On the structure of the automorphism group of a minimal nonabelian p-group (metacyclic case)

In this paper we find the complete structure for the automorphism groups of metacyclic minimal nonabelian 2-groups. This, together with [6,7], gives the complete answer to the Question 15 from [5] (respectively Question 20 from [4]) in the case of metacyclic groups. We also correct some inaccuracies and extend the results from [13]

Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis

<p>Abstract</p> <p>Background</p> <p>Tuberous sclerosis (TSC) is a hamartoma syndrome in which renal and lung tumors cause the greatest morbidity. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT. Recent studies indicate that inhibition of mTORC1 with RAD001 (everolimus) leads to rebound activation of AKT, which could protect tumors from drug-induced cell death. Here we examine the potential benefit of inhibition of both mTOR and AKT signaling in a mouse model of TSC, using a dual pan class I PI3K/mTOR catalytic small molecule inhibitor NVP-BEZ235.</p> <p>Results</p> <p>Using ENU to enhance <it>Tsc2</it>^+-kidney tumor development, both RAD001 (10 mg/kg PO 5 d/week) and NVP-BEZ235 (45 mg/kg PO QD) had equivalent effects in suppressing tumor development during a 4 week treatment period, with a 99% reduction in tumor cell mass. Marked reduction in activation of mTORC1, induction of cell cycle arrest, and absence of apoptotic cell death was seen in mice treated with either drug. However, when either was discontinued, there was prompt recovery of tumor growth, with extensive proliferation.</p> <p>Conclusion</p> <p>Both mTORC1 blockade alone and combined PI3K-mTOR blockade lead to suppression of tumor development but not tumor elimination in this TSC model.</p

Therapeutic Trial of Metformin and Bortezomib in a Mouse Model of Tuberous Sclerosis Complex (TSC)

Tuberous sclerosis complex (TSC) is a human genetic disorder in which loss of either TSC1 or TSC2 leads to development of hamartoma lesions, which can progress and be life-threatening or fatal. The TSC1/TSC2 protein complex regulates the state of activation of mTORC1. Tsc2+/− mice develop renal cystadenoma lesions which grow progressively. Both bortezomib and metformin have been proposed as potential therapeutics in TSC. We examined the potential benefit of 1 month treatment with bortezomib, and 4 month treatment with metformin in Tsc2+/− mice. Results were compared to vehicle treatment and treatment with the mTORC1 inhibitor rapamycin for 1 month. We used a quantitative tumor volume measurement on stained paraffin sections to assess the effect of these drugs. The median tumor volume per kidney was decreased by 99% in mice treated with rapamycin (p = 0.0004). In contrast, the median tumor volume per kidney was not significantly reduced for either the bortezomib cohort or the metformin cohort. Biochemical studies confirmed that bortezomib and metformin had their expected pharmacodynamic effects. We conclude that neither bortezomib nor metformin has significant benefit in this native Tsc2+/− mouse model, which suggests limited benefit of these compounds in the treatment of TSC hamartomas and related lesions

Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma

Mesothelioma is diagnosed in approximately 2,500 patients in the United States every year, most often arising in the pleural space, but also occurring as primary peritoneal mesothelioma. The vast majority of patients with mesothelioma die from their disease within 3 years. We developed a new mouse model of mesothelioma by bladder or intra-peritoneal injection of adenovirus Cre into mice with conditional alleles of each of Tp53 and Tsc1. Such mice began to develop malignant ascites about 6 months after injection, which was due to peritoneal mesothelioma, based on tumor morphology and immunohistochemical staining. Mesothelioma cell lines were established which showed loss of both Tsc1 and Tp53, with mTORC1 activation. Treatment of mice with malignant ascites due to mesothelioma with rapamycin led to a marked reduction in ascites, extended survival, and a 95–99% reduction in mesothelioma tumor volume, in comparison to vehicle-treated mice. To see if TSC1/TSC2 loss was a common genetic event in human mesothelioma, we examined 9 human mesothelioma cell lines, and found that 4 of 9 showed persistent activation of mTORC1 though none had loss of TSC1 or TSC2. A tissue microarray analysis of 198 human mesothelioma specimens showed that 33% of cases had reduced TSC2 expression and 60% showed activation of mTOR, indicating that mTOR activation is common in human mesothelioma and suggesting that it is a potential therapeutic target

The comparison of multipotential for differentiation of progenitor mesenchymal-like stem cells obtained from livers of young and old rats.

