| 1. |
- Häggblad Sahlberg, Sara, et al.
(author)
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The effect of a dimeric Affibody molecule (ZEGFR:1907)2 targeting EGFR in combination with radiation in colon cancer cell lines
- 2012
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 40:1, s. 176-184
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Journal article (peer-reviewed)abstract
- The epidermal growth factor receptor (EGFR) is frequently overexpressed in colorectal cancer and is therefore an attractive target for treatment. (ZEGFR:1907)2 is a newly developed dimeric affibody molecule with high affinity to the extracellular part of EGFR. In this study, we evaluated the cytotoxic effects of (ZEGFR:1907)2 in combination with external radiation and the possible inhibitory effects in the EGFR signalling pathways in the colon cancer cell lines HT-29 and HCT116. The effects were compared with an EGFR antibody (cetuximab) and the tyrosine kinase inhibitors (erlotinib and sunitinib). These cell lines are genotypically different with respect to e.g. KRAS and BRAF mutational status, recently shown to be of clinical significance for therapeutic effects. Both cell lines express approximately 100,000-150,000 EGFRs per cell but differ in the radiation response (HCT116, SF2=0.28 and HT-29, SF2=0.70). Exposure to (ZEGFR:1907)2 produced a small, but significant, reduction in survival in HCT116 but did not affect HT-29 cells. Similar results were obtained after exposure to EGF and the EGFR antibody cetuximab. The EGFR tyrosine kinase targeting inhibitor erlotinib and the multi-tyrosine kinase inhibitor sunitinib reduced survival in both cell lines. However, none of the drugs had any significant radiosensitizing effects in combination with radiation. Akt and Erk are central proteins in the EGFR downstream signalling and in the cellular response to ionizing radiation. The activation of Akt (Ser 473) and Erk (Thr202/Tyr204) by radiation was both dose- and time-dependent. However the activation of EGFR was not clearly affected by radiation. Neither (ZEGFR:1907)2 nor any of the other drugs were able to completely inactivate Akt or Erk. On the contrary, erlotinib stimulated Akt phosphorylation in both cell lines and in HCT116 cells Erk was activated. Overall the results illustrate the complexity in response to radiation and drugs in cells with differential phenotypic status.
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| 2. |
- Abel, Frida, 1974, et al.
(author)
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Mutations in the N-terminal domain of DFF45 in a primary germ cell tumor and in neuroblastoma tumors.
- 2004
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In: International journal of oncology. - 1019-6439 .- 1791-2423. ; 25:5, s. 1297-302
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Journal article (peer-reviewed)abstract
- DFF45 has essential functions in the final stage of apoptosis by acting both as a folding chaperone and a DNase inhibitor of DFF40. The gene encoding DFF45 (DFFA) maps to the consensus deleted region in primary neuroblastoma (NB; 1p36.2-3) and within the homozygously deleted region in an NB cell line (1p36.2). DFF45 is therefore an attractive candidate NB tumor suppressor. In a previous study we found a rare allele variant, causing a non-polar to a polar amino acid exchange (Ile69Thr) in a preserved hydrophobic patch of DFF45, and we also found DFFA to be preferentially expressed in favorable NB tumors. We have extended the previous study and performed mutation analyses in another 56 NB tumors (100 in total) as well as a set of other tumors for coding mutations in DFFA. We have also performed studies of the DFFA expression in tumors using real-time PCR. We found a missense mutation (Ile15Met) in the remaining allele of a teratoma with heterozygous deletion of 1p, and a three base-pair deletion in an NB of unknown stage causing a deletion of amino acid 37 in DFF45. The one-base substitution detected in the teratoma was not present in the patients constitutional DNA, i.e. it is a true mutation present in the tumor DNA only. In conclusion, three different coding alterations have been found in the region encoding the N-terminal regulatory domain of DFF45, responsible for binding and achieving its chaperone and inhibitor functions on other proteins. Moreover, by real-time RT-PCR expression study, we found the mRNA level of DFFA to be significantly (p=0.038) reduced by a factor of 1.7 times in NB tumors of unfavorable outcome.
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| 3. |
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| 4. |
- Ahnström, Marie, et al.
(author)
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Altered expression of cyclin E and the retinoblastoma protein influences the effect of adjuvant therapy in breast cancer
- 2009
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 34:2, s. 441-448
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Journal article (peer-reviewed)abstract
- Cyclin E and the retinoblastoma protein (Rb) are both important regulators of the G(1) phase in the cell cycle. Overexpression of cyclin E and lost expression of Rb has previously been observed in breast tumours at frequencies of 10-50% and 20-30%, respectively. We explored the prognostic role of cyclin E and Rb in breast cancer patients randomised for tamoxifen (TAM), CMF (cyclophosphamide, metotrexate, 5-fluorouracil) chemotherapy and radiotherapy (RT) and how their expression affects the patients response to treatment. Protein expression was assessed with immunohistochemistry. We found overexpression of cyclin E in 32.1% (71/221) of the tumours and loss of Rb expression in 25.0% (59/236). Increased expression of cyclin E correlated to dysfunctional p53 (P=0.003) while loss of Rb correlated to normal p53 status (P=0.001). Our results suggest that patients with high cyclin E tumours have less benefit from tamoxifen (ER+, TAM vs. no TAM; RR=0.97; 95% CI, 0.36-2.60) than patients whose tumours show low expression (ER+, TAM vs. no TAM; RR =0.41; 95% CI, 0.24-0.72). Cyclin E also tended to predict the benefit from radiotherapy with a local recurrence rate of 0.31 (RT vs. CMF; 95% CI, 0.12-0.93) for patients with low expression and 0.68 (RT vs. CMF; 95% CI, 0.2-2.32) for patients with high expression of cyclin E. When the p53 status was taken in consideration the results showed that patients with both normal p53 and normal Rb expression had considerably lower locoregional recurrence rate when treated with radiotherapy instead of CMF (RR=0.17; 95% CI, 0.052-0.58) as compared to patients with either altered Rb or p53 or both (RR=0.70; 95% CI, 0.28-1.73).
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| 5. |
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| 6. |
- Akhtar, Monira, et al.
