82 research outputs found
Identification of novel genetic and prognostic markers in hereditary and sporadic cancer: "two sides of the same coin"
No full textThis thesis has focused on the discovery and characterization of novel diagnostic and prognostic markers in various cancer entities, with a special emphasis on colorectal cancer (CRC).
In Switzerland the incidence of colorectal cancer ranks third in males and second in females, with about 4000 new patients diagnosed each year. Incidence trends over the last decades have remained constant in both sexes, whereas mortality rates have been decreasing. Decreasing mortality is thought to be related to improved treatment during the past years as well as generalisation of colorectal cancer screening in the Swiss population. About 80% of colorectal cancers are thought to have occurred by chance (sporadic) with the remainder displaying either familial aggregation (about 15%) or mendelian inheritance (about 5%).
In the first part of this work we identify and characterize a novel target gene locus for microsatellite instability (MSI) consisting of a mononucleotide (T/U)16 tract, EWS16T, located in the 3’ UTR of the Ewing sarcoma break point region 1 (EWSR1) gene in 319 patients with hereditary and sporadic CRC. We show that the EWS16T locus discriminates MMR proficient from deficient cancers with high diagnostic sensitivity (100%) and specificity (100%). It could thus substantially improve and facilitate MSI analysis in routine daily practice. In addition, biochemical analyses indicate that EWS16T contractions alter poly(A) site selection by promoting SFPQ-mediated distal poly(A) site usage in EWSR1 pre-mRNAs and result in decreased mRNA as well as EWS protein expression. Our findings thus directly implicate the RNA-/DNA-binding Ewing sarcoma protein in MSI-associated colorectal tumorigenesis.
In the second part we characterize a new tumour suppressor gene designated SH2D4A located on the short arm of chromosome 8. We demonstrate that SH2D4A physically interacts with the EGFR/STAT3 pathway and controls cell proliferation. Upon EGF signaling, SH2D4A recruits the serine/threonine phosphatase PP1β to the receptor complex and represses activated STAT3 via dephosphorylation. SH2D4A expression reduces anchorage-independent tumour cell growth and its loss promotes the expression of c-Myc, Cyclin D1 and Jun B. In addition we show that SH2D4A expression is partially lost in human colorectal cancers as a result of chromosomal instability, mutations and epigenetic changes. Finally, diminished SH2D4A protein expression was found to correlate with advanced disease stages and was associated with poor prognosis.
In the third part we investigate HGMA1/HGM2 protein expression 210 and 1202 patients with pancreatic and breast cancers, respectively. HMGA1 and HMGA2 over-expression was found in a significant number of breast and pancreatic carcinoma samples, and its over-expression positively correlated with grade and stage of the disease. Conversely, no HMGA1 and HMGA2 expression was observed in cancer-free breast and pancreas tissues. Taken together, our findings show that high expression levels of HMGA1 and HMGA2 are related to an unfavorable histological type and a poor prognosis in both, pancreatic and breast cancer. Moreover, these findings further support the notion that these proteins represent appropriate targets for the therapy of human cancer, as suggested by numerous in vitro and in vivo studies.
In the fourth part of the thesis we evaluate the potential role of the cancer stem cell (CSC) proteins EpCAM, CD44s, CD166 and CD133 in tumors of the ampulla of Vater. CSC expression was determined in 175 carcinoma, 111 adenoma and 152 cancer free-mucosa specimens arranged on a tissue microarray format. The expression of all evaluated marker proteins differed significantly between cancer-free mucosa, adenoma and carcinoma samples. EpCAM expression was significantly correlated with better patient survival. In contrast, increased expression of CD44s, CD166 and CD133 from normal mucosa samples to adenoma and carcinoma was linked to tumor progression but no statistically significant correlation with survival observed. Our findings therefore indicate that in ampullary carcinomas loss of EpCAM expression may be associated with a more aggressive tumor phenotype.
