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1.
  • Arlehag, L, et al. (författare)
  • ATM expression in rectal cancers with or without preoperative radiotherapy
  • 2005
  • Ingår i: Oncology Reports. - 1021-335X .- 1791-2431. ; 14:2, s. 313-317
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with ATM (Ataxia-Telangiectasia mutated) mutation show increased sensitivity to radiation and have a higher risk of developing malignancies. The present study aimed to investigate whether ATM expression was related to radiotherapy, and clinicopathological and biological variables in rectal cancers. ATM expression was immunohistochemically examined in 78 rectal cancers from patients who participated in a Swedish rectal cancer trial of preoperative radiotherapy. Of 78 patients, 44 underwent surgery alone, and 34 underwent both preoperative radiotherapy and surgery. Fifty-eight cases had normal rectal mucosa adjacent to the tumour. The results showed that, compared to normal mucosa, tumours had less nuclear (p=0.03) but more cytoplasmic expression of ATM (p=0.004). In tumours, less expression of ATM, either in the nucleus (p=0.07) or in the cytoplasm (p=0.02 for staining intensity, and p=0.07 for staining percentage), tended to be correlated with male patients. Also, ATM expression was not related to radiotherapy or other clinicopathological and biological variables (p > 0.05). In conclusion, the pattern of ATM expression was changed from normal mucosa to tumour. Less expression of ATM may be related to males.
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2.
  • Bourghardt Peebo, Beatrice, 1968-, et al. (författare)
  • Expression of the focal adhesion protein PINCH in normal and alkali-injured corneas and the role of PMNs
  • 2007
  • Ingår i: Acta Ophthalmologica Scandinavica. - : Wiley. - 1395-3907 .- 1600-0420. ; 85:4, s. 395-400
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To evaluate the role of particularly interesting new cysteine-histidine-rich protein (PINCH) in corneal wound healing and early neovascularization and to assess the influence of granulocytes. Methods: A standardized corneal alkali wound was inflicted under general anaesthesia to the right eye of 14 New Zealand White rabbits. Seven of the rabbits received i.v. 5 mg/kg fucoidin every 2 hours to prevent granulocytes from entering the wound area. After 36 hours, the rabbits were killed, the corneas excised, fixed in 4% formaldehyde and embedded in paraffin. The sections were double-stained with antibodies against PINCH and with haematoxylin. Results: In the normal cornea and limbus, PINCH was weakly expressed in the corneal epithelium and in a wedge of the conjunctival stroma. In the wounded corneas, PINCH expression was seen in the frontline of repopulating endothelial and epithelial cells, and in active keratocytes. The vascular endothelium and the granulocytes expressed PINCH, as did the conjunctival epithelium. In the fucoidin-treated rabbits, PINCH expression was markedly reduced. The vascular endothelial cells and the few granulocytes did not express PINCH in these rabbits. Conclusions: PINCH is only slightly expressed in the normal cornea. A corneal wound induces PINCH expression in the repopulating cells, in the vascular endothelial cells of the limbus, in the limbal epithelium and in the granulocytes. Exclusion of granulocytes reduces expression of PINCH and there is no expression at all in the vascular endothelium. © 2007 The Authors Journal compilation 2007 Acta Ophthalmol Scand.
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3.
  • Bu, Huajie, et al. (författare)
  • Genotype < 21CAs/>= 21CAs and allele < 21CAs of the MANBA gene in melanoma risk and progression in a Swedish population
  • 2009
  • Ingår i: Molecular medicine reports. - : Spandidos Publications Ltd.. - 1791-2997 .- 1791-3004. ; 2:2, s. 259-263
  • Tidskriftsartikel (refereegranskat)abstract
    • Cutaneous melanoma is characterized by poor patient outcome in its later stages. The search for genetic markers is therefore crucial for the identification of populations at risk for melanoma. Highly polymorphic CA repeats in 3 proximity in the MANBA gene were examined by PCR-capillary electrophoresis in 185 Swedish melanoma patients and 441 tumor-free age- and gender-matched individuals. The associations of the polymorphisms with melanoma risk, the pigment phenotypes of the patients and tumor characteristics were analyzed. A significant difference in allelic distribution between melanoma patients and tumor-free individuals was observed. The frequency of the MANBA genotype <21CAs/>= 21CAs was significantly higher in melanoma patients than in the controls. When comparing allele distribution in patients and their matched controls, the allele <21 CAs was found to be associated with the female gender (39.8 vs. 31.2%, P=0.041, OR=1.46, 95% Cl 1.02-2.10), but not with male gender (34.4 vs. 30.9%, P=0.39). Within the melanoma group, there were no differences in the distribution of the MANBA alleles associated with patient gender or age before or after 55 years at diagnosis, nor was there any association between the MANBA genotype and pigment phenotype or tumor sites. The MANBA allele <21CAs was, however, associated with thin melanomas at diagnosis (Breslow thickness <= 1.5 mm and Clark levels I and II). In conclusion, these data suggest that MANBA polymorphisms might be an indicator of tumor growth and progression and, together with other markers, could be used to identify individuals at increased risk of melanoma.
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4.
  • Bu, Huajie, et al. (författare)
  • Importance of polymorphisms at NF-κB1 and NF-κBIα genes in melanoma risk, clinicopathological features and tumor progression in Swedish melanoma patients
  • 2007
  • Ingår i: Journal of Cancer Research and Clinical Oncology. - : Institutionen för biomedicin och kirurgi. - 0171-5216 .- 1432-1335. ; 133:11, s. 859-866
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study, functional polymorphisms of NF-κB1 and NF-κBIα genes were examined in 185 melanoma patients and 438 tumor-free individuals. Associations of the polymorphisms with melanoma risk, age and pigment phenotypes of the patients and clinico-pathological tumor characteristics were analyzed. DNAs were isolated from mononuclear cells of venous blood. Polymorphisms of the genes were genotyped by a PCR-RFLP technique, and transcription level of NF-κBIα was examined by a quantitative real-time reverse transcription PCR. Results showed that both ATTG insertion polymorphism of NF-κB1 and A to G polymorphism of NF-κBIα genes were correlated with melanoma risk, especially, in a combination of ATTG2/ATTGT2 and GG. NF-κB1 ATTG2/ATTG2 and NF-κBIα GG genotypes were associated with male gender and age > 65 years (at diagnosis). Patients with ATTG1/ATTG1 genotype had thinner tumors and lower Clark levels at diagnosis. Frequency of ATTG1/ATTG1 genotype was higher in patients with melanomas on intermittently sun-exposed pattern of the body and NF-κBIα GG was more frequent in the patients with melanomas at rarely exposed sites. There were no differences in the gene transcription level between patients with different NF-κBIα genotypes. These data suggest that NF-κB1 and NF-κBIα genes might be susceptible genes for melanoma risk and functional polymorphisms of these genes might be biological predictors for melanoma progression.
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5.
  • Bu, H, et al. (författare)
  • Significance of glutathione S-transferases M1, T1 and P1 polymorphisms in Swedish melanoma patients.
  • 2007
  • Ingår i: Oncology Reports. - 1021-335X .- 1791-2431. ; 17:4, s. 859-864
  • Tidskriftsartikel (refereegranskat)abstract
    • Polymorphisms of GSTM1, GSTT1 and GSTP1 were examined in melanoma patients and tumor-free individuals. Relationships between the polymorphisms and tumor characteristics and pigment phenotypes of the patients were analyzed. There was no significant difference in GSTM1 null and GSTT1 null genotypes nor GSTP1 GG genotype between melanoma patients and controls. In melanoma patients, these polymorphisms were not correlated with early or later onset of melanomas or gender of the patients. Frequency of GSTM1 null genotype was higher in patients with melanoma >2.5 mm than in those with tumors <1.0 mm, and higher frequency was found in nodular melanoma than in the other tumor types. GSTP1 GG genotype was more often found in the patients with brown and mixed eye color or brown and black hair than those with blue and green eyes or blond hair. It is unlikely that polymorphisms of GSTM1, GSTT1 and GSTP1 are general risk factors for melanoma in the Swedish population. GSTM1 null genotype was correlated with Breslow thickness and tumor type, which might serve as an additional biomarker for a rapid tumor progression. GSTP1 GG increases risk for melanoma in the subgroup of individuals with dark eyes or hair.
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6.
  • Fredriksson, Camilla, 1969- (författare)
  • Keratinocytes in tissue engineering of human skin: invitro and in vivo studies
  • 2008
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Full thickness wounds, such as deep burns, need restoration of both the dermal and epidermal layers of the skin. In normal wound healing, re-epithelialization occurs by migration and proliferation of keratinocytes from the wound edges and by differentiation of stem cells from remaining hair follicles. Restoration of dermis occurs by influx of growth factors secreted by macrophages, platelets, and fibroblasts; by fibroblast proliferation and subsequent synthesis and remodeling of collagenous dermal matrix. In the case of full-thickness acute burn injuries and chronic wounds (e.g. pressure ulcers, venous ulcers and diabetic foot ulcers), these processes are defective. With the principles of tissue engineering in mind (to correct, improve and maintain tissues and their functions), researchers have developed promising materials and methods to make it possible to restore either the dermal (Integra® DRT, Alloderm®) or the epidermal layer (split thickness skin grafts (STSG), cultured epithelial autografts (CEA), autologous keratinocytes in single cell suspension). It is now well established that superior results are obtained if both dermal and epidermal components are combined, for example in a bilayered skin equivalent. Apligraf® is recommended for use on venous ulcers and is the only bilayered living skin equivalent currently approved by the FDA. Studies on different factors affecting the wound healing capacity as well as techniques in use provide valuable information for further development.In this licentiate thesis, we evaluated different transplantation techniques for delivering cultured human keratinocytes in single cell suspension, a measure becoming more frequently used in addition to STSG and CEA for restoring the epidermal layer of the skin. We found that the pressure device, commonly used to spray cell suspension onto the wound with pressures as high as 200 kPa, killed around 0% of the cells. In comparison, an ordinary syringe with the attachment of a spray nozzle showed almost 90% viable cells post transplantation and provided an equally good distribution of the cell suspension.We also studied different silver containing dressings regarding silver accumulation in human skin. In addition, we graded the re-epithelialization to evaluate whether the dressings caused any delay in the wound healing process. We found that the silver dressings tested, with few exceptions, caused dermal accumulation of silver, primarily aggregated around blood vessels. We could also show that most of the dressings had negative effect on the re-epithelialization.For the restoration of the dermal layer of the skin, Integra® DRT functions as a scaffold for guided tissue regeneration of the dermis. We had the possibility to study a case of necrotizing fasciitis were the treatment consisted of the use of Integra® DTR together with sub-atmospheric pressure (after initial surgical debridement) and later transplantation of split thickness skin grafts. This measure proved to be safe as well as giving satisfactory pliable and aesthetically acceptable result.
