| 1. |
- Annertz, Karin, et al.
(författare)
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Alpha B-crystallin - a validated prognostic factor for poor prognosis in squamous cell carcinoma of the oral cavityl
- 2014
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 134:5, s. 543-550
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Tidskriftsartikel (refereegranskat)abstract
- Conclusion: Alpha B-crystallin was found to be an independent prognostic marker for poor prognosis in oral cavity tumours. For oropharyngeal cancer, alpha B-crystallin had no prognostic value. Objective: The aim of this study was to see if earlier findings of alpha B-crystallin as an independent prognostic marker, and SPARC/osteonectin, PAI-1 and uPA as a prognostic combination for poor outcome in squamous cell carcinoma (SCC) of the head and neck could be confirmed in a new set of tumours. Methods: In a consecutive series of patients, assessed and primarily treated at a tertiary referral centre, histological sections from 55 patients with oral and SCC (OOPHSSC) with complete clinical data and follow-up were obtained. Oral and oropharyngeal tumours were studied separately. Immunohistochemical detection of alpha B-crystallin, SPARC/osteonectin, PAI-1 and uPA expression was performed. Results: Thirty-five patients had an oral tumour and 20 patients an oropharyngeal tumour. Twenty-five oral tumours stained negatively and 10 positively for alpha B-crystallin. For oropharyngeal tumours the figures were 15 negatively and 5 positively. Median disease-specific survival (DSS) for both sites was 33.8 and 11.9 months, for negative and positive alpha B-crystallin staining, respectively (p=0.046). For the oral cavity, median DSS was 27.3 months for negative tumours and 7.5 months for positive tumours (p=0.012). Corresponding figures for oropharyngeal tumours were 33.8 and 34.1 months (p=0.95). Thus, significance in survival was only found in oral cavity tumours. In multivariate analyses there were no significant differences in DSS in the oropharyngeal group when adjusted for tumour size (T status) and presence of neck node metastasis (N status). In the oral cavity group, the significantly better DSS for negative tumours became even stronger when adjusted for T and N status. No statistical difference was found in DSS between positive and negative staining for SPARC/osteonectin, PAI-1 or uPA.
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| 2. |
- Bagge, Niklas, 1987-, et al.
(författare)
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Full Scale Test of a PC Bridge to Calibrate Assessment Methods
- 2021
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Ingår i: IABSE Congress Ghent 2021. - Zurich, Switzerland : International Association for Bridge and Structural Engineering (IABSE). ; , s. 965-973
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Konferensbidrag (refereegranskat)abstract
- In this paper, experiences on the development of an assessment method for existing bridges are presented. The method is calibrated using the results of full-scale testing to failure of a prestressed bridge in Sweden. To evaluate the key parameters for the structural response, measured by deflections, strains in tendons and stirrups and crack openings, a sensitivity study based on the concept of fractional factorial design is incorporated to the assessment. Results showed that the most significant parameters are related to the tensile properties of the concrete (tensile strength and fracture energy) and the boundary conditions. A finite element (FE) model in which the results of the sensitivity analysis were applied, was able to predict accurately the load-carrying capacity of the bridge and its failure mode. Two additional existing prestressed concrete bridges, that will be used to improve further the method, are also described, and discussed.
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| 3. |
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| 4. |
- Bräunig, Sandro, et al.
(författare)
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Three-dimensional spatial mapping of the human hematopoietic microenvironment in healthy and diseased bone marrow
- 2023
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Ingår i: Cytometry Part A. - 1552-4922. ; 103:10, s. 763-776
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Tidskriftsartikel (refereegranskat)abstract
- The bone marrow hematopoietic microenvironment (HME) plays a pivotal role in regulating normal and diseased hematopoiesis. However, the spatial organization of the human HME has not been thoroughly investigated yet. Therefore, we developed a three-dimensional (3D) immunofluorescence model to analyze changes in the cellular architecture in control and diseased bone marrows (BMs). BM biopsies from patients with myeloproliferative neoplasms (MPNs) were stained sequentially for CD31, CD34, CD45, and CD271 with repetitive bleaching steps to realize five color images with DAPI as a nuclear stain. Hematopoietically normal age-matched BM biopsies served as controls. Twelve subsequent slides per sample were stacked to create three-dimensional bone marrow reconstructions with the imaging program Arivis Visions 4D. Iso-surfaces for niche cells and structures were created and exported as mesh objects for spatial distribution analysis in the 3D creation suite Blender. We recapitulated the bone marrow architecture using this approach and produced comprehensive 3D models of endosteal and perivascular BM niches. MPN bone marrows displayed apparent differences compared to the controls, especially concerning CD271 staining density, megakaryocyte (MK) morphology, and distribution. Furthermore, measurements of the spatial relationships of MKs and hematopoietic stem and progenitor cells with vessels and bone structures in their corresponding niche environments revealed the most pronounced differences in the vascular nice in polycythemia vera. Taken together, using a repetitive staining and bleaching approach allowed us to establish a 5-color analysis of human BM biopsies, which is difficult to achieve with conventional staining approaches. Based on this, we generated 3D BM models which recapitulated key pathological features and, importantly, allowed us to define the spatial relationships between different bone marrow cell types. We, therefore, believe that our method can provide new and valuable insights into bone marrow cellular interaction research.