In the fifth part we develop a specific monoclonal antibody for the highly immunogenic member of the MAGE-A family of cancer/testis tumor-associated antigens (C/T TAAs). The antibody was used to stain a multi-tumor tissue microarray comprising more than 2,500 paraffin-embedded specimens of different histological origin. C/T TAA appears to be expressed in a high percentage (>50%) of cancer cells from different tumor types such as lung, skin, gynecological, stomach and gall bladder cancers. The future characterization of MAGE-A10-specific antibodies might set the stage for the development of targeted active immunotherapy by clarifying potential indications and by allowing the selection of patients eligible for treatment and monitoring of its effectiveness
Neutropenia in cancer patients, risk prediction models of neutropenia, and supportive measures
No full textEpidemiology studies the causes and distribution of population health and disease conditions in defined populations. It identifies risk factors for disease which may help to prevent disease and promote health.
Each year, the American Cancer Society describes the epidemiology of cancer in the USA. Breast cancer and CLL are the most common cancers in women and adults, respectively. European data for CLL are limited. For both cancers, chemotherapy is an important treatment option. But side effects such as neutropenia and infections remain the principal dose-limiting toxicities, which may affect the effectiveness of cancer chemotherapy. Several studies evaluated risk factors for chemotherapy-induced neutropenia (CIN; absolute neutrophil count [ANC] <1.5x10^9/L) and febrile neutropenia (FN; ANC <0.5x10^9/L and oral temperature =38° for more than 1 hour): e.g. older age, recent infection, prior chemotherapy, and planned relative dose intensity greater than 85% of standard chemotherapy dosing. The prophylactic use of granulocyte colony-stimulating factors (G-CSFs) has been shown to be protective.
Based on the above mentioned risk factors, a number of risk prediction models have been developed over the years. Very often, the risk prediction models considered patient-related, tumour-related, treatment-related, or genetic factors. The majority of these models are not validated using an independent dataset. Systematic reviews of G-CSFs to prevent neutropenia are available, but do not include new long-acting G-CSFs or observational study designs.
To address the epidemiology of CLL, the incidence and risk factors of CIN and FN, and to develop and externally validate a risk prediction model for the occurrence of FN including a broad range of risk factors, three quantitative studies were conducted and published. The fourth published study summarised the efficacy, effectiveness and safety of G-CSFs for the prevention of CIN and FN.
For the first study, the author conducted a cohort analysis of the UK Clinical Practice Research Datalink (CPRD) to identify the epidemiology of CLL, the incidence of neutropenia, and changes in medical resource utilisation of CLL patients. Due to limited data regarding the incidence of neutropenia, the study focused on the epidemiology of CLL and medical resource utilisation of CLL patients. The incidence of CLL was 6.2 per 100’000 person-years and remained stable between 2006 and 2011. Medical resource utilisation in CLL patients increased over the time period from 2000 to 2012. Primary care data from the UK CPRD seemed to be valid to determine the incidence of CLL. These data may not reflect the total of medical resource use in CLL patients as chemotherapy and treatment of related complications such as infections and neutropenia are mainly performed in secondary or tertiary care.
The second study addressed the identification of risk factors and the development of a risk prediction model for FN in a hospital-based breast cancer cohort. Risk factors for FN were lower platelet count and haemoglobin, higher alanine aminotransferase (ALT), and specific allele variants of two single nucleotide polymorphisms (SNPs) in a gene involved in multidrug resistance. Genetic testing beforehand might be helpful to identify patients at a very high risk of FN. Predictive performance of the model was improved by adding genetic information but overall remained limited.
The third study used an available risk prediction model for FN in Non-Hodgkin lymphoma (NHL) patients and applied its prediction rules to an independent dataset of NHL patients. Age, weight, baseline white blood cell count, and planned chemotherapy dose were confirmed to predict the risk of FN. However, there was a decrease of the predictive performance in the independent validation dataset. This limits its use in clinical practice. But if successful risk prediction models are developed and externally validated, these may help to optimally target prophylaxis with G-CSFs to those patients at high risk of FN.
Finally, a systematic literature review was conducted to identify studies evaluating the efficacy, effectiveness and safety of G-CSFs in the prevention of CIN and FN. Most studies showed better efficacy and effectiveness for the long-acting pegfilgrastim than daily filgrastim. Efficacy and safety profiles of new long-acting G-CSFs such as lipegfilgrastim and balugrastim were comparable to pegfilgrastim. In times of increasing health care costs and scarce resources, the cost-efficient use of supportive measures is necessary.