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7.
  • Gao, Jingfang, 1966-, et al. (författare)
  • Association of NFKBIA polymorphism with colorectal cancer risk and prognosis in Swedish and Chinese populations
  • 2007
  • Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 42:3, s. 345-350
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. The inhibitory proteins, IκBs, regulate the activity of nuclear factor kappa-beta (NF-κB), which is implicated in tumorigenesis by regulating expression of a variety of genes involved in cellular transformation, proliferation, invasion, angiogenesis and metastasis. Variants in the genes encoding IκBs may be involved in cancer development through the activation of NF-κB. The objective of this study was to investigate the susceptibility of an A to G variation (rs696) in the 3′ UTR of NFKBIA (encoding IκBα) to colorectal cancer (CRC) and the association of this polymorphism with clinicopathologic variables in CRC patients. Material and methods. A case-control study was carried out on a Swedish (155 CRCs, 438 controls) and a Chinese population (199 CRCs, 577 controls). The genotype of NFKBIA was determined by PCR-restriction fragment length polymorphism. Results. The frequency of the AG genotype was increased in the Chinese patients ≥50 years of age compared with the Chinese controls (odds ratio (OR) = 3.06, 95% confidence interval (CI) = 1.55-6.02, p=0.001), even when adjusted for age (OR = 3.20, 95% CI = 1.61-6.38, p=0.001). The GG genotype of NFKBIA was related to a poorer survival rate in the Swedish patients, independent of gender, age, tumour location, Dukes' stage and differentiation (hazard ratio = 3.10, 95% Cl = 1.28-7.60, p=0.01). Conclusions. Chinese individuals ≥50 years of age carrying the AG genotype of NFKBIA may be at an increased risk of developing CRC, and the GG genotype of NFKBIA may be considered as a prognostic factor for Swedish CRC patients. © 2007 Taylor & Francis.
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8.
  • Gao, Jingfang, et al. (författare)
  • Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer
  • 2009
  • Ingår i: DIGESTIVE AND LIVER DISEASE. - : Elsevier BV. - 1590-8658. ; 41:2, s. 116-122
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose. The aim of this study was to get a deeper understanding into how adults with cerebral palsy (CP) experience physiotherapy and physical activity in a perspective from childhood to adulthood; and how personal and environmental factors influence possibilities for physiotherapy and physical activity. Method. Data was collected through interviews with 22 community-living adults (35-68 years) with CP, from five counties in Sweden. The questions were open-ended and the interviews were taped and transcribed to written language. The material was analysed through qualitative content analysis, a classification process resulting in different themes. Results. The narratives from the 22 informants, based on experiences from childhood to adulthood, resulted in a description of prerequisites for carrying out physiotherapy and physical activity. Five different themes were identified: (i) Being enjoyable, (ii) Giving effects, (iii) Being comprehensible, (iv) Being integrated in daily life, and (v) Supportive healthcare with competent professionals. Conclusion. The information from the interviews elucidates the importance of a lifelong support from healthcare professionals. Physiotherapists with attentiveness to different life situations in combination with good understanding and knowledge in CP could facilitate continuous physical activity in people growing up and ageing with CP.
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9.
  • Gao, Jingfang, 1966-, et al. (författare)
  • MANBA polymorphism was related to increased risk of colorectal cancer in Swedish but not in Chinese populations
  • 2008
  • Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 47:3, s. 372-378
  • Tidskriftsartikel (refereegranskat)abstract
    • β-mannosidase, encoded by MANBA, has been suggested to be implicated in cancers, while genetic variations in the MANBA in relation to colorectal cancer (CRC) risk has not been examined. In this study, we investigated the relationship of a polymorphic CA repeat in MANBA gene with CRC risk in 152 Swedish CRC patients and 441 Swedish controls, and 196 Chinese CRC patients and 577 Chinese controls, as well as the clinicopathologic significance of this polymorphism on CRC patients, by using capillary electrophoresis. The MANBA genotypes were related to CRC risk in the Swedish population (p=0.03), but not in the Chinese population. In the Swedish population, individuals with < 22 CAs/> 22 CAs had significantly increased risk for CRC compared with those with ≥22 CAs/≥ 22 CAs (gender-age-adjusted analysis: OR 1.93, 95% CI 1.06-3.51). There was no relationship between the polymorphism and clinicopathologic variables. These findings suggest the different susceptibilities of this polymorphism to CRC development in the two populations. © 2008 Taylor & Francis.
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10.
  • Gao, Jingfang, 1966- (författare)
  • Molecular and Biological Characteristics of Stroma and Tumor Cells in Colorectal Cancer
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Carcinogenesis is a progressive process involving multiple genetic alterations in tumor cells and complex interactions in the tumor-host microenvironment. To better understand the contribution of molecular alterations in tumor cells and stromal variables to the development of colorectal cancer (CRC) and identify prognostic factors, in this study we examined the clinicopathological and biological significance of stromal variables, including particularly interesting new cysteine-histidine rich protein (PINCH), inflammatory infiltration, angiogenesis and lymphangiogenesis, as well as hRAD50/hMRE11/hNBS1 proteins and hRAD50 mutation in tumor cell in CRC.PINCH protein expression in the stroma was increased from normal mucosa to primary tumors and further to lymph node metastases. In particular, PINCH expression was most intense at the tumor invasive margin, which was related to low inflammatory infiltration and independently related to an unfavorable prognosis. Low inflammatory infiltration at the tumor invasive margin was related to advanced tumor stage, worse differentiation and microsatellite instability (MSI). Further, it was independently related to an unfavorable prognosis. Increased blood and lymphatic vessel density was observed in the primary tumors compared with the corresponding normal mucosa. However, neither angiogenesis nor lymphangiogenesis was associated with tumor stage and patients’ survival. Moreover, PINCH was present in a proportion of endothelial cells of the tumor vasculature, and PINCH expression in tumor-associated stroma was positively related to blood vessel density.In primary tumor cells of CRC, strong expression of hRAD50, hMRE11 or hNBS1 was related to microsatellite stability (MSS). A high percentage of hMRE11 expression was associated with less local recurrence and high apoptotic activity. Further, we observed that the expression of hRAD50, hMRE11 or hNBS1 among normal mucosa, primary tumors and metastases in MSS CRC differed from that in MSI CRC. In MSS CRC, the expression intensity of hRAD50, hMRE11 and hNBS1 was consistently increased with respect to normal mucosa, but there was no difference between the primary tumors and metastases. In the primary MSS tumors, the expression of individual or combination of hRAD50/hMRE11/hNBS1 was associated with a favorable prognosis in the same series of the CRCs. Moreover, strong/high hRAD50 in MSS primary tumors was related to earlier tumor stage, better differentiation and high inflammatory infiltration, whereas strong hNBS1 expression tended to be independently related to a favorable prognosis in MSS CRC with earlier tumor stage. However, in MSI CRC, there were neither differences in the expression of hRAD50/hMRE11/hNBS1 among normal mucosa, primary tumors and metastases, nor any association of the protein expressions with clinicopathological variables. On the other hand, frameshift mutations of (A)9 at coding region of hRAD50 were only found in MSI CRC.Our study indicates that 1) PINCH is likely a regulator of angiogenesis, and PINCH expression at the tumor invasive margin is an independent prognostic indicator in CRC. 2) Inflammatory infiltration at the tumor invasive margin is also an independent prognostic indicator in CRC. The lack of association between high inflammatory infiltration and MSI may help to explain the non-association of MSI with survival in CRC patients. 3) Angiogenesis and lymphangiogenesis occur in the early stage of CRC development, but do not associate with CRC progression and patients’ prognosis. 4) hRAD50/hMRE11/hNBS1 may act dependently and independently, playing different roles in MSS and MSI CRC development. In MSS CRC, the strong expression of the three proteins, associated with a favorable prognosis, may present the cellular response against tumor progression. Expression of hNBS1 may be a prognostic indicator for MSS CRC patients in the earlier tumor stage. In MSI CRC, the frameshift mutations at the coding region of hRAD50 may contribute to tumor development.
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11.
  • Gao, Jingfang, et al. (författare)
  • RAD50/MRE11/NBS1 proteins in relation to tumour development and prognosis in patients with microsatellite stable colorectal cancer
  • 2008
  • Ingår i: Histology and Histopathology. - : Histology and Histopathology. - 0213-3911 .- 1699-5848. ; 23:12, s. 1495-1502
  • Tidskriftsartikel (refereegranskat)abstract
    • RAD50/MRE11/NBS1 complex is essential for DNA double-strand break repair and for maintaining genomic integrity. In this study, we immunohistochemically examined MRE11, NBS1 and RAD50 expression in primary CRCs (n = 208), the corresponding distant (n= 41) and adjacent normal mucosa ( n= 130), and lymph node metastases ( n= 26), and investigated their clinicopathological significance in colorectal cancers ( CRCs). We found that the intensity and percentage of MRE11 and NBS1 in primary CRCs were positively correlated with each other and with RAD50 (P < 0.0001). Strong expression of MRE11, NBS1 or combined RAD50/MRE11/NBS1 was related to MSS, positive hMLH1 expression, earlier tumour stage (TNM stage I and II) and favourable survival (P < 0.05). A high percentage of MRE11 expression was associated with less local recurrence and high apoptotic activity (P < 0.05). In MSS CRCs, the expression of MRE11 and NBS1 was stronger than that in normal mucosa (P < 0.05), and strong expression of NBS1 in primary tumour was related to favourable survival of patients in TNM stage I and II (univariate analysis: P = 0.03; multivariate analysis: P = 0.07). In MSI CRCs, neither MRE11 nor NBS1 expression showed differences among normal mucosa, primary tumour and metastasis, or among clinicopathological variables. In conclusion, RAD50/MRE11/NBS1 proteins interacted with each other, which had different clinicopathological significance in MSS and MSI CRCs, and further, each component of the complex might have additional roles. NBS1 might be a prognostic factor for patients with MSS tumour in TNM stage I and II.
