| 1. |
- Hashemi, Jamileh, et al.
(författare)
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Molecular Characterization of Acquired Tolerance of Tumor Cells to Picropodophyllin (PPP)
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3, s. e14757-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Picropodophyllin (PPP) is a promising novel anti-neoplastic agent that efficiently kills tumor cells in vitro and causes tumor regression and increased survival in vivo. We have previously reported that PPP treatment induced moderate tolerance in two out of 10 cell lines only, and here report the acquired genomic and expression alterations associated with PPP selection over 1.5 years of treatment. Methodology/Principal Findings: Copy number alterations monitored using metaphase and array-based comparative genomic hybridization analyses revealed largely overlapping alterations in parental and maximally tolerant cells. Gain/amplification of the MYC and PVT1 loci in 8q24.21 were verified on the chromosome level. Abnormalities observed in connection to PPP treatment included regular gains and losses, as well as homozygous losses in 10q24.1-q24.2 and 12p12.3-p13.2 in one of the lines and amplification at 5q11.2 in the other. Abnormalities observed in both tolerant derivatives include amplification/gain of 5q11.2, gain of 11q12.1-q14.3 and gain of 13q33.3-qter. Using Nexus software analysis we combined the array-CGH data with data from gene expression profilings and identified genes that were altered in both inputs. A subset of genes identified as downregulated (ALDH1A3, ANXA1, TLR4 and RAB5A) or upregulated (COX6A1, NFIX, ME1, MAPK and TAP2) were validated by siRNA in the tolerant or parental cells to alter sensitivity to PPP and confirmed to alter sensitivity to PPP in further cell lines. Conclusions: Long-term PPP selection lead to altered gene expression in PPP tolerant cells with increase as well as decrease of genes involved in cell death such as PTEN and BCL2. In addition, acquired genomic copy number alterations were observed that were often reflected by altered mRNA expression levels for genes in the same regions.
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| 2. |
- Kwiecinska, Anna, et al.
(författare)
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Amplification of 2p as a Genomic Marker for Transformation in Lymphoma
- 2014
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 53:9, s. 750-768
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Tidskriftsartikel (refereegranskat)abstract
- To outline further genetic mechanisms of transformation from follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL), we have performed whole genome array-CGH in 81 tumors from 60 patients [29 de novo DLBCL (dnDLBCL), 31 transformed DLBCL (tDLBCL), and 21 antecedent FL]. In 15 patients, paired tumor samples (primary FL and a subsequent tDLBCL) were available, among which three possessed more than two subsequent tumors, allowing us to follow specific genetic alterations acquired before, during, and after the transformation. Gain of 2p15-16.1 encompassing, among others, the REL, BCL11A, USP34, COMMD1, and OTX1 genes was found to be more common in the tDLBCL compared with dnDLBCL (P < 0.001). Furthermore, a high-level amplification of 2p15-16.1 was also detected in the FL stage prior to transformation, indicating its importance during the transformation event. Quantitative real-time PCR showed a higher level of amplification of REL, USP34, and COMMD1 (all involved in the NF kappa B-pathway) compared with BCL11A, which indicates that the altered genes disrupting the NF kappa B pathway may be the driver genes of transformation rather than the previously suggested BCL11A. Moreover, a 17q21.33 amplification was exclusively found in tDLBCL, never in FL (P < 0.04) or dnDLBCL, indicating an upregulation of genes of importance during the later phase of transformation. Taken together, our study demonstrates potential genomic markers for disease progression to clinically more aggressive forms. We also confirm the importance of the TP53-, CDKN2A-, and NF kappa B-pathways for the transformation from FL to DLBCL.
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| 3. |
- Owolabi, Mayowa O., et al.