The studies this work is based on showed that the availability of and access to appropriate data sources are necessary to develop and systematically validate risk prediction models. The findings contribute to the development of an evidence-based, efficient and cost-efficient approach to prevent neutropenia in cancer patients
Population genetic analysis of two species of non-indigenous riparian weeds in northeast England in the context of their spatial ecology
No full textThe population genetic structure of two species of invasive non-indigenous riparian weeds in the Northeast of England was investigated using microsatellite markers. Heracleum mantegazzianum and Impatiens glandulifera were introduced into the UK from Asia. The first records of the species in the Tees, Tyne and Wear catchment areas were in 1944 and 1892 respectively. Both species have spread rapidly, and are present over a wide area of the catchments. The pattern of genetic variation was investigated in order to determine the importance of anthropogenic introduction, and life-history and dispersal strategies to the distribution of the species. Twelve populations of each species were sampled from the Tees, Tyne and Wear catchments as well as an independent population for comparison. Genomic libraries were constructed and screened for dinucleotide repeat microsatellite loci. Four polymorphic loci of H. mantegazzianum and three of I. glandulfera were identified, and each species was also screened for variation using one universal chloroplast microsatellite locus. A large amount of variation was found in both species as the loci of H. mantegazzianum had between nine and twenty alleles and those of I. glandulifera between eight and sixteen alleles. Results revealed greater overall variation between populations from different catchments than those in the same catchment. Within a catchment, there was evidence of isolation by distance for both species in one out of two catchments examined. Populations of I. glandulifera showed greater temporal variation and there was more variation both overall and within a catchment in this species. This is likely to be due to the larger number of individuals present, and the wider distribution of this species. Low levels of chloroplast variation were found in both species. This may reflect a lack of variation in the material introduced into the UK
An evaluation of the Agrobacterium tumefaciens Virulence gene system as a potential diagnostic test for Neuroblastoma.
No full textNeuroblastoma is a common pediatric cancer, the prognosis for which is markedly dependent upon the progression of the disease at the time of diagnosis. It has been argued that a mass screening programme for all infants would aid early detection of neuroblastoma and reduce mortality. Neuroblastoma is unusual amongst childhood cancers since the basis for such a test exsists - otherwise asymptomatic patients excrete abnormal amounts of specific phenolic compounds in their urine. The presence of these metabolites at elevated levels is taken as diagnostic of the disease. A number of pilot screening programmes in different parts of the world have shown that a quick, inexpensive and reliable method of screening is needed. One candidate for this is a test based upon the responses of Agrobacterium tumefaciens to compounds with structures similar to those produced as a result of tumour metabolism. This bacterium responds to such phenolic ligands chemotactically and by induction of virulence gene expression. Data presented in this work shows that phenolics secreted by neuroblastoma tumours are incapable of inducing virulence gene expression but are capable of acting as chemoattractants. The role of phosphorylation in VirA/G mediated phenolic chemotaxis is investigated. Evidence is presented that phosphorylation of Vir and G is required for chemotaxis. A novel, highly reproducible and comparible measure bacterial chemotaxis, the chemotactic index is derived and applied
The Pathophysiological effects of adjuvant preoperative chemotherapy and/or radiotherapy on patients with advanced rectal cancer
No full textIntroduction
The modern treatment of colorectal cancer consists of surgery, with or without adjuvant pre-operative radiotherapy, chemotherapy or chemoradiotherapy (APT) for
selected cases. In the United Kingdom, therapy may be given prior to surgery in an attempt to facilitate surgical excision and improve survival. However, there is some
evidence that APT in other cancers may adversely affect the patient’s health and increase the risk of operative morbidity. The association between functional capacity, represented by the maximum oxygen consumption per unit time (VO2max) as measured by cardiopulmonary exercise testing (CPEX), and the perioperative outcome is well established. A reduction in cardiopulmonary reserve may increase the perioperative mortality and morbidity; however, sufficient data to demonstrate this are not available yet.
This study examined the affect of APT on the cardiopulmonary status, body composition, cytokines assay, nutritional status and quality of life in patients with
colorectal cancer.
