulin induces laminitis in horses remains unclear. Cell proliferation occurs in the lamellae during insulin-induced laminitis and in other species high concentrations of insulin can activate receptors for the powerful cell mitogen, insulin-like growth factor (IGF)-1. The first aim of this study was to determine if IGF-1 receptors (IGF-1R) are activated in the hoof during insulin-induced laminitis. Gene expression for IGF-1R and the insulin receptor (InsR) was measured using qRT-PCR, in lamellar tissue from control horses and from horses undergoing a prolonged euglycaemic, hyperinsulinaemic clamp (p-EHC), during the mid-developmental (24 h) and acute (46 h) phases of insulin-induced laminitis. Gene expression for both receptors was decreased 13–32-fold (P < 0.05) at both time-points in the insulin-treated horses. A second aim was to determine if the down-regulation of the receptor genes could be accounted for by an increase in circulating IGF-1. Serum IGF-1 was measured at 0, 10, 25 and 46 h post-treatment in horses given a p-EHC for approximately 46 h, and in matched controls administered a balanced, electrolyte solution. There was no increase in serum IGF-1 concentrations during the p-EHC, consistent with down-regulation of both receptors by insulin. Stimulation of the IGF-1R by insulin may lead to inappropriate lamellar epidermal cell proliferation and lamellar weakening, a potential mechanism for hyperinsulinaemic laminitis. Targeting this receptor may provide insights into the pathogenesis or identify a novel therapy for hyperinsulinaemic laminitis.

Commentary on papers by Professor Fletcher and Mr Martin

In light of the time available today, I will limit my comments to addressing that aspect of Professor Fletcher’s paper in which he refers to the 2012 report he co-authored with Professor Wessels of the Netherlands for the American Law Institute (ALI) and the International Insolvency Institute (III) on Transnational Insolvency: Global Principles for Cooperation in International Insolvency Cases. I will comment on the potential benefits for Australian courts as well as insolvency administrators and their advisers in referring to the ALI-III Report - in light of Australia’s adoption of the UNCITRAL Model Law. In so doing, I would like to acknowledge the support of the Australian Academy of Law, under the leadership of The Hon Dr Kevin Lindgren for the research project underpinning these comments, as well as to acknowledge the contributions of my colleagues Associate Professor Sheryl Jackson and Mark Wellard.

Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA

We report that tumor cells devoid of their mitochondrial genome (mtDNA) show delayed tumor growth and that tumor formation is associated with acquisition of mtDNA from host cells. This leads to partial recovery of mitochondrial function in cells derived from primary tumors grown from cells without mtDNA and a shorter lag in tumor growth. Cell lines from circulating tumor cells showed further recovery of mitochondrial respiration and an intermediate lag to tumor growth, while cells from lung metastases exhibited full restoration of respiratory function and no lag in tumor growth. Stepwise assembly of mitochondrial respiratory supercomplexes was correlated with acquisition of respiratory function. Our findings indicate horizontal transfer of mtDNA from host cells in the tumor microenvironment to tumor cells with compromised respiratory function to re-establish respiration and tumor-initiating efficacy. These results suggest a novel pathophysiological process for overcoming mtDNA damage and support the notion of high plasticity of malignant cells.

KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. Asbestos exposure (through inhalation) is the most well established risk factor for mesothelioma. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Lysine acetyltransferases (KATs) including KAT5 have been linked with the development of cisplatin resistance. This gene may therefore be altered in MPM and could represent a novel candidate target for intervention. Using RT-PCR screening the expression of all known KAT5 variants was found to be markedly increased in malignant tumors compared to benign pleura. When separated according to histological subtype, KAT5 was significantly overexpressed in both the sarcomatoid and biphasic subgroups for all transcript variants. A panel of MPM cell lines including the normal pleural cells LP9 and Met5A was screened for expression of KAT5 variants. Treatment of cells with a small molecule inhibitor of KAT5 (MG-149) caused significant inhibition of cellular proliferation (p<0.0001), induction of apoptosis and was accompanied by significant induction of pro-inflammatory cytokines/chemokines.

Raman microscopic study of the Li amphibole holmquistite, from the Martin Marietta Quarry, Bessemer City, NC, USA

The Raman spectrum of holmquistite, a Li-containing orthorhombic amphibole from Bessemer City, USA has been measured. The OH-stretching region is characterized by bands at 3661, 3646, 3634 and 3614 cm–1 assigned to 3 Mg–OH, 2 Mg + Fe2+–OH, Mg + 2Fe2+–OH and 3 Fe2+–OH, respectively. These Mg and Fe2+ cations are located at the M1 and M3 sites and have a Fe2+/(Fe2+ + Mg) ratio of 0.35. The 960–1110 cm–1 region represents the antisymmetric Si–O–Si and O–Si–O stretching vibrations. For holmquistite, strong bands are observed around 1022 and 1085 cm–1 with a shoulder at 1127 cm–1 and minor bands at 1045 and 1102 cm–1. In the region 650–800 cm–1 bands are observed at 679, 753 and 791 cm–1 with a minor band around 694 cm–1 attributed to the symmetrical Si–O–Si and Si–O vibrations. The region below 625 cm–1 is characterized by 14 vibrations related to the deformation modes of the silicate double chain and vibrations involving Mg, Fe, Al and Li in the various M sites. The 502 cm–1 band is a Li–O deformation mode while the 456, 551 and 565 cm–1 bands are Al–O deformation modes.

The Expanded Human Kallikrein (KLK) gene family : genomic organisation, tissue specific expression and potential functions

The tissue kallikreins are serine proteases encoded by highly conserved multigene families. The rodent kallikrein (KLK) families are particularly large, consisting of 13 26 genes clustered in one chromosomal locus. It has been recently recognised that the human KLK gene family is of a similar size (15 genes) with the identification of another 12 related genes (KLK4-KLK15) within and adjacent to the original human KLK locus (KLK1-3) on chromosome 19q13.4. The structural organisation and size of these new genes is similar to that of other KLK genes except for additional exons encoding 5 or 3 untranslated regions. Moreover, many of these genes have multiple mRNA transcripts, a trait not observed with rodent genes. Unlike all other kallikreins, the KLK4-KLK15 encoded proteases are less related (25–44%) and do not contain a conventional kallikrein loop. Clusters of genes exhibit high prostatic (KLK2-4, KLK15) or pancreatic (KLK6-13) expression, suggesting evolutionary conservation of elements conferring tissue specificity. These genes are also expressed, to varying degrees, in a wider range of tissues suggesting a functional involvement of these newer human kallikrein proteases in a diverse range of physiological processes.