(author)
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Cell type and context-specific function of PLAG1 for IGF2 P3 promoter activity
- 2012
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 41:6, s. 1959-1966
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Journal article (peer-reviewed)abstract
- The fetal transcription factor PLAG1 is found to be overexpressed in cancers, and has been suggested to bind the insulin like growth factor 2 (IGF2) P3 promoter, and to activate the IGF2 gene. The expression of IGF2 has partly been linked to loss of CTCF-dependent chromatin insulator function at the H19 imprinting control region (ICR). We investigated the role of PLAG1 for IGF2 regulation in Hep3B and JEG-3 cell lines. Chromatin immunoprecipitation revealed cell type-specific binding of PLAG1 to the IGF2 P3 promoter, which was substantially insensitive to recombinant PLAG1 overexpression in the endogenous context. We hypothesized that the H19 chromatin insulator may be involved in the cell type-specific PLAG1 response. By using a GFP reporter gene/insulator assay plasmid construct with and without the H19 ICR and/or an SV40 enhancer, we confirm that the effect of the insulator is specifically associated with the activity of the IGF2 P3 promoter in the GFP reporter system, and furthermore, that the reporter insulator is functional in JEG-3 but not in Hep3B cells. FACS analysis was used to assess the function of PLAG1 in low endogenously expressing, but Zn-inducible stable PLAG1 expressing JEG-3 cell clones. Considerable increase in IGF2 expression upon PLAG1 induction with a partial insulator overriding activity was found using the reporter constructs. This is in contrast to the effect of the endogenous IGF2 gene which was insensitive to PLAG1 expression in JEG-3, while modestly induced the already highly expressed IGF2 gene in Hep3B cells. We suggest that the PLAG1 binding to the IGF2 P3 promoter and IGF2 expression is cell type-specific, and that the PLAG1 transcription factor acts as a transcriptional facilitator that partially overrides the insulation by the H19 ICR.
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| 7. |
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| 8. |
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| 9. |
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| 10. |
- Altai, Mohamed, et al.
(author)
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Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin
- 2016
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 49:3, s. 1185-1194
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Journal article (peer-reviewed)abstract
- Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide In-111. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)(3) purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, In-111-(HE)(3)-Z(HER2)-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.
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| 11. |
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| 12. |
- Andersson, Jennie, et al.
(author)
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In Vitro Therapy Modeling of HER2 Targeting Therapy in Disseminated Prostate Cancer
- 2014
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 45:5, s. 2153-2158
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Journal article (peer-reviewed)abstract
- Prostate cancer (PCa) is the most common cancer type among men. Treatments against advanced PCa are limited and in many cases only palliative. In a later, androgent independent, stage of PCa androgen receptors can be activated without interaction with ligand, i.e., by receptors of tyrosine kinase (RTK) family in the outlaw pathway. Human epidermal growth factor receptors HER2 and EGFR belong to RTK-family. HER2 is one of the main actors in the outlaw pathway with EGFR as the preferable heterodimerizing partner. We hypothesized that information on HER2 expression in advanced PCa could be useful for selection of patients for anti-RTK therapy and monitoring of therapy response. A panel of PCa cell lines (LNCap, PC3, DU-145) was subjected to a 8-week treatment using drugs influencing the RTK: trastuzumab (anti‑HER2), 17-DMAG (Hsp90 inhibitor), alone or in combination, and their HER2 and EGFR expressions were compared with non-treated cells. Treatment with trastuzumab decreased proliferation of LNCap and DU-145 cell lines, while 17-DMAG and trastuzumab/17‑DMAG combination affected all three cell lines. HER2 expression was significantly increased in PC3 cells, the most resistant cell line. On the contrary, in responding cells (LNCap and DU-145) HER2 expression decreased, accompanied by increased EGFR expression. However, additional treatment of cells with cetuximab (anti‑EGFR) did not give any additive effect to trastuzumab. In this study the response to anti-RTK therapy proved to vary between different PCa cell lines. We have demonstrated that RTK targeting treatments may affect the phenotypic profile of PCa tumor cells that correlates with therapy outcome. Observation of such changes during treatment could be used for monitoring and an improved therapy outcome.
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| 13. |
- Andersson, Ken G., et al.
(author)
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Feasibility of imaging of epidermal growth factor receptor expression with ZEGFR:2377 affibody molecule labeled with Tc-99m using a peptide-based cysteine-containing chelator
- 2016
-
In: International Journal of Oncology. - : SPANDIDOS. - 1019-6439 .- 1791-2423. ; 49:6, s. 2285-2293
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Journal article (peer-reviewed)abstract
- The epidermal growth factor receptor (EGFR) is overexpressed in a number of malignant tumors and is a molecular target for several specific anticancer antibodies and tyrosine kinase inhibitors. The overexpression of EGFR is a predictive biomarker for response to several therapy regimens. Radionuclide molecular imaging might enable detection of EGFR overexpression by a non-invasive procedure and could be used repeatedly. Affibody molecules are engineered scaffold proteins, which could be selected to have a high affinity and selectivity to predetermined targets. The anti-EGFR ZEGFR:2377 affibody molecule is a potential imaging probe for EGFR detection. The use of the generator-produced radionuclide Tc-99m should facilitate clinical translation of an imaging probe due to its low price, availability and favorable dosimetry of the radionuclide. In the present study, we evaluated feasibility of ZEGFR:2377 labeling with Tc-99m using a peptide-based cysteine-containing chelator expressed at the C-terminus of ZEGFR:2377. The label was stable in vitro under cysteine challenge. In addition, Tc-99m-ZEGFR:2377 was capable of specific binding to EGFR-expressing cells with high affinity (274 pM). Studies in BALB/C nu/nu mice bearing A431 xenografts demonstrated that Tc-99m-ZEGFR:2377 accumulates in tumors in an EGFR-specific manner. The tumor uptake values were 3.6 1 and 2.5 0.4% ID/g at 3 and 24 h after injection, respectively. The corresponding tumor-to-blood ratios were 1.8 0.4 and 8 3. The xenografts were clearly visualized at both time-points. This study demonstrated the potential of Tc-99m-labeled ZEGFR:2377 for imaging of EGFR in vivo.
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| 14. |
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| 15. |
- Au, Gough G, et al.
(author)
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Oncolysis of vascular malignant human melanoma tumors by Coxsackievirus A21.
