| 1. |
- Bastami, Salumeh, et al.
(author)
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Inhibitory effect of opiates on LPS mediated release of TNF and IL-8
- 2013
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In: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 52:5, s. 1022-1033
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Journal article (peer-reviewed)abstract
- Most patients with advanced cancer experience severe pain and are often treated with opiates. Cancer patients are especially susceptible to opportunistic infections due to treatment with immunosuppressive and cytostatic drugs. Since opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of morphine, tramadol, fentanyl and ketobemidone on the functioning of the immune system with special reference to TNF and IL-8 release. Method. U-937 cells were preincubated with different concentrations of opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of opioids on the levels of cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All opioids with the exception of fentanyl were capable of inhibiting TNF release from U-937 cells. Morphine had no effect on IL-8 release but the effect of other opiates was almost the same as the effect on TNF. All opioids with the exception of fentanyl were capable of inhibiting production of mRNA for TNF and IL-8. The observed effects of opiates were not always reversible by naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of opiates. Our data suggests that the order of potency with regard to inhibition of cytokine release is as follows: tramadol > ketobemidone > morphine > fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of tramadol and ketobemidone and to improve opioid treatment strategies in patients with cancer.
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| 2. |
- Edman, Kristina, 1958-, et al.
(author)
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Attitudes and demands of dental care, Sweden 2003-2013, and clinical correlates of oral health-related quality of life in 2013
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Journal article (other academic/artistic)abstract
- Objective. The aim of the present study was to investigate attitudes to, and demands of dental care, and to assess possible associations with socioeconomic and clinical variables over a period of ten years. A further aim was to investigate the association between OHRQoL assessed by OIDP, and socioeconomic, dental care habits, smoking and oral status. Materials and methods. Three cross-sectional epidemiological studies were performed in the county of Dalarna, Sweden, in 2003, 2008 and 2013. Random samples of 1542–2244 individuals, aged 30-85 years, who answered a questionnaire about socio-economic, socio-behavioral factors, oral health-related quality of life were radiographically and clinically examined. Results. The importance of preventive treatment, regular recalls, meeting the same caregiver as on previous visits, and information on treatment cost have become less important. Difficulty in booking treatment time was reported by 17% in 2013, compared with 11% in 2003 and 12% in 2008 (p<0.05). In individuals with alveolar bone loss, meeting the same caregiver as on previous visits was important (p<0.05). In individuals with temporomandibular disorder (TMD) and manifest caries, information on treatment cost was important, while prevention became less important (p<0.05). Oral impact on daily performance (OIDP) was reported by 31% of the individuals in the study, and frequent impact was reported by 10%. Individuals with manifest caries lesions, less than 20 remaining teeth, and TMD reported OIDP to a significantly higher degree, compared to orally healthy individuals. Conclusion. Attitudes important in maintaining and improving good oral health, such as preventive care and regular recalls to dentistry, became less important during this period of 10 years, and difficulty in booking treatment time was reported more frequently in 2013. Oral impact was found to be associated with irregular dental visits and limited economy for dental care, less than 20 remaining teeth, TMD and manifest caries.
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| 3. |
- Edman, Kristina, 1958-, et al.
(author)
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Attitudes to dental care, Sweden 2003-2013, and clinical correlates of oral health-related quality of life in 2013
- 2018
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In: International Journal of Dental Hygiene. - : Wiley. - 1601-5029 .- 1601-5037. ; 16:2, s. 257-266
-
Journal article (peer-reviewed)abstract
- Objective: To investigate attitudes to dental care, and to assess possible associations with socio‐economic and clinical variables over a period of ten years, and to investigate the association between OHRQoL assessed by oral impact on daily performance (OIDP), and socio‐economic, dental care habits, smoking and oral status.Materials and methods: Cross‐sectional studies performed in the county of Dalarna, Sweden, in 2003, 2008 and 2013. Random samples of 1,107‐1,115 dentate individuals, aged 30‐85 years, who answered a questionnaire and who were radiographically and clinically examined were included.Results: The importance of preventive treatment, regular recalls and meeting the same caregiver as on previous visits became less important. In individuals with alveolar bone loss, meeting the same caregiver as on previous visits was important (P<.05). In individuals with manifest caries, information on treatment cost was important, while prevention became less important (P<.05). OIDP was reported by 31% of the individuals in the study, and frequent impact was reported by 10%. Individuals with manifest caries lesions, less than 20 remaining teeth, and temporomandibular disorders (TMD) reported OIDP to a significantly higher degree, compared to orally healthy individuals.Conclusion: Attitudes important in maintaining and improving good oral health, such as preventive care and regular recalls to dentistry, became less important during this period of 10 years. Oral impact was found to be associated with irregular dental visits and limited economy for dental care, individuals with less than 20 remaining teeth, TMD and manifest caries.