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| 5. |
- Cirenajwis, Helena, et al.
(författare)
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Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12297-12309
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Tidskriftsartikel (refereegranskat)abstract
- Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.
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| 6. |
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| 7. |
- Jin, Charlotte, et al.
(författare)
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Cytogenetic abnormalities in 106 oral squamous cell carcinomas
- 2006
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Ingår i: Cancer Genetics and Cytogenetics. - : Elsevier BV. - 0165-4608. ; 164:1, s. 44-53
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Tidskriftsartikel (refereegranskat)abstract
- We report karyotypic features of 106 short-term cultured oral squamous cell carcinomas (SCC), 51 new and 55 previously reported cases, with clonal chromosome aberrations. The major cytogenetic findings were as follows: simple karyotypic changes were present in 38 cases (36%) and 68 tumors (64%) displayed complex karyotypes. The most common numerical changes were +7, +8, +9, +16, +18, +20, and -4, -10, -13, -14, -18, -19, -21, -22, and -Y. Structural rearrangements frequently (43% of the breaks) affected the centromeric regions, resulting in the formation of isochromosomes and whole-arm translocations. Among the recurrent structural aberrations identified, the most common were i(1q), i(3q), i(5p), i(8q), del(16)(q22), and hsr. With the exception of chromosomal band 11q13, which was involved in 25 tumors, only centromeric or near-centromeric bands were commonly involved: 3p11 approximately q11 (59 cases), 8p11 approximately q11 (57), 1p11 approximately q11 (48), 13p11 approximately q11 (46), 5p11 approximately q11 (41), 14p11 approximately q11 (41), and 15p11 approximately q11 (37). Losses of genetic material dominated over gains. The most frequent imbalances included loss of 2q33 approximately qter, 3p, 4p, 6q, 8p, 10p, 11q, 13p, 14p, and 15p, and chromosomes 18, 21, 22, and Y, and gain of chromosomes 7 and 20, 8q, and 11q13. No major karyotypic differences could be discerned between the present series of oral SCC and a previously reported series of laryngeal SCC, indicating that common genetic pathways are involved in the initiation and progression of SCC irrespective of site of origin.
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| 8. |
- Saal, Lao, et al.
(författare)
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PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma
- 2005
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Ingår i: Cancer Research. - 1538-7445. ; 65:7, s. 2554-2559
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Tidskriftsartikel (refereegranskat)abstract
- Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway either through loss of PTEN or mutation of the catalytic subunit alpha of PI3K (PIK3CA) occurs frequently in human cancer. We identified PIK3CA mutations in 26% of 342 human breast tumor samples and cell lines at about equal frequency in tumor stages I to IV. To investigate the relationship between PTEN and PIK3CA, we generated a cohort of tumors that had lost PTEN expression and compared it with a matched control set that had retained PTEN. A highly significant association between PIK3CA mutations and retention of PTEN protein expression was observed. In addition, PIK3CA mutations were associated with expression of estrogen and progesterone receptors (ER/PR), lymph node metastasis, and ERBB2 overexpression. The fact that PIK3CA mutations and PTEN loss are nearly mutually exclusive implies that deregulated phosphatidylinositol-3,4,5-triphosphate WIN is critical for tumorigenesis in a significant fraction of breast cancers and that loss Of PIP3 homeostasis by abrogation of either PIK3CA or PTEN relieves selective pressure for targeting of the other gene. The correlation of PIK3CA mutation to ER/PR-positive tumors and PTEN loss to ER/PR-negative tumors argues for disparate branches of tumor evolution. Furthermore, the association between ERBB2 overexpression and PIK3CA mutation implies that more than one input activating the PI3K/AKT pathway may be required to overcome intact PTEN. Thus, mutation of PIK3CA is frequent, occurs early in carcinoma development, and has prognostic and therapeutic implications.