- 2005
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In: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 26:6, s. 1471-6
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Journal article (peer-reviewed)abstract
- Cultured melanoma cell lines despite exhibiting similar in vitro morphology, display significant phenotypic and growth rate differences when propagated as in vivo xenografts. Previously we have shown that Coxsackievirus A21 (CVA21) lytically infects in vitro cultures of malignant melanoma cells and is efficient at reducing the tumor burden of mice bearing slow-growing SK-Mel-28 melanoma xenografts. The oncolytic activity of CVA21 against in vivo melanoma xenografts, which possess rapid growth rates and more extensive vascular structure than SK-Mel-28 xenografts warrants further investigation. In the present study we evaluated the oncolytic action of CVA21 against rapidly growing melanoma xenografts (ME4405) which exhibit a highly vascular phenotype. Flow cytometric analysis indicated that in vitro cultures of ME4405 cells expressed comparable levels of the CVA21 cellular receptors, ICAM-1 (intercellular adhesion molecules-1) and DAF (decay accelerating factor) to SK-Mel-28 cells. Despite similar levels of CVA21 receptor expression, SK-Mel-28 cells appear to be more susceptible to viral lysis than ME4405 cells, even though the kinetics of virus replication in both lines was comparable. Intratumoral, intraperitoneal or intravenous administration of CVA21 were equally effective in reducing the tumor volume of ME4405 xenografts in immunodeficient mice, and provides further evidence for the use of CVA21 as a novel oncolytic agent against varying phenotypes of malignant melanoma.
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| 16. |
- Barta, Pavel, et al.
(author)
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Protein interactions with HER-family receptors can have different characteristics depending on the hosting cell line
- 2012
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 40:5, s. 1677-1682
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Journal article (peer-reviewed)abstract
- Cell lines are common model systems in the development of therapeutic proteins and in the research on cellular functions and dysfunctions. In this field, the protein interaction assay is a frequently used tool for assessing the adequacy of a protein for diagnostic and therapeutic purposes. In this study, we investigated the extent to which the interaction characteristics depend on the choice of cell line for HER-family receptors. The interaction characteristics of two therapeutic antibodies (trastuzumab and cetuximab) and one Affibody molecule (ZHER2:342), interacting with the intended receptor were characterized with high precision using an automated real-time interaction method, in different cell lines (HaCaT, A431, HEP-G2, SKOV3, PC3, DU-145). Clear differences in binding affinity and kinetics, up to one order of magnitude, were found for the interaction of the same protein binding to the same receptor on different cells for all three proteins. For HER-family receptors, it is therefore important to refer to the measured affinity for a protein-receptor interaction together with the hosting cell line. The ability to accurately measure affinity and kinetics of a protein-receptor interaction on cell lines of different origins may increase the understanding of underlying receptor biology, and impact the selection of candidates in the development of therapeutic or diagnostic agents.
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| 17. |
- Belkic, Karen, et al.
(author)
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Imaging surveillance programs for women at high breast cancer risk in Europe : Are women from ethnic minority groups adequately included?
- 2015
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 47:3, s. 817-839
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Journal article (peer-reviewed)abstract
- Women from ethnic minority groups, including immigrants and refugees are reported to have low breast cancer (BC) screening rates. Active, culturally-sensitive outreach is vital for increasing participation of these women in BC screening programs. Women at high BC risk and who belong to an ethnic minority group are of special concern. Such women could benefit from ongoing trials aimed at optimizing screening strategies for early BC detection among those at increased BC risk. Considering the marked disparities in BC survival in Europe and its enormous and dynamic ethnic diversity, these issues are extremely timely for Europe. We systematically reviewed the literature concerning European surveillance studies that had imaging in the protocol and that targeted women at high BC risk. The aim of the present review was thereby to assess the likelihood that women at high BC risk from minority ethnic groups were adequately included in these surveillance programs. Twenty-seven research groups in Europe reported on their imaging surveillance programs for women at increased BC risk. The benefit of strategies such as inclusion of magnetic resonance imaging and/or more intensive screening was clearly documented for the participating women at increased BC risk. However, none of the reports indicated that sufficient outreach was performed to ensure that women at increased BC risk from minority ethnic groups were adequately included in these surveillance programs. On the basis of this systematic review, we conclude that the specific screening needs of ethnic minority women at increased BC risk have not yet been met in Europe. Active, culturally-sensitive outreach is needed to identify minority women at increased BC risk and to facilitate their inclusion in on-going surveillance programs. It is anticipated that these efforts would be most effective if coordinated with the development of European-wide, population-based approaches to BC screening.
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| 18. |
- Belpomme, D., et al.
(author)
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The growing incidence of cancer : Role of lifestyle and screening detection (Review)
- 2007
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 30:5, s. 1037-1049
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Research review (peer-reviewed)abstract
- The increasing incidence of a variety of cancers after the Second World War confronts scientists with the question of their origin. In Western countries, expansion and ageing of the population, as well as progress in cancer detection using new diagnostic and screening tests cannot fully account for the observed growing incidence of cancer. Our hypothesis is that environmental factors play a more important role in cancer genesis than it is usually agreed: i) over the last 2-3 decades, alcohol consumption and tobacco smoking in men have significantly decreased; ii) obesity is increasing in many countries, but the growing incidence of cancer also concerns cancers not related to obesity nor to other lifestyle-related factors; iii) there is evidence that the environment has changed over the same time scale as the recent rise in cancer incidence, and that this change included the accumulation of many new carcinogenic factors in the environment; iv) genetic susceptibility to cancer due to genetic polymorphism cannot have changed over one generation and actually favours the role of exogenous factors through gene-environment interactions; v) age is not the unique factor to be considered since the rising incidence of cancers is seen across all age categories, including children; vi) the fetus is specifically vulnerable to exogenous factors. A fetal exposure during a critical window period may explain why current epidemiological studies may be negative in adults. We therefore propose that the involuntary exposure to many carcinogens in the environment contributes to the rising trend in cancer incidence.
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| 19. |
- Benetkiewicz, Magdalena, et al.
(author)
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Chromosome 22 array-CGH profiling of breast cancer delimited minimal common regions of genomic imbalances and revealed frequent intra-tumoral genetic heterogeneity
- 2006
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In: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 29:4, s. 935-945
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Journal article (peer-reviewed)abstract
- Breast cancer is a common malignancy and the second most frequent cause of death among women. Our aim was to perform DNA copy number profiling of 22q in breast tumors using a methodology which is superior, as compared to the ones applied previously. We studied 83 biopsies from 63 tumors obtained from 60 female patients. A general conclusion is that multiple distinct patterns of genetic aberrations were observed, which included deletion(s) and/or gain(s), ranging in size from affecting the whole chromosome to only a few hundred kb. Overall, the analysis revealed genomic imbalances of 22q in 22% (14 out of 63) of tumors. The predominant profile (11%) was monosomy 22. The smallest identified candidate region, in the vicinity of telomere of 22q, encompasses approximately 220 kb and was involved in all but one of the tumors with aberrations on chromosome 22. This segment is dense in genes and contains 11 confirmed and one predicted gene. The availability of multiple biopsies from a single tumor provides an excellent opportunity for analysis of possible intra-tumor differences in genetic profiles. In 15 tumors we had access to two or three biopsies derived from the same lesion and these were studied independently. Four out of 15 (26.6%) tumors displayed indications of clonal intra-tumor genotypic differences, which should be viewed as a high number, considering that we studied in detail only a single human chromosome. Our results open up several avenues for continued genetic research of breast cancer.
