| 1. |
- Rivera, Patricio, et al.
(författare)
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Mammary tumor development in dogs is associated with BRCA1 and BRCA2
- 2009
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 69:22, s. 8770-8774
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a major contributor to overall morbidity and mortality in women. Several genes predisposing to breast cancer have been identified, but the majority of risk factors remain unknown. Even less is known about the inherited risk factors underlying canine mammary tumors (CMT). Clear breed predispositions exist, with 36% of English springer spaniels (ESS) in Sweden being affected. Here, we evaluate 10 human breast cancer genes (BRCA1, BRCA2, CHEK2, ERBB2, FGFR2, LSP1, MAP3K1, RCAS1, TOX3, and TP53) for association with CMTs. Sixty-three single-nucleotide polymorphisms (SNPs; four to nine SNPs per gene) were genotyped by iPLEX in female ESS dogs, 212 CMT cases and 143 controls. Two genes, BRCA1 and BRCA2, were significantly associated with CMT (Bonferroni corrected P = 0.005 and P = 0.0001, respectively). Borderline association was seen for FGFR2. Benign and malignant cases were also analyzed separately. Those findings supported the association to BRCA1 and BRCA2 but with a stronger association to BRCA1 in malignant cases. Both BRCA1 and BRCA2 showed odds ratios of approximately 4. In conclusion, this study indicates that BRCA1 and BRCA2 contribute to the risk of CMT in ESS, suggesting that dogs may serve as a good model for human breast cancer.
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| 2. |
- Acuña, Ulyana Muñoz, et al.
(författare)
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New acyclic bis phenylpropanoid and neolignans, from Myristica fragrans Houtt., exhibiting PARP-1 and NF-κB inhibitory effects.
- 2016
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Ingår i: Food Chemistry. - : Elsevier. - 0308-8146 .- 1873-7072. ; 202, s. 269-275
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Tidskriftsartikel (refereegranskat)abstract
- The bioassay-guided fractionation of the aril of Myristica fragrans (mace spice) yielded five phenolic compounds, one new acyclic bis phenylpropanoid (1) and four previously known phenolic compounds: compounds (1) (S) 1-(3,4,5-trimethoxyphenyl)-2-(3-methoxy-5-(prop-1-yl) phenyl)-propan-1-ol, (2) benzenemethanol; α-[1-[2,6-dimethoxy-4-(2-propen-1-yl)phenoxy]ethyl]-3,4-dimethoxy-1-acetate, (3) odoratisol A, phenol, 4-[(2S,3S)-2,3-dihydro-7-methoxy-3-methyl-5-(1E)-1-propenyl-2-benzofuranyl]-2,6-dimethoxy, (4) 1,3-benzodioxate-5-methanol,α-[1-[2,6-dimethoxy-4-(2-propenyl)phenoxy]ethyl]-acetate, (5) licarin C; benzofuran,2,3-dihydro-7-methoxy-3-methyl-5-(1E)-1-yl-2-(3,4,5-trimethoxyphenyl). An NMR tube Mosher ester reaction was used in an approach to characterize and determine the assignment of the absolute configuration of the new isolated chiral alcohol (1). The PARP-1 inhibitory activity was evaluated for compound (1) (IC50=3.04μM), compound (2) (IC50=0.001μM), compound (4) (IC50=22.07μM) and compound (5) (IC50=3.11μM). Furthermore, the isolated secondary metabolites were tested for NF-κB and K-Ras inhibitory activities. When tested in the p65 assay, compounds (2) and (4) displayed potent NF-κB inhibition (IC50=1.5 nM and 3.4nM, respectively).
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| 3. |
- Arendt, Maja Louise, et al.
(författare)
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PIK3CA is recurrently mutated in canine mammary tumors, similarly to in human mammary neoplasia
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Biological features of neoplastic disease affecting mammary gland tissue are shared between canines and humans. Research performed in either species has translational value and early phase clinical trials performed in canines with spontaneous disease could be informative for human trials. The purpose of this study was to investigate the somatic genetic aberrations occurring in canine mammary neoplasia by exome capture and next generation sequencing. Based on 55 tumor-normal pairs we identified the PIK3CA gene as the most commonly mutated gene in canine mammary tumors, with 25% of samples carrying mutations in this gene. A recurrent missense mutation was identified, p.H1047R, which is homologous to the human PIK3CA hotspot mutation found in different types of breast neoplasia. Mutations homologous to other known human mutation hotspots such as the PIK3CA p.E545K and the KRAS p.G12V/D were also identified. We identified copy number aberrations affecting important tumor suppressor and oncogenic pathways including deletions affecting the PTEN tumor suppressor gene. We suggest that activation of the KRAS or PIK3CA oncogenes or loss of the PTEN suppressor gene may be important for mammary tumor development in dogs. This data endorses the conservation of cancer across species and the validity of studying cancer in non-human species.
