| 1. |
- Barczyk, K., et al.
(författare)
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Serum cytochrome c indicates in vivo apoptosis and can serve as a prognostic marker during cancer therapy
- 2005
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 116:2, s. 167-173
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Tidskriftsartikel (refereegranskat)abstract
- Despite significant progress in cancer therapy, the outcome of the treatment is often unfavorable. Better treatment monitoring would not only allow an individual more effective, patient-adjusted therapy, but also it would eliminate some of the side effects. Using a cytochrome c ELISA that was modified to increase sensitivity, we demonstrate that serum cytochrome c is a sensitive apoptotic marker in vivo reflecting therapy-induced cell death burden. Furthermore, increased serum cytochrome c level is a negative prognostic marker. Cancer patients whose serum cytochrome c level was normal 3 years ago have a twice as high probability to be still alive, as judged from sera samples collected for years, analyzed recently and matched with survival data. Moreover, we show that serum cytochrome c and serum LDH-activity reflect different stages and different forms of cell death. Cellular cytochrome c release is specific for apoptosis, whereas increased LDH activity is an indicator of (secondary) necrosis. Whereas serum LDH activity reflects the "global" degree of cell death over a period of time, the sensitive cytochrome c-based method allows confirmation of the individual cancer therapy-induced and spontaneous cell death events. The combination of cytochrome c with tissue-specific markers may provide the foundation for precise monitoring of apoptosis in vivo, by "lab-on-the-chip" technology. (c) 2005 Wiley-Liss, Inc.
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| 2. |
- Parris, Toshima Z, 1978, et al.
(författare)
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Additive effect of the AZGP1, PIP, S100A8, and UBE2C molecular biomarkers improves outcome prediction in breast carcinoma
- 2014
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 134:7, s. 1617-1629
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Tidskriftsartikel (refereegranskat)abstract
- The deregulation of key cellular pathways is fundamental for the survival and expansion of neoplastic cells, which in turn can have a detrimental effect on patient outcome. To develop effective individualized cancer therapies, we need to have a better understanding of which cellular pathways are perturbed in a genetically defined subgroup of patients. Here, we validate the prognostic value of a 13-marker signature in independent gene expression microarray datasets (n = 1,141) and immunohistochemistry with full-faced FFPE samples (n = 71). The predictive performance of individual markers and panels containing multiple markers was assessed using Cox regression analysis. In the external gene expression dataset, six of the 13 genes (AZGP1, NME5, S100A8, SCUBE2, STC2, and UBE2C) retained their prognostic potential and were significantly associated with disease-free survival (P < 0.001). Protein analyses refined the signature to a four-marker panel (AZGP1, PIP, S100A8, and UBE2C) significantly correlated with cycling, high grade tumors and lower disease-specific survival rates. AZGP1 and PIP were found in significantly lower levels in invasive breast tissue compared with adjacent normal tissue, whereas elevated levels of S100A8 and UBE2C were observed. A predictive model containing the four-marker panel in conjunction with established clinical variables outperformed a model containing the clinical variables alone. Our findings suggest that deregulated AZGP1, PIP, S100A8, and UBE2C are critical for the aggressive breast cancer phenotype, which may be useful as novel therapeutic targets for drug development to complement established clinical variables. © 2013 Wiley Periodicals, Inc.
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| 3. |
- Dahlström, Lisen Arnheim, et al.
(författare)
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Prospective study of human papillomavirus and risk of cervical adenocarcinoma.