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| 20. |
- Bjersand, Kathrine, et al.
(author)
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Ex vivo assessment of cancer drug sensitivity in epithelial ovarian cancer and its association with histopathological type, treatment history and clinical outcome
- 2022
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 61:4
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Journal article (peer-reviewed)abstract
- Epithelial ovarian cancer (EOC) is divided into type I and type II based on histopathological features. Type I is clinically more indolent, but also less sensitive to chemotherapy, compared with type II. The basis for this difference is not fully clarified. The present study investigated the pattern of drug activity in type I and type II EOC for standard cytotoxic drugs and recently introduced tyrosine kinase inhibitors (TKIs), and assessed the association with treatment history and clinical outcome. Isolated EOC tumor cells obtained at surgery were investigated for their sensitivity to seven standard cytotoxic drugs and nine TKIs using a short-term fluorescent microculture cytotoxicity assay (FMCA). Drug activity was compared with respect to EOC subtype, preoperative chemotherapy, cross-resistance and association with progression-free survival (PFS). Out of 128 EOC samples, 120 samples, including 21 type I and 99 type II, were successfully analyzed using FMCA. Patients with EOC type I had a significantly longer PFS time than patients with EOC type II (P=0.01). In line with clinical experience, EOC type I samples were generally more resistant than type II samples to both standard cytotoxic drugs and the TKIs, reaching statistical significance for cisplatin (P=0.03) and dasatinib (P=0.002). A similar pattern was noted in samples from patients treated with chemotherapy prior to surgery compared with treatment-naive samples, reaching statistical significance for fluorouracil, irinotecan, dasatinib and nintedanib (all P<0.05). PFS time gradually shortened with increasing degree of drug resistance. Cross-resistance between drugs was in most cases statistically significant yet moderate in degree (r<0.5). The clinically observed relative drug resistance of EOC type I, as well as in patients previously treated, is at least partly due to mechanisms in the tumor cells. These mechanisms seemingly also encompass kinase inhibitors. Ex vivo assessment of drug activity is suggested to have a role in the optimization of drug therapy in EOC.
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| 21. |
- Bogaerts, Eliene, et al.
(author)
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The roles of transforming growth factor- similar to, Wnt, Notch and hypoxia on liver progenitor cells in primary liver tumours ( Review)
- 2014
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 44:4, s. 1015-1022
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Research review (peer-reviewed)abstract
- Primary liver tumours have a high incidence and mortality. The most important forms are hepatocellular carcinoma and intrahepatic cholangiocarcinoma, both can occur together in the mixed phenotype hepatocellular-cholangiocarcinoma. Liver progenitor cells (LPCs) are bipotential stem cells activated in case of severe liver damage and are capable of forming both cholangiocytes and hepatocytes. Possibly, alterations in Wnt, transforming growth factor-, Notch and hypoxia pathways in these LPCs can cause them to give rise to cancer stem cells, capable of driving tumourigenesis. In this review, we summarize and discuss current knowledge on the role of these pathways in LPC activation and differentiation during hepatocarcinogenesis.
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| 22. |
- Bohl Kullberg, E, et al.
(author)
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Introductory experiments on ligand liposomes as delivery agents for boronneutron capture therapy
- 2003
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In: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 23:2, s. 461-467
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Journal article (peer-reviewed)abstract
- Liposomes are, when coupled to receptor ligands, candidates for receptor mediated delivery of boron for tumour therapy since they have capacity to deliver large amounts of boron per receptor interaction. With EGF-liposomes we present a pegylated ligand liposome delivery vehicle, containing water soluble boronated phenanthridine, WSP1, or water soluble boronated acridine, WSA1, for EGFR targeting. In the case of WSA1 a ligand dependent uptake was obtained and the boron uptake was as good as if free WSA1 was given. No ligand dependent boron uptake was seen for WSP1 containing liposomes. Thus, WSA1 is a candidate for further studies. Approximately 10(5) boron atoms were in each liposome. A critical assessment indicates that after optimization up to 10(6) boron atoms can be loaded. Since it is known that, for therapeutic effect, approximately 10(8)-10(9) boron atoms are needed in a single tumour cell it is realized that 10(2)-10(3) receptor interactions are needed to meet the demand. Tests applying cultured glioma cells indicate, without optimization of the delivery conditions, a boron uptake in the ppm range, which is necessary for successful BNCT. Thus, it seems possible to kill micro-invasive tumour cells with targeted liposomes if the delivery conditions are optimal.
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| 23. |
- Boldrup, Linda, et al.
(author)
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Expression of p63, COX-2, EGFR and beta-catenin in smokers and patients with squamous cell carcinoma of the head and neck reveal variations in non-neoplastic tissue and no obvious changes in smokers.
- 2005
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In: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 27:6, s. 1661-1667
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Journal article (peer-reviewed)abstract
- Squamous cell carcinoma of the head and neck (SCCHN), the 6th most common malignancy in the world, is associated with smoking and has a low 5-year survival rate. Various changes have been described at different stages of SCCHN tumour development, including overexpression of p63, a protein important for development of normal epidermal structures. p63 has been suggested to activate beta-catenin, and nuclear accumulation of beta-catenin is an important event in many cancers. Elevated COX-2 activity and overexpression of EGFR protein has been shown in a variety of human cancers, including SCCHN. An important question for the pathogenesis of SCCHN is when the genetic changes take place during the natural course of the disease, and whether they appear in clinically normal oral mucosa to predispose tumour development. We mapped the expression of p63, COX-2, EGFR, beta-catenin, and PP2A in oral mucosa from smokers/non-smokers and from patients with SCCHN. We also considered if changes occurring in tumours are present in the clinically normal tissue adjacent to the tumour. No direct influence of heavy smoking on the levels of the proteins studied could be seen. Tumours and clinically normal non-neoplastic tissue from SCCHN patients showed increased expression of COX-2 and PP2A. Interestingly, non-neoplastic tissue adjacent to SCCHN also showed increased beta-catenin, although this was not seen in tumours. The data support the notion that pre-existing alterations in clinically normal epithelium exist in patients with SCCHN and could be important for the pathogenesis of the disease and for local recurrences.