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12.
  • Gao, Jingfang, et al. (författare)
  • Relationships of tumor inflammatory infiltration and necrosis with microsatellite instability in colorectal cancers
  • 2005
  • Ingår i: World Journal of Gastroenterology. - 1007-9327. ; 11:14, s. 2179-2183
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: The relationships between microsatellite instability (MSI) and survival in colorectal cancer patients are not consistent. The favorable survival of patient with MSI has been suggested to be related to pronounced inflammatory infiltration; however, the reason for non-association of MSI with survival is unclear. Our aims were to investigate the associations of inflammatory infiltration and tumor necrosis (TN) with microsatellite status and clinicopathological factors in colorectal cancer patients in whom MSI was not related to survival. Methods: Three hundred and one colorectal adenocar-cinomas were evaluated for inflammatory infiltration and 300 for TN under light microscope. Results: Low infiltration at invasive margin (c2 = 3.94, P = 0.047) and in whole tumor stroma (c2 = 3.89, P = 0.049) was associated with MSI, but TN was not (c2 = 0.10, P = 0.75). Low infiltration was related to advanced stage (c2 = 8.67, P = 0.03), poorer differentiation (c2 = 8.84, P = 0.03), DNA non-diploid (c2 = 10.04, P = 0.002), higher S-phase fraction (c2 = 11.30, P = 0.004), positive p53 expression (c2 = 7.94, P = 0.01), and worse survival (P = 0.03 for both univariate and multivariate analyses). Abundant TN was related to advanced stage (c2 = 17.74, P = 0.001) and worse survival (P = 0.02 for univariate, and P = 0.05 for multivariate analysis). Conclusion: The result that high inflammatory infiltration was not related to MSI might help explain the non-association of MSI with survival in colorectal cancer patients.
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13.
  • Gao, Jingfang, et al. (författare)
  • The different roles of hRAD50 in microsatellite stable and unstable colorectal cancers
  • 2008
  • Ingår i: Disease Markers. - : Hindawi Limited. - 0278-0240 .- 1875-8630. ; 24:2, s. 127-134
  • Tidskriftsartikel (refereegranskat)abstract
    • RAD50 protein is essential for DNA double-strand break repair and maintaining genomic integrity. In this study, we investigated the clinicopathological significance of hRAD50 expression and mutation in microsatellite stable (MSS) and unstable (MSI) colorectal cancers (CRCs). hRAD50 expression was examined in primary CRC (n=268), the corresponding distant (n=69) and adjacent normal mucosa (n=138), and lymph node metastasis (n=44) by immunohistochemistry. hRAD50 mutation was analyzed in 87 primary CRCs by PCR-SSCP-DNA sequencing. hRAD50 expression was increased in MSS primary CRCs, but not MSI ones, compared with distant/adjacent normal mucosa (p<0.05). There was no difference in the hRAD50 expression between primary and metastatic CRCs. The increased hRAD50 expression in MSS primary CRCs was related (p<0.05) or tended to be related (p=0.05) to early tumor stage, better differentiation, high inflammatory infiltration, p53 overexpression. Frameshift mutations of (A)_{9} at coding region of hRAD50 were only found in MSI CRCs. Our results suggest that hRAD50 may play different roles in the development of MSS and MSI CRCs: increased hRAD50 expression in MSS CRCs {may be a cellular response against tumor from further progression}, while hRAD50 mutation may be involved in the development of MSI CRCs.
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14.
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15.
  • Gao, Xueshan, et al. (författare)
  • Mitochondrial DNA Damage in Iron Overload
  • 2009
  • Ingår i: JOURNAL OF BIOLOGICAL CHEMISTRY. - 0021-9258. ; 284:8, s. 4767-4775
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic iron overload has slow and insidious effects on heart, liver, and other organs. Because iron-driven oxidation of most biologic materials (such as lipids and proteins) is readily repaired, this slow progression of organ damage implies some kind of biological "memory." We hypothesized that cumulative iron-catalyzed oxidant damage to mtDNA might occur in iron overload, perhaps explaining the often lethal cardiac dysfunction. Real time PCR was used to examine the " intactness" of mttDNA in cultured H9c2 rat cardiac myocytes. After 3 -5 days exposure to high iron, these cells exhibited damage to mtDNA reflected by diminished amounts of near full-length 15.9-kb PCR product with no change in the amounts of a 16.1-kb product from a nuclear gene. With the loss of intact mtDNA, cellular respiration declined and mRNAs for three electron transport chain subunits and 16 S rRNA encoded by mtDNA decreased, whereas no decrements were found in four subunits encoded by nuclear DNA. To examine the importance of the interactions of iron with metabolically generated reactive oxygen species, we compared the toxic effects of iron in wild-type and rhoo cells. In wild-type cells, elevated iron caused increased production of reactive oxygen species, cytostasis, and cell death, whereas the rhoo cells were unaffected. We conclude that long-term damage to cells and organs in iron-overload disorders involves interactions between iron and mitochondrial reactive oxygen species resulting in cumulative damage to mtDNA, impaired synthesis of respiratory chain subunits, and respiratory dysfunction.
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16.
  • He, Lu-Jun, et al. (författare)
  • Genetic polymorphisms of N-acetyltransferase 2 and colorectal cancer risk.
  • 2005
  • Ingår i: World Journal of Gastroenterology. - 1007-9327 .- 2219-2840. ; 11:27, s. 4268-4271
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: To identify the distribution of N-acetyltrasferase 2(NAT2) polymorphism in Hebei Han Chinese and the effects of the polymorphism on the development of colorectal cancer. METHODS: We performed a hospital-based case-control study of 237 healthy individuals and 83 colorectal cancer patients of Hebei Han Chinese. DNA was extracted from peripheral blood and cancer tissues. The genotypes of the polymorphisms were assessed by PCR-restriction fragment length polymorphism (RFLP). RESULTS: There were four NAT2 alleles of WT, M1, M2, and M3 both in the healthy subjects and in the patients, and 10 genotypes of WT/WT, WT/M1, WT/M2, WT/M3, M1/M1, M1/M2, M1/M3, M2/M2, M2/M3, M3/M3. M2 allele was present in 15.61% of healthy subjects and 29.52% of patients (chi(2) = 15.31, P<0.0001), and M3 allele was present in 30.59% of healthy subjects and 16.87% of patients (chi(2) = 25.33, P<0.0001). There were more WT/M2 (chi(2) = 34.42, P<0.0001, odd ratio = 4.99, 95%CI = 2.27-9.38) and less WT/M3 (chi(2) = 3.80, P = 0.03) in the patients than in the healthy subjects. In 70.3% of the patients, there was a difference in NAT2 genotype between their tumors and blood cells. Patients had more WT/M2 (chi(2) = 5.11, P = 0.02) and less M2/M3 (chi(2) = 4.27, P = 0.039) in their blood cells than in the tumors. Furthermore, 53.8% (7/13) of M2/M3 in tumors were from WT/M2 of blood cells. CONCLUSION: There is a possible relationship between the NAT2 polymorphisms and colorectal cancer in Hebei Han Chinese. The genotype WT/M2 may be a risk factor for colorectal cancer.
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17.
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18.
  • Kertat, Khadija, et al. (författare)
  • The Gln/Gln genotype of XPD codon 751 as a genetic marker for melanoma risk and Lys/Gln as an important predictor for melanoma progression : A case control study in the Swedish population
  • 2008
  • Ingår i: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 20:1, s. 179-183
  • Tidskriftsartikel (refereegranskat)abstract
    • The Xeroderma pigmentosum complementation group D (XPD) is a critical protein in the nucleotide excision repair system for DNA damage. Genetic variations in XPD exert an important effect on the capacity of DNA repair. In this study, we examined Lys751Gln polymorphism at the XPD gene in 244 melanoma patients and 251 healthy individuals (as controls) from the south-eastern region of Sweden. The associations of polymorphism with melanoma risk, as well as with melanoma features and pigment phenotypes of the melanoma patients were analysed. DNA was extracted from the mononuclear cells of venous blood of the melanoma patients and controls. XPD codon 751 was genotyped by the PCR restriction fragment length polymorphism technique. Results showed that there was no difference in the distribution of the XPD codon 751 genotypes between the melanoma patients and healthy controls. However, the Gln/Gln genotype was found to be associated with melanoma risk in the male population. Furthermore, the frequency of the Gln/Gln genotype was significantly higher in the early stages of melanomas, whereas Lys/Gln was more frequent in the later stages and in the patients with melanoma located on intermittently UV-exposed areas. No correlations between the polymorphisms and phenotypes of the patients were found. In conclusion, Gln/Gln was a useful genetic marker for melanoma risk in the males, while Lys/Gln was an important predictor for melanoma progression.
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19.
  • Knutsen Holmqvist, Annica, 1974-, et al. (författare)
  • Inflammatory infiltration, fibrosis, necrosis and mucinous content in relation to clinicopathological and molecular factors in rectal cancers with or without preoperative radiotherapy.