- 2010
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Ingår i: International journal of cancer. Journal international du cancer. - : Wiley. - 1097-0215 .- 0020-7136. ; 127:8, s. 1923-30
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Tidskriftsartikel (refereegranskat)abstract
- Human papillomaviruses (HPV) are established as a major cause of cervical carcinoma. However, causality inference is dependent on prospective evidence showing that exposure predicts risk for future disease. Such evidence is available for squamous cell carcinoma, but not for cervical adenocarcinoma. We followed a population-based cohort of 994,120 women who participated in cytological screening in Sweden for a median of 6.7 years. Baseline smears from women who developed adenocarcinoma during follow-up (118 women with in situ disease and 164 with invasive disease) and their individually matched controls (1,434 smears) were analyzed for HPV using PCR. Conditional logistic regression was used to estimate odds ratios (OR) of future adenocarcinoma with 95% confidence intervals (CI). Being positive for HPV 16 in the first cytologically normal smear was associated with increased risks for both future adenocarcinoma in situ (OR: 11.0, 95% CI: 2.6-46.8) and invasive adenocarcinoma (OR: 16.0, 95% CI: 3.8-66.7), compared to being negative for HPV 16. Similarly, an HPV 18 positive smear was associated with increased risks for adenocarcinoma in situ (OR: 26.0, 95% CI: 3.5-192) and invasive adenocarcinoma (OR: 28.0, 95% CI: 3.8-206), compared to an HPV 18 negative smear. Being positive for HPV 16/18 in 2 subsequent smears was associated with an infinite risk of both in situ and invasive adenocarcinoma. In conclusion, infections with HPV 16 and 18 are detectable up to at least 14 years before diagnosis of cervical adenocarcinoma. Our data provide prospective evidence that the association of HPV 16/18 with cervical adenocarcinoma is strong and causal.
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| 4. |
- Baltzer, Nicholas, et al.
(författare)
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Risk stratification in cervical cancer screening by complete screening history : Applying bioinformatics to a general screening population
- 2017
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 141:1, s. 200-209
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Tidskriftsartikel (refereegranskat)abstract
- Women screened for cervical cancer in Sweden are currently treated under a one-size-fits-all programme, which has been successful in reducing the incidence of cervical cancer but does not use all of the participants' available medical information. This study aimed to use women's complete cervical screening histories to identify diagnostic patterns that may indicate an increased risk of developing cervical cancer. A nationwide case-control study was performed where cervical cancer screening data from 125,476 women with a maximum follow-up of 10 years were evaluated for patterns of SNOMED diagnoses. The cancer development risk was estimated for a number of different screening history patterns and expressed as Odds Ratios (OR), with a history of 4 benign cervical tests as reference, using logistic regression. The overall performance of the model was moderate (64% accuracy, 71% area under curve) with 61-62% of the study population showing no specific patterns associated with risk. However, predictions for high-risk groups as defined by screening history patterns were highly discriminatory with ORs ranging from 8 to 36. The model for computing risk performed consistently across different screening history lengths, and several patterns predicted cancer outcomes. The results show the presence of risk-increasing and risk-decreasing factors in the screening history. Thus it is feasible to identify subgroups based on their complete screening histories. Several high-risk subgroups identified might benefit from an increased screening density. Some low-risk subgroups identified could likely have a moderately reduced screening density without additional risk.
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| 5. |
- Chen, Lei, et al.
(författare)
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Deriving evolutionary tree models of the oncogenesis of endometrial adenocarcinoma.
- 2007
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Ingår i: International journal of cancer. Journal international du cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 120:2, s. 292-6
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial adenocarcinoma (EAC) is the fourth leading cause of cancer death in women worldwide, but not much is known about the underlying genetic factors involved in the development of this complex disease. In the present work, we used 3 different algorithms to derive tree models of EAC oncogenesis from data on the frequencies of genomic alterations in rat chromosome 10 (RNO10). The tumor material was derived from progenies of crosses between the EAC susceptible BDII inbred rat strain and two non susceptible inbred rat strains. Data from allelic imbalance scans of RNO10 with microsatellite markers on solid tumor material and corresponding tissue cultures were used. For the analysis, RNO10 was divided into 24 segments containing a total of 59 informative microsatellite markers. The derived tree models show that genomic alterations have occurred in 11 of the 24 segments. In addition, the models provide information about the likely order of the alterations as well as their relationship with each other. Interestingly, there was a high degree of consistency among the different tree models and with the results of previous studies, which supports the reliability of the tree models. Our results may be extended into a general approach for tree modeling of whole genome alterations during oncogenesis.