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| 9. |
- Uttman, Leif, et al.
(författare)
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Protective ventilation in experimental acute respiratory distress syndrome after ventilator-induced lung injury: a randomized controlled trial
- 2012
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Ingår i: British Journal of Anaesthesia. - : Elsevier BV. - 1471-6771 .- 0007-0912. ; 109:4, s. 584-594
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Tidskriftsartikel (refereegranskat)abstract
- Low tidal volume (V-T), PEEP, and low plateau pressure (P-PLAT) are lung protective during acute respiratory distress syndrome (ARDS). This study tested the hypothesis that the aspiration of dead space (ASPIDS) together with computer simulation can help maintain gas exchange at these settings, thus promoting protection of the lungs. ARDS was induced in pigs using surfactant perturbation plus an injurious ventilation strategy. One group then underwent 24 h protective ventilation, while control groups were ventilated using a conventional ventilation strategy at either high or low pressure. Pressurevolume curves (P-el/V), blood gases, and haemodynamics were studied at 0, 4, 8, 16, and 24 h after the induction of ARDS and lung histology was evaluated. The P-el/V curves showed improvements in the protective strategy group and deterioration in both control groups. In the protective group, when respiratory rate (RR) was approximate to 60 bpm, better oxygenation and reduced shunt were found. Histological damage was significantly more severe in the high-pressure group. There were no differences in venous oxygen saturation and pulmonary vascular resistance between the groups. The protective ventilation strategy of adequate pH or Pa-CO2 with minimal V-T, and high/safe P-PLAT resulting in high PEEP was based on the avoidance of known lung-damaging phenomena. The approach is based upon the optimization of V-T, RR, PEEP, I/E, and dead space. This study does not lend itself to conclusions about the independent role of each of these features. However, dead space reduction is fundamental for achieving minimal V-T at high RR. Classical physiology is applicable at high RR. Computer simulation optimizes ventilation and limiting of dead space using ASPIDS. Inspiratory P-el/V curves recorded from PEEP or, even better, expiratory P-el/V curves allow monitoring in ARDS.
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| 10. |
- Valind, Anders, et al.
(författare)
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Macrophage infiltration promotes regrowth in MYCN-amplified neuroblastoma after chemotherapy
- 2023
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Ingår i: OncoImmunology. - 2162-4011 .- 2162-402X. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite aggressive treatment, the 5-year event-free survival rate for children with high-risk neuroblastoma is <50%. While most high-risk neuroblastoma patients initially respond to treatment, often with complete clinical remission, many eventually relapse with therapy-resistant tumors. Novel therapeutic alternatives that prevent the recurrence of therapy-resistant tumors are urgently needed. To understand the adaptation of neuroblastoma under therapy, we analyzed the transcriptomic landscape in 46 clinical tumor samples collected before (PRE) or after (POST) treatment from 22 neuroblastoma patients. RNA sequencing revealed that many of the top-upregulated biological processes in POST MYCN amplified (MNA +) tumors compared to PRE MNA + tumors were immune-related, and there was a significant increase in numerous genes associated with macrophages. The infiltration of macrophages was corroborated by immunohistochemistry and spatial digital protein profiling. Moreover, POST MNA + tumor cells were more immunogenic compared to PRE MNA + tumor cells. To find support for the macrophage-induced outgrowth of certain subpopulations of immunogenic tumor cells following treatment, we examined the genetic landscape in multiple clinical PRE and POST tumor samples from nine neuroblastoma patients revealing a significant correlation between an increased amount of copy number aberrations (CNA) and macrophage infiltration in POST MNA + tumor samples. Using an in vivo neuroblastoma patient-derived xenograft (PDX) chemotherapy model, we further show that inhibition of macrophage recruitment with anti-CSF1R treatment prevents the regrowth of MNA + tumors following chemotherapy. Taken together, our work supports a therapeutic strategy for fighting the relapse of MNA + neuroblastoma by targeting the immune microenvironment.
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