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| 4. |
- Edman, Kristina, et al.
(author)
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Comparison of oral status in an adult population 35-75 year of age in the county of Dalarna, Sweden in 1983 and 2008
- 2012
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In: Swedish Dental Journal. - Jönköping : Swedish Dental Association. - 0347-9994. ; 36:2, s. 61-70
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Journal article (peer-reviewed)abstract
- The aim was to study the prevalence and distribution of number of teeth, number of intact and decayed teeth and prevalence and distribution of removable dentures and periodontal disease over 25 years 1983-2008. Two cross-sectional studies (EpiWux) were performed in the County of Dalarna, Sweden in 1983 and 2008. In the 1983 study a random sample of 1012 individuals were invited to participate in this epidemiological and clinical study and 1440 individuals in 2008. A total number of 1695 individuals, stratified into geographical areas (rural and urban areas), in the age groups 35, 50,65 and 75 answered a questionnaire and were also clinically and radiographically examined. The number of edentulous individuals decreased from 15% in 1983 to 3 % in 2008. Number of teeth increased from 22.7 in 1983 to 24.2 in 2008 and decayed surfaces per tooth showed a three-time reduction over this period of time. As a consequence of better oral status the prevalence of complete removable dentures in both jaws decreased from 15 % in 1983 to 2 % in 2008. Individuals with moderate periodontitis decreased from 45 % in 1983 to 16 % in 2008. Conclusion: Covering a period of 25 years the present study can report dramatic improvements in all aspects of dental status that were investigated. This is encouraging for dental care professionals, but will not necessarily lead to less demand for dental care in the future as the population is aging with a substantial increase in number of teeth.
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| 5. |
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| 6. |
- Edman, Kristina, 1958-, et al.
(author)
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Prevalence of dental caries and influencing factors, time trends over a 30-year period in an adult population : Epidemiological studies between 1983 and 2013 in the county of Dalarna, Sweden
- 2016
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In: Acta Odontologica Scandinavica. - : Informa UK Limited. - 0001-6357 .- 1502-3850. ; 74:5, s. 385-392
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Journal article (peer-reviewed)abstract
- Objective. The aim of this study was to investigate the prevalence of dental caries in an adult population using four different cross-sectional studies over a 30-year period and to assess its possible associations with socio-economic and socio-behavioral factors. Materials and methods. Four cross-sectional epidemiological studies were performed in the county of Dalarna, Sweden, in 1983, 2003, 2008, and 2013. Random samples of 1012–2243 individuals, aged 20–85 years, who answered a questionnaire about socio-economic and socio-behavioral factors, were radiographically and clinically examined. Results. The proportion of individuals with at least one decayed surface (DS) was 58% in 1983 and significantly lower, 34% in 2008 (p<0.05) and 33% in 2013; the mean number of DS was 2.0 in 1983 and 1.1 in 2013 in the age group 35 to 75 (p < 0.05). In the age group 85, the mean number of DS was 1.2 in 2008 and 2.4 in 2013. Adjusted for age and number of teeth, irregular dental visits, limited financial resources for dental care, smoking, education below university, male gender, daily medication, and single living were positively and statistically associated with manifest caries. Conclusion. The declining trend in the prevalence of manifest caries seems to be broken. In the oldest age group mean number of DS was higher in 2013 compared with 2008, indicating a possible beginning of an increase. This needs special attention as this group increases in the population, retaining natural teeth high up in age. Manifest caries was found to be associated with socio-economic and socio-behavioral factors.
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| 7. |
- Gunnarsson, Cecilia, 1970-, et al.