  • 2006
  • Ingår i: Oncology Reports. - 1021-335X .- 1791-2431. ; 16:2, s. 321-327
  • Tidskriftsartikel (refereegranskat)abstract
    • The association between inflammatory infiltration, fibrosis, necrosis and mucinous content in rectal cancers, and their relationship to preoperative radiotherapy (RT) clinicopathological and biological factors (p53, apoptosis and Cox-2) is not fully characterised. We analysed these histopathological parameters and their relationships in rectal cancer patients who participated in a clinical trial of preoperative RT. One hundred and forty-eight preoperative biopsies and 153 surgically resected tumours were examined. Of the surgical specimens, 81 had surgery alone and 72 received RT before surgery. A higher grade of inflammatory infiltration was related to favourable survival in the whole group of patients (p=0.004, for multivariate analysis p=0.01) as well as in the subgroups of patients with (p=0.04) or without RT (p=0.01). After RT, tumours showed a decreased infiltration (p=0.0003) and increased necrosis (p=0.006), strong necrosis was related to favourable survival (p=0.046). Necrosis (p=0.054) and fibrosis (p=0.06) tended to be increased in p53-negative tumours after RT. Inflammatory infiltration was a strong prognostic factor in rectal cancer patients, regardless of RT. RT tended to induce necrosis and fibrosis in p53-negative tumours.
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20.
  • Lewander, Andreas, 1973-, et al. (författare)
  • Polymorphism in the promoter region of the NFKB1 gene increases the risk of sporadic colorectal cancer in Swedish but not in Chinese populations
  • 2007
  • Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 42:11, s. 1332-1338
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. An insertion/deletion polymorphism (-94ins/delATTG) in the promoter region of the NFKB1 gene correlates to an increased risk of ulcerative colitis, a known risk factor for colorectal cancer, but this polymorphism has not been studied in colorectal cancer patients. The purpose of this study was to investigate whether this polymorphism is related to colorectal cancer risk and clinicopathological variables. Material and methods. Case samples were taken from four groups of Swedish patients: 193 unselected patients, 90 patients with ≥3 affected 1st-degree relatives, 85 patients with 2 affected 1st-degree relatives, and 109 sporadic cancer patients, and one group of 193 unselected Chinese patients. Controls included 439 Swedish and 458 Chinese healthy individuals. Genotypes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Results. The deletion increased the risk of colorectal cancer among Swedish unselected patients (OR=3.81, 95% CI: 2.17-6.69, p<0.0001 for heterozygote deletion, and OR=4.65, 95% CI: 2.43-8.89, p<0.0001 for homozygote deletion) and sporadic cancer patients (OR=7.73, 95% CI: 3.06-19.57, p<0.0001 for heterozygote deletion, and OR=6.58, 95% CI: 2.35-18.43, p<0.0001 for homozygote deletion) compared to homozygote insertion (wild-type), but not among the other Swedish or Chinese patients (p>0.05). Similar evidence was seen in age-adjusted analyses (p<0.0001). The polymorphism did not correlate to clinicopathological variables (p>0.05). Conclusions. Deletion of the polymorphism was associated with increased susceptibility to sporadic colorectal cancers in the Swedish population, but not in the Swedish patients with a family history of colorectal cancer or in Chinese patients. © 2007 Taylor & Francis.
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21.
  • Liu, H.-Y., et al. (författare)
  • Association of E1AF mRNA expression with tumor progression and matrilysin in human rectal cancer
  • 2007
  • Ingår i: Oncology. - : S. Karger AG. - 0030-2414 .- 1423-0232. ; 73:5-6, s. 384-388
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To examine E1AF mRNA expression and to determine whether it is correlated with tumor progression and matrilysin in human rectal cancer. Methods: Real-time RT-PCR was used to determine E1AF and matrilysin expression in 100 matched rectal cancers and normal tissues. Results: Among the 100 rectal cancers, 69 cases of E1AF mRNA overexpression were observed. E1AF mRNA overexpression correlated well with matrilysin. In carcinomas, E1AF mRNA overexpression correlated significantly with depth of invasion, lymph node metastasis, venous involvement and advanced pTNM stage. Conclusions: E1AF was correlated significantly with tumor progression of human rectal cancer and may be an important factor in rectal cancer progression. Copyright © 2008 S. Karger AG.
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22.
  • Loftas, Per, et al. (författare)
  • EXPRESSION OF FXYD-3 IS AN INDEPENDENT PROGNOSTIC FACTOR IN RECTAL CANCER PATIENTS WITH PREOPERATIVE RADIOTHERAPY
  • 2009
  • Ingår i: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS. - : Elsevier BV. - 0360-3016. ; 75:1, s. 137-142
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: FXYD-3 (MAT-8) is overexpressed in several types of cancers; however, its clinical relevance in rectal cancers has not been studied. Therefore, we examined FXYD-3 expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative radiotherapy (RT) to determine whether FXYD-3 was overexpressed in rectal cancers and correlated with RT, survival, and other clinicopathologic variables. Methods and Materials: The study included 140 rectal cancer patients who participated in a clinical trial of preoperative RT, 65 with and 75 without RT before surgery. FXYD-3 expression was immumohistochemically examined in distant (n = 70) and adjacent (n = 101) normal mucosa, primary tumors (n = 140), and lymph node metastasis (n = 36). Results: In the whole cohort, strong FXYD-3 expression was correlated with infiltrative tumor growth (p = 0.02). In the RT group, strong FXYD-3 expression alone (p = 0.02) or combined with phosphatase of regenerating liver was associated with an unfavorable prognosis (p = 0.02), independent of both TNM stage and tumor differentiation. In tumors with strong FXYD-3 expression, there was less tumor necrosis (p = 0.02) and a trend toward increased incidence of distant metastasis (p = 0.08) after RT. None of these effects was seen in the non-RT group. FXYD-3 expression in the primary tumors tended to he increased compared with normal mucosa regardless of RT. Conclusion: FXYD-3 expression was a prognostic factor independent of tumor stage and differentiation in patients receiving preoperative RT for rectal cancer.
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23.
  • Lööf, Jasmine, et al. (författare)
  • Significance of an exon 2 G4C14-to-A4T14 polymorphism in the p73 gene on survival in rectal cancer patients with or without preoperative radiotherapy
  • 2009
  • Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 92:2, s. 215-220
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose: An exon 2 G4C14→A4T14 polymorphism in the p73 gene was shown to be related to survival in several types of cancers, including colorectal cancer. The purpose was to investigate if this polymorphism was related to survival in rectal cancer patients with or without preoperative radiotherapy. Material and Methods: DNA extracted from tissue of 138 rectal cancer patients that received preoperative radiotherapy or had surgery alone was typed for the polymorphism by PCR using confronting two-pair primers. Results: Among patients, 69% had GC/GC genotype, 27% GC/AT and 4% AT/AT. In the radiotherapy group, patients carrying the AT (GC/AT+AT/AT) allele had stronger expression of p53 (p=0.001) and survivin protein (p=0.03) than those carrying the GC/GC genotype. Further, among patients receiving preoperative radiotherapy the GC/GC genotype tended to be related to better survival (p=0.20). Patients with GC/GC genotype, along with negative p53 and weak survivin expression showed better survival than the other patients (p=0.03), even after adjusting for TNM stage and tumor differentiation (p=0.01, RR, 7.63, 95% CI, 1.50-38.74). In the non-radiotherapy group, the polymorphism was not related to survival (p=0.74). Conclusions: Results suggest that the p73 G4C14→A4T14 polymorphism could be one factor influencing outcome of preoperative radiotherapy in rectal cancer patients.
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24.
  • Maguire, P., et al. (författare)
  • Estrogen receptor beta (ESR2) polymorphisms in familial and sporadic breast cancer
  • 2005
  • Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 94:2, s. 145-152
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen is involved in both normal mammary development and in breast carcinogenesis. A family history of disease and exposure to estrogen are major risk factors for developing breast cancer. Estrogen exerts its biological effects through binding to the estrogen receptors, estrogen receptor alpha (ESR1) and the more recently discovered estrogen receptor beta (ESR2). Genetic variation in genes involved in estrogen biosynthesis, metabolism and signal transduction have been suggested to play a role in breast cancer risk. We therefore tested the hypothesis that common genetic variants of the ESR2 gene may be associated with increased risk for breast cancer and this risk may vary between breast cancer groups. We investigated three common ESR2 polymorphisms, rs1256049 (G1082A), rs4986938 (G1730A) and rs928554 (Cx+56 A?G) for association to breast cancer risk. A total of 723 breast cancer cases and 480 controls were included in the study. Of the breast cancer cases, 323 were sporadic and 400 were familial, the familial cases were further divided into familial high-risk and familial low-risk breast cancer cases. We found no overall statistically significant association for any of the single polymorphisms studied. Haplotype analysis suggested one haplotype associated with increased risk in sporadic breast cancer patients (OR = 3.0, p = 0.03). Further analysis is needed to elucidate the role of estrogen receptor beta in breast cancer susceptibility. © Springer 2005.
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25.
  • Meng, N, et al. (författare)
  • RECK, a novel matrix metalloproteinase regulator
  • 2008
  • Ingår i: Histology and Histopathology. - : Hernandéz. - 0213-3911 .- 1699-5848. ; 23:8, s. 1003-1010
  • Forskningsöversikt (refereegranskat)abstract
    • Extracellular matrix (ECM) macromolecules are important for creating the cellular environments required during development and morphogenesis of tissues. Matrix metalloproteinases (MMPs) are a family of Zn-dependent endopeptidases that collectively are capable of cleaving virtually all ECM substrates, and play an important role in some physiological and pathological processes. MMP activity can be inhibited by some natural and artificial inhibitors. A newly found membrane-anchored regulator of MMPs, the reversion-inducing-cysteine-rich protein with kazal motifs (RECK), is downregulated when the cells undergo a process of malignant transformation, and is currently the subject of considerable research activity because of its specific structure and function. In this review, we have chosen to concentrate our efforts on the structure, function, regulation, and future prospect of RECK in order to provide a new target for prevention and treatment of tumours
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26.