(författare)
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Gaps in Guidelines for the Management of Diabetes in Low- and Middle-Income Versus High-Income Countries : A Systematic Review
- 2018
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Ingår i: Diabetes Care. - : AMER DIABETES ASSOC. - 0149-5992 .- 1935-5548. ; 41:5, s. 1097-1105
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Forskningsöversikt (refereegranskat)abstract
- OBJECTIVE The extent to which diabetes (DM) practice guidelines, often based on evidence from high-income countries (HIC), can be implemented to improve outcomes in low-and middle-income countries (LMIC) is a critical challenge. We carried out a systematic review to compare type 2 DM guidelines in individual LMIC versus HIC over the past decade to identify aspects that could be improved to facilitate implementation. RESEARCH DESIGN AND METHODS Eligible guidelines were sought from online databases and websites of diabetes associations and ministries of health. Type 2 DM guidelines published between 2006 and 2016 with accessible full publications were included. Each of the 54 eligible guidelines was assessed for compliance with the Institute of Medicine (IOM) standards, coverage of the cardiovascular quadrangle (epidemiologic surveillance, prevention, acute care, and rehabilitation), translatability, and its target audiences. RESULTS Most LMIC guidelines were inadequate in terms of applicability, clarity, and dissemination plan as well as socioeconomic and ethical-legal contextualization. LMIC guidelines targeted mainly health care providers, with only a few including patients (7%), payers (11%), and policy makers (18%) as their target audiences. Compared with HIC guidelines, the spectrum of DM clinical care addressed by LMIC guidelines was narrow. Most guidelines from the LMIC complied with less than half of the IOM standards, with 12% of the LMIC guidelines satisfying at least four IOM criteria as opposed to 60% of the HIC guidelines (P < 0.001). CONCLUSIONS A new approach to the contextualization, content development, and delivery of LMIC guidelines is needed to improve outcomes.
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| 4. |
- Sulaiman, Luqman
(författare)
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Genetic and epigenetic mechanisms in primary hyperparathyroidism
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by abnormally excessive secretion of parathyroid hormone (PTH) and elevated serum calcium. PHPT patients can develop a wide range of complications affecting many body organs such as the skeleton, kidneys and heart. In the majority of patients, PHPT is due to a solitary adenoma and less frequently due to multiglandular disease. Very rarely PHPT is caused by a parathyroid carcinoma. This thesis aimed at a better understanding of the genetic as well as epigenetic mechanisms involved in this disease in order to improve future patients management. In study I we have investigated large parathyroid adenomas (≥ 4 grams) and detected frequent MEN1, but rare HRPT2/CDC73 mutations and low MIB1 proliferation index. The majority of the tumors had loss of parafibromin expression and positive APC expression. Furthermore, gain of chromosome 5 was the most unique and frequent copy number alteration detected in this group, while very rarely detected in unselected adenomas. We concluded that a subset of large parathyroid adenomas have distinct genetic profile and pronounced clinical features reflected by significantly higher serum calcium. In study II we examined the role of constitutional APC mutations in parathyroid tumors from two patients with APC mutation-associated familial colorectal cancers. Pathological revision confirmed the benign nature of both tumors. None of them had somatic mutations or DNA copy number alterations of the APC gene and both tumors displayed strong APC and parafibromin expression with low MIB index. Although the APC 1A promoter was hypermethylated, promoter APC 1B was unmethylated and this was consistent with normal APC mRNA expression. Our results supported the benign nature of the parathyroid tumors and excluded a possible association between constitutional APC mutations and parathyroid tumorigenesis. In study III we defined the molecular cytogenetic profile of CDC73/HRPT2-mutated parathyroid tumors. All the carcinomas displayed frequent DNA copy number losses on chromosome 1p and 13 while the adenomas did not display any significant alterations. All the carcinomas were diploid at the CDC73 gene locus, but three adenomas had loss at this locus. The CDC73 promoter was unmethylated in all the tumors. The carcinomas displayed more loss of heterozygosity (LOH) events than the adenomas, and two carcinomas had LOH at the CDC73 locus. These results suggest that CDC73-mutated parathyroid adenomas exhibit a partly unique cytogenetic profile in addition to that of carcinomas and unselected adenomas. In study IV analyses of promoter methylation status in a panel of benign and malignant parathyroid tumors revealed frequent hypermethylation of APC 1A, β-catenin and RASSF1A promoters in the adenomas which correlated with reduced mRNA expression. Parathyroid carcinomas were hypermethylated for APC 1A and exclusively for SFRP1. No changes in global methylation could be detected and tumor groups with known MEN1 or CDC73 mutations did not display different methylation profile. We concluded that aberrant promoter methylation of APC 1A, β-catenin, RASSF1A and SFRP1 can play a role in parathyroid tumorigenesis and hypermethylation of SFRP1 can act as a potential epigenetic marker for parathyroid carcinomas.
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