(author)
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Expression of COX-2 and steroid converting enzymes in breast cancer
- 2006
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In: Oncology Reports. - 1021-335X .- 1791-2431. ; 16:2, s. 219-224
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Journal article (peer-reviewed)abstract
- COX-2 is upregulated in many breast tumors, and one of the products of COX-2 is PGE2 that is suggested to upregulate aromatase through cAMP signaling in breast cancer. Although aromatase can increase the estrogen levels in tumors, 17β-hydroxysteroid dehydrogenase (17HSD) activity is finally needed for the estrone/estradiol regulation. The aim of this study was to investigate if the protein expression of enzymes involved in estrogen synthesis shows covariation with the expression of COX-2. We also wanted to correlate these results with prognosis. We analyzed the expression of COX-2, aromatase, 17HSD1 and 17HSD2 with immunohistochemistry using tissue microarrays composed of 356 primary breast tumors. In the present study COX-2 was correlated to aromatase (P<0.00001), 17HSD1 (P=0.0073), and 17HSD2 (P<0.00001). Patients with ER positive tumors expressing low amounts of 17HSD2 had decreased breast cancer survival (P=0.013). Elevated expression of COX-2 and aromatase was more frequent among larger tumors (P=0.017 and P=0.013). COX-2 expression correlates with the levels of the examined steroid converting enzymes and may contribute to increased estrogen levels in the tumor. In breast cancer cells, the regulatory function of 17HSD2 could be lost, and in the present study patients with low or non-detectable levels of 17HSD2 had worse prognosis than had breast cancer patients with higher levels of the enzyme.
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| 8. |
- Holmqvist (Knutsen), Annica, et al.
(author)
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PINCH expression in relation to radiation response in co-cultured colon cancer cells and in rectal cancer patients
- 2013
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In: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 30:5, s. 2097-2104
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Journal article (peer-reviewed)abstract
- Particularly interesting new cysteine-histidine rich protein (PINCH), involved in cell spreading, motility and proliferation, has been shown to enhance radioresistance in colon cancer cell lines. The expression of PINCH in relation to radiation was studied in co-cultured colon cancer cells. Furthermore, the clinical significance between PINCH and radiotherapy (RT) was analyzed in rectal cancer patients with or without RT. The relative PINCH expression in colon cancer (KM12C) cells cultured separately and in co-culture was examined by western blotting and real-time PCR, and was analyzed over a period of 8 and 24 h after radiation. PINCH expression was immunohistochemically examined in 137 primary rectal tumors for which 65 cases did not receive RT and 72 cases received RT. PINCH expression tended to decrease from that in the separately cultured KM12C cells without radiation to that in cells with radiation at 8 h (P=0.060); while in the co-cultured cells, no significant difference was found (P=0.446). In patients with RT, strong PINCH expression was related to worse survival, when compared to patients with weak expression, independent of TNM stage, degree of differentiation, age and p53 status (P=0.029, RR 4.03, 95% CI 1.34-12.1). No survival relationship for the patients without RT was observed (P=0.287). A statistical interaction analysis between PINCH, RT and survival showed a trend towards significance (P=0.057). In conclusion, PINCH predicts survival in rectal cancer patients with RT, but not in patients without RT. The expression of PINCH may be regulated by radiation and by environmental factors surrounding the cells.
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| 9. |
- Holmqvist Knutsen, Annica, 1974-, et al.
(author)
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PINCH is an independent prognostic factor in rectal cancer patients without preoperative radiotherapy : A study in a Swedish rectal cancer trial of preoperative radiotherapy
- 2012
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In: BMC Cancer. - : BioMed Central. - 1471-2407. ; 12:65
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Journal article (peer-reviewed)abstract
- Background and Purpose: The clinical significance between particularly interesting new cysteine-histidine rich protein (PINCH) expression and radiotherapy (RT) in tumours is not known. In this study, the expression of PINCH and its relationship to RT, clinical, pathological and biological factors were studied in rectal cancer patients. Material and Methods: PINCH expression determined by immunohistochemistry was analysed at the invasive margin and inner tumour area in 137 primary rectal adenocarcinomas (72 cases without RT and 65 cases with RT). PINCH expression in colon fibroblast cell line (CCD-18 Co) was determined by Western blot. Results: In patients without RT, strong PINCH expression at the invasive margin of primary tumours was related to worse survival, compared to patients with weak expression, independent of TNM stage and differentiation (p = 0.03). No survival relationship in patients with RT was observed (p = 0.64). Comparing the non-RT with RT subgroup, there was no difference in PINCH expression in primary tumours (invasive margin (p = 0.68)/inner tumour area (p = 0.49). Conclusions: PINCH expression at the invasive margin was an independent prognostic factor in patients without RT. RT does not seem to directly affect the PINCH expression.
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| 10. |
- Jerevall, Piiha-Lotta, et al.
