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1.
  • Klionsky, Daniel J., et al. (författare)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • Forskningsöversikt (refereegranskat)abstract
    • In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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3.
  • Arance, Ana, et al. (författare)
  • Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination.
  • 2023
  • Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 41:1, s. 75-85
  • Tidskriftsartikel (refereegranskat)abstract
    • Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136).Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review.A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count).Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.
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4.
  • Bousquet, Jean, et al. (författare)
  • ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice
  • 2021
  • Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 76:1, s. 168-190
  • Forskningsöversikt (refereegranskat)abstract
    • Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
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5.
  • Fernandes, Juliana Folloni, et al. (författare)
  • Transplantation of Hematopoietic Stem Cells for Primary Immunodeficiencies in Brazil: Challenges in Treating Rare Diseases in Developing Countries.
  • 2018
  • Ingår i: Journal of clinical immunology. - : Springer Science and Business Media LLC. - 1573-2592 .- 0271-9142. ; 38:8, s. 917-926
  • Tidskriftsartikel (refereegranskat)abstract
    • The results of hematopoietic stem cell transplant (HSCT) for primary immunodeficiency diseases (PID) have been improving over time. Unfortunately, developing countries do not experience the same results. This first report of Brazilian experience of HSCT for PID describes the development and results in the field. We included data from transplants in 221 patients, performed at 11 centers which participated in the Brazilian collaborative group, from July 1990 to December 2015. The majority of transplants were concentrated in one center (n=123). The median age at HSCT was 22months, and the most common diseases were severe combined immunodeficiency (SCID) (n=67) and Wiskott-Aldrich syndrome (WAS) (n=67). Only 15 patients received unconditioned transplants. Cumulative incidence of GVHD grades II to IV was 23%, and GVHD grades III to IV was 10%. The 5-year overall survival was 71.6%. WAS patients had better survival compared to other diseases. Most deaths (n=53) occurred in the first year after transplantation mainly due to infection (55%) and GVHD (13%). Although transplant for PID patients in Brazil has evolved since its beginning, we still face some challenges like delayed diagnosis and referral, severe infections before transplant, a limited number of transplant centers with expertise, and resources for more advanced techniques. Measures like newborn screening for SCID may hasten the diagnosis and ameliorate patients' conditions at the moment of transplant.
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6.
  • Phung, Bengt, et al. (författare)
  • The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma
  • 2019
  • Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 27:12, s. 7-3586
  • Tidskriftsartikel (refereegranskat)abstract
    • The X-linked DDX3X gene encodes an ATP-dependent DEAD-box RNA helicase frequently altered in various human cancers, including melanomas. Despite its important roles in translation and splicing, how DDX3X dysfunction specifically rewires gene expression in melanoma remains completely unknown. Here, we uncover a DDX3X-driven post-transcriptional program that dictates melanoma phenotype and poor disease prognosis. Through an unbiased analysis of translating ribosomes, we identified the microphthalmia-associated transcription factor, MITF, as a key DDX3X translational target that directs a proliferative-to-metastatic phenotypic switch in melanoma cells. Mechanistically, DDX3X controls MITF mRNA translation via an internal ribosome entry site (IRES) embedded within the 5' UTR. Through this exquisite translation-based regulatory mechanism, DDX3X steers MITF protein levels dictating melanoma metastatic potential in vivo and response to targeted therapy. Together, these findings unravel a post-transcriptional layer of gene regulation that may provide a unique therapeutic vulnerability in aggressive male melanomas.
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7.