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| 24. |
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| 25. |
- Cortés-González, Jeff R, et al.
(author)
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Early salvage radiation therapy combined with short-term hormonal therapy in recurrent prostate cancer after radical prostatectomy: Single-institution 4-year data on outcome, toxicity, health-related quality of life and co-morbidities from 184 consecutive patients treated with 70 Gy.
- 2013
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In: International journal of oncology. - : Spandidos Publications. - 1791-2423 .- 1019-6439. ; 42:1, s. 109-17
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Journal article (peer-reviewed)abstract
- The aim of this study was to investigate the role of 70Gy salvage radiotherapy (SRT) combined with short-term neoadjuvant hormonal therapy (NHT) in the treatment of recurrent disease after radical prostatectomy (RP), and to consider quality of life (QoL), survival outcomes and impact of co-morbidities on treatment-related rectal-genitourinary toxicity. Electronic records of 184 SRT patients treated consecutively between October 2001 and February 2007 were analyzed. Median age was 64 years (median follow-up 48months). NHT was given to 165 patients (median 3 months). Pre-RP and pre-SRT PSA, PSA doubling time, Gleason score (GS), seminal vesicle invasion (SVI) and detectable post-SRT PSA were recorded. Any detectable PSA or PSA >0.1 ng/ml + nadir was considered biochemical failure (BcF). The Charlson co-morbidity index was used to correlate co-morbidities and rectal-genitourinary toxicity. Scores from the health-related QoL EORTC QLQ-C30 and PR-25 questionnaires were also evaluated. In 116 (63%) patients, a long-lasting curative effect was indicated by undetectable PSA levels. In univariate analysis, using BcF as an outcome variable, p<0.001 was found for GS, pre-SRT PSA, SVI and detectable post-SRT PSA. Multivariate analysis showed p=0.01 for SVI, p=0.09 for GS, and detectable post-SRT PSA (p=0.01); with metastases as an outcome variable, only SVI was significant (p=0.007). Cancer-specific and overall survival were 99 and 95%, respectively. Although microscopy showed SVI or GS 8-10 in the prostatectomy specimens 17/40(43%) and 13/29 (45%), respectively, of patients still showed undetectable PSA at long-term follow-up (median 55 months) after SRT. Likewise, 11/31 (36%) patients with pre-SRT PSA >1.0 ng/ml and 80/134 (60%) patients with PSA doubling time (PSADT) <10 still showed undetectable PSA after 50 months. Slightly elevated acute and late rectal-genitourinary grade 3-4 toxicity was observed. No association with co-morbidity/toxicity was found. EORTC QLQ-C30 scores were similar to or slightly better than reference values. SRT with 70 Gy combined with 3-month NHT results in long-term undetectable PSA in >50% of patients with recurrence after RP with acceptable rectal-genitourinary toxicity and without negatively affecting long-term QoL. Non-metastatic patients should not be disqualified from receiving SRT although presenting with poor prognostic factors at surgery.
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| 26. |
- Cui, Baoxia, et al.
(author)
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Mutation of PIK3CA : possible risk factor for cervical carcinogenesis in older women
- 2009
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 34:2, s. 409-416
-
Journal article (peer-reviewed)abstract
- PIK3CA encodes the p110alpha catalytic subunit of PI 3-kinase, which regulates signaling pathways important for neoplasia, cell proliferation and apoptosis. Somatic mutations in this gene have been detected in several solid human tumors. We investigated these mutations in cervical carcinoma and its precursors, and their association with HPV infection and patient clinical data. The mutations were analyzed using post-PCR direct genomic DNA sequencing. Samples included 9 cervical cancer cell lines, 184 invasive cervical carcinomas, and 30 cervical neoplasias. Missense mutations of PIK3CA were identified in 15/184 (8.15%) invasive cervical carcinomas. One novel mutation G1638C (Q546H) was found. Three mutations were identified in the cervical cancer lines. No mutations were found in the precursors. The difference in mutation frequency between invasive and pre-invasive lesions was not significant (p=0.1372). In relation to age and HPV, the mutation rate was significantly higher in patients>or=60 years (p=0.001), while the rate of HPV infection was higher in patients
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| 27. |
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| 28. |
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| 29. |
- Dambrauskas, Zilvinas, et al.
(author)
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Expression of major histocompatibility complex class I-related chain A/B (MICA/B) in pancreatic carcinoma.
- 2014
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 44:1, s. 99-104
-
Journal article (peer-reviewed)abstract
- Major histocompatibility complex classI-related chain A and B (MICA/B) are two stress-inducible ligands that bind to the immunoreceptor NKG2D and play an important role in mediating cytotoxicity of NK and Tcells. Release of MIC molecules from the cell surface is thought to constitute an immune escape mechanism of tumor cells and thus could be associated with more aggressive course of tumor growth. In this study, we investigated the expression of MICA/B in ductal pancreatic carcinoma and serum in relation to tumor stage, differentiation and survival. MICA/B expression in tumor tissues and sera from patients with pancreatic cancer were analyzed by immunohistochemical staining (IHC), western blotting and ELISA, respectively. MICA/B expression was present in 17 of 22 (77%) of the tumors but not in normal pancreatic ductal epithelial cells. Poorly differentiated tumors showed more pronounced MICA/B expression compared to differentiated tumors, but did not correlate significantly to other tumor characteristics. MICA/B-negative tumors displayed significantly lower incidence of lymph node metastases (p<0.01), and less mortality within 3 years following resection (p<0.02). In conclusion, tissue levels of MICA/B expression were elevated in pancreatic cancer cells without elevated levels in serum, despite well-recognized acute phase reactants in serum. Poorly differentiated tumors showed high MICA/B expression, which was related to extended tumor lymph node metastases and less frequent long-term survival.
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| 30. |
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| 31. |
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| 32. |
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| 33. |
- Ekberg, Thomas, et al.