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| 6. |
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| 7. |
- Fulda, S., et al.
(författare)
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Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system
- 1998
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Ingår i: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 76:1, s. 105-114
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Tidskriftsartikel (refereegranskat)abstract
- We have identified the CD95 system as a key mediator of chemotherapy-induced apoptosis in leukemia and neuroblastoma cells. Here, we report that sensitivity of various solid tumor cell lines for drug-induced cell death corresponds to activation of the CD95 system, Upon drug treatment, strong induction of CD95 ligand (CD95-L) and caspase activity were found in chemosensitive tumor cells (Hodgkin, Ewing's sarcoma, colon carcinoma and small cell lung carcinoma) but not in tumor cells which responded poorly to drug treatment (breast carcinoma and renal cell carcinoma). Blockade of CD95 using F(ab')(2) anti-CD95 antibody fragments markedly reduced drug-induced apoptosis, suggesting that drug-triggered apoptosis depended on CD95-L/receptor interaction. Moreover, drug treatment induced CD95 expression, thereby increasing sensitivity for CD95-induced apoptosis, Drug-induced apoptosis critically depended on activation of caspases (ICE/Ced-3-like proteases) since the broad-spectrum inhibitor of caspases zVAD-fmk strongly reduced drug-mediated apoptosis, The prototype substrate of caspases, poly(ADP-ribose) polymerase, was cleaved upon drug treatment, suggesting that CD95-L triggered autocrine/paracrine death via activation of caspases, Our data suggest that chemosensitivity of solid tumor cells depends on intact apoptosis pathways involving activation of the CD95 system and processing of caspases. Our findings may have important implications for new treatment approaches to increase sensitivity and to overcome resistance of solid tumors. (C) 1998 Wiley-Liss, Inc.
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| 8. |
- Isaksson-Mettävainio, Martin, et al.
(författare)
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High SMAD4 levels appear in MSI and hypermethylated colon cancers, and indicate a better prognosis
- 2012
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Ingår i: International Journal of Cancer. - Geneve : International union against cancer. - 0020-7136 .- 1097-0215. ; 131, s. 779-788
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is one of the most common causes of cancer related deaths in western countries. CRC are commonly divided in cancers showing microsatellite stability (MSS) or microsatellite instability (MSI). A more novel classification is dependent on promoter hypermethylation of CpG islands (the CpG island methylator phenotype, CIMP), where cancers show high, low or negative methylation status. SMAD4, located on chromosome 18q, has been thoroughly investigated during the last years. Loss of SMAD4 expression has been reported to correlate with poor CRC patient prognosis. In this study we analyze the impact of SMAD4 expression on prognosis in relation to MSI screening status and CIMP status. 479 paraffin-embedded specimens of CRC were examined for nuclear SMAD4 expression using immunohistochemistry. The tumors were scored loss (-), moderate (+) and high (++) expressing tumors. Loss of SMAD4 correlated significantly with decreased survival in all colon cancer patients. High SMAD4 expression, on the other hand, was significantly associated with increased survival, especially in colon cancer patients which has undergone potential curative surgery. In addition, in MSI tumors and CIMP-high tumors, high SMAD4 expression was significantly related to increase in survival, while loss of SMAD4 resulted in a significantly poorer prognosis. SMAD4 expression was not correlated to prognosis in rectal cancer cases. We conclude, loss of SMAD4 indicates a poor prognosis in colon cancer patients. The novel findings that high SMAD4 expression predicts a better prognosis suggests that SMAD4 immunohistochemistry could constitute a prognostic marker in combination with CIMP and MSI screening status.
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