  • Meng, Wen-Jian, et al. (författare)
  • Microsatellite instability did not predict individual survival in sporadic stage II and III rectal cancer patients
  • 2007
  • Ingår i: Oncology. - : S. Karger AG. - 0890-9091 .- 0030-2414 .- 1423-0232. ; 72:1-2, s. 82-88
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Tumors with high-frequency microsatellite instability (MSI-H) have unique biological behavior and the predictive role of microsatellite instability (MSI) status on survival of colorectal cancer is still debated. The prognostic significance of MSI status in sporadic stage II and III rectal cancer patients needs to be more precisely defined. So we investigated the relationship between MSI status and clinicopathological features and prognosis in these patients. Methods: DNAs from fresh-frozen paired samples of tumors and corresponding normal tissue from 128 stage II and III rectal cancer patients were analyzed for MSI by PCR amplification using markers recommended by a National Cancer Institute workshop on MSI. To assess prognostic significance, Cox proportional hazards modeling was used. Results: Twelve (9.3%) tumors in our study were MSI-H, 28 (21.9%) were low-frequency MSI (MSI-L) and 88 (68.8%) were microsatellite stable (MSS). Most of the MSI-H tumors compared with MSI-L and MSS tumors were found in female patients (p = 0.031), had mucinous histology (p = 0.023), high grade of differentiation (p = 0.002) and high level of preoperative serum carcinoembryonic antigen (p = 0.005). Rectal cancer patients with MSI-H did not show a better clinical outcome than those with MSI-L/MSS, neither in all cases (p = 0.986) nor in stage II and stage III disease analyzed separately (p = 0.705 and p = 0.664, respectively). Conclusions: Data provided here demonstrated there was high incidence of MSI-H and MSI was not a prognostic factor in sporadic stage II and III rectal cancers from the Chinese Han population included in this study. Tumor stage is more suitable than MSI status for prediction of individual survival in sporadic stage II and III rectal cancer patients. Copyright © 2007 S. Karger AG.
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27.
  • Meng, Wen-Jian, et al. (författare)
  • Novel mutations and sequence variants in exons 3-9 of human T Cell Factor-4 gene in sporadic rectal cancer patients stratified by microsatellite instability
  • 2007
  • Ingår i: World Journal of Gastroenterology. - 1007-9327 .- 2219-2840. ; 13:27, s. 3747-3751
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: To establish the role of human T Cell Factor-4 (hTCF-4) gene exons 3-9 mutation status in association with sporadic rectal cancer with microsatellite instability (MSI). Methods: Microsatellite markers were genotyped in 93 sporadic rectal cancer patients. Eleven cases were found to be high-frequency MSI (MSI-H). Sequence analysis of the coding region of the exons 3-9 of hTCF-4 gene was carried out for the 11 MSI-H cases and 10 controls (5 microsatellite stability (MSS) cases and 5 cases with normal mucosa). The sequencing and MSI identification were used. Results: Several novel mutations and variants were revealed. In exon 4, one is a 4-position continuous alteration which caused amino acid change from Q131T and S132I (391insA, 392 G > A, 393 A > G and 395delC) and another nucleotide deletion (395delC) is present in MSI-H cases (5/10 and 4/10, respectively) but completely absent in the controls. Conclusion: Novel mutations in exon 4 of hTCF-4 gene were revealed in this study, which might be of importance in the pathogenesis of sporadic rectal cancer patients with MSI-H. © 2007 WJG. All rights reserved.
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28.
  • Moparhti, Satish Babu, et al. (författare)
  • Expression of MAC30 protein is related to survival and biological variables in primary and metastatic colorectal cancers
  • 2007
  • Ingår i: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 30:1, s. 91-95
  • Tidskriftsartikel (refereegranskat)abstract
    • MAC30 is highly expressed in several types of tumors including colorectal cancers, however, its clinicopathological and biological significance in colorectal cancers is currently not known. The aim of our study was to investigate MAC30 expression in distant normal mucosa, adjacent normal mucosa, primary tumors and metastases of colorectal cancer, and to determine the relationship between MAC30 expression and clinicopathological and biological variables. MAC30 expression was immunohistochemically examined in distant normal mucosa (n = 54), adjacent normal mucosa (n = 123), primary tumors (n = 217) and lymph node metastases (n = 56) from colorectal cancer patients. MAC30 cytoplasmic expression was increased from distant normal mucosa to primary tumor and to metastasis (p < 0.0001-0.04). Furthermore, 40% primary and 37% metastatic tumors showed stronger cytoplasmic expression of MAC30 at the tumor invasive margins compared to inner tumor areas. Strong cytoplasmic expression of MAC30 in the metastasis was related to a poor prognosis (p = 0.04). MAC30 cytoplasmic expression was positively related to expression of proliferating cell nuclear antigen (p = 0.04), p53 (p = 0.04), nucleoporin 88 (p = 0.001), legumain (p = 0.004) and particularly interesting new cysteine-histidine rich protein (p = 0.004). However, MAC30 expression in the nucleus and stroma did not have any clinicopathological and biological significance (p > 0.05). In conclusion, MAC30 protein may play a role in development of colorectal cancer, and can be considered as a prognostic factor.
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29.
  • Moparthi, Satish Babu, et al. (författare)
  • pRb2/p130 protein in relation to clinicopathological and biological variables in rectal cancers with a clinical trial of preoperative radiotherapy
  • 2009
  • Ingår i: INTERNATIONAL JOURNAL OF COLORECTAL DISEASE. - : Springer Science and Business Media LLC. - 0179-1958 .- 1432-1262. ; 24:11, s. 1303-1310
  • Tidskriftsartikel (refereegranskat)abstract
    • pRb2/p130 plays a key role in cell proliferation and is a considerable progress about expression patterns of pRb2/p130 in number of malignancies. However, pRb2/p130 expression and its significance in rectal cancer remain unknown. The purpose of the present study was to investigate pRb2/p130 protein patterns and their correlations with clinicopathological and biological factors in rectal cancer patients with or without preoperative radiotherapy (RT). pRb2/p130 protein was examined by immunohistochemistry in 130 primary tumors, along with the corresponding 61 distant normal mucosa specimens, 85 adjacent normal mucosa specimens, 34 lymph node metastases, and 93 primary tumor biopsies from rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. The pRb2/p130 protein was mainly localized in the cytoplasm of tumor cells. In nonradiated cases, the lack of pRb2/p130 was related to advanced tumor-node-metastases stage, poorer differentiation, weak fibrosis, less inflammatory infiltration, higher Ki-67, and positive Cox-2 expression (p andlt; 0.05). In radiated cases, the lack of pRb2/p130 was related to nonstaining of Cox-2 and survivin (p andlt; 0.05). pRb2/p130 protein in primary tumors tended to be increased after RT (27% vs 16%, p = 0.07). pRb2/p130 was mainly localized in the cytoplasm rather than in the nucleus in rectal cancer. After RT, pRb2/p130 protein seems to be increased in primary tumors, and further the relationship of the pRb2/p130 with the clinicopathological and biological variables changed compared to the nonradiated cases. However, we did not find that the pRb2/p130 was directly related to RT, tumor recurrence, and patients survival.
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30.
  • Murthy, RV, et al. (författare)
  • Legumain expression in relation to clinicopathologic and biological variables in colorectal cancer
  • 2005
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 11:6, s. 2293-2299
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Legumain, a novel asparaginyl endopeptidase, has been observed to be highly expressed in several types of tumors including colorectal cancer. However, there is no study examining the relationship of legumain expression to clinocopatbologic and biological variables in colorectal cancers. Experimental Design: We investigated legumain expression in 164 primary colorectal cancers, 34 corresponding distant normal mucosa samples, 89 adjacent normal mucosa samples, and 33 lymph node metastases using immunohistochemistry. We also did Western blotting analysis on three additional colorectal cancers and three colonic cell lines. Results: Legumain expression was increased in primary tumors compared with distant or adjacent normal mucosa (P < 0.05), but there was no significant change between primary tumors and metastases (P > 0.05). Legumain expression was positively related to poorer differentiation/ mucinous carcinoma (P = 0.04), higher degree of necrosis (P = 0.03) and apoptosis (P < 0.0001), positive proliferating cell nuclear antigen (P < 0.0001) and p53 expression (P = 0.049), and had a positive tendency towards stromelysin 3 (P = 0.058) and PINCH positivity (P = 0.05). The patients with tumors that showed both weak and lower percentage of the legumain expression, either in tumor (P = 0.01) or in stroma (P = 0.04), had a better prognosis. Conclusions: The legumain expression may be involved in colorectal cancer development and have a prognostic value in the patients. ©2005 American Association for Cancer Research.
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31.
  • Pachkoria, Ketevan, et al. (författare)
  • Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy
  • 2005
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 63:3, s. 739-744
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Radiotherapy has reduced local recurrence of rectal cancers, but the result is not satisfactory. Further biologic factors are needed to identify patients for more effective radiotherapy. Our aims were to investigate the relationship of cyclooxygenase-2 (Cox-2) expression to radiotherapy, and clinicopathologic/biologic variables in rectal cancers with or without radiotherapy. Methods and Materials: Cox-2 expression was immunohistochemically examined in distal normal mucosa (n = 28), in adjacent normal mucosa (n = 107), in primary cancer (n = 138), lymph node metastasis (n = 30), and biopsy (n = 85). The patients participated in a rectal cancer trial of preoperative radiotherapy. Results: Cox-2 expression was increased in primary tumor compared with normal mucosa (p < 0.0001), but there was no significant change between primary tumor and metastasis. Cox-2 positivity was or tended to be related to more p53 and Ki-67 expression, and less apoptosis (p ≤ 0.05). In Cox-2-negative cases of either biopsy (p = 0.01) or surgical samples (p = 0.02), radiotherapy was related to less frequency of local recurrence, but this was not the case in Cox-2-positive cases. Conclusion: Cox-2 expression seemed to be an early event involved in rectal cancer development. Radiotherapy might reduce a rate of local recurrence in the patients with Cox-2 weakly stained tumors, but not in those with Cox-2 strongly stained tumors. © 2005 Elsevier Inc.
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32.