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| 4. |
- Asplund, Dan, et al.
(författare)
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Pretreatment quality of life in patients with rectal cancer is associated with intrusive thoughts and sense of coherence
- 2017
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Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 0179-1958 .- 1432-1262. ; 32:11, s. 1639-1647
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Quality of life may predict survival. In addition to clinical variables, it may be influenced by psychological factors, some of which may be accessible for intervention. The primary objective of this study was to investigate the association of intrusive thoughts and the patients' sense of coherence with pretreatment quality of life in patients with newly diagnosed rectal cancer. Methods Patients were prospectively included in 16 hospitals in Sweden and Denmark. They answered an extensive questionnaire after receiving their treatment plan. Clinical data were retrieved from national quality registries for rectal cancer. Results Of 1248 included patients, a total of 1085 were evaluable. Pretreatment global health-related and overall quality of life was lower in patients planned for palliative compared with curative treatment (median 53 vs. 80 on the EuroQoL visual analogue scale, p < 0.001 and odds ratio 0.56, 95% confidence interval 0.36-0.88, respectively). Quality of life was associated with intrusive thoughts (odds ratio 0.33, 95% confidence interval 0.24-0.45) and sense of coherence (odds ratio 0.44, 95% confidence interval 0.370.52) irrespective of the treatment plan. Conclusions Pretreatment quality of life was influenced by the intent of treatment as well as by intrusive thoughts and the patients' sense of coherence. Interventions could modify these psychological factors, and future studies should focus on initiatives to improve quality of life for this group of patients.
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| 5. |
- Behrens, Thomas, et al.
(författare)
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Pesticide exposure in farming and forestry and the risk of uveal melanoma
- 2012
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Ingår i: Cancer Causes and Control. - : Springer. - 0957-5243 .- 1573-7225. ; 23:1, s. 141-151
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Tidskriftsartikel (refereegranskat)abstract
- Since pesticides are disputed risk factors for uveal melanoma, we studied the association between occupational pesticide exposure and uveal melanoma risk in a case-control study from nine European countries.Incident cases of uveal melanoma and population as well as hospital controls were included and frequency-matched by country, 5-year age groups and sex. Self-reported exposure was quantified with respect to duration of exposure and pesticide application method. We calculated the exposure intensity level based on application method and use of personal protective equipment. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression analyses and adjusted for several potential confounders.293 case and 3,198 control subjects were interviewed. We did not identify positive associations with activities in farming or forestry, pesticide application or pesticide mixing. No consistent positive associations were seen with exposure intensity level scores either. The only statistically significantly raised association in this study was for exposure to chemical fertilizers in forestry (OR = 8.93; 95% CI 1.73-42.13), but this observation was based on only six exposed subjects. Results did not change when we restricted analyses to morphologically verified cases and excluded proxy interviews as well as cancer controls. We did not observe effect modification by sex or eye color.Risk estimates for pesticide exposures and occupational activities in agriculture and forestry were not increased and did not indicate a hormonal mechanism due to these exposures.
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| 6. |
- Betsholtz, Christer, et al.
(författare)
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PDGF, Pericytes and the Pathogenesis of Idiopathic Basal Ganglia Calcification (IBGC)
- 2014
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Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 24:4, s. 387-395
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factors (PDGFs) are important mitogens for various types of mesenchymal cells, and as such, they exert critical functions during organogenesis in mammalian embryonic and early postnatal development. Increased or ectopic PDGF activity may also cause or contribute to diseases such as cancer and tissue fibrosis. Until recently, no loss-of-function (LOF) mutations in PDGF or PDGF receptor genes were reported as causally linked to a human disease. This changed in 2013 when reports appeared on presumed LOF mutations in the genes encoding PDGF-B and its receptor PDGF receptor-beta (PDGF-R) in familial idiopathic basal ganglia calcification (IBGC), a brain disease characterized by anatomically localized calcifications in or near the blood microvessels. Here, we review PDGF-B and PDGF-R biology with special reference to their functions in brain-blood vessel development, pericyte recruitment and the regulation of the blood-brain barrier. We also discuss various scenarios for IBGC pathogenesis suggested by observations in patients and genetically engineered animal models of the disease.
