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- Jerhammar, Fredrik, 1979-
(författare)
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Predictive Markers of Treatment Resistance in Head and Neck Squamous Cell Carcinoma
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Head and neck cancer is a common malignancy with approximately 600 000 new cases yearly. Disappointingly, the overall survival has not increased over the last decades. The concept of personalized medicine, i.e. to treat every patient with an individually planned treatment regime has gathered increased interest, but requires the establishment of novel biomarkers that can predict treatment response.The aim of this thesis is to propose novel predictive single markers or combinations of markers of response to radiation, cisplatin and cetuximab. The general methodology is to evaluate common differences of cell lines resistant to radiation, cisplatin or cetuximab compared to sensitive counterparts.In paper I, we analysed the expression of 14 proteins involved in growth control and/or apoptosis by western blot and related them to intrinsic radiosensitivity (IR) in nine cell lines. No factor had a significant correlation to IR on its own. A combination of EGFR, survivin, Bak, Smad4, and Hsp70 had the best correlation to IR (R=0.886, p=0.001). Additionally, we analysed the presence of p53 mutations in the cell lines. All cell lines had at least one missense, splice site or loss of transcript mutation. To be able to combine protein expression and presence of p53 mutations we created a system designated the number of negative points (NNP). With this system we could extract that expression of EGFR, survivin, and p53 missense or splice site mutations had the best correlation to IR (R=0.990, p<0.001).In paper II we conducted a gene expression microarray analysis of three cell lines, from which common deregulations in two cisplatin resistant cell lines was compared to a cisplatin sensitive cell line. From a bioinformatic approach of gene ontology and molecular network analysis, we defined a transcriptional profile of 20 genes. Finally, key findings were analysed in a larger panel of cell lines, where high MMP-7 expression correlated with higher cisplatin resistance.Paper III compared 4 cell lines with high IR to a radiosensitive equivalent. Using a similar bioinformatic approach as paper II, we established a transcriptional profile of 14 genes. Analysis in a larger panel of cell lines revealed that FN1 expression predicts higher IR.Paper IV establishes the cetuximab sensitivity of 35 cell lines of which 12 were resistant and five were sensitive to cetuximab. After whole genome gene copy number analysis of five cetuximab resistant and five cetuximab sensitive cell lines, and verification of key findings in a larger cell line panel, the results show that the amplification of the YAP1 gene is coupled to cetuximab resistance.In summary, this thesis proposes a number of novel markers of resistance to radiation, cisplatin, and cetuximab which could influence treatment choice in the future, following verifications in primary tumor material.
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| 2. |
- Nehlin Gordh, Christina, 1958-
(författare)
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Alcohol Use and Secondary Prevention in Psychiatric Care
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Although alcohol plays an important role in psychiatric morbidity, there is a general lack of strategies within psychiatric care to intervene at alcohol problems in an early stage (secondary prevention). The aim of this thesis was to increase knowledge of adequate forms of secondary alcohol prevention in psychiatric care. The capacity of three brief screening instruments was investigated in a psychiatric outpatient sample (n=1811). The results indicate that the HED (heavy episodic drinking) screener, strongly recommended for health care settings, is not sufficiently sensitive in a psychiatric setting. Instead, the full AUDIT (Alcohol Use Disorders Identification Test) is recommended.The knowledge and attitudes of psychiatric staff members to problem-drinking patients were studied and the effects of a three-hour training course were investigated. Confidence in self-perceived capacity to intervene in more severe alcohol problems was raised among all staff after training. Awareness of early signs of problem drinking was raised among psychologists and social workers. The therapeutic attitude of the psychiatric staff was higher when compared with primary care staff.Two forms of brief intervention were delivered by clinical psychiatric staff. At 12 months, 29% of all participants had improved their drinking habits, moving from hazardous to non-hazardous level (21%) or from harmful to hazardous level (8%). In the improved group, mean AUDIT score was reduced from 11.0 points at baseline to 5.5 points. Differences in outcome between the two interventions could not be identified.Nine high-risk drinking young female psychiatric patients were interviewed, focusing on reasons for excessive drinking and factors facilitating a change in drinking habits. Alcohol played an important role in the lives of the young women. It made them feel social and helped them deal with unbearable emotions. It was also used as a means of self-harm, representing the first stage in an escalating self-harm process. They expressed a need for help from their caregivers in addressing the underlying reasons for drinking.Secondary alcohol prevention strategies including appropriate screening methods, staff training and the elaboration of tailored interventions are urgently needed in psychiatric care. The findings of this thesis can be used when forming such strategies.
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| 3. |
- Jerevall, Piiha-Lotta, 1980-
(författare)
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Homeobox B13 in breast cancer : Prediction of tamoxifen benefit
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A major issue in the management of breast cancer is to identify patients who are less likely to be cured after primary treatment and would benefit from adjuvant chemotherapy. Of great importance is also identification of patients with only local disease who traditionally would be given chemotherapy but would survive without. In this thesis we have validated the utility of the two-gene ratio HOXB13:IL17BR, which previously has been demonstrated to predict disease-free survival in tamoxifen-treated breast cancer patients. We have also studied the prognostic and predictive utility of a single gene as a biomarker in breast cancer medicine.We could confirm that HOXB13:IL17BR may classify patients with different treatment benefit; only patients with a low value showed benefit from prolonged duration of tamoxifen therapy, whereas for the group with high ratios, the long-term recurrence rate did not improve with longer treatment duration.The combination of HOXB13:IL17BR and the molecular grade index (MGI), another prognostic marker, has been shown to outperform either alone in predicting risk of breast cancer recurrence. We validated the prognostic utility of HOXB13:IL17BR+MGI in a large randomized patient cohort and found that this risk classification identified more than 50% of the tamoxifen-treated lymph node-negative patients as having a less than 3% risk of distant recurrence and breast cancer death. Furthermore, we developed and tested a continuous risk model of HOXB13:IL17BR+MGI called Breast Cancer Index (BCI), for estimation of recurrence risk at the individual level. Our study shows that BCI has the ability to identify more than 50% of patients with a low risk of recurrence more accurately than using traditional risk assessment. These results suggest that BCI may help clinicians to make better informed treatment decisions and spare toxic chemotherapy for a large group of breast cancer patients.The protein expression of HOXB13 was also shown to be a valuable predictor in postmenopausal patients. High expression was associated with worse outcome after tamoxifen therapy. In a premenopausal cohort, patients with hormone receptor-positive tumors showed benefit from tamoxifen regardless of HOXB13 expression. Further analysis indicated that estrogen receptor β (ERβ) modified the performance of HOXB13 as a predictor of treatment effect and should be taken into account when identifying patients less likely to respond to the therapy given.In conclusion, BCI identifies patients with a very low risk of distant recurrence. It may be utilized in the management of breast cancer patients to optimize the use of chemotherapy. HOXB13 protein expression may be used as a marker for tamoxifen benefit, but its performance in premenopausal patients might be modified by ERβ.
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