  • Pfeifer, Daniella, et al. (författare)
  • Expression of the p73 protein in rectal cancers with or without preoperative radiotherapy
  • 2006
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier. - 0360-3016 .- 1879-355X. ; 65:4, s. 1143-1148
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To investigate p73 expression in normal mucosa, primary tumor, and metastasis in relation to radiotherapy (RT) response and clinicopathologic/biologic variables in rectal cancers. Methods and Materials: p73 was immunohistochemically examined on biopsies (unirradiated, n = 102), distant (from the large bowel, n = 82), and adjacent (adjacent to primary tumor, n = 89) normal mucosa samples, primary tumors (n = 131), and lymph node metastasis (n = 32) from rectal cancer patients participating in a clinical trial of preoperative RT. Seventy-four patients received surgery alone and 57 received additional RT. Results: Cytoplasmic p73 was increased in the primary tumor compared with the distant or adjacent mucosa (p ≤ 0.0001). Nuclear (p = 0.02) and cytoplasmic (p = 0.003) p73 was higher in irradiated distant mucosa samples than in unirradiated ones, and nuclear p73 tended to be increased in irradiated primary tumors compared with unirradiated ones (p = 0.06). p73 was positively related to cyclooxygenase-2 expression in irradiated tumors (p = 0.03). p73-negative tumors tended to have a lower local recurrence after RT compared with unirradiated cases (p = 0.06). Conclusions: Normal epithelial cells seem more sensitive to RT than tumor cells regarding p73 expression. Patients with p73-negative rectal tumors may have a lower risk of local recurrence after RT.
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33.
  • Pfeifer, Daniella (författare)
  • p73 in colorectal cancer
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Colorectal cancer (CRC) is the third most common cancer in the world, with about 5000 new cases in Sweden every year. CRC is caused by mutation (inherited or acquired) in genes, by gene variants and changed expression of proteins. The primary way to achieve a curative result for CRC is to remove the tumor by surgery. To reduce risk of recurrence chemo- or radiotherapy are given as a complement to surgery. p73 is a structural and functional homologue of tumor suppressor p53. However, p73 is rarely mutated in tumors, but rather overexpressed as compared to normal tissue. There are two main isoforms of p73, the transactivation capable TAp73 and the truncated ΔNp73, which are involved in an autoregulatory loop with TAp73 and p53.The aim of this study was to investigate the role of p73 and related proteins in the development and treatment of CRC. A G4C14-to-A4T14 polymorphism of p73 was studied in CRC patients and healthy controls (Paper I), and rectal cancer patients who were randomized to treatment with either surgery alone or preoperative radiotherapy and surgery (Paper II). The AT/AT genotype of the p73 polymorphism may increase risk of CRC development and CRC patients with the AT allele had a better prognosis. When dividing the cases into colon and rectal cancer it was seen that in colon cancer the AT allele tended to be more favorable for overall survival, while in rectal cancer the GC allele seemed to be more favorable. Rectal cancer patients, with a combination of GC/GC genotype, wild type p53 and weak survivin expression survived longer after preoperative radiotherapy. This was not observed in the patients only receiving surgery. The protein expression of p73 was further studied in the rectal cancer patients randomized to treatment with either surgery alone or preoperative radiotherapy and surgery (Paper III). p73 was expressed higher in tumor tissue than in normal mucosa. Patients with p73 negative tumors had a lower risk of local recurrence after radiotherapy, as opposed to patients that had p73 positive tumors or patients with p73 negative tumors that did not receive radiotherapy. Effects of γ-radiation was further studied in colon cancer cell lines KM12C, KM12SM and KM12L4a regarding cell cycle, survival fraction (clonogenicity), apoptosis and protein expression patterns of mutated p53, TAp73, ΔNp73, survivin and PRL-3 (Paper IV). KM12C displayed low survival fraction, low apoptosis, no cell cycle arrest and an upregulation of the antiapoptotic ΔNp73 after irradiation. KM12L4a showed a high survival fraction, but high apoptosis, arresting of the cell cycle and upregulation of the radio-resistance factor survivin. The effects of overexpression and knockdown of survivin on TAp73, ΔNp73 and p53 expression in colon cancer cell lines HCT-116p53+/+ and HCT-116p53-/- with and without γ-radiation were studied (Paper V). Overexpression of survivin decreased wild type p53, whilst downregulation of survivin lead to a simultaneous downregulation of TAp73 and ΔNp73, mRNA and protein, both with and without γ- radiation. Knockdown of survivin also demonstrated an increase in apoptosis.In conclusion, we showed that the G4C14-to-A4T14 polymorphism of p73 and p73 protein expression may be involved in CRC development, radiotherapy response and survival. We further showed that TAp73, ΔNp73 and p53 were regulated by survivin in colon cancer cells.
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34.
  • Pfeifer, Daniella, et al. (författare)
  • Polymorphism of the p73 gene in relation to colorectal cancer risk and survival
  • 2005
  • Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 26:1, s. 103-107
  • Tidskriftsartikel (refereegranskat)abstract
    • The results regarding a GC/AT polymorphism in the p73 gene in relation to cancer risk are inconsistent, and the significance of loss of heterozygosity (LOH) of the gene is unclear. In the present study, we investigated whether this polymorphism was related to the risk of colorectal cancer, and whether there were relationships between the polymorphism and LOH, protein expression or clinicopathological variables. 179 patients with colorectal cancer and 260 healthy controls were genotyped for the polymorphism by PCR-restriction fragment length polymorphism (RFLP). Fifty informative cases were examined for LOH in tumours. Immunohistochemistry was performed on distant (n = 42) and adjacent normal mucosa (n = 33), primary tumour (n = 6 9) and lymph node metastasis (n = 12). The frequencies of the genotypes were 63% for wild-type (GC/GC), 30% for heterozygotes (GC/AT) and 7% for variants (AT/AT) in patients, and 62, 36 and 2% in controls, respectively. The frequencies of the genotypes in the patients and controls were significantly different (P = 0.02). The patients carrying the AT allele had a better prognosis than those with the GC/GC genotype (OR = 0.42, 95% CI = 1.15-5.02, P = 0.02). No LOH was observed at the p73 locus. Expression of p73 protein was increased from normal mucosa to primary tumours (P = 0.02), but was not significantly changed between primary tumours and metastases (P = 1.0). In conclusion, the AT/AT homozygotes may have a greater risk of developing colorectal cancer, while the patients who carried the AT allele had a better prognosis.
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35.
  • Pfeifer, Daniella, et al. (författare)
  • Protein expression following gamma-irradiation relevant to growth arrest and apoptosis in colon cancer cells with mutant p53
  • 2009
  • Ingår i: Journal of Cancer Research and Clinical Oncology. - : Springer Science and Business Media LLC. - 0171-5216 .- 1432-1335. ; 135:11, s. 1583-1592
  • Tidskriftsartikel (refereegranskat)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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36.
  • Schael, S, et al. (författare)
  • Precision electroweak measurements on the Z resonance
  • 2006
  • Ingår i: Physics Reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 427:5-6, s. 257-454
  • Forskningsöversikt (refereegranskat)abstract
    • We report on the final electroweak measurements performed with data taken at the Z resonance by the experiments operating at the electron-positron colliders SLC and LEP. The data consist of 17 million Z decays accumulated by the ALEPH, DELPHI, L3 and OPAL experiments at LEP, and 600 thousand Z decays by the SLID experiment using a polarised beam at SLC. The measurements include cross-sections, forward-backward asymmetries and polarised asymmetries. The mass and width of the Z boson, m(Z) and Gamma(Z), and its couplings to fermions, for example the p parameter and the effective electroweak mixing angle for leptons, are precisely measured: m(Z) = 91.1875 +/- 0.0021 GeV, Gamma(Z) = 2.4952 +/- 0.0023 GeV, rho(l) = 1.0050 +/- 0.0010, sin(2)theta(eff)(lept) = 0.23153 +/- 0.00016. The number of light neutrino species is determined to be 2.9840 +/- 0.0082, in agreement with the three observed generations of fundamental fermions. The results are compared to the predictions of the Standard Model (SM). At the Z-pole, electroweak radiative corrections beyond the running of the QED and QCD coupling constants are observed with a significance of five standard deviations, and in agreement with the Standard Model. Of the many Z-pole measurements, the forward-backward asymmetry in b-quark production shows the largest difference with respect to its SM expectation, at the level of 2.8 standard deviations. Through radiative corrections evaluated in the framework of the Standard Model, the Z-pole data are also used to predict the mass of the top quark, m(t) = 173(+10)(+13) GeV, and the mass of the W boson, m(W) = 80.363 +/- 0.032 GeV. These indirect constraints are compared to the direct measurements, providing a stringent test of the SM. Using in addition the direct measurements of m(t) and m(W), the mass of the as yet unobserved SM Higgs boson is predicted with a relative uncertainty of about 50% and found to be less than 285 GeV at 95% confidence level. (c) 2006 Elsevier B.V. All rights reserved.
  •  
37.
  • Shabo, Ivan, et al. (författare)
  • Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time.
  • 2009
  • Ingår i: International journal of cancer. Journal international du cancer. - : Wiley. - 1097-0215. ; 125:8, s. 1826-1831
  • Tidskriftsartikel (refereegranskat)abstract
    • Expression of the macrophage antigen CD163 in breast cancer cells is recently shown to be related to early distant recurrence and shortened survival. In this study, 163 patients with rectal cancer, included in the Swedish rectal cancer trial and followed up for a median of 71 months, were examined for the expression of CD163 in the primary tumors. The cancer cells expressed CD163 in the primary tumors in 23% (n = 32) of the patients. In pretreatment biopsies from 101 patients, 10 had CD163-positive cancers and these patients had earlier local recurrence (p < 0.044) and reduced survival time (p < 0.045) compared with those with CD163-negative tumors. When studying surgical specimens from 61 patients randomized to preoperative irradiation (5 x 5 Gy delivered in 1 week), it was found that 31% were CD163 positive whereas the corresponding figure was only 17% for 78 patients who were nonirradiated (p < 0.044), which tentatively may be consistent with X-rays inducing fusion. In CD163-positive tumors there was a reduced apoptotic activity as measured with the Termina deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) technique (p = 0.018). There tended also to be an increased proliferation activity measured as an expression of Ki-67 non significant (NS). It is concluded that primary rectal cancers may express CD-163, and this phenotypic macrophage trait is related to early local recurrence, shorter survival time and reduced apoptosis. Furthermore, the expression of CD163 is more common after irradiation.