Methods
This is a pilot observational study performed on two groups of patients, no intervention was used at this stage. Group one received combined ChemoRadiotherapy and Group two received only pelvic radiotherapy. Cardiopulmonary function was measured with exercise bicycle to achieve Anaerobic
Threshold (AT) and Maximum Oxygen consumption (VO2max) using CPEX testing. Anthropometric parameters such as mid-arm circumference (MAC), Triceps skin fold (TSF), grip strength measurements (GS), Body weight, height and body mass index as well as extracellular water (ECW), intracellular water (ICW), total body water (TBW) and fat free mass (FFM) were measured using a Bio-electrical impedance analyser. 9 cytokines were measured using a Luminex assay in addition to CRP and albumin assessment. Nutritional status and quality of life were evaluated using two validated questionnaires (EORTC QLQ-C30 and PG-SGA). These assessments were made before and within two weeks after the administration of APT. Wilcoxon rank sum test represented in median and interquartile range was used to compare results before and after the exposure to APT.
Results
Between January 2010 and January 2011, a total of 36 patients with rectal cancer were recruited, 24 patients in group 1 had combined chemoradiotherapy (mean age 59.4, 18 males and 6 females) and 12 patient in group 2 had radiotherapy only (mean age 71.8, 10 males and 2 females). Group 1 had a significant decline in VO2max with p=0.005, an increase in the ventilatory equivalent ratio for CO2
(VE/VCO2) with p= 0.001, a reduction in TSF, MAC, GS and TBW with p- values of 0.007, 0.006, 0.010 and 0.000 respectively after APT exposure. Group 2 had no significant changes in their CPEX data, however, they showed a marked decline in TSF, MAC, GS, TBW and FFM with p- values of 0.013, 0.013, 0.002 and 0.034 respectively after APT exposure. Both groups showed a highly significant overall
reduction in the health related quality of life data with no significant changes in their plasma cytokines, CRP and albumin post APT.
Conclusions
These data suggest that APT has a significant effect upon the cardiopulmonary capacity with reduced VO2max as well as an increased VE/VCO2. There were also signs of fluid depletion and reduced muscle bulk represented by a significant reduction in TBW, FFM, MAC and TSF. Therefore, these important physiological changes could be deleterious and affect the peri and post-operative recovery and
increase the morbidity of surgery in colorectal cancer patients. In view of this, a period of optimisation following APT and prior to surgery may serve to minimise the
risk of such complications
Genetic risk variants in intestinal inflammatory disorders
No full textPhDThis thesis includes work on the genetics of intestinal inflammatory disorders, concentrating
on coeliac disease and Crohn’s disease. It explores how common genetic variants influence
risk of complex phenotypes including immunological intolerance to gluten (coeliac disease)
and intolerance to therapeutic agents (azathioprine and mercaptopurine) used in the
treatment of intestinal inflammatory diseases. Finally it presents work aiming to move from
genetic associations with complex phenotypes to understanding of how these variants
modulate immunological processes.
Results of a large genome wide association study that identified more than 13 new genetic risk
regions influencing susceptibility to coeliac disease are presented. Results of a genome wide
association study of azathioprine and 6-mercaptopurine-induced pancreatitis in inflammatory
bowel disease-affected individuals are presented. Finally, a cell cytokine release assay for the
prostaglandin EP4 receptor was developed, with a view to investigating how SNPs associated
with Crohn’s disease in the 5p13.1 region influence EP4 receptor signalling and contribute to
disease pathogenesis. This work highlights some of the challenges in moving from SNP-disease
associations identified in GWASs to understanding how genetic variants change biological
processes
JAK2 V617F gene mutation in the laboratory work-up of myeloproliferative disorders: Experience of a major referral center in lebanon