(author)
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Prognostic utility of HOXB13:IL17BR and Molecular Grade Index in early-stage breast cancer patients from the Stockholm trial
- 2011
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In: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 104:11, s. 1762-1769
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Journal article (peer-reviewed)abstract
- Background: A dichotomous index combining two gene expression assays, HOXB13:IL17BR (H:I) and molecular grade index (MGI), was developed to assess risk of recurrence in breast cancer patients. The study objective was to demonstrate the prognostic utility of the combined index in early-stage breast cancer. Methods: In a blinded retrospective analysis of 588 ER-positive tamoxifen-treated and untreated breast cancer patients from the randomized prospective Stockholm trial, H:I and MGI were measured using real-time RT-PCR. Association with patient outcome was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. A continuous risk index was developed using Cox modeling. Results: The dichotomous H:I+MGI was significantly associated with distant recurrence and breast cancer death. The >50% of tamoxifen-treated patients categorized as low-risk had <3% 10-year distant recurrence risk. A continuous risk model (Breast Cancer Index (BCI)) was developed with the tamoxifen-treated group and the prognostic performance tested in the untreated group was 53% of patients categorized as low-risk with an 8.3% 10-year distant recurrence risk. Conclusion: Retrospective analysis of this randomized, prospective trial cohort validated the prognostic utility of H:I+MGI and was used to develop and test a continuous risk model that enables prediction of distant recurrence risk at the patient level.
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| 11. |
- Liu, Na, et al.
(author)
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Nuclear expression of lysyl oxidase enzyme is an independent prognostic factor in rectal cancer patients.
- 2017
-
In: Oncotarget. - : Impact journals. - 1949-2553. ; 8:36, s. 60015-60024
-
Journal article (peer-reviewed)abstract
- Emerging evidence has implicated a pivotal role for lysyl oxidase (LOX) in cancer progression and metastasis. Whilst the majority of work has focused on the extracellular matrix cross-linking role of LOX, the exact function of intracellular LOX localisation remains unclear. In this study, we analysed the LOX expression patterns in the nuclei of rectal cancer patient samples and determined the clinical significance of this expression. Nuclear LOX expression was significantly increased in patient lymph node metastases compared to their primary tumours. High nuclear LOX expression in tumours was correlated with a high rate of distant metastasis and increased recurrence. Multivariable analysis showed that high nuclear LOX expression was also correlated with poor overall survival and disease free survival. Furthermore, we are the first to identify LOX enzyme isoforms (50 kDa and 32 kDa) within the nucleus of colon cancer cell lines by confocal microscopy and Western blot. Our results show a powerful link between nuclear LOX expression in tumours and patient survival, and offer a promising prognostic biomarker for rectal cancer patients.
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| 12. |
- Malmström, Annika, et al.
(author)
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Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial
- 2017
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In: Acta Oncologica. - : TAYLOR & FRANCIS LTD. - 0284-186X .- 1651-226X. ; 56:12, s. 1776-1785
-
Journal article (peer-reviewed)abstract
- Introduction: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ.Patients and methods: Patients, after surgery for GBM or AA, age 60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200mg/m(2) days 1-5 every 28 days, followed by RT 60Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75mg/m(2) was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety.Results: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p=.76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p=.022). For patients with GBM, no difference in survival was observed (p=.10). MGMT and IDH status affected outcome.Conclusions: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.
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| 13. |
- Meng, Wen-Jian, et al.