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38.
  • Sun, Xiao-Feng, 1959- (författare)
  • Clinicopathological and biological features of DNA tetraploid colorectal cancers
  • 2006
  • Ingår i: Cancer Journal. - : Ovid Technologies (Wolters Kluwer Health). - 0765-7846 .- 1292-8658 .- 1528-9117. ; 12:6, s. 501-506
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Most studies of colorectal cancers focus on a comparison of DNA diploid to non-diploid tumors consisting of tetraploid and aneuploid tumors. Tetraploid tumors alone have not been well studied. In the present study, clinicopathological and biological features of tetraploid colorectal cancers in contrast to those of diploid and aneuploid ones were investigated. PATIENTS AND METHODS: DNA ploidy in 278 primary colorectal adenocarcinomas was determined by flow cytometry. RESULTS: Among 278 cases, 8% of the cases were tetraploidy, 44% were aneuploidy, and 48% were diploidy. Compared to diploid tumors, tetraploid tumors were more frequent in advanced stage, high index of S-phase fraction and apoptosis, higher expression of Cox-2, c-erbB-2 and heat shock protein, but had decreased inflammatory infiltration (P < 0.05). Compared to aneuploid tumors, tetraploid tumors had a high frequency of microsatellite instability, high expression of Cox-2 and heat shock protein (P < 0.05). Unlike tetraploid tumors, aneuploid tumors had increased p53 expression but did not have microsatellite instability (P < 0.05). Tetraploidy and aneploidy predicted a worse prognosis in the subgroups of stages A-C, proximal colon, p53 negative expression and higher S-phase fraction (P < 0.05). CONCLUSIONS: DNA tetraploid tumors seem, to some extent, to exhibit distinct characteristics of clinicopathology and biology compared with aneuploid or diploid colorectal cancers. Copyright © 2006 Jones and Bartlett Publishers, Inc.
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39.
  • Sun, Xiao-Feng, 1959-, et al. (författare)
  • Clinicopathological significance of stromal variables : Angiogenesis, lymphangiogenesis, inflammatory infiltration, MMP and PINCH in colorectal carcinomas
  • 2006
  • Ingår i: Molecular Cancer. - : Springer Science and Business Media LLC. - 1476-4598. ; 5
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer research has mainly focused on alterations of genes and proteins in cancer cells themselves that result in either gain-of-function in oncogenes or loss-of-function in tumour-suppressor genes. However, stromal variables within or around tumours, including blood and lymph vessels, stromal cells and various proteins, have also important impacts on tumour development and progression. It has been shown that disruption of stromal-epithelial interactions influences cellular proliferation, differentiation, death, motility, genomic integrity, angiogenesis, and other phenotypes in various tissues. Moreover, stromal variables are also critical to therapy in cancer patients. In this review, we mainly focus on the clinicopathological significance of stromal variables including angiogenesis, lymphangiogenesis, inflammatory infiltration, matrix metalloproteinase (MMP), and the particularly interesting new cysteine-histidine rich protein (PINCH) in colorectal cancer (CRC). © 2006 Sun and Zhang, licensee BioMed Central Ltd.
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40.
  • Sun, Xiao-Feng, 1959-, et al. (författare)
  • NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases
  • 2007
  • Ingår i: Histology and Histopathology. - 0213-3911 .- 1699-5848. ; 22:10-12, s. 1387-1398
  • Tidskriftsartikel (refereegranskat)abstract
    • Nuclear factor-κB (NF-κB) is responsible for the expression by regulating many genes for immune response, cell adhesion, differentiation, proliferation, angiogenesis and apoptosis. The function of NF-κB is inhibited by binding to NF-κB inhibitor (IκB), and imbalance of NF-κB and IκB has been associated with development of many diseases, including tumours. In this review, we focus on polymorphisms of the NFKB and NFKBI genes in relation to development of common inflammatory diseases including ulcerative colitis (UC), Crohn's disease (CD), rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, giant cell arthritis, type 1 diabetes, multiple sclerosis, celiac disease, and Parkinson's disease, as well as susceptibility of several cancers, such as oral squamous cell carcinoma, colorectal cancer (CRC), hepatocellular carcinoma, breast cancer and myeloma.
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41.
  • Sun, Xiao-Feng, 1959-, et al. (författare)
  • Polymorphisms in sulfotransferase 1A1 and glutathione S-transferase P1 genes in relation to colorectal cancer risk and patients' survival
  • 2005
  • Ingår i: World Journal of Gastroenterology. - 1007-9327 .- 2219-2840. ; 11:43, s. 6875-6879
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: To examine whether polymorphisms in SULT1A1 and GSTP1 genes contribute to colorectal cancer development and whether they are associated with clinicopathological variables are not well identified. Methods: We examined the genotypes of 125 colorectal cancer patients and 666 healthy controls in a Swedish population by using PCR restriction fragment length polymorphism (RFLP). Results: SULT1A1 *2/*2 genotype (OR = 2.49, 95%CI = 1.48-4.19, P = 0.0002) and *2 allele (OR = 1.56, 95%CI = 1.16-2.10, P = 0.002) had an effect on colorectal cancer susceptibility, while GSTP1 genotype was without effect. However, GSTP1 G-type predicted a worse prognosis in the patients independently of gender, age, Dukes' stage, growth pattern, and differentiation (P = 0.03). Conclusion: Polymorphism in SULT1A1 may predispose to colorectal cancer and GSTP1 may be a biological indicator of prognosis in the patients. © 2005 The WJG Press and Elsevier Inc. All rights reserved.
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42.
  • Tian, Chao, et al. (författare)
  • Overexpression of connective tissue growth factor WISP-1 in Chinese primary rectal cancer patients
  • 2007
  • Ingår i: World Journal of Gastroenterology. - 1007-9327 .- 2219-2840. ; 13:28, s. 3878-3882
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: To clarify the expression change of Wnt-induced secreted protein-1 (WISP-1) in human rectal cancer and to determine whether it is correlated with invasion and metastasis of human rectal cancer. Methods: Eighty-six paired samples of rectal cancer and surgically resected distant normal rectal tissue were collected and allocated into cancer group and control group respectively. WISP-1 mRNA was detected by relative quantitative real-time RT-PCR and WISP-1 protein was examined by immunohistochemical staining. Results: WISP-1 gene overexpression was found in 65% (56/86) primary rectal cancers, 2-30 times that of the level in normal matched rectal tissues (P = 0.001). The mRNA expression level was correlated with Duke's staging, histological differentiation grade and lymph node status. The WISP-1 protein expression was in accordance with mRNA expression level. The positive degree of immunohistochemical staining in the cancer group (1.40 ± 0.35) was different from that in control group (1.04 ± 0.08, P < 0.001). Moreover, in cancer group the positive staining degree in high-level mRNA cancers (1.46 ± 0.37, n = 56) was higher than that in low-level mRNA (1.28 ± 0.28, n = 30, P = 0.018). Conclusion: Aberrant levels of WISP-1 expression may play a role in rectal tumorigenesis. WISP-1 may be used as a specific clinical diagnosis and prognosis marker in rectal cancer. © 2007 WJG. All rights reserved.
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43.
  • Wallin, Åsa, 1976-, et al. (författare)
  • Anticancer effect of SN-38 on colon cancer cell lines with different metastatic potential
  • 2008
  • Ingår i: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 19:6, s. 1493-1498
  • Tidskriftsartikel (refereegranskat)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.
  •  
44.
  • Wallin, Åsa, 1976- (författare)
  • Molecular Studies of Irradiation and SN-38 on Colorectal Cancer
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Colorectal cancer (CRC) is one of most common cancer diseases worldwide. In Swedenapproximately 5,000 new cases of CRC are generated each year, which makes it the thirdmost common cancer disease among both men and women. The past decades ofimproved treatment strategies have considerably increased the five-year survival for CRCpatients. However more could be achieved in this area, in particular for metastatic CRC,which is the cause of most CRC-related deaths. Therefore it is important to study thebiological response to certain treatments induced in CRC to find valuable predictiveand/or prognostic factors to select patients for better suited treatments.The aim of this thesis was to gain insight into the molecular changes that occurfollowing irradiation or treatment with SN-38 in rectal cancer patients or colon cancercell lines by studying the RNA expression, protein expression, DNA cell cycledistribution and apoptotic response. The expression of phosphatase of regenerating liver(PRL) proteins was investigated in rectal cancers from 125 patients included in arandomized clinical trial of preoperative radiotherapy (RT). Increased expression of PRLswas seen at the invasive margin of primary and metastatic cancers compared with theinner area of the tumors. Moreover, strong PRL staining at the invasive margin correlatedto distant recurrence and worse survival of patients in the RT group but not in non-RTgroup (Paper I). Radiosensitivity was studied by treating KM12C, KM12SM andKM12L4a colon cancer cell lines with radiation. KM12C is of low metastatic naturecompared with the highly metastatic KM12SM and KM12L4a. Upregulation of ΔNp73and PRL-3 might contribute to the radioresistant phenotype in KM12C. In contrast,KM12L4a shows a high frequency of apoptosis and lack of upregulation of ΔNp73, PRL-3 and survivin, which might explain its radiosensitive phenotype (Paper II). KM12C,KM12SM and KM12L4a were treated with SN-38 which inhibits topoisomerase 1 (topo-1). The results show that SN-38 induces G2/S arrest and possess the capacity to triggerapoptosis in the three cell lines (Paper III). To further elucidate SN-38 effect on these celllines, the gene expression profile following SN-38 treatment was studied. Oligonucleotidearrays consisting of ~27,000 spots were hybridized with sample and reference cDNA.Both unsupervised and supervised hierarchical clustering analysis, and functional analysiswere performed. Supervised hierarchical clustering gives a strong signal of 1453discriminated genes, the vast majority being upregulated. Both upregulated anddownregulated genes point toward a favorable impact of SN-38 regarding the apoptoticpathways. For example RhoB and Bax are upregulated together with downregulation ofKras and survivin, which promotes apoptosis (Paper IV).In conclusion, PRLs may be valuable biomarkers for RT resistance, predicting apoor prognosis in rectal cancer patients. Targeting radio-resistance factors, such asΔNp73 and survivin may contribute to an increased sensitivity to RT. SN-38 affects cellproliferation and apoptosis.