(author)
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Expression of EGFR, HER2, HER3, and HER4 in metastatic squamous cell carcinomas of the oral cavity and base of tongue
- 2005
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In: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 26:5, s. 1177-85
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Journal article (peer-reviewed)abstract
- The expressions of all four receptors in the epidermal growth factor receptor family, EGFR. HER2, HER3, and HER4 were evaluated by immunohistochemistry in 19 cases of metastatic squamous cell carcinoma of the oral cavity and base of tongue. EGFR had a similar and high expression in both primary tumours and the corresponding metastases, while the expression in normal epithelium was lower in most cases. HER2 was not expressed to the same extent as EGFR. However, when HER2 was well expressed, it was in most cases expressed to the same extent and intensity in the primary tumours, metastases, and normal epithelium. The expression of HER3 and HER4 varied and was mainly cytoplasmic in all cases studied. No overexpression of HER3 and HER4 in tumours was seen as compared to normal epithelium. In order to further investigate the distribution of HER3, two HER3 expressing cell lines originating from tongue cancer were analysed in vitro, using radiolabelled anti-HER3 antibodies directed to the extracellular domains of the receptor. The results indicated that HER3 was not present in measurable amounts in the cellular membrane. There is a need for improved diagnostics and therapy for the studied type of tumours, e.g. using radiolabelled antibodies or ligands, and EGFR seemed suitable as target since the expression was high, membrane associated and similar in the primary tumours and the corresponding metastases.
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| 34. |
- El-Salhy, Magdy, 1951-, et al.
(author)
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Comparison between triple therapy with octreotide, galanin and serotonin vs. irinotecan or oxaliplatin in combination with 5-fluorouracil/leukovorin in human colon cancer.
- 2005
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In: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 27:3, s. 687-691
-
Journal article (peer-reviewed)abstract
- Human colon cancer cells were injected sub-cutaneously into 30 nude mice. After 8 days, the animals were divided into 3 equal groups. The first and second groups received an i.p. injection with 5-fluorouracil/leukovorin (5-FU/LV) for 5 days (20 mg and 10 mg/kg body weight respectively). On the first day of 5-FU/LV treatment, the first group received an i.p. injection of irinotecan (2.5 mg/kg body weight), and the second group received an i.p. injection with oxaliplatin (1 mg/kg body weight). The third group were injected i.p. with 100 microl saline solution containing octreotide, galanin and serotonin. Injections were given 3 times daily for 5 days with a total dose of 150 microg/kg body weight/day. Three days after the treatment, the animals were sacrificed. Whereas the animals treated with triple therapy held a stable body weight, animals treated with 5-FU/LV-irinotecan and 5-FU/LV-oxaliplatin had gradual weight loss, which amounted to approximately 25% of their body weight at the end of the experiment. Moreover, 2 mice in the group treated with 5-FU/LV-irinotecan died, most probably due to side effects. There was no statistically significant difference between the 3 groups regarding tumour proliferation, apoptosis, blood vessel density, EGF- and VEGF-expression. Treatment with triple therapy using octreotide, galanin and serotonin appear to be comparable to 5-FU/LV in combination with irinotecan and oxaliplatin. However, triple therapy seems to have a better safety profile.
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| 35. |
- Engström, Alexander, Ph.D, 1987-, et al.
(author)
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Conditioned media from macrophages of M1, but not M2 phenotype, inhibit the proliferation of the colon cancer cell lines HT-29 and CACO-2
- 2014
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In: International Journal of Oncology. - Athens, Greece : Spandidos. - 1019-6439 .- 1791-2423. ; 44:2, s. 385-392
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Journal article (peer-reviewed)abstract
- Solid tumors are infiltrated by stroma cells including macrophages and these cells can affect tumor growth, metastasis and angiogenesis. We have investigated the effects of conditioned media (CM) from different macrophages on the proliferation of the colon cancer cell lines HT-29 and CACO-2. CM from THP-1 macrophages and monocyte-derived human macrophages of the M1 phenotype, but not the M2 phenotype, inhibited proliferation of the tumor cells in a dose-dependent manner. Lipopolysaccaharide and interferon gamma was used for differentiation of macrophages towards the M1 phenotype and CM were generated both during differentiation (M1(DIFF)) and after differentiation (M1). M1 and M1(DIFF) CM as well as THP-1 macrophage CM resulted in cell cycle arrest in HT-29 cells with a decrease of cells in S phase and an increase in G(2)/M phase. Treatment of HT-29 cells with M1(DIFF), but not M1 or THP-1 macrophage CM, resulted in apoptosis of about 20% of the tumor cells and this was accompanied by lack of recovery of cell growth after removal of CM and subsequent culture in fresh media. A protein array was used to identify cytokines released from M1 and M2 macrophages. Among the cytokines released by M1 macrophages, tumor necrosis factor alpha and CXCL9 were tested by direct addition to HT-29 cells, but neither affected proliferation. Our results indicate that M1 macrophages inhibit colon cancer cell growth and have the potential of contributing to reducing tumor growth in vivo.
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| 36. |
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| 37. |
- Evertsson, Sofia, 1972-, et al.
(author)
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Apoptosis in relation to proliferating cell nuclear antigen and Dukes' stage in colorectal adenocarcinoma
- 1999
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In: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 15:1, s. 53-58
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Journal article (peer-reviewed)abstract
- Colorectal cancer is a disease that is associated with default in the balance of apoptotic regulation. In the present study apoptosis was examined in 158 colorectal adenocarcinomas using the terminal deoxynucleotidyl transferase mediated digoxigenin nick end labeling (TUNEL) method. The median apoptotic index (AI) was 0.95% (range 0-6. 68%). Eighty-two tumours exhibited AI 0.95%. We revealed a positive correlation between apoptosis and proliferation determined as the expression of proliferating cell nuclear antigen (PCNA, p=0.002). The frequency of apoptosis increased from Dukes' stage A, B, C to D (p=0.01). No correlations were found between apoptosis and the patients' sex, age, tumour location, growth pattern, differentiation, prognosis, bcl-2, p53 or K-ras. Our findings suggest that we should further investigate the relationship between apoptosis and cellular proliferative activity in colorectal cancer to evaluate whether this might provide additional information in the selection of patients for effective adjuvant therapy.
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| 38. |
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| 39. |
- Fransson, Susanne, 1975, et al.