(author)
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Expressions of miR-302a, miR-105, and miR-888 Play Critical Roles in Pathogenesis, Radiotherapy, and Prognosis on Rectal Cancer Patients : A Study From Rectal Cancer Patients in a Swedish Rectal Cancer Trial of Preoperative Radiotherapy to Big Database Analyses
- 2020
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In: Frontiers in Oncology. - : Frontiers. - 2234-943X. ; 10
-
Journal article (peer-reviewed)abstract
- Differential expressions and functions of various micoRNAs (miRNAs) have been intensively studied in both colon and rectal cancers. However, the importance of miRNAs on radiotherapy (RT) response and clinical outcome in rectal cancer patients remains unclear. In this study, we used real-time polymerase chain reaction to examine the expressions of miR-302a, miR-105, and miR-888 in normal mucosa and cancer tissue from rectal cancer patients with and without preoperative RT. The biological function of miR-302a, miR-105, and miR-888 expression was further analyzed and identified through the public databases: TCGA (The Cancer Genome Atlas) and GEPIA (Gene Expression Profiling Interactive Analysis). The results showed that the expression of miR-105 in rectal cancer was higher than that in normal mucosa in RT (P = 0.042) and non-RT patients (P = 0.003) and was associated with mucinous histological type (P = 0.004), COX-2 (P = 0.042), and p73 expression (P = 0.030). The expression of miR-302a was shown more frequently in cancers with necrosis (P = 0.033) and with WRAP53 expression (P = 0.015), whereas miR-888 expression occurred more frequently in tumors with protein the expression of survivin (P = 0.015), AEG-1 (astrocyte elevated gene-1) (P = 0.003), and SATB1 (special AT-rich sequence binding protein 1) (P = 0.036). Moreover, TargetScan also predicted AEG-1 and SATB1 as putative targets for miR-888. The miRNA-gene network analysis showed that ABI2 was associated with all the three miRNAs, with lower expression and good diagnostic value in rectal cancers. The TCGA database demonstrated the association of miR-105 expression with high carcinoembryonic antigen level (P = 0.048). RT reduced the expressions of miR-302a, miR-105, and miR-888. Prognostic analysis showed that miR-888 expression was independently associated with worse survival of patients without RT [overall survival, P = 0.001; disease-free survival, P = 0.009]. Analysis of biological function revealed that the protein serine/threonine kinase activity and PI3K-AKT signaling pathway were the most significantly enriched functions and pathways, respectively. Our findings suggest that miR-105 is involved in rectal cancer pathogenesis and miR-888 is associated with prognosis. MiR-302a, miR-105, and miR-888 have potential influence on the pathogenesis, RT, and prognosis of rectal cancer.
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| 14. |
- Meng, Wen-Jian, et al.
(author)
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Special AT-rich sequence binding protein 1 expression correlates with response to preoperative radiotherapy and clinical outcome in rectal cancer
- 2015
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In: Cancer Biology & Therapy. - : Taylor & Francis. - 1538-4047 .- 1555-8576. ; 16:12, s. 1738-1745
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Journal article (peer-reviewed)abstract
- Our recent study showed the important role of special AT-rich sequence binding protein 1 (SATB1) in the progression of human rectal cancer. However, the value of SATB1 in response to radiotherapy (RT) for rectal cancer hasn't been reported so far. Here, SATB1 was determined using immunohistochemistry in normal mucosa, biopsy, primary cancer, and lymph node metastasis from 132 rectal cancer patients: 66 with and 66 without preoperative RT before surgery. The effect of SATB1 knockdown on radiosensitivity was assessed by proliferation-based assay and clonogenic assay. The results showed that SATB1 increased from normal mucosa to primary cancer, whereas it decreased from primary cancer to metastasis in non-RT patients. SATB1 decreased in primary cancers after RT. In RT patients, positive SATB1 was independently associated with decreased response to preoperative RT, early time to metastasis, and worse survival. SATB1 negatively correlated with ataxia telangiectasia mutated (ATM) and pRb2/p130, and positively with Ki-67 and Survivin in RT patients, and their potential interaction through different canonical pathways was identified in network ideogram. Taken together, our findings disclose for the first time that radiation decreases SATB1 expression and sensitizes cancer cells to confer clinical benefit of patients, suggesting that SATB1 is predictive of response to preoperative RT and clinical outcome in rectal cancer.
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| 15. |
- Olsson, Hans, et al.
(author)
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Methods for evaluating HER2 status in breast cancer : comparison of IHC, FISH, and real-time PCR analysis of formalin-fixed paraffin-embedded tissue
- 2013
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In: Pathology and Laboratory Medicine International. - : Dove Medical Press. - 1179-2698. ; 5, s. 31-37
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Journal article (peer-reviewed)abstract
- The human epidermal growth factor receptor 2 gene (HER2) is amplified in approximately 15%–20% of all breast cancers. This results in overexpression of the HER2 protein, which is associated with worse clinical outcomes in breast cancer patients. Several studies have shown that trastuzumab, a monoclonal antibody that interferes with the HER2/neu receptor, can improve overall survival in patients with HER2-positive breast cancer. Immunohistochemistry (IHC), combined with different methods for in situ hybridization, is currently used for routine assessment of HER2 status. The aim of the present study was to determine whether real-time polymerase chain reaction (PCR) can serve as a supplementary method for evaluation of HER2 status in primary breast cancer. For this purpose, 145 formalin-fixed paraffin-embedded primary breast cancer samples were tested by real-time PCR amplification of HER2, using amyloid precursor protein as a reference. The results were compared with HER2 status determined by fluorescence in situ hybridization (FISH) and IHC. The specificity, sensitivity, and reproducibility of real-time PCR were evaluated, and a comparison of formalin-fixed and fresh-frozen samples was performed. This showed concordance of 93% between real-time PCR and FISH, and 86% between real-time PCR and IHC. Therefore, we suggest that real-time PCR can be a useful supplementary method for assessment of HER2 status.