  •  
45.
  • Wallin, Åsa R., 1976-, et al. (författare)
  • Expression of PRL proteins at invasive margin of rectal cancers in relation to preoperative radiotherapy
  • 2006
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 65:2, s. 452-458
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: PRL-3 (phosphatase of regenerating liver) is involved in metastasis of colorectal cancer; however, its therapeutic implication in cancer patients has not been studied. We investigated the relationships of PRL expression to radiotherapy (RT) in rectal cancer patients.Methods and Materials: Phosphatase of regenerating liver expression was immunohistochemically examined in distant (n = 36) and adjacent (n = 82) normal mucosa, primary tumor (n = 125), biopsy specimens (n = 96), and lymph node metastasis (n = 30) from rectal cancer patients participating in a clinical trial of preoperative RT.Results: Phosphatase of regenerating liver expression was increased from the distant to adjacent mucosa and to the primary tumor (p < 0.05). PRL was highly expressed at the invasive margin in 28% of the primary tumors and 26% of the metastases. In the RT group, strong PRL expression at the invasive margin was related to distant recurrence (p = 0.006) and poor survival (p = 0.01), but not in the non-RT group. The survival significance remained even after adjusting for Dukes’ stage and differentiation (p = 0.02). Additional multivariate analyses showed that the correlation with prognostic significance of PRL differed between the RT and non-RT groups (p = 0.01).Conclusion: Phosphatase of regenerating liver expression (rather than PRL-3 alone) at the invasive margin predicted resistance to RT and unfavorable survival in rectal cancer patients with preoperative RT.
  •  
46.
  • Wang, Chao-Jie, et al. (författare)
  • Clinicopathological significance of microRNA-31, -143 and -145 expression in colorectal cancer
  • 2009
  • Ingår i: Disease Markers. - 0278-0240 .- 1875-8630. ; 26:1, s. 27-34
  • Tidskriftsartikel (refereegranskat)abstract
    • We are just beginning to understand how microRNAs (miRNAs) are involved in tumor-related processes in humans. Applying real-time RT-PCR, we investigated the miR-31, miR-143 and miR-145 expression in 98 primary CRC specimens, along with the corresponding normal mucosa specimens, and analyze the relationship of their expression with clinicopathological features. Our results showed the miR-31 expression was up-regulated in CRC compared to normal mucosa (p = 0.001). Furthermore, miR-31 expression was positively related to advanced TNM stage (p = 0.026) and deeper invasion of tumors (p = 0.024). MiR-145 was down-regulated in both colon (p = 0.001) and rectal (p = 0.012) cancer. MiR-143 was only down-regulated in colon cancer (p = 0.023) but not in rectal cancer (p = 0.351). There was no relationship of miR-143 and miR-145 expression with other clinicopathological features (p > 0.05), except that the miR-145 expression was related to cancer site (p = 0.03). In conclusion, the miR-31 overexpression may be involved in the development and progression of CRC. The miR-143 and miR-145 may play a certain role in the development of colon and/or rectal cancers but not in progression of the disease.
  •  
47.
  • Wang, Chao-Jie, et al. (författare)
  • Survivin Expression Quantified by Image Pro-plus Compared With Visual Assessment
  • 2009
  • Ingår i: APPLIED IMMUNOHISTOCHEMISTRY and MOLECULAR MORPHOLOGY. - : Lippincott Williams & Wilkins. - 1062-3345 .- 1541-2016 .- 1533-4058. ; 17:6, s. 530-535
  • Tidskriftsartikel (refereegranskat)abstract
    • Over the past decades, immunohistochemistry has gained significance and already taken a crucial position in diagnosis of diseases and prognosis of patients. However, manual interpretation of immunohistochemistry and reproducibility of the scoring systems can be highly Subjective. In the article, the immunohistochemical staining of survivin in 98 rectal cancers was analyzed by using Image Pro-Plus (IPP) [3 parameters: density mean, area sum, and integrated optical density (IOD)] and the results were compared with visual assessment (2 parameters: intensity and percentage). The correlations between the 2 methods were examined, significant correlations were observed between density mean and staining intensity (Spearman correlation coefficient, r(s) = 0.806, P andlt; 0.001) IOD and staining intensity (r(s) = 0.9147 P andlt; 0.001) area sum and staining percentage (r(s) = 0.883, P andlt; 0.001), IOD and staining percentage (r(s) = 0.884, P andlt; 0.001). There was no significant difference between survivin expression and clinicopathologic variables (P andgt; 0.05) by visual assessment. However, by IPP analysis, both the density mean and IOD were higher in better-differentiated cancers than in worse differentiated ones (P = 0.02 and 0.03). There was a substantial agreement between the 2 methods. Density mean and IOD of IPP were representative parameters to assess the immunostaining quantification, and increased sensitivity in scoring and provided a more reliable and reproducible analysis of protein expression, especially, more information of the protein expression in relation to clinicopathologic variables can be provided by IPP analysis.
  •  
48.
  • Wang, Mo-Jin, et al. (författare)
  • The Ile646Val (2073A > G) Polymorphism in the Kinase-Binding Domain of A-Kinase Anchoring Protein 10 and the Risk of Colorectal Cancer
  • 2009
  • Ingår i: ONCOLOGY. - : S. Karger AG. - 0030-2414 .- 1423-0232. ; 76:3, s. 199-204
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The purpose of this study is to investigate whether the Ile646Val (2073A>G) polymorphism in the kinase-binding domain of A-kinase anchoring protein 10 (AKAP10) is related to the risk of colorectal cancer (CRC), clinicopathological variables and the environmental factors for the development of CRC. Methods: Applying TaqMan allelic discrimination, we investigated AKAP10 Ile646Val (2073A>G) polymorphism in 288 Chinese CRC patients and 281 healthy controls. Results: Logistic regression analysis revealed a significant association of AKAP10 Ile646Val (2073A>G) polymorphism with increased CRC risk (adjusted OR = 1.44, 95% CI 1.01-2.07, p = 0.02). Stratification analysis showed that the increased risk associated with the variant genotypes (GG+AG) was more evident in male subjects (adjusted OR = 1.48, 95% CI 0.94-2.34, p = 0.03). Compared with the AA genotype, the adjusted OR for the variant genotypes was 1.81 (95% CI 1.08 - 3.05, p = 0.01) among young subjects (age ! 57 years). Among individuals who did not smoke or who smoked lightly, there was a significantly increased risk with the variant genotypes (adjusted OR = 1.66, 95% CI 1.08 - 2.56, p = 0.02). We did not observe a relationship between the AKAP10 polymorphism and other clinicopathological and environmental factors. Conclusions: Our data suggested that the AKAP10 2073A>G variation is associated with an increased risk of CRC in the Chinese population.
  •  
49.
  • Wang, Ming-Wei, et al. (författare)
  • Expression of PINCH protein in gliomas and its clinicopathological significance
  • 2007
  • Ingår i: Oncology. - : S. Karger AG. - 0890-9091 .- 0030-2414 .- 1423-0232. ; 72:5-6, s. 343-346
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Particularly interesting new cysteine-histidine-rich protein (PINCH), as a LIM domain adapter protein, functions in the integrin and growth factor signal transduction pathway, and is upregulated in tumor-associated stroma in several types of cancers. However, no study of PINCH has been carried out in gliomas, therefore we examined PINCH expression in gliomas and its clinicopathological significance. Methods: PINCH expression was immunohistochemically examined in 82 gliomas, along with 26 matched adjacent normal brain samples and 10 recurred gliomas. Results: PINCH was strongly expressed in the primary (35%, p = 0.0001) or recurred tumors (40%, p = 0.004) and weak in normal brain tissue. PINCH expression was significantly increased in high-grade gliomas (55 vs. 24%, high- vs. low-grade gliomas, p = 0.004). There was no association of PINCH expression with gender, age, tumor number, size, histological type and tumor location (p > 0.05). Conclusions: PINCH expression may be involved in glioma development and differentiation. Copyright © 2008 S. Karger AG.
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50.
  • Wang, Ming-Wei, et al. (författare)
  • FXYD3 Expression in Gliomas and its Clinicopathological Significance
  • 2009
  • Ingår i: Oncology Research. - : Computers, Materials and Continua (Tech Science Press). - 0965-0407 .- 1555-3906. ; 18:4, s. 133-139
  • Tidskriftsartikel (refereegranskat)abstract
    • FXYD3, interacting with Na+/K+-ATPase, is considered a cell surface regulator modulating the function of ion pumps and ion channels. The FXYD3 gene was originally cloned from murine mammary tumors and then from human breast tumors. However, no study of FXYD3 has been carried out in gliomas; therefore, we examined FXYD3 expression in gliomas and its clinicopathological significance. FXYD3 expression was immunohistochemically examined in 71 primary gliomas, along with 37 matched adjacent normal brain samples and 8 recurred gliomas. The frequency of strong FXYD3 expression was higher in the primary tumors in either unmatched (p = 0.046) or matched cases (p = 0.02), compared to normal brain tissue. FXYD3 expression was significantly more increased in females than males (p = 0.01), and in multiple site gliomas than single sites (p = 0.02). There was no difference of FXYD3 expression regarding age, tumor location, size, histological type, and tumor grade (p greater than 0.05). The results suggest that FXYD3 expression may be involved in glioma development, especially in multiple gliomas and female patients.
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