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| 7. |
- Blockhuys, Stephanie, 1983, et al.
(författare)
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Evaluation of copper chaperone ATOX1 as prognostic biomarker in breast cancer
- 2020
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Ingår i: Breast Cancer. - : Springer Science and Business Media LLC. - 1880-4233 .- 1340-6868. ; 27:3, s. 505-509
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Tidskriftsartikel (refereegranskat)abstract
- Copper is involved in different hallmarks of cancer, including metastasis, but responsible copper-binding proteins and pathways are not clear. The copper chaperone ATOX1 was recently shown to play a role in breast cancer cell migration, which is a key step in metastasis. Since most cancer-related deaths are due to metastasis, we hypothesized that ATOX1 mRNA expression may be associated with breast cancer disease progression and thus, a prognostic biomarker in breast cancer. We therefore studied the association of ATOX1 expression levels with clinicopathological parameters and survival for 1904 breast cancer patients using the METABRIC data set. Our results indicate ATOX1 expression levels as a potential prognostic biomarker for ER-positive subtypes and early stages of breast cancer. Pre-clinical studies and clinical trials are desired to identify the molecular roles of ATOX1 in these conditions.
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| 8. |
- Degerman, Sofie, et al.
(författare)
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Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias
- 2014
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Ingår i: Neoplasia. - : Elsevier BV. - 1522-8002 .- 1476-5586. ; 16:7, s. 606-615
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Tidskriftsartikel (refereegranskat)abstract
- We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.
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| 9. |
- Eussen, Simone JPM, et al.
(författare)
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Plasma folate, related genetic variants, and colorectal cancer risk in EPIC
- 2010
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 19:5, s. 1328-1340
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Tidskriftsartikel (refereegranskat)abstract
- Findings of the present study tend to weaken the evidence that folate plays an important role in CRC carcinogenesis. However, larger sample sizes are needed to adequately address potential gene-environment interactions.
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| 10. |
- Forsberg, Elin, et al.
(författare)
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Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary CAR-T cells are immune cells equipped with a claw that enable them to bind cancer cells. Usually, CAR-T cells are made using immune cells from blood. Here, we tested the hypothesis that also immune cells that reside in the tumor, so called tumor-infiltrating lymphocytes, can also be modified to carry the claw. This may mean that these cells, called CAR-TILs, will be able to attack cancer cells in two ways, using the claw or binding using its normal protein on the cell surface, the so-called T cell receptor. We show that CAR-TILs can be generated, and that they can kill melanoma cells in cell culture and in mice. Finally, to prepare for clinical trials, we also assess if CAR-TILs can be safe in a human cancer patient-like model, a companion dog suffering from cancer. Our data suggest that CAR-TILs may be a way to treat patients with melanoma but human clinical trials are needed. Patients with metastatic melanoma have a historically poor prognosis, but recent advances in treatment options, including targeted therapy and immunotherapy, have drastically improved the outcomes for some of these patients. However, not all patients respond to available treatments, and around 50% of patients with metastatic cutaneous melanoma and almost all patients with metastases of uveal melanoma die of their disease. Thus, there is a need for novel treatment strategies for patients with melanoma that do not benefit from the available therapies. Chimeric antigen receptor-expressing T (CAR-T) cells are largely unexplored in melanoma. Traditionally, CAR-T cells have been produced by transducing blood-derived T cells with a virus expressing CAR. However, tumor-infiltrating lymphocytes (TILs) can also be engineered to express CAR, and such CAR-TILs could be dual-targeting. To this end, tumor samples and autologous TILs from metastasized human uveal and cutaneous melanoma were expanded in vitro and transduced with a lentiviral vector encoding an anti-HER2 CAR construct. When infused into patient-derived xenograft (PDX) mouse models carrying autologous tumors, CAR-TILs were able to eradicate melanoma, even in the absence of antigen presentation by HLA. To advance this concept to the clinic and assess its safety in an immune-competent and human-patient-like setting, we treated four companion dogs with autologous anti-HER2 CAR-TILs. We found that these cells were tolerable and showed signs of anti-tumor activity. Taken together, CAR-TIL therapy is a promising avenue for broadening the tumor-targeting capacity of TILs in patients with checkpoint immunotherapy-resistant melanoma.
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