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| 16. |
- Pathak, Surajit, et al.
(author)
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Tafazzin Protein Expression Is Associated with Tumorigenesis and Radiation Response in Rectal Cancer : A Study of Swedish Clinical Trial on Preoperative Radiotherapy
- 2014
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In: PLOS ONE. - San Francisco : Public Library Science. - 1932-6203. ; 9:5
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Journal article (peer-reviewed)abstract
- Background: Tafazzin (TAZ), a transmembrane protein contributes in mitochondrial structural and functional modifications through cardiolipin remodeling. TAZ mutations are associated with several diseases, but studies on the role of TAZ protein in carcinogenesis and radiotherapy (RT) response is lacking. Therefore we investigated the TAZ expression in rectal cancer, and its correlation with RT, clinicopathological and biological variables in the patients participating in a clinical trial of preoperative RT.Methods: 140 rectal cancer patients were included in this study, of which 65 received RT before surgery and the rest underwent surgery alone. TAZ expression was determined by immunohistochemistry in primary cancer, distant, adjacent normal mucosa and lymph node metastasis. In-silico protein-protein interaction analysis was performed to study the predictive functional interaction of TAZ with other oncoproteins.Results: TAZ showed stronger expression in primary cancer and lymph node metastasis compared to distant or adjacent normal mucosa in both non-RT and RT patients. Strong TAZ expression was significantly higher in stages I-III and non-mucinious cancer of non-RT patients. In RT patients, strong TAZ expression in biopsy was related to distant recurrence, independent of gender, age, stages and grade (p = 0.043, HR, 6.160, 95% CI, 1.063-35.704). In silico protein-protein interaction study demonstrated that TAZ was positively related to oncoproteins, Livin, MAC30 and FXYD-3.Conclusions: Strong expression of TAZ protein seems to be related to rectal cancer development and RT response, it can be a predictive biomarker of distant recurrence in patients with preoperative RT.
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| 17. |
- Perez-Tenorio, Gizeh, et al.
(author)
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Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer
- 2011
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In: Breast Cancer Research and Treatment. - : Springer Science Business Media. - 0167-6806 .- 1573-7217. ; 128:3, s. 713-723
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Journal article (peer-reviewed)abstract
- The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. S6K1/S6K2 gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR- subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer.
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| 18. |
- Perez-Tenorio, Gizeh, 1971-, et al.
(author)
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Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer
- 2008
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Journal article (peer-reviewed)abstract
- The mammalian target of rapamycin (mTOR) and its substrates the ribosomal S6 kinases (S6K)1 and 2 integrate nutrient and hormonal/growth factor mediated signals and are implicated indiabetes, obesity and cancer. The genes encoding S6K1 (RPS6KB1) and S6K2 (RPS6KB2) aresituated close to well known amplicons but information regarding its expression and clinicalvalue is scarce. In this study we quantified RPS6KB1/2 gene copy number, establishedassociations with other clinical factors and explored their clinical value in breast cancer. RPS6KB1/2 copy number was determined by fast real-time PCR in 207 breast tumors.RPS6KB1 was amplified (≥ 4 copies) in 10.7% (22/206) and RPS6KB2 in 4.3% (9/207) of thetumors. Amplification of RPS6KB1 was associated with HER2 gene amplification (P=0.025)and protein expression (P=0.014) while RPS6KB2 correlated with ER+ status (P=0.046) and CCND1 amplification (P<0.00001). In a multivariate analysis, both genes were independentprognostic factors indicating higher risk to develop recurrences. In terms of loco regionalcontrol, amplification of the RPS6KB1 gene predicted less response to radiotherapy (P=0.035) while RPS6KB2 gene copy gain (≥ 3 copies) indicated increased benefit from tamoxifen (P=0.03) among ER+ patients. S6K1/2 gene amplification could be used as an indicator oftherapy response among postmenopausal breast cancer patients.
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| 19. |
- Pfeifer, Daniella, et al.