(author)
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Estimation of copy number aberrations: Comparison of exome sequencing data with SNP microarrays identifies homozygous deletions of 19q13.2 and iin neuroblastoma
- 2016
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 48:3, s. 1103-1116
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Journal article (peer-reviewed)abstract
- In the pediatric cancer neuroblastoma, analysis of recurrent chromosomal aberrations such as loss of chromosome 1p, 11q, gain of 17q and MYCN amplification are used for patient stratification and subsequent therapy decision making. Different analysis techniques have been used for detection of segmental abnormalities, including fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH)-microarrays and multiplex ligation-dependent probe amplification (MLPA). However, as next-generation sequencing becomes available for clinical use, this technique could also be used for assessment of copy number alterations simultaneously with mutational analysis. In this study we compare genomic profiles generated through exome sequencing data with profiles generated from high resolution Affymetrix single nucleotide polymorphism (SNP) microarrays on 30 neuroblastoma tumors of different stages. Normalized coverage reads for tumors were calculated using Control-FREEC software and visualized through a web based Shiny application, prior to comparison with corresponding SNP-microarray data. The two methods show high-level agreement for breakpoints and copy number of larger segmental aberrations and numerical aneuploidies. However, several smaller gene containing deletions that could not readily be detected through the SNP-microarray analyses were identified through exome profiling, most likely due to difference between spatial distribution of microarray probes and targeted regions of the exome capture. These smaller aberrations included focal ATRX deletion in two tumors and three cases of novel deletions in chromosomal region 19q13.2 causing homozygous loss of multiple genes including the CIC (Capicua) gene. In conclusion, genomic profiles generated from normalized coverage of exome sequencing show concordance with SNP microarray generated genomic profiles. Exome sequencing is therefore a useful diagnostic tool for copy number variant (CNV) detection in neuroblastoma tumors, especially considering the combination with mutational screening. This enables detection of theranostic targets such as ALK and ATRX together with detection of significant segmental aneuploidies, such as 2p-gain, 17q-gain, 11q-deletion as well as MYCN amplification.
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| 40. |
- Fransson, Susanne, et al.
(author)
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Stage-dependent expression of PI3K/Akt‑pathway genes in neuroblastoma
- 2013
-
In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 42:2, s. 609-616
-
Journal article (peer-reviewed)abstract
- The phosphoinositide-3 kinase (PI3K) pathway plays a critical role in cancer cell growth and survival and has also been implicated in the development of the childhood cancer neuroblastoma. In neuroblastoma high mRNA expression of the PI3K catalytic isoform PIK3CD is associated to favorable disease. Yet, activation of Akt is associated with poor prognosis. Since the contribution of the numerous members of this pathway to neuroblastoma pathogenesis is mainly unknown, genes of the PI3K/Akt pathway were analyzed at the mRNA level through microarrays and quantitative real-time RT-PCR (TaqMan) and at the protein level using western blot analysis. Five genes showed lower mRNA expression in aggressive compared to more favorable neuroblastomas (PRKCZ, PRKCB1, EIF4EBP1, PIK3RI and PIK3CD) while the opposite was seen for PDGFRA. Clustering analysis shows that the expression levels of these six genes can predict aggressive disease. At the protein level, p110δ (encoded by PIK3CD) and p85α isomers (encoded by PIK3R1) were more highly expressed in favorable compared to aggressive neuroblastoma. Evaluation of the expression of these PI3K genes can predict aggressive disease, and indicates stage-dependent involvement of PI3K-pathway members in neuroblastoma.
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| 41. |
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| 42. |
- Garousi, Javad, et al.
(author)
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PET imaging of epidermal growth factor receptor expression in tumours using Zr-89-labelled ZEGFR:2377 affibody molecules
- 2016
-
In: International Journal of Oncology. - : Spandidos. - 1019-6439 .- 1791-2423. ; 48:4, s. 1325-1332
-
Journal article (peer-reviewed)abstract
- Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor, which is overexpressed in many types of cancer. The use of EGFR-targeting monoclonal antibodies and tyrosine-kinase inhibitors improves significantly survival of patients with colorectal, non-small cell lung cancer and head and neck squamous cell carcinoma. Detection of EGFR overexpression provides important prognostic and predictive information influencing management of the patients. The use of radionuclide molecular imaging would enable non-invasive repeatable determination of EGFR expression in disseminated cancer. Moreover, positron emission tomography (PET) would provide superior sensitivity and quantitation accuracy in EGFR expression imaging. Affibody molecules are a new type of imaging probes, providing high contrast in molecular imaging. In the present study, an EGFR-binding affibody molecule (ZEGFR:2377) was site-specifically conjugated with a deferoxamine (DFO) chelator and labelled under mild conditions (room temperature and neutral pH) with a radionuclide Zr-89. The Zr-89-DFO-ZEGFR:2377 tracer demonstrated specific high affinity (160 +/- 60 pM) binding to EGFR-expressing A431 epidermoid carcinoma cell line. In mice bearing A431 xenografts, Zr-89-DFO-ZEGFR: 2377 demonstrated specific uptake in tumours and EGFR-expressing tissues. The tracer provided tumour uptake of 2.6 +/- 0.5% ID/g and tumour-to-blood ratio of 3.7 +/- 0.6 at 24 h after injection. Zr-89-DFO-ZEGFR: 2377 provides higher tumour-to-organ ratios than anti-EGFR antibody Zr-89-DFO-cetuximab at 48 h after injection. EGFR-expressing tumours were clearly visualized by microPET using Zr-89-DFO-ZEGFR: 2377 at both 3 and 24 h after injection. In conclusion, Zr-89-DFO-ZEGFR: 2377 is a potential probe for PET imaging of EGFR-expression in vivo.
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| 43. |
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| 44. |
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| 45. |
- Graflund, Marianne, et al.
(author)
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MIB-1, p53, bcl-2, and WAF-1 expression in pelvic lymph nodes and primary tumors in early stage cervical carcinomas : correlation with clinical outcome
- 2002
-
In: International Journal of Oncology. - Athens, Greece : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 20:5, s. 1041-1047
-
Journal article (peer-reviewed)abstract
- A complete series of 40 cervical carcinomas with pelvic lymph node metastases were analysed immunohistochemically for prognostic markers. The aims of this study were to examine whether the detection of MIB-1, p53, bcl-2, and WAF-1 could be used as a prognostic marker for tumor recurrence and survival rate. During the period of observation (mean 222, range 72-360 months) 22 (55%) recurrences were encountered and 20 patients died of the disease. There were 35 squamous cell carcinomas (87.5%), 2 adenosquamous carcinomas (5.0%), and 3 pure adenocarcinomas (7.5%). One tumor (2.5%) was well differentiated, 12 tumors (30%) were moderately differentiated, and 27 tumors (67.5%) were poorly differentiated. The primary tumor grade (P=0.037) and radicality of the surgical margins (P=0.021) were significant prognostic factors with regard to tumor recurrence. The site and number of lymph nodes with metastases had no prognostic value. P53, bcl-2, and WAF-1 were not predictive factors for recurrences or the cancer-specific survival rate. The concordant expression of WAF-1 in the primary tumor and in lymph node metastases was lower than for p53 and bcl-2. The proliferative activity (MIB-1) seemed to be lower in tumor cells metastasized to the pelvic lymph nodes than in cells of the primary tumor. Expression of MIB-1 in lymph nodes was predictive of disease-free survival in both univariate and multivariate proportional hazard Cox analyses.
