641 research outputs found
Chromosome aberrations and oncogenes in human cancer
The combined application of cytogenetic and molecular
genetic techniques has elucidated the involvement of cellular
oncogenes in tumor specific chromosomal abnormalities. Although
these studies further underline the fundamental role of chromosomal
abnormalities in tumor-development, as yet virtually
nothing is known of the generation of these aberrations. DNA
sequence analysis of BL and CML specific chromosomal breakpoint
regions revealed no clue to a possible translocation mechanism.
However, a report by Fialkow et al. (1981) indicates that in
CML, the acquisition of the Ph1 chromosome is preceded by an
initial phase of marked genetic instability. A similar phase of
genetic instability of Ig or TCR loci may occur during the
process of somatic rearrangements of these genes. During these
phases, presumably various translocations occur and those with
a selective growth advantage will eventually result in a clinically
apparent leukemia.
It has been suggested that fragile sites may act as predisposing factors for certain specific chromosomal rearrangements
(Yunis and Soreng, 1984~ LeBeau and Rowley, 1984). The chromosomal
location of a number of these fragile sites coincides
with specific chromosomal breakpoint regions. Furthermore,
leukemic patients were identified as carriers of a fragile site
at the observed chromosomal breakpoint (Yunis, 1983~ LeBeau,
1986). Although several genes, among which some oncogenes, have
been mapped to an identical chromosomal region as a fragile
site, at present the exact nature and function of the genes
located at these sites remains an enigma.
Molecular techniques as Southern blotting and chromosomal
walking have demonstrated in a few tumor specific aberrations
the localization of (putative) oncogenes in the direct vicinity
of the chromosomal breakpoint region. However, in other tumor
specific aberrations the exact nature of the association between
cytogenetic changes and alterations at the DNA or gene
level remains obscure. The application of new techniques as
Pulsed Field Gradient (PFG) gel electrophoresis (Schwartz and
Cantor, 1984~ Carle and Olson, 1984), which allows the separation
of large (50-2000 kb) DNA fragments could help to corroborate
a possible involvement of oncogenes in these cases.
Furthermore, the use of PFG gels could lead to the detection of
deletions which are not visible at the cytogenetic level. An
example concerning deletions of part of chromosome lp32, which
resulted in the activation of the trk oncogene in a human colon
carcinoma has recently been reported (Martin-Zanca et al.,
1986)
Etiology of Esophageal Atresia and Tracheoesophageal Fistula: “Mind the Gap”
Esophageal atresia and tracheoesophageal fistula (EA/TEF) are major congenital malformations affecting 1:3500 live births. Current research efforts are focused on understanding the etiology of these defects. We describe well-known animal models, human syndromes, and associations involving EA/TEF, indicating its etiologically heterogeneous nature. Recent advances in genotyping technology and in knowledge of human genetic variation will improve clinical counseling on etiologic factors. This review provides a clinical summary of environmental and genetic factors involved in EA/TEF
Generation of three iPSC lines from two patients with heterozygous FOXF1 mutations associated to Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins
Diagnosing Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins (ACD/MPV) based on a genetic alteration in the FOXF1 gene, is complicated by the poor understanding of the causal relation between FOXF1 variants and the ACD/MPV phenotype. Here, we report the generation of human iPSC lines from two ACD/MPV patients, each carrying a different heterozygous FOXF1 mutation, which enables disease modeling for further research on the effect of FOXF1 variants in vitro. The iPSC lines were generated from skin fibroblasts using the non-integrating Sendai virus. The lines expressed pluripotency genes, retained the heterozygous mutation and were capable of trilineage differentiation
Genetics of Uveal Melanoma and Cutaneous Melanoma: Two of a Kind?