  • Salles-Filho, Sergio Luiz Monteiro, et al. (författare)
  • Monitoring and Evaluation as a Way to Complete and to Implement a Policy : The Case of Brazilian National Innovation Policy
  • 2022
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • The present National Innovation Policy (henceforth called PNI) was instituted in Brazil by Decree No. 10.537, of October 28, 2020, within the federal public administration. The policy's objective is to guide, coordinate and articulate strategies, programs, and actions across several public entities to foster innovation in the productive sector. Thus, it aims to increase the productivity and competitiveness of companies and other institutions throughout the innovation process. The policy is structured around six axes: funding innovation, innovation culture, technological background, market development, educational systems, and intellectual property. Objectives and guidelines are defined for each of these Axes. However, neither a previous Theory of Change, a Logical Framework, nor a monitoring and evaluation system was established to guide the implementation. Operationally speaking, the policy was implemented by gathering ongoing actions from eighteen different federal ministries and agencies and then assigning them to the axes above. It was an ad hoc measure to put the policy into practice. As can be inferred, the selected actions did not emerge as a breakdown from axes. In 2021 the design and implementation of a monitoring and evaluation model (M&E) were commissioned to an independent evaluation group. The objective was to develop an original methodology and indicators for monitoring and evaluating outputs, outcomes and impacts of the PNI. The challenge of the model is twofold: to adjust the matching amongst actions, axes, and the policy's objectives, and to implement a common framework for M&E able to coordinate the involved agencies. A Theory of Change and a Logical Framework were ex-post designed and validated, and based on these references, the model was conceived. It defined a classical template for monitoring the ongoing actions (using flags and lights according to execution), adding indicators of outcomes and impacts. It is an integrated M&E model that, once implemented, will require that new actions be justified not only in terms of their outputs but also on the expected outcomes and impacts. Standard indicators of science, technology and innovation outcomes and impacts from different sources as for OECD, UNESCO, Global Innovation Index and Sustainable Development Goals (SDG/UN) have been gathered and organized to be employed in the M&E process. Non-standard indicators are also foreseen so that the model can measure internationally comparable and specific indicators. The whole model is now under development and validation among stakeholders. We expect this process to go beyond the domain of M&E and influences the way priorities are defined, and governance is established and run. By involving different actors, incorporating the SDGs into the policy's core, the evaluation process facilitated the policy's implementation and coordination. Furthermore, the articulation between the different stakeholders, promoted by the M&E, minimized fragmentation and uncoordinated actions within the scope of the policy's formulation. It is in this sense that the evaluation process is a way to transform the policy itself
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8.
  • Adrian, Gabriel, et al. (författare)
  • Rescue Effect Inherited in Colony Formation Assays Affects Radiation Response
  • 2018
  • Ingår i: Radiation Research. - 0033-7587. ; 189:1, s. 44-52
  • Tidskriftsartikel (refereegranskat)abstract
    • It is well known that nonirradiated cells can exhibit radiation damage (bystander effect), and recent findings have shown that nonirradiated cells may help protect irradiated cells (rescue effect). These findings call into question the traditional view of radiation response: cells cannot be envisioned as isolated units. Here, we investigated traditional colony formation assays to determine if they also comprise cellular communication affecting the radiation response, using colony formation assays with varying numbers of cells, modulated beam irradiation and media transfer. Our findings showed that surviving fraction gradually increased with increasing number of irradiated cells. Specifically, for DU-145 human prostate cancer cells, surviving fraction increased 1.9-to-4.1-fold after 5-12 Gy irradiation; and for MM576 human melanoma cells, surviving fraction increased 1.9-fold after 5 Gy irradiation. Furthermore, increased surviving fraction was evident after modulated beam irradiation, where irradiated cells could communicate with nonirradiated cells. Media from dense cell culture also increased surviving fraction. The results suggest that traditional colony formation assays comprise unavoidable cellular communication affecting radiation outcome and the shape of the survival curve. We also propose that the increased in-field surviving fraction after modulated beam irradiation is due to the same effect.
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9.