No full textAims: JAK2 V617F mutation is gaining more acceptance in laboratory testing as part of the differential diagnosis work-up of myeloproliferative disorders (MPD). This report is the first of its kind from Lebanon that analyzes the distribution of this mutation among a series of referred cases to a major tertiary referral center. Methods: Real-time polymerase chain reaction using JAK2 V617F MutaScreen assay (IPSOGEN Cancer Profiler) was performed on 229 patients. Results: JAK2 V617F mutation was found to be positive in 100percent of polycythemia vera cases, 68.29percent of essential thrombocythemia cases, and 55.28percent of all MPD cases whereas negative in idiopathic erythrocytosis, reactive thrombocytosis, and other non-MPD cases such as acute chronic myeloid leukemias. Conclusion: Our unique study in this sample of Lebanese patients shows extensive similarities of positivity of JAK2 V617F as compared with the international literature and for the same categories of clinical entities. This will constitute a baseline for future clinical studies that would also help determine prognosis of cases based on the absence or presence of this mutation. © Mary Ann Liebert, Inc.Briere JB, 2007, ORPHANET J RARE DIS, V2, DOI 10.1186-1750-1172-2-3; Cankovic M, 2009, AM J CLIN PATHOL, V132, P713, DOI 10.1309-AJCPFHUQZ9AGUEKA; Finazzi G, 2006, BEST PRACT RES CL HA, V19, P471, DOI 10.1016-j.beha.2005.07.006; Frohling S, 2006, BLOOD, V107, P1242; Goldman JM, 2005, NEW ENGL J MED, V352, P1744, DOI 10.1056-NEJMp058083; Horn T, 2006, J MOL DIAGN, V8, P299, DOI 10.2353-jmoldx.2006.050128; Martinez-Aviles L, 2007, HAEMATOL-HEMATOL J, V92, P1717, DOI 10.3324-haematol.12011; McLornan Donal, 2006, Ulster Med J, V75, P112; Paradis FW, 2010, BMC MED GENET, V11, DOI 10.1186-1471-2350-11-54; Saharinen P, 2000, MOL CELL BIOL, V20, P3387, DOI 10.1128-MCB.20.10.3387-3395.2000; Steensma DP, 2006, J MOL DIAGN, V8, P397, DOI 10.2353-jmoldx.2006.060007; Szpurka H, 2006, BLOOD, V108, P2173, DOI 10.1182-blood-2006-02-005751; Tefferi A, 2005, MAYO CLIN PROC, V80, P1220; Wolstencroft EC, 2007, J MOL DIAGN, V9, P42, DOI 10.2353-jmoldx.2007.06008313111
High prevalence of MTHFR gene A1298C polymorphism in Lebanon
No full textBackground: Mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene could reduce the enzyme activity and lead to hyperhomocysteinemia, a condition that has been associated with several vascular conditions, in particular, coronary artery disease and deep vein thrombosis. Aim: The aim of this study was to assess the prevalence of the two most common polymorphisms, C677T and A1298C, which have not been well studied in the Lebanese population. Methods: We randomly selected 205 healthy individuals originating from different Lebanese provinces and religious communities. The CVD StripAssay was used to test for MTHFR gene polymorphisms. Results: We found that for C677T, the prevalence of C-C, C-T, and T-T genotypes was 65.3percent, 30.8percent, and 3.9percent, respectively, with an overall carrier rate of 34.6percent and allelic frequency of 0.19. However, the A1298C genotypic prevalence of A-C, A-A, and C-C was 50.2percent, 25.9percent, and 23.9percent, respectively, with an overall carrier rate of 74.14percent and an allelic frequency of 0.49. Conclusions: Compared to all other populations reported so far, the Lebanese population harbors the highest prevalence of the MTHFR A1298C polymorphism. 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HEALTH AND SAFETY REGULATION OF SMALL, HIGH-RISK SUBPOPULATIONS
No full textThe choice of decision framework used to set regulatory tolerance levels for hazardous substances can be divided into rigid and flexible tolerance levels. Rigid decision frameworks include zero or deminimis that fix risk levels for some subpopulation. and/or highly tolerances The accelerating identification of highly sensitive exposed individuals and the division of the population into ever smaller subpopulations at higher risk could prove to be tremendously burdensome on regulatory systems, particularly for rigid decision frameworks. Rigid tolerance levels, philosophically based on "rights" to zero or arbitrarily low excess risks for individuals, do not contain sufficient flexibility to account for small high-risk subpopulations. Furthermore, the equal protection for all such groups is an illusion, mainly because of the potentially large number of such subgroups and the relatively fixed regulatory resources. Thus, deminimis regulation is seen as a minimal but inadequate improvement over zero risk regulation. with improved measures of the heterogeneous demand for risk reduction by various high-risk subpopulations, augmented cost-benefit analyses leading to flexible tolEr2.nces could provide a richer analytic framework for more efficient regulatory decisions. Additionally, it may be useful to attempt to c2.tegorize hazards and subpopulations on the basis of the ability to self-protect.De minimis, sensitive, decision framework, cost benefit, Food Consumption/Nutrition/Food Safety, Health Economics and Policy,