Cutaneous melanoma and uveal melanoma both derive from melanocytes but show remarkable differences in tumorigenesis, mode of metastatic spread, genetic alterations, and therapeutic response. In this review we discuss the differences and similarities along with the genetic research techniques available and the contribution to our current understanding of melanoma. The several chromosomal aberrations already identified prove to be very strong predictors of decreased survival in CM and UM patients. Especially in UM, where the overall risk of metastasis is high (45%), genetic research might aid clinicians in selecting high-risk patients for future systemic adjuvant therapies
Dose fractionation effects in primary and metastatic human uveal melanoma cell lines
PURPOSE: To investigate the effects of split-dose irradiation on primary
and metastatic uveal melanoma cell lines, with a clonogenic survival
assay. METHODS: Appropriate cell concentrations of four primary and four
metastatic human uveal melanoma cell lines were cultured for irradiation
with single doses and with two equal fractions separated by 5 hours. After
irradiation, colony formation was allowed for 7 to 21 days. Two cutaneous
melanomas were also tested for comparison. All survival curves were
analyzed using the linear quadratic (LQ) model. Specific parameters for
the intrinsic radiosensitivity (alpha-component, SF2), for the capacity of
repair of DNA damage (beta-component), as well as the alpha/beta ratio
were calculated. RESULTS: After single-dose irradiation a wide range in
the values of the alpha- and beta-component was obtained for both primary
and metastatic uveal melanomas, which resulted in a wide range of
alpha/beta ratios. In contrast, calculations based on split-dose data,
with which the beta-component could be estimated independent of the
alpha-component, indicated that estimates for the capacity of sublethal
DNA damage repair was very similar in all cell lines. This indicated that
intrinsic factors dominated the radiosensitivity of these cell lines.
Split-dose irradiation had little influence on the intrinsic
radiosensitivity (alpha-component), but cell survival increased for all
cell lines. For the two cutaneous melanomas comparable split-dose results
were obtained. CONCLUSIONS: For both primary and metastatic uveal melanoma
cell lines, data from single and fractionated doses indicate large
variations in radiosensitivity, which are mainly dominated by the
intrinsic radiosensitivities. Doses of approximately 8 Gy in five
fractions would be sufficient to eradicate 10(9) cells (approximately 1
cm3) of the most radioresistant tumor cell lines, but this schedule is an
overkill for the radiosensitive tumor cell lines. Based on specific
morphologic and histologic tumor markers, more individualized dose
fractionation schedules could improve the therapeutic ratio for uveal
melanomas
Uveal melanoma modeling in mice and zebrafish
Despite extensive research and refined therapeutic options, the survival for metastasized uveal melanoma (UM) patients has not improved significantly. UM, a malignant tumor originating from melanocytes in the uveal tract, can be asymptomatic and small tumors may be detected only during routine ophthalmic exams; making early detection and treatment difficult. UM is the result of a number of characteristic somatic alterations which are associated with prognosis. Although UM morphology and biology have been extensively studied, there are significant gaps in our understanding of the early stages of UM tumor evolution and effective treatment to prevent metastatic disease remain elusive. A better understanding of the mechanisms that enable UM cells to thrive and successfully metastasize is crucial to improve treatment efficacy and survival rates. For more than forty years, animal models have been used to investigate the biology of UM. This has led to a number of essential mechanisms and pathways involved in UM aetiology. These models have also been used to evaluate the effectiveness of various drugs and treatment protocols. Here, we provide an overview of the molecular mechanisms and pharmacological studies using mouse and zebrafish UM models. Finally, we highlight promising therapeutics and discuss future considerations using UM models such as optimal inoculation sites, use of BAP1mut-cell lines and the rise of zebrafish models.</p
Uveal melanoma modeling in mice and zebrafish
Despite extensive research and refined therapeutic options, the survival for metastasized uveal melanoma (UM) patients has not improved significantly. UM, a malignant tumor originating from melanocytes in the uveal tract, can be asymptomatic and small tumors may be detected only during routine ophthalmic exams; making early detection and treatment difficult. UM is the result of a number of characteristic somatic alterations which are associated with prognosis. Although UM morphology and biology have been extensively studied, there are significant gaps in our understanding of the early stages of UM tumor evolution and effective treatment to prevent metastatic disease remain elusive. A better understanding of the mechanisms that enable UM cells to thrive and successfully metastasize is crucial to improve treatment efficacy and survival rates. For more than forty years, animal models have been used to investigate the biology of UM. This has led to a number of essential mechanisms and pathways involved in UM aetiology. These models have also been used to evaluate the effectiveness of various drugs and treatment protocols. Here, we provide an overview of the molecular mechanisms and pharmacological studies using mouse and zebrafish UM models. Finally, we highlight promising therapeutics and discuss future considerations using UM models such as optimal inoculation sites, use of BAP1mut-cell lines and the rise of zebrafish models.</p
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