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| 46. |
- Göstring, Lovisa, et al.
(author)
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Quantification of internalization of EGFR-binding Affibody molecules : Methodological aspects
- 2010
-
In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 36:4, s. 757-763
-
Journal article (peer-reviewed)abstract
- Tumor cell internalization of targeting agents is of interest, since internalization influences the local retention time of a radionuclide and thereby imaging quality in PET and SPECT and effects of radionuclide therapy. In cases where nuclear methods are not applicable at the cellular level, quantitative fluorescent techniques are useful as described in this article. Two fluorescence-based methods to study cellular internalization were applied: the CypHer and the Alexa488-quenching methods, both utilized in fluorescence microscopy and flow cytometry. Two EGFR-binding Affibody molecules were analyzed in A431 cells: the monomer Z1907 and the dimer (Z1907)2. EGF, cetuximab and non-specific Affibody molecules were used as controls. For comparison, internalization of 111In-labeled Z1907 was studied with the acid wash internalization assay. The Cypher method is straightforward, but requires equal labeling of all compounds for accurate quantification. The Alexa488-quenching method is preferable since it is independent of the dye-to-protein ratio. According to this method, about 45% of EGF and 19-24% of the bound Affibody molecules and cetuximab were internalized within one hour. Similar results were seen with 111In-Z1907 in the acid wash method, while (Z1907)2 was not removed by acid and thus could not be studied this way. The fluorescence-based Alexa488-quenching method is well suited to quantitatively analyze internalization of targeting agents, also those that resist acid wash. The internalized fraction showed that both the monomeric and dimeric Affibody molecules are expected to give good uptake and thereby good retention of metallic radionuclides which will render good tumor to background values.
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| 47. |
- Göthlin Eremo, Anna, 1980-, et al.
(author)
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HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen
- 2015
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In: International Journal of Oncology. - Athens : Spandidos publications. - 1019-6439 .- 1791-2423. ; 47:4, s. 1311-1320
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Journal article (peer-reviewed)abstract
- The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4-hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER-negativity (P<0.0005), PgR-negativity (P<0.0005), tumor size >20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence-free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance.
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| 48. |
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| 49. |
- Hallak, Sorana, et al.
(author)
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Prophylactic inguinal-femoral irradiation as an alternative to primary lymphadenectomy in treatment of vulvar carcinoma
- 2007
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In: International Journal of Oncology. - Athens, Greece : Lychnia. - 1019-6439 .- 1791-2423. ; 31:5, s. 1077-1085
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Journal article (peer-reviewed)abstract
- In a complete geographic series of 294 cases of primary vulvar carcinomas prophylactic inguinal-femoral irradiation was used as a standard postoperative therapy. Inguinal lymph node dissection was performed in only 27 cases (9%) and was not part of the standard surgery. The histology was squamous cell carcinoma in 269 cases (92%). The primary surgery was total vulvectomy, partial vulvectomy, or local resection of the tumor. The main type of radiotherapy was adjuvant inguinal irradiation. Two separate, symmetrical and rectangular inguinal fields were irradiated with combined photon and electron beams. In the complete series 127 recurrences (43%) were recorded. Local (24%) and regional recurrences (19%) were most frequent. Type of surgery was not associated with the risk of tumor recurrence. The 5-year overall survival rate was 53% and the relapse-free survival (RFS) rate was 55%. Tumor grade was significantly (P=0.007) associated with the RFS. The inguinal RFS rate was 75% both for patients treated with adjuvant inguinal irradiation without lymphadenectomy and patients treated with primary lymph adenectomy +/- inguinal irradiation. Postoperative complications were recorded in 22%. Postoperative complications occurred most frequently in the subgroup undergoing inguinal lymphadenectomy. Chronic lymph edemas were the most serious late tissue reactions.
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| 50. |
- Hardell, Lennart, et al.
(author)
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Case-control study of the association between malignant brain tumours diagnosed between 2007 and 2009 and mobile and cordless phone use
- 2013
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 43:6, s. 1833-1845
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Journal article (peer-reviewed)abstract
- Previous studies have shown a consistent association between long-term use of mobile and cordless phones and glioma and acoustic neuroma, but not for meningioma. When used these phones emit radiofrequency electromagnetic fields (RF-EMFs) and the brain is the main target organ for the hand-held phone. The International Agency for Research on Cancer (IARC) classified in May, 2011 RF-EMF as a group 2B, i.e. a possible' human carcinogen. The aim of this study was to further explore the relationship between especially long-term (>10 years) use of wireless phones and the development of malignant brain tumours. We conducted a new case-control study of brain tumour cases of both genders aged 18-75 years and diagnosed during 2007-2009. One population-based control matched on gender and age (within 5 years) was used to each case. Here, we report on malignant cases including all available controls. Exposures on e.g. use of mobile phones and cordless phones were assessed by a self-administered questionnaire. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index using the whole control sample. Of the cases with a malignant brain tumour, 87% (n=593) participated, and 85% (n=1,368) of controls in the whole study answered the questionnaire. The odds ratio (OR) for mobile phone use of the analogue type was 1.8, 95% confidence interval (CI)=1.04-3.3, increasing with >25 years of latency (time since first exposure) to an OR=3.3, 95% CI=1.6-6.9. Digital 2G mobile phone use rendered an OR=1.6, 95% CI=0.996-2.7, increasing with latency >15-20 years to an OR=2.1, 95% CI=1.2-3.6. The results for cordless phone use were OR=1.7, 95% CI=1.1-2.9, and, for latency of 15-20 years, the OR=2.1, 95% CI=1.2-3.8. Few participants had used a cordless phone for >20-25 years. Digital type of wireless phones (2G and 3G mobile phones, cordless phones) gave increased risk with latency >1-5 years, then a lower risk in the following latency groups, but again increasing risk with latency >15-20 years. Ipsilateral use resulted in a higher risk than contralateral mobile and cordless phone use. Higher ORs were calculated for tumours in the temporal and overlapping lobes. Using the meningioma cases in the same study as reference entity gave somewhat higher ORs indicating that the results were unlikely to be explained by recall or observational bias. This study confirmed previous results of an association between mobile and cordless phone use and malignant brain tumours. These findings provide support for the hypothesis that RF-EMFs play a role both in the initiation and promotion stages of carcinogenesis.
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