(author)
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Protein expression following gamma-irradiation relevant to growth arrest and apoptosis in colon cancer cells with mutant p53
- 2009
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In: Journal of Cancer Research and Clinical Oncology. - : Springer Science and Business Media LLC. - 0171-5216 .- 1432-1335. ; 135:11, s. 1583-1592
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Journal article (peer-reviewed)abstract
- We previously found that p53, p73, survivin and PRL were implicated in the outcome of radiotherapy in rectal cancer patients. In the present study, we tried to understand mechanisms of colon cancer cell line response to radiation based on protein expression related to proliferation and apoptosis. KM12C, KM12SM and KM12L4a, cell lines with one origin, were radiated with 0, 10 or 15 Gy γ-radiation. Radiosensitivity was determined with cell cycle and apoptosis analysis, and protein expression of TAp73, ΔNp73, mutated p53, survivin and PRL-3 was determined by Western blot. KM12C showed transient G2-arrest, low apoptosis and up-regulation of resistance factors such as PRL-3. In KM12C expression of ΔNp73 increased after 10Gy, but not after 15Gy. KM12SM had permanent G2-arrest, low apoptosis and showed up-regulation of the anti-apoptotic survivin and down-regulation of the pro-apoptotic TAp73 and the radioresistance factor PRL-3 was down-regulated. KM12L4a, the most radiosensitive cell line, showed up-regulation of TAp73 and down-regulation/no up-regulation of resistance factors such as ΔNp73, survivin and PRL-3 after radiation. In conclusion, the KM12C cell line was more radioresistant than KM12L4a regarding apoptosis and certain apoptotic proteins. The radiosensitivity of KM12L4a might partly depend on the lack of up-regulation of proteins negative for the outcome of radiotherapy.
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| 20. |
- Stål, Olle, et al.
(author)
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Validation of Prognostic Utility of HOXB13:IL17BR and Molecular Grade Index in Early Stage Breast Cancer : in CANCER RESEARCH, vol 69, issue 24, pp 504S-504S
- 2009
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Conference paper (peer-reviewed)abstract
- Background. HOXB13:IL17BR (H:I) is a two gene expression index, which has been shown to be an independent prognostic factor in estrogen receptor (ER)-positive lymph node-negative (N0) breast cancer. A molecular grade index (MGI) measures the expression of five proliferation-related genes. An algorithm based on dichotomized H:I and MGI stratifying patients into three risk groups has been shown to be superior to either alone in predicting risk of distant metastasis in ER+/N0 patients. Further validation in larger cohorts is needed to establish its clinical performance. A continuous predictor combining H:I and MGI is desirable for making individualized risk assessment in the clinical setting. Methods. During 1976 through 1990 the Stockholm Breast Cancer Group conducted a randomized clinical trial comparing adjuvant tamoxifen with control in 1780 postmenopausal women considered to be at low risk of recurrence (N0 and tumor size < 3 cm). We measured H:I and MGI using a real time PCR assay in 769 patients from this trial based on sample availability. Correlation of gene expression indices with distant metastasis and death due to breast cancer was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. Modeling was also used to develop a continuous risk index as a function of both H:I and MGI. Results. Using pre-specified cutoff points and combination algorithm, H:I, MGI and their combination each was significantly associated with both distant metastasis-free survival and breast cancer-specific survival (Table 1). Furthermore, we used the ER+ tamoxifen-treated subset (n=314) to develop a continuous risk model (Breast Cancer Index or BCI) combining both H:I and MGI. The prognostic utility of BCI was then successfully validated in the untreated subset in this trial and three additional previously published cohorts. BCI consistently identified ∼50% patients with a very low 10-year recurrence risk (< 5%). Discussion. This large retrospective analysis of a randomized clinical trial cohort validated the prognostic utility of H:I, MGI, and their combination. With the continuous risk model, this RT-PCR-based assay allows prediction of risk of recurrence at the individual level, which may help tailor personalized treatment strategy.
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| 21. |
- Trinks, Cecilia, et al.
(author)
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Human leukemic cell lines express a truncated intracellular 160 kDa ERBB2 receptor
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Other publication (other academic/artistic)abstract
- It has recently been demonstrated that ERBB specific tyrosine kinase inhibitors display antineoplastic activity in human leukemic cell devoid of functional ERBB receptors. The present study was undertaken in order to identify any putative target for these drugs. Flow cytometry experiments demonstrate the presence of an immunoreactive ERBB2 protein of intracellular localization and Western blot analysis visualized an ERBB2 protein of approximately 160 kDa. Exposing leukemia cells to tunicamycin did not alter the size of the truncated ERBB2 protein. The ERBB2 gene was alternative spliced with an absence of exon 5 containing the start codon for the full-length protein. In conclusion we demonstrate a nonglycosylated 160 kDa ERBB2-receptor protein with an alternative in-frame start codon in human leukemia cell lines.