Avaliação toxicológica em peixes da espécie Oreochromis niloticus expostos às águas do Rio Cubatão do Sul/SC: estudo genotóxico, epigenético e de estresse oxidativo
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro Tecnológico, Programa de Pós-Graduação em Engenharia Ambiental, Florianópolis, 2013.A poluição aquática é considerada uma das principais preocupações ambientais nas áreas urbanas. O aumento populacional, com o crescimento desordenado da urbanização próximo às margens dos rios introduz nestes ambientes, de forma direta e indireta, diversos compostos orgânicos e inorgânicos, muitos destes com potencial genotóxico e mutagênico. Num esforço de identificar os efeitos da exposição de organismos aquáticos a estes agentes potencialmente genotóxicos, este estudo teve por objetivo verificar o potencial genotóxico e mutagênico das águas do Rio Cubatão do Sul, importante manancial de captação e distribuição de água potável para a Região da Grande Florianópolis, sobre a espécie de peixe Oreochromis niloticus. O Rio Cubatão do Sul foi subdividido em 4 estações amostrais, de maneira a abranger as diferentes ocupações ao longo do curso de água, onde foram coletadas amostras de água quinzenalmente para a exposição de O. niloticus em laboratório por 280 dias. Foram realizados testes de frequência de células micronucleadas, testes epigenéticos e de verificação do estresse oxidativo. O teste do micronúcleo foi realizado com a determinação da frequência de células micronucleadas em eritrócitos de O. niloticus, a verificação do estresse oxidativo foi realizada com a quantificação das taxas do malondialdeído e as alterações epigenéticas verificadas através da quantificação do percentual de 5-metilcitosina. Os resultados indicaram que as amostras de água analisadas do Rio Cubatão do Sul provocaram efeitos tóxicos durante todo o período de estudo. A elevação na frequência de micronúcleos, assim como aumentos expressivos nas taxas de malondialdeído e 5-metilcitosina demonstraram que esta mistura ambiental complexa das águas do Rio Cubatão do Sul foram capazes de ocasionar danos genotóxicos em O. niloticus. A genotoxicidade verificada foi atribuída às fontes não pontuais de poluição provenientes do escoamento superficial de efluentes domésticos e agrícolas sem tratamento e serve de alerta ambiental, pois o Rio Cubatão do Sul é utilizado como manancial de água para abastecimento humano Aquatic pollution is considered a major environmental concerns in urban areas. The population increase, with the uncontrolled growth of urbanization near the river banks introduces, directly and indirectly, various organic and inorganic compounds, many of these with potential genotoxic and mutagenic. In an effort to identify the effects of exposure of aquatic organisms to these potentially genotoxic agents, this study aimed to verify the genotoxic and mutagenic potential of the waters of the Cubatão do Sul River, an important source of funding and distribution of drinking water for the region of Florianópolis on the fish species Oreochromis niloticus. The Cubatão do Sul River was divided into 4 sampling stations in order to cover the different occupations along the watercourse. The water samples were collected each 15 days, for exposure of O. niloticus in the laboratory for the period of 280 days. It was performed tests of frequency of micronucleated cells, epigenetic tests and the verification of oxidative stress. The micronucleus test was carried out to determine the frequency of cells with micronuclei in erythrocytes of O. niloticus, the verification of oxidative stress was performed with the quantification of the rates of malondialdehyde and the epigenetic alterations verified by quantifying the percentage of 5- methylcytosine. The water samples from the Cubatão do Sul River resulted in toxic effects throughout the study period. The increase in the frequency of micronuclei, as well as significant increases in rates of malondialdehyde and 5-methylcytosine demonstrated that this complex environmental mixture of water from Cubatão do Sul River was able to cause genotoxic damage in O. niloticus. The genotoxicity observed was attributed to non-point source pollution from runoff of agricultural and domestic effluents without treatment and serves as environmental alert because the Cubatão do Sul River is used as a source of water for human consumption
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