| 1. |
- Edlund, Karolina, et al.
(författare)
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CD99 is a novel prognostic stromal marker in non-small cell lung cancer
- 2012
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 131:10, s. 2264-2273
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Tidskriftsartikel (refereegranskat)abstract
- The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumourstroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC and VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p = 0.037) and multivariate (p = 0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p = 0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer-associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.
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| 2. |
- Agholme, Fredrik, et al.
(författare)
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Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats
- 2011
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Ingår i: Acta Orthopaedica. - : Taylor and Francis. - 1745-3674 .- 1745-3682. ; 82:5, s. 628-632
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Sclerostin is produced by osteocytes and is an inhibitor of bone formation. Thus, inhibition of sclerostin by a monoclonal antibody increases bone formation and improves fracture repair. Sclerostin expression is upregulated in unloaded bone and is downregulated by loading. We wanted to determine whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model.Methods: 10-week-old male rats (n = 48) were divided into 4 groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A (Botox). 3 days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive Botox injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma.Results: Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force.Interpretation: Scl-Ab increases bone formation and screwfixation to a similar degree in loaded and unloaded bone.
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| 3. |
- Agholme, Fredrik, et al.
(författare)
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Sclerostin Antibody Treatment Enhances Metaphyseal Bone Healing in Rats
- 2010
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Ingår i: JOURNAL OF BONE AND MINERAL RESEARCH. - : American Society for Bone and Mineral Research. - 0884-0431. ; 25:11, s. 2412-2418
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Tidskriftsartikel (refereegranskat)abstract
- Sclerostin is the product of the SOST gene Loss of-function mutations in the SOST gene result in a high bone-mass phenotype demonstrating that sclerostin is a negative regulator of bone mass Primarily expressed by osteocytes in bone sclerostin is reported to bind the LRP5/6 receptor thereby antagonizing canonical Wnt signaling and negatively regulating bone formation We therefore investigated whether systemic administration of a sclerostin neutralizing antibody would increase the regeneration of traumatized metaphyseal bone in rats Young male rats had a screw inserted in the proximal tibia and were divided into six groups given 25 mg/kg of sclerostin antibody or control twice a week subcutaneously for 2 or 4 weeks In four groups, the screws were tested for pull out strength At the time of euthanasia a similar screw also was inserted in the contralateral tibia and pull-out tested immediately Sclerostin antibody significantly increased the pull out force by almost 50% compared with controls after 2 and 4 weeks Also the screws inserted at the time of euthanasia showed increased pull out force Micro-computed tomography (mu CT) of the remaining two groups showed that the antibody led to a 30% increase in bone volume fraction in a region surrounding the screw There also was a general increase in trabecular thickness in cancellous bone Thus as measured by the amount of bone and its mechanical resistance the sclerostin antibody increased bone formation during metaphyseal repair but also in untraumatized bone
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| 4. |
- Agholme, Fredrik, et al.
(författare)
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The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions
- 2011
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Ingår i: BONE. - : Elsevier Science B.V., Amsterdam.. - 8756-3282. ; 48:5, s. 988-996
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Tidskriftsartikel (refereegranskat)abstract
- The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unclear how it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, mu CT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botulinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233%. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.
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| 5. |
- Anderud, Jonas, et al.
(författare)
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Guided bone augmentation using a ceramic space-maintaining device
- 2014
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Ingår i: Oral surgery, oral medicine, oral pathology and oral radiology. - : Elsevier. - 2212-4403 .- 2212-4411. ; 118:5, s. 532-538
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The purpose of this study was to evaluate 3-dimensionally whether vertical bone augmentation can be achieved using a hollow hydroxyapatite space-maintaining device in a rabbit calvarial model. Furthermore, different inner surface topographies, different permeabilities, and different porosities of the ceramic were tested to determine the optimal conditions for bone regeneration.
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| 6. |
- Bartuma, Hammurabi, et al.
(författare)
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Gene expression and single nucleotide polymorphism array analyses of spindle cell lipomas and conventional lipomas with 13q14 deletion.