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| 22. |
- Trinks, Cecilia, et al.
(author)
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The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells
- 2011
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In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier Science B.V., Amsterdam. - 0006-291X .- 1090-2104. ; 410:3, s. 422-427
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Journal article (peer-reviewed)abstract
- Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 mu M caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.
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| 23. |
- Wallin, Åsa, 1976-, et al.
(author)
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Anticancer effect of SN-38 on colon cancer cell lines with different metastatic potential
- 2008
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In: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 19:6, s. 1493-1498
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Journal article (peer-reviewed)abstract
- SN-38 is an active metabolite of the topoisomerase I inhibitor irinotecan. The mechanism behind its antitumor effect in colorectal cancer is not fully understood. In this study, we examined the response of colon cancer cell lines with different metastatic potential to SN-38. The parental human colon cancer cell line KM12C and its two highly metastatic derivatives KM12SM and KM12L4a were cultivated in 5% CO2 at 37°C for 24 h and then exposed to SN-38 (2.5 µg/ml) at 37°C for 4, 24 and 48 h, respectively. The cell cycle was measured by flow cytometry, apoptotic activity was determined by flow cytometry and immunocytochemistry and the expression of topoisomerase I, Bax and survivin proteins were examined by Western blot. The exposure of the cells to SN-38 induced S-phase and G2 arrest (P<0.0001) and the KM12L4a cells had the highest response in a time-dependent manner (P<0.0001). The rates of apoptosis in the KM12SM (P=0.001) and KM12L4a cell lines (P=0.01) were increased time-dependently, though there was no such change in the KM12C cells. The expression of topoisomerase I protein was decreased in each cell line tested and the expression of Bax protein was increased, especially in KM12L4a. In conclusion, the effect of SN-38 on the colon cancer cell lines was mediated via conducting S-phase and G2 arrest and apoptosis. This effect was found in the cell lines with higher metastatic potentials, indicating that SN-38 can be used to treat advanced colon cancers.
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| 24. |
- Wen, Yugang, et al.
(author)
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Predictive Role of Biopsy Based Biomarkers for Radiotherapy Treatment in Rectal Cancer
- 2020
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In: Journal of Personalized Medicine. - : MDPI. - 2075-4426. ; 10:4
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Journal article (peer-reviewed)abstract
- Background and Purpose: Radiation therapy has long been contemplated as an important mode in the treatment of rectal cancer. However, there are few ideal tools available for clinicians to make a radiotherapy decision at the time of diagnosis for rectal cancer. The purpose of this study was to assess whether biomarkers expressed in the biopsy could help to choose the suitable therapy and provide predictive and/or prognostic information. Experimental Design: In total, 30 biomarkers were analyzed in 219 biopsy samples before treatment to discover the possibility of using them as an indicator for radiotherapy selection, diagnosis, survival and recurrence. Results: Twenty-two biomarkers (COX2-RT, COX2-NonRT, etc.; 36.67%) had diagnostic value. For survival, four biomarkers (NFKBP65, p130, PINCH and PPAR) were significant in regulating gene promoter activity and overall survival, while four had a trend (AEG1, LOX, SATB1 and SIRT6). Three biomarkers (COX2, PINCH and WRAP53) correlated with disease-free survival, while eight had a trend (AEG1, COX2, Ki67, LOX, NFKBP65, PPAR and SATB1). Four biomarkers (COX2-RT, NFKBP65cyto-RT, P130cyto-NonRT and PPARcyto-RT) were independent prognostic factors for recurrence. NFKBP65 and SIRT6 were significantly correlated with lymph node metastasis regardless of radiation. Patients with high AEG1, LOX, NFKBP65, PPAR and SATB1 had or showed a positive trend for better survival after radiotherapy, while those with positive PINCH and WRAP53 expression would not benefit from radiotherapy. Conclusions: AEG1, LOX, NFKBP65cyto, PPAR and SATB1 could be used as indicators for choosing radiotherapy. COX2-RT, COX2-NonRT and some other biomarkers may provide additional help for diagnosis.
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