  • Bergqvist, Viktoria, et al. (författare)
  • Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis
  • 2017
  • Ingår i: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 66:5, s. 581-592
  • Tidskriftsartikel (refereegranskat)abstract
    • Immune checkpoint inhibitors (ICPI), such as ipilimumab [anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody] and nivolumab or pembrolizumab [anti-programmed cell death protein-1 (PD-1) antibodies], improve survival in several cancer types. Since inhibition of CTLA-4 or PD-1 leads to non-selective activation of the immune system, immune-related adverse events (irAEs) are frequent. Enterocolitis is a common irAE, currently managed with corticosteroids and, if necessary, anti-tumor necrosis factor-α therapy. Such a regimen carries a risk of serious side-effects including infections, and may potentially imply impaired antitumor effects. Vedolizumab is an anti-integrin α4β7 antibody with gut-specific immunosuppressive effects, approved for Crohn’s disease and ulcerative colitis. We report a case series of seven patients with metastatic melanoma or lung cancer, treated with vedolizumab off-label for ipilimumab- or nivolumab-induced enterocolitis, from June 2014 through October 2016. Clinical, laboratory, endoscopic, and histologic data were analyzed. Patients initially received corticosteroids but were steroid-dependent and/or partially refractory. One patient was administered infliximab but was refractory. The median time from onset of enterocolitis to start of vedolizumab therapy was 79 days. Following vedolizumab therapy, all patients but one experienced steroid-free enterocolitis remission, with normalized fecal calprotectin. This was achieved after a median of 56 days from vedolizumab start, without any vedolizumab-related side-effects noted. The patient in whom vedolizumab was not successful, due to active ulcerative colitis, received vedolizumab prophylactically. This is the first case series to suggest that vedolizumab is an effective and well-tolerated therapeutic for steroid-dependent or partially refractory ICPI-induced enterocolitis. A larger prospective study to evaluate vedolizumab in this indication is warranted.
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10.
  • Cabrita, Rita, et al. (författare)
  • Tertiary lymphoid structures improve immunotherapy and survival in melanoma
  • 2020
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 577:7791, s. 561-565
  • Tidskriftsartikel (refereegranskat)abstract
    • Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
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11.
  • Cabrita, Rita, et al. (författare)
  • Tertiary lymphoid structures improve immunotherapy and survival in melanoma.
  • 2020
  • Ingår i: Nature. - : Nature Publishing Group. - 1476-4687 .- 0028-0836. ; 577:7791, s. 561-565
  • Tidskriftsartikel (refereegranskat)abstract
    • Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
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12.
  • Cabrita, Rita, et al. (författare)
  • The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response
  • 2020
  • Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The PTEN gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor (MITF) gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of MITF expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy.
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13.
  • Carneiro, Ana, et al. (författare)
  • A prognostic model for soft tissue sarcoma of the extremities and trunk wall based on size, vascular invasion, necrosis, and growth pattern.
  • 2011
  • Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; Dec, s. 1279-1287
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND:: In soft tissue sarcoma, better distinction of high-risk and low-risk patients is needed to individualize treatment and improve survival. Prognostic systems used in clinical practice identify high-risk patients based on various factors, including age, tumor size and depth, histological type, necrosis, and grade. METHODS:: Whole-tumor sections from 239 soft tissue sarcomas of the extremities were reviewed for the following prognostic factors: size, vascular invasion, necrosis, and growth pattern. A new prognostic model, referred to as SING (Size, Invasion, Necrosis, Growth), was established and compared with other clinically applied systems. RESULTS:: Size, vascular invasion, necrosis, and peripheral tumor growth pattern provided independent prognostic information with hazard ratios of 2.2-2.6 for development of metastases in multivariate analysis. When these factors were combined into the prognostic model SING, high risk of metastasis was predicted with a sensitivity of 74% and a specificity of 85%. Moreover, the prognostic performance of SING compared favorably with other widely used systems. CONCLUSIONS:: SING represents a promising prognostic model, and vascular invasion and tumor growth pattern should be considered in soft tissue sarcoma prognostication. Cancer 2010. © 2010 American Cancer Society.
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14.
  • Carneiro, Ana, et al. (författare)
  • Ezrin expression predicts local recurrence and development of metastases in soft tissue sarcomas.
  • 2011
  • Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 64, s. 689-694
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Ezrin is a cytoskeletal protein involved in tumour growth and invasion. Ezrin expression has been suggested to play a role in metastasis in paediatricosteosarcoma and rhabdomyosarcoma. Aim To evaluate the prognostic role of ezrin in a large series of soft tissue sarcoma of the extremities and trunk wall. Methods Ezrin expression was evaluated by immunohistochemistry on tissue microarrays from a mixed series of 256 soft tissue sarcomas. The expression patterns were correlated to local recurrence and metastasis as well as to established prognostic factors in soft tissue sarcoma. Results Increased ezrin expression predicted development of metastasis (HR=1.8, 95% CI 1.1 to 2.8; p=0.007) and local recurrence, also after adjustment for surgical margin (HR=2.4, 95% CI 1.4 to 4.3; p=0.02). Correlations to established prognostic factors showed strong associations between ezrin and necrosis (OR=3.9, p<0.0001) and ezrin and growth pattern (OR=3.1, p=0.03). Conclusions Ezrin independently predicts development of local recurrences and metastases in soft tissue sarcomas. The possibility of preoperative evaluation makes ezrin a potential marker for identification of high-risk sarcoma patients who would benefit from neoadjuvant therapy.
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15.
  • Carneiro, Ana, et al. (författare)
  • Genetic profiling - implications for refined diagnosis and treatment of soft tissue sarcomas
  • 2009
  • Ingår i: Acta Orthopaedica. - 1745-3682. ; 80, s. 15-23
  • Tidskriftsartikel (refereegranskat)abstract
    • Soft tissue sarcomas (STS) are challenging as they represent a morphologically and genetically heterogeneous groups of tumors. A multitude of genetic changes, often in the form of fusion genes, were recognized during the 1980's and now constitute a diagnostic lexicon in several STS subtypes, whereas many of the more common subtypes are genetically complex without distinct alterations. Refined STS management requires improved diagnostic reproducibility, novel prognosticators, and introduction of targeted therapies. In recent years, a number of genetic profiling studies - analyzing copy-number alterations as well as gene expression changes - have deepened our understanding of STS development through demonstration of recurrently deregulated tumorigenic pathways. The challenge is now to bring the genetic profiles into clinical decision-making. This review, in conjunction with the Scandinavian Sarcoma Group's (SSG) 30 years jubilee, discusses how the information from genetic profiling studies may be translated into clinical practice for refined diagnostics, prognostics, and treatment of STS.
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16.
  • Carneiro, Ana, et al. (författare)
  • Indistinguishable genomic profiles and shared prognostic markers in undifferentiated pleomorphic sarcoma and leiomyosarcoma: different sides of a single coin?
  • 2009
  • Ingår i: Laboratory Investigation. - : Elsevier BV. - 1530-0307 .- 0023-6837. ; 89, s. 668-675
  • Tidskriftsartikel (refereegranskat)abstract
    • Soft tissue sarcoma (STS) diagnostics and prognostics are challenging, particularly in highly malignant and pleomorphic subtypes such as undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS). We applied 32K BAC arrays and gene expression profiling to 18 extremity soft tissue LMS and 31 extremity soft tissue UPS with the aim of identifying molecular subtype signatures and genomic prognostic markers. Both the gains/losses and gene expression signatures revealed striking similarities between UPS and LMS, which were indistinguishable using unsupervised hierarchical cluster analysis and significance analysis for microarrays. Gene expression analysis revealed just nine genes, among them tropomyosin beta, which were differentially expressed. Loss of 4q31 (encompassing the SMAD1 locus), loss of 18q22, and tumor necrosis were identified as independent predictors of metastasis in multivariate stepwise Cox regression analysis. Combined analysis applying loss of 4q31 and 18q22 and the presence of necrosis improved the area under receiver operating characteristic curve for metastasis prediction from 0.64 to 0.86. The extensive genetic similarities between extremity soft tissue UPS and LMS suggest a shared lineage of these STS subtypes and the new and independent genetic prognosticators identified hold promise for refined prognostic determination in high-grade, genetically complex STS.Laboratory Investigation advance online publication, 16 March 2009; doi:10.1038/labinvest.2009.18.
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17.
  • Carneiro, Ana P. B., et al. (författare)
  • A framework for mapping the distribution of seabirds by integrating tracking, demography and phenology
  • 2020
  • Ingår i: Journal of Applied Ecology. - : Wiley. - 0021-8901 .- 1365-2664. ; 57:3, s. 514-525
  • Tidskriftsartikel (refereegranskat)abstract
    • The identification of geographic areas where the densities of animals are highest across their annual cycles is a crucial step in conservation planning. In marine environments, however, it can be particularly difficult to map the distribution of species, and the methods used are usually biased towards adults, neglecting the distribution of other life-history stages even though they can represent a substantial proportion of the total population. Here we develop a methodological framework for estimating population-level density distributions of seabirds, integrating tracking data across the main life-history stages (adult breeders and non-breeders, juveniles and immatures). We incorporate demographic information (adult and juvenile/immature survival, breeding frequency and success, age at first breeding) and phenological data (average timing of breeding and migration) to weight distribution maps according to the proportion of the population represented by each life-history stage. We demonstrate the utility of this framework by applying it to 22 species of albatrosses and petrels that are of conservation concern due to interactions with fisheries. Because juveniles, immatures and non-breeding adults account for 47%-81% of all individuals of the populations analysed, ignoring the distributions of birds in these stages leads to biased estimates of overlap with threats, and may misdirect management and conservation efforts. Population-level distribution maps using only adult distributions underestimated exposure to longline fishing effort by 18%-42%, compared with overlap scores based on data from all life-history stages. Synthesis and applications. Our framework synthesizes and improves on previous approaches to estimate seabird densities at sea, is applicable for data-poor situations, and provides a standard and repeatable method that can be easily updated as new tracking and demographic data become available. We provide scripts in the R language and a Shiny app to facilitate future applications of our approach. We recommend that where sufficient tracking data are available, this framework be used to assess overlap of seabirds with at-sea threats such as overharvesting, fisheries bycatch, shipping, offshore industry and pollutants. Based on such an analysis, conservation interventions could be directed towards areas where they have the greatest impact on populations.
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18.
  • Carneiro, Ana, et al. (författare)
  • Prognostic impact of array-based genomic profiles in esophageal squamous cell cancer
  • 2008
  • Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 8:98
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Esophageal squamous cell carcinoma (ESCC) is a genetically complex tumor type and a major cause of cancer related mortality. Although distinct genetic alterations have been linked to ESCC development and prognosis, the genetic alterations have not gained clinical applicability. We applied array-based comparative genomic hybridization (aCGH) to obtain a whole genome copy number profile relevant for identifying deranged pathways and clinically applicable markers. Methods: A 32 k aCGH platform was used for high resolution mapping of copy number changes in 30 stage I-IV ESCC. Potential interdependent alterations and deranged pathways were identified and copy number changes were correlated to stage, differentiation and survival. Results: Copy number alterations affected median 19% of the genome and included recurrent gains of chromosome regions 5p, 7p, 7q, 8q, 10q, 11q, 12p, 14q, 16p, 17p, 19p, 19q, and 20q and losses of 3p, 5q, 8p, 9p and 11q. High-level amplifications were observed in 30 regions and recurrently involved 7p11 (EGFR), 11q13 (MYEOV, CCND1, FGF4, FGF3, PPFIA, FAD, TMEM16A, CTTS and SHANK2) and 11q22 (PDFG). Gain of 7p22.3 predicted nodal metastases and gains of 1p36.32 and 19p13.3 independently predicted poor survival in multivariate analysis. Conclusion: aCGH profiling verified genetic complexity in ESCC and herein identified imbalances of multiple central tumorigenic pathways. Distinct gains correlate with clinicopathological variables and independently predict survival, suggesting clinical applicability of genomic profiling in ESCC.
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19.
  • Carneiro, Ana (författare)
  • Refined diagnosis and prognosis in soft tissue sarcoma - genetic profiles, biomarkers and prognostic models
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • This work aimed at evaluate diagnosis and prognosis in soft tissue sarcoma (STS): In study I, 32K bacterial artificial chromosome (BAC) arrays and gene expression profiling were applied to 18 leiomyosarcomas and 31 undifferentiated pleomorphic sarcomas (UPS), with the aim of identifying molecular subtype signatures. Both the gains/losses profiles and the gene expression signatures revealed striking similarities between the two tumour types. Leiomyosaromas and UPS were indistinguishable using unsupervised hierarchical cluster analysis and significance analysis for microarrays, which suggests a shared lineage. In study II, whole-tumour sections from 239 STS were reviewed for size, vascular invasion, necrosis, and peripheral growth pattern. All factors provided independent prognostic information with hazard ratios (HRs) of 2.2-2.6 for development of metastases in multivariate analysis. When combined into a prognostic model, referred to as SING (Size, Invasion, Necrosis, Growth), high-risk tumours were identified with a sensitivity of 74% and a specificity of 85%. SING compared favourably with other currently used prognostic systems. In study III, the prognostic value and clinical applicability of five proliferation markers were assessed: Ki-67, Top2a, p21, p27Kip1 and S-phase fraction in a mixed series of 196 STS of the extremities and the trunk wall, encompassing MFH/UPS, leiomyosarcomas and liposarcomas. High S-phase fraction and high expression of Ki- 67 and Top2a significantly correlated to risk for metastasis with HRs of 1.9-4.4. Classification and regression tree analysis showed that Ki-67, Top2a and S-phase identified different prognostic subgroups. This explorative analysis suggests that proliferation markers could have a role in STS prognostication, in particular when few other factors can be evaluated, as in the preoperative setting. In study IV, ezrin expression was evaluated by immunohistochemistry on tissue microarrays from a mixed series of 256 STS. Positive ezrin expression predicted development of metastasis (HR=1.8) and local recurrence (HR=1.8) and was strongly correlated to necrosis and growth pattern. Ezrin represents therefore a potential marker for identification of high-risk sarcoma patients.
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20.
  • Cirenajwis, Helena, et al. (författare)
  • Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy.
  • 2015
  • Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12297-12309
  • 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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21.
  • Cirenajwis, Helena, et al. (författare)
  • NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics
  • 2017
  • Ingår i: Molecular Oncology. - : Wiley. - 1574-7891. ; 11:4, s. 438-451
  • Tidskriftsartikel (refereegranskat)abstract
    • In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple-wild-type status and correlated with tumor and patient characteristics. We found that the NF1-mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co-occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain-containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1-mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease-specific survival, DSS; HR, 1.9; 95% CI, 1.21-3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28-2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.
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22.
  • Coelho, Ana Maria Mendonça, et al. (författare)
  • MECHANISMS OF THE BENEFICIAL EFFECT OF HYPERTONIC SALINE SOLUTION IN ACUTE PANCREATITIS.
  • 2010
  • Ingår i: Shock. - 1540-0514. ; 34, s. 502-507
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND/AIMS:: Administration of hypertonic saline (HS) solution to rats with acute pancreatitis (AP) decreases mortality and systemic inflammation. We hypothesized that these effects are relates not only to systemic inflammatory reduction but also to reduction of the pancreatic lesion. METHODS:: AP was induced in Wistar rats by injection of 2.5% sodium taurocholate. Animals were divided in groups: C (without AP), NT (not treated AP), NS (AP treated with NaCl 0.9%), and HS (AP treated with NaCl 7.5%). RESULTS:: Trypsinogen activation peptides (TAP) and amylase activity were increased in ascitic fluid and serum and were not affected by treatment with HS. Pancreas inflammation was evaluated by increased myeloperoxidase (MPO) activity, malonyldialdehyde (MDA) formation and histopathology for severity of pancreatic lesions. HS did not affect these parameters. Expression of cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) was markedly increased in the pancreas of the AP group and was reduced by treatment with HS. This treatment also reduced the levels of TNF-alpha and IL-6 but not of IL-10 in the pancreatic tissue. CONCLUSIONS:: These results show that HS modulates cytokines production and expression of enzymes responsible for inflammatory mediators production in the pancreas without affecting the severity of the pancreatic lesions.
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23.
  • Dominguez, Mev, et al. (författare)
  • Evaluation of MLH1 I219V Polymorphism in Unrelated South American Individuals Suspected of Having Lynch Syndrome.
  • 2012
  • Ingår i: Anticancer research. - 1791-7530. ; 32:10, s. 4347-4351
  • Tidskriftsartikel (refereegranskat)abstract
    • Some single-nucleotide polymorphisms are associated with higher risk of colorectal cancer development and are suggested to explain part of the genetic contribution to Lynch syndrome. Aim: To evaluate the mutL homolog 1 (MLH1) I219V polymorphism in 124 unrelated South American individuals suspected of having Lynch syndrome, based on frequency, association with pathogenic MLH1 and mutS homolog 2 (MSH2) mutation and clinical features.
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24.
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25.
  • Fernebro, Josefin, et al. (författare)
  • Genetic profiling differentiates second primary tumors from metastases in adult metachronous soft tissue sarcoma.
  • 2008
  • Ingår i: Sarcoma. - : Hindawi Limited. - 1357-714X .- 1369-1643. ; 2008:2009 Feb 2
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose. Patients with soft tissue sarcomas (STS) are at increased risk of second primary malignancies, including a second STS, but distinction between metastases and a second primary STS is difficult. Patients and Methods. Array-based comparative genomic hybridization (aCGH) was applied to 30 multiple STS of the extremities and the trunk wall from 13 patients. Different histotypes were present with malignant fibrous histiocytomas/undifferentiated pleomorphic sarcomas being the predominant subtype. Results. aCGH profiling revealed genetic complexity with multiple gains and losses in all tumors. In an unsupervised hierarchical cluster analysis, similar genomic profiles and close clustering between the first and subsequent STS were identified in 5 cases, suggesting metastatic disease, whereas the tumors from the remaining 8 patients did not cluster and showed only weak pairwise correlation, suggesting development of second primary STS. Discussion. The similarities and dissimilarities identified in the first and second STS suggest that genetic profiles can be used to distinguish soft tissue metastases from second primary STS. The demonstration of genetically different soft tissue sarcomas in the same patient suggests independent tumor origin and serves as a reminder to consider development of second primary STS, which has prognostic and therapeutic implications.
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26.
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27.
  • Greiff, Lennart, et al. (författare)
  • Non-radical primary diagnostic biopsies affect survival in cutaneous head and neck melanoma
  • 2021
  • Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 141:3, s. 309-319
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: It is unclear if a non-radical diagnostic biopsy entails a higher risk for metastasis and poorer survival for patients with cutaneous head and neck melanoma (cHNM). Aims/objectives: To assess whether or not initial diagnostic biopsy modality and radicality (clear, positive, or narrow histopathological margins) influence recurrence and survival in patients with cHNM. Materials and methods: Histopathological radicality of initial diagnostic biopsies and outcome for 368 consecutive cHNM patients, clinically asymptomatic of metastatic disease and referred to a tertiary care academic center for sentinel lymph node staging from 2004 through 2018, were retrospectively analyzed. Results: Patients with positive (n = 133) or narrow (0.1–0.5 mm) (n = 34) histopathological margins had significantly worse loco-regional (p=.004) and distant control (p=.004) as well as lower overall (p=.017) and melanoma specific (p=.0002) survival than 201 patients with clear margins. Multivariate analysis indicated positive or narrow histopathological margins as independent negative prognostic factors for melanoma specific survival (HR 2.16, p=.015), together with deeper Breslow (HR 1.17, p=.00001) and ulceration (HR 2.49, p=.003). Conclusions and significance: Non-radical primary diagnostic biopsies increase the risk for metastatic disease and impair survival in cHNM. Accordingly, radical melanoma diagnostic procedures should be encouraged in the head and neck region when possible.
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28.
  • Harbst, Katja, et al. (författare)
  • Multiregion whole-exome sequencing uncovers the genetic evolution and mutational heterogeneity of early-stage metastatic melanoma
  • 2016
  • Ingår i: Cancer Research. - 0008-5472. ; 76:16, s. 4765-4774
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%-38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P <0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome.
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29.
  • Helkkula, Teo, et al. (författare)
  • BioMEL : a translational research biobank of melanocytic lesions and melanoma
  • 2024
  • Ingår i: BMJ Open. - 2044-6055. ; 14:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Diagnosing invasive cutaneous melanoma (CM) can be challenging due to subjectivity in distinguishing equivocal nevi, melanoma in situ and thin CMs. The underlying molecular mechanisms of progression from nevus to melanoma must be better understood. Identifying biomarkers for treatment response, diagnostics and prognostics is crucial. Using biomedical data from biobanks and population-based healthcare data, translational research can improve patient care by implementing evidence-based findings. The BioMEL biobank is a prospective, multicentre, large-scale biomedical database on equivocal nevi and all stages of primary melanoma to metastases. Its purpose is to serve as a translational resource, enabling researchers to uncover objective molecular, genotypic, phenotypic and structural differences in nevi and all stages of melanoma. The main objective is to leverage BioMEL to significantly improve diagnostics, prognostics and therapy outcomes of patients with melanoma. Methods and analysis The BioMEL biobank contains biological samples, epidemiological information