- 2011
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 50, s. 619-632
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Tidskriftsartikel (refereegranskat)abstract
- Spindle cell lipomas (SCL) are circumscribed, usually s.c. tumors that typically occur on the posterior neck, shoulder, and back of middle aged men. Cytogenetically, almost all SCL are characterized by deletions of chromosome arm 13q, often in combination with loss of 16q. Deletions of 13q are seen also in approximately 15% of conventional lipomas. Through single nucleotide polymorphism (SNP) array analyses, we identified two minimal deleted regions (MDR) in 13q14 in SCL. In MDR1, four genes were located, including the tumor suppressor gene RB1. MDR1 in SCL overlapped with the MDR detected in conventional lipomas with 13q14 deletion. In MDR2 in SCL there were 34 genes and the two microRNA (miRNA) genes miR-15a and miR-16-1. Global gene expression analysis was used to study the impact of the deletions on genes mapping to the two SCL-associated MDR. Five genes (C13orf1, DHRS12, ATP7B, ALG11, and VPS36) in SCL and one gene (C13orf1) in conventional lipomas with 13q-deletions were found to be significantly underexpressed compared with control tissues. Quantitative real-time PCR showed that miR-16-1 was expressed at lower levels in SCL than in the control samples. No mutations were found at sequencing of RB1, miR-15a, and miR-16-1. Our findings further delineate the target region for the 13q deletion in SCL and conventional lipomas and show that the deletions are associated with down-regulated expression of several genes, notably C13orf1, which was the only gene to be significantly down-regulated in both tumor types. © 2011 Wiley-Liss, Inc.
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| 7. |
- D'souza, Melroy A., et al.
(författare)
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The clinicopathological spectrum and management of intraductal papillary mucinous neoplasm of the bile duct (IPMN-B)
- 2013
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa Healthcare. - 0036-5521 .- 1502-7708. ; 48:4, s. 473-479
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Intraductal papillary mucinous neoplasm of the bile duct (IPMN-B) is a rare but increasingly diagnosed clinical entity. Typical cholangioscopic findings usually include intraductal protruding papillary tumors that secrete mucus.METHODS: Clinical, radiological and histopathological data of seven consecutive patients who were found to have IPMN-B were analyzed.RESULTS: Six of the seven patients presented with obstructive jaundice/cholangitis as the presenting complaint. ERCP and other imaging were equivocal in five of these patients and peroral cholangioscopy (POCS, single-operator cholangioscopy system) was performed. This revealed mucin-producing intraductal tumors with numerous frond-like papillary projections; a macroscopic appearance consistent with IPMN-B. Preoperative biopsy revealed adenoma, with low-grade dysplasia in two patients and high-grade dysplasia in three. Three patients underwent Whipple resection; one underwent total pancreatectomy with left hepatectomy, one patient a pancreas preserving duodenectomy with common bile duct reimplantation and one patient an extended right hepatectomy. These patients were found to have IPMN-B with adenomatous changes with varying grades of dysplasia and even cholangiocarcinoma on final histopathology. One patient first underwent endoscopic papillectomy and on follow-up was found to have cholangiocarcinoma with metastases to the liver.CONCLUSION: POCS can be a key diagnostic investigation in the evaluation of patients with papillary tumors of the bile duct. IPMN-B has a heterogenous pathology and varying grades of dysplasia and even carcinoma may exist in the same patient. Surgical management should be radical and based on tumor extent.
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| 8. |
- Hansén Nord, Karolin, et al.
(författare)
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Concomitant deletions of tumor suppressor genes MEN1 and AIP are essential for the pathogenesis of the brown fat tumor hibernoma.
- 2010
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; Dec, s. 21122-21127
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Tidskriftsartikel (refereegranskat)abstract
- Hibernomas are benign tumors with morphological features resembling brown fat. They consistently display cytogenetic rearrangements, typically translocations, involving chromosome band 11q13. Here we demonstrate that these aberrations are associated with concomitant deletions of AIP and MEN1, tumor suppressor genes that are located 3 Mb apart and that underlie the hereditary syndromes pituitary adenoma predisposition and multiple endocrine neoplasia type I. MEN1 and AIP displayed a low expression in hibernomas whereas the expression of genes up-regulated in brown fat-PPARA, PPARG, PPARGC1A, and UCP1-was high. Thus, loss of MEN1 and AIP is likely to be pathogenetically essential for hibernoma development. Simultaneous loss of two tumor suppressor genes has not previously been shown to result from a neoplasia-associated translocation. Furthermore, in contrast to the prevailing assumption that benign tumors harbor relatively few genetic aberrations, the present analyses demonstrate that a considerable number of chromosome breaks are involved in the pathogenesis of hibernoma.
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| 9. |
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| 10. |
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