The presence of stem cells differentiating to hepatocytes and cholangiocytes has been previously reported in livers of young rats. Here, we have isolated, cultured, and characterized mesenchymal stem cells (MSCs) from livers of young and old rats and tested their multipotential for differentiation. The mesenchymal stem cells in liver sections were identified by the presence of markers, respectively for primary stem cells Thy-1 and CD34, for differentiation to early cholangiocytes GST and CK19, and for differentiation to hepatocytes GSTalpha and CK18. Ki67 was detected as the cell proliferation marker. Cells isolated from livers of either age group were tested in a culture for their viability following storage and were characterized for the presence of most of the markers detected in cells in situ. The results revealed age-dependent changes in the number of recovered primary MSCs. In both age groups we have observed cells changing under differentiating conditions to liver cell lineages, such as cholangiocytes and hepatocytes, as well as to non-liver cells such as adipocytes, astrocytes, neuroblasts, and osteoblasts. Our data revealed that from the livers of rats 20 months and older the primary MSCs could be isolated and expanded; however, they were significantly fewer, even though their differentiation multipotential was preserved. The mechanism involved in the differentiation of liver MSCs seemed to depend on a constellation of signals in Notch signalling pathways. Thus, our results support the idea of potential use of liver as a source of MSCs, not only for liver reconstruction but also for cell therapy in general

Experimental Plant Biology: Why Not?! Genistein: a natural isoflavone with a potential for treatment of genetic diseases

Abstract Genistein [4 ,5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one] is a natural isoflavone occurring in many plants known to possess various biological activities, ranging from phyto-oestrogenic to antioxidative actions. Recent studies indicated that this isoflavone can also be considered as a drug for as yet untreatable genetic diseases. In the present review, we discuss a plausible use of genistein in treatment of two genetic disorders: CF (cystic fibrosis) and MPS (mucopolysaccharidosis). Although various biological actions of genistein are employed in these two cases, in vitro studies, tests on animal models and pilot clinical trials suggest that this plant-derived compound might be a real hope for patients suffering from severe inherited disorders with relatively complicated pathomechanisms, including those affecting the central nervous system

Experimental Plant Biology: Why Not?! Genistein: a natural isoflavone with a potential for treatment of genetic diseases

Abstract Genistein [4 ,5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one] is a natural isoflavone occurring in many plants known to possess various biological activities, ranging from phyto-oestrogenic to antioxidative actions. Recent studies indicated that this isoflavone can also be considered as a drug for as yet untreatable genetic diseases. In the present review, we discuss a plausible use of genistein in treatment of two genetic disorders: CF (cystic fibrosis) and MPS (mucopolysaccharidosis). Although various biological actions of genistein are employed in these two cases, in vitro studies, tests on animal models and pilot clinical trials suggest that this plant-derived compound might be a real hope for patients suffering from severe inherited disorders with relatively complicated pathomechanisms, including those affecting the central nervous system

Angiomyolipoma Have Common Mutations in TSC2 but No Other Common Genetic Events

Renal angiomyolipoma are part of the PEComa family of neoplasms, and occur both in association with Tuberous Sclerosis Complex (TSC) and independent of that disorder. Previous studies on the molecular genetic alterations that occur in angiomyolipoma are very limited. We evaluated 9 angiomyolipoma for which frozen tissue was available from a consecutive surgical series. Seven of 8 samples subjected to RT-PCR-cDNA sequencing showed mutations in TSC2; none showed mutations in TSC1 or RHEB. Six of the seven mutations were deletions. We searched for 983 activating and inactivating mutations in 115 genes, and found none in these tumors. Similarly analysis for genomic regions of loss or gain, assessed by Affymetrix SNP6.0 analysis, showed no abnormalities. Loss of heterozygosity in the TSC2 region was commonly seen, except in patients with low frequency TSC2 mutations. We conclude that sporadic renal angiomyolipoma usually have mutations in TSC2, but not TSC1 or RHEB, and have no other common genomic events, among those we searched for. However, chromosomal translocations and gene fusion events were not assessed here. TSC2 inactivation by mutation is a consistent and likely necessary genetic event in the pathogenesis of most angiomyolipoma

Physico-geographical mesoregions of Poland : verification and adjustment of boundaries on the basis of contemporary spatial data

The programme of identification, cataloguing and evaluation of Polish landscapes, part of the implementation of the European Landscape Convention, has caused an increase in interest in physico-geographical regionalisation over recent years. The commonly accepted regionalisation of Poland developed by J. Kondracki (Kondracki & Richling 1994) is sufficient for work at an overview scale (e.g. 1:500,000), whereas its spatial accuracy is too low to make use of it for the purpose of Polish landscape cataloguing. The aim of this article is to present a more up-to-date and detailed division of Poland into mesoregions, adjusted to the 1:50,000 scale. In comparison with older work, the number of mesoregions has increased from 316 to 344. In many cases, some far-reaching changes in meso- and macroregions were made. Nevertheless, in most cases the previous system of units was maintained, with more detailed adjustment of boundaries based on the latest geological and geomorphological data and the use of GIS tools for the DEM analysis. The division presented here is a creatively developing new work aligning the proposals of the majority of Polish researchers. At the same time, it is a regionalisation maintaining the idea of the work developed by J. Kondracki as well as his theoretical assumptions and the criteria used to distinguish units, which makes it a logical continuation of his regional division