| 1. |
- Gustafsson Asting, Annika, et al.
(författare)
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Receptor and enzyme expression for prostanoid metabolism in colorectal cancer related to tumor tissue PGE2.
- 2010
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Ingår i: International journal of oncology. - 1791-2423. ; 36:2, s. 469-478
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Tidskriftsartikel (refereegranskat)abstract
- Prostaglandins support progression of colorectal cancer by several mechanisms. This conclusion is based on epidemiological and drug intervention long-term studies or retrieved from animal and cell culture experiments. The aim of the present study was to map receptor and enzyme expression for prostanoid metabolism in the presence of high or low PGE2 content within colon cancer tissue at primary tumor operation and after short-term preoperative provision of non-steroidal anti-inflammatory drug (NSAID). Twenty-three unselected patients with colon cancer were randomly selected to receive indomethacin (NSAID) or sham treatment for 3 days before surgery. Normal colon and tumor tissue were collected at operation for RNA extraction. Tissue PGE2 levels were measured by radioimmunoassay. Gene expression was quantified by microarray and real-time PCR. COX-1 expression increased proportionally to COX-2 expression in colon cancer tissue from untreated patients. Indomethacin reduced PGE2 content in normal and tumor tissue with subsequently decreased IP, HPGD and PPARgamma receptor expression in both tumor and normal colon tissue, while subtype EP1-4 receptors were not significantly influenced by indomethacin treatment. MPGES-1 expression was not related to overall PGE2 content in tumor and colon tissue, but decreased significantly in normal tissue during indomethacin exposure. Reduction of tumor tissue PGE2 was related to significant alteration in expression of several hundred genes indicating decreased cell cycling and increased apoptosis during indomethacin treatment, probably related to upregulation of acute phase reactants in tumor tissue. Increased prostanoid activity in colon cancer tissue is related to cross-talk between tumor and stroma cells.
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| 2. |
- Kodeda, Karl, et al.
(författare)
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Genomic CGH-assessed structural DNA alterations in rectal carcinoma as related to local recurrence following primary operation for cure.
- 2012
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Ingår i: International journal of oncology. - : Spandidos Publications. - 1791-2423 .- 1019-6439. ; 41:4, s. 1397-1404
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Tidskriftsartikel (refereegranskat)abstract
- Several factors determine overall outcome and possible local recurrence after curative surgery for rectal carcinoma. Surgical performance is usually believed to be the most pertinent factor, followed by adjuvant oncological treatment and tumor histopathology. However, chromosomal instability is common in colorectal cancer and tumor clones are assumed to differ in aggressiveness and potential of causing local recurrence. The aim of this study was, therefore, to evaluate if genetic alterations in primary rectal carcinoma are predictive of local recurrences. A large clinical database with linked bio-bank allowed for careful matching of two patient groups (R0) resected for rectal carcinoma. One group had developed early, isolated local recurrences and the other group seemed cured after 93months follow-up. DNA from the primary tumors was analysed with array-CGH (comparative genomic hybridization) including 55,000 genomic probes. DNA from all primary tumors in both groups displayed previously reported and well-recognised DNA aberrations in colorectal carcinoma. Significant copy number gains were confirmed in the 4q31.1-31.22 region in DNA from tumors with subsequent local recurrence. Twenty-two affected genes in this region code for products with high relevance in tumor biology (p53 regulation, cell cycle activity, transcription). DNA from rectal carcinoma displayed well-known aberrations as described for colon carcinoma with no obvious prediction of local rectal recurrence. Gains in the 4q31.1-31.22 DNA region are highly potential for local recurrence despite R0 resection to be confirmed in larger patient materials.
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| 3. |
- Kodeda, Karl, et al.
(författare)
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Local recurrence of rectal cancer: a population based cohort study of diagnosis, treatment and outcome.
- 2012
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Ingår i: Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. - : Wiley. - 1463-1318. ; 14:5, s. 230-7
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Local recurrence is an important endpoint of rectal cancer treatment, but details of this form of treatment failure are less well described. The aim of this study was to acquire deeper knowledge of local recurrence regarding symptoms, diagnostic work-up, clinical management, health-care utilization and outcome. Method: Of 671 patients with rectal cancer, 57 were diagnosed with local recurrence within 5 years after surgery. Their records were analysed. Results: At diagnosis of local recurrence 49(86%) of 57 patients were symptomatic and 40 (70%) were diagnosed between scheduled follow-up visits. The predominant symptom was pain. Forty five of the 57 (79%) had a palpable tumour. Most were deemed incurable at presentation and less than 10 (18%) were operated on with curative intent. Five years after the initial rectal cancer surgery, two patients were alive, with one free of disease. Despite the need for multiple interventions, including surgery, only 4 out of 40 patients were classified as being well palliated in the terminal stage. Conclusion: Follow-up after rectal cancer surgery by annual clinical examination is not sufficient to detect local recurrence when it is asymptomatic. Local recurrence of rectal cancer is often associated with intractable symptoms. These patients require frequent interventions and can rarely be cured if diagnosed at an advanced stage. Strategies for early detection of local recurrence and the management thereof require improvement.
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| 4. |
- Kodeda, Karl, et al.
(författare)
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Rectal washout and local recurrence of cancer after anterior resection.
- 2010
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 97:10, s. 1589-97
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: Adenocarcinomas of the rectum shed viable cells, which have the ability to implant. Intraoperative rectal washout decreases the amount and viability of these cells, but there is no conclusive evidence of the effect of rectal washout on local recurrence after rectal cancer surgery. METHODS:: Data were analysed from a population-based registry of patients who had anterior resection from 1995 to 2002 and were followed for 5 years. Rectal washout was performed at the discretion of the surgeon. National inclusion of patients with rectal cancer and follow-up was near complete (approximately 97 and 98 per cent respectively). RESULTS:: A total of 4677 patients were analysed (3749 who had washout, 851 no washout and 77 with information missing); 52.0 per cent of patients in the washout group and 41.4 per cent in the no-washout group had preoperative radiotherapy (P < 0.001). Local recurrence rates were 6.0 and 10.2 per cent respectively (P < 0.001). Univariable and multivariable logistic regression analyses produced odds ratios that favoured washout: 0.56 (95 per cent confidence interval (c.i.) 0.43 to 0.72) and 0.61 (0.46 to 0.80) respectively (both P < 0.001). In multivariable analysis restricted to patients who had curative surgery, the odds ratio was 0.59 (95 per cent c.i. 0.44 to 0.78; P < 0.001). CONCLUSION:: There was a more favourable outcome in patients after rectal washout than without. Copyright (c) 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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| 5. |
- Lagerstedt, Kristina, 1976, et al.
(författare)
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Genes with relevance for early to late progression of colon carcinoma based on combined genomic and transcriptomic information from the same patients.
- 2010
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Ingår i: Cancer informatics. - 1176-9351. ; 9, s. 79-91
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetic and epigenetic alterations in colorectal cancer are numerous. However, it is difficult to judge whether such changes are primary or secondary to the appearance and progression of tumors. Therefore, the aim of the present study was to identify altered DNA regions with significant covariation to transcription alterations along colon cancer progression. METHODS: Tumor and normal colon tissue were obtained at primary operations from 24 patients selected by chance. DNA, RNA and microRNAs were extracted from the same biopsy material in all individuals and analyzed by oligo-nucleotide array-based comparative genomic hybridization (CGH), mRNA- and microRNA oligo-arrays. Statistical analyses were performed to assess statistical interactions (correlations, co-variations) between DNA copy number changes and significant alterations in gene and microRNA expression using appropriate parametric and non-parametric statistics. RESULTS: Main DNA alterations were located on chromosome 7, 8, 13 and 20. Tumor DNA copy number gain increased with tumor progression, significantly related to increased gene expression. Copy number loss was not observed in Dukes A tumors. There was no significant relationship between expressed genes and tumor progression across Dukes A-D tumors; and no relationship between tumor stage and the number of microRNAs with significantly altered expression. Interaction analyses identified overall 41 genes, which discriminated early Dukes A plus B tumors from late Dukes C plus D tumor; 28 of these genes remained with correlations between genomic and transcriptomic alterations in Dukes C plus D tumors and 17 in Dukes D. One microRNA (microR-663) showed interactions with DNA alterations in all Dukes A-D tumors. CONCLUSIONS: Our modeling confirms that colon cancer progression is related to genomic instability and altered gene expression. However, early invasive tumor growth seemed rather related to transcriptomic alterations, where changes in microRNA may be an early phenomenon, and less to DNA copy number changes.
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| 6. |
- Lönnroth, Christina, 1946, et al.
(författare)
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Downregulation of Prominin 1/CD133 expression in colorectal cancer by NSAIDs following short-term preoperative treatment
- 2012
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Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 41:1, s. 15-23
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Tidskriftsartikel (refereegranskat)abstract
- Expression of Prominin 1/CD133 is associated with poor prognosis and chemoresistance in several types of solid tumors. The aim of the present study was, therefore, to evaluate Prominin 1/CD133 expression in colorectal carcinoma after short-term preoperative treatment by non-steroidal anti-inflammatory drugs (NSAIDs). Patients aimed at curative operation for colon cancer were randomized to receive NSAIDs (indomethacin 50 mg x2 or celecoxib 100 mg x2) three days preoperatively. Antisecretory prophylaxis (esomeprasol 40 mg x1) was provided to all patients and served as sham intake. CD133 expression in tumor tissue was also assessed in tumors from Dukes B patients selected for either long or short postoperative survival. No patients received perioperative chemoradiotherapy. Tumor tissue was collected at surgery for quantification of mRNAs (Prom I and Wnt4) by qPCR. Immunohistochemistry stained for CD133, Ep-CAM, CD34 and CD45. PGE(2) content in tumor tissue was determined. Transcript of CD133 in tumor tissue was lower in patients treated with NSAIDs (0.28 +/- 0.07 vs. 0.51 +/- 0.08; p<0.03) as well as some other stem cell-related transcripts. In treated patients 36% of all tumors stained positive for CD133 compared to 71% in sham-treated control patients (p<0.05). Short survivors with Dukes' B tumors displayed 78% CD133 expression as compared to 33% of tumors in long-term survivors (p<0.002). Tumor tissue PGE(2) content was negatively related to patient survival. Our results show that short-term preoperative NSAID treatment downregulates colon cancer tissue expression of Prominin 1/CD133, a stem cell marker indicative of survival prognosis as confirmed.
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| 7. |
- Lönnroth, Christina, 1946, et al.
(författare)
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Preoperative low dose NSAID treatment influences the genes for stemness, growth, invasion and metastasis in colorectal cancer.
- 2014
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Ingår i: International journal of oncology. - : Spandidos Publications. - 1791-2423 .- 1019-6439. ; 45:6, s. 2208-2220
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical data, and an increasing list of clinical investigations, show anti‑inflammatory agents to favourably influence the biology of colorectal tumor. We have earlier reported on re‑expression of activated immune cells after three days preoperative treatment of patients with colorectal carcinoma, randomized to receive oral NSAID(indomethacin or celebrex). Antisecretory prophylaxis(esomeprasol) was provided to all patients and served as sham treatment. Concomittant to MHC locus activation, Prominin1/CD133, a marker associated with stemness and poor prognosis in several solid tumors, was downregulated. The aim of the present study was to evaluate expression of additional regulators belonging to the stem cell niche, OCT4, SOX2 and BMP7, aswellas some microRNAs, reported to act as tumor suppressors or oncomiRs. Peroperative tumor biopsies were analyzed by microarrays, quantitative real‑time PCR and immunohistochemistry(IHC). The stem cell master regulator SOX2 was increased by NSAIDs(p<0.01), aswellas the tumor suppressor miR‑630(p<0.01), while BMP7, a marker for poor prognosis in CRC, was downregulated by NSAID(indomethacin, p<0.02). The upregulation of SOX2, but not of its heterodimer binding partner OCT4, could imply a negative feed‑back loop, with a switch‑off for stemness preservation of tumor cells. This is supported by the overall evaluation of gene expression profiles with subsequent events, indicating less aggressive tumors following NSAID treatment.
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| 8. |
- Novotny, Ann, 1982-, et al.
(författare)
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A pharmacological analysis of the cholinergic regulation of urokinase-type plasminogen activator, and plasminogen activator inhibitor-1 secretion in the human colon cancer cell line, HT-29
- 2010
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 646:1-3, s. 22-30
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Tidskriftsartikel (refereegranskat)abstract
- Urokinase-type plasminogen activator (uPA) is an important factor for tumour cell invasion and metastasis. We recently showed that acetylcholine is an autocrine/paracrine growth factor for the human colon cancer cell line, HT-29, in part via the α7 subtype of the nicotinic acetylcholine receptors. In the current study, we investigated whether acetylcholine participates in the regulation of the protein expressions of also uPA and its receptor (uPAR) in the HT-29 cell line. Such were investigated by immunocytochemistry and Western blotting, and quantitation of uPA secretion was undertaken by ELISA. Stimulation of the cells for 24 h with nicotine caused increased uPA secretion with peak effect (78% above the control) occurring at a nicotine concentration of 10 nM. This effect was markedly inhibited by α-Bungarotoxin, thus showing the involvement of α7 nicotinic acetylcholine receptors. Basal uPA secretion was found to be partly dependent on ongoing activation of nicotinic receptors, suggesting tonic production of acetylcholine. Conversely, there was no cholinergic influence on the expression of uPAR. The current findings demonstrate novel aspects of receptor-mediated regulation of tumour metastatic potential via uPA secretion. This may suggest future pharmaceutical strategies in treatment of colorectal cancer.
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| 9. |
- Novotny, Ann, 1982, et al.
(författare)
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A pharmacological analysis of the cholinergic regulation of urokinase-type plasminogen activator secretion in the human colon cancer cell line, HT-29.
- 2010
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Ingår i: European journal of pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 646:1-3, s. 22-30
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Tidskriftsartikel (refereegranskat)abstract
- Urokinase-type plasminogen activator (uPA) is an important factor for tumour cell invasion and metastasis. We recently showed that acetylcholine is an autocrine/paracrine growth factor for the human colon cancer cell line, HT-29, in part via the alpha7 subtype of the nicotinic acetylcholine receptors. In the current study, we investigated whether acetylcholine participates in the regulation of the protein expressions of also uPA and its receptor (uPAR) in the HT-29 cell line. Such were investigated by immunocytochemistry and Western blotting, and quantitation of uPA secretion was undertaken by ELISA. Stimulation of the cells for 24h with nicotine caused increased uPA secretion with peak effect (78% above the control) occurring at a nicotine concentration of 10nM. This effect was markedly inhibited by alpha-Bungarotoxin, thus showing the involvement of alpha7 nicotinic acetylcholine receptors. Basal uPA secretion was found to be partly dependent on ongoing activation of nicotinic receptors, suggesting tonic production of acetylcholine. Conversely, there was no cholinergic influence on the expression of uPAR. The current findings demonstrate novel aspects of receptor-mediated regulation of tumour metastatic potential via uPA secretion. This may suggest future pharmaceutical strategies in treatment of colorectal cancer.
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| 10. |
- Novotny, Ann, 1982, et al.
(författare)
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Is acetylcholine a signaling molecule for human colon cancer progression?
- 2011
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 46:4, s. 446-455
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Non-neuronal acetylcholine (ACh) has been suggested to be a mediator for the development of various types of cancer. We analyzed a possible role for this molecule in carcinogenesis and/or progression of human colon cancer, in patient biopsies harvested from the colon during surgery. We addressed whether ACh synthesis (by choline acetyltransferase) and/or degradation (by ACh esterase), as well as the expression of the alpha alpha 7-subtype of the nicotinic ACh receptors, and the peptide ligand at the alpha alpha 7 receptors, secreted mammalian Ly6/urokinase-type plasminogen activator receptor-related protein-1, respectively, are deranged in tumor tissue as compared with macroscopically tumor-free colon tissue. Methods. A total of 38 patients were grouped for analysis based on their respective Dukes stage (either Dukes A ++ B or C ++ D). A mucosal tissue sample was harvested from macroscopically tumor-free colon tissue (i.e. control tissue), as well as from the tumor, and protein lysates were prepared for quantitative Western blotting. Full-thickness specimens were taken for immunohistochemistry. Results. For all the above named markers, there was a significant difference between control and tumor tissue with regard to protein levels, and there was, in addition, a significant difference in protein levels between the Dukes A ++ B and C ++ D groups. Conclusion. The current findings may suggest a role for ACh in colon carcinogenesis/cancer progression; the data obtained could have prognostic and/or therapeutic significance for this disease.
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| 11. |
- Wahlqvist, Mats, 1954, et al.
(författare)
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Patient-centred attitudes among medical students: Gender and work experience in health care make a difference
- 2010
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Ingår i: Medical Teacher. - 1466-187X. ; 32:4
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background: Previous studies of medical students’ patient-centred attitudes show a decline across undergraduate education and overall higher scores for female students. Aims: To assess undergraduate students’ patient-centred attitudes at various stages of education and to explore possible associations between attitudes and age, gender and work experience in health care. Methods: In autumn 2005, medical students in Gothenburg (n=797) were asked to answer Patient-Practitioner Orientation Scale (PPOS), a validated instrument exploring attitudes towards the doctor-patient relationship. Data including gender, age, current term and students’ work experience in health care were collected. Results: Six hundred students of 797 (75%) answered the questionnaire. No decrease of students’ PPOS score across the curriculum was observed. PPOS scores from female students were higher compared to males (p<0.0001) and female scores were significantly higher in the later terms compared with earlier (p=0.0011). Female students had more experience from working in health care (p=0.0023). Extended work experience was associated with higher PPOS only among females (p=0.0031). Conclusions: No decline of students’ patient-centred attitudes may indicate an ongoing shift. Gender differences in patient-centred attitudes were reproduced. Work experience in health care presents a new gender difference. These gender differences should be considered when training patient-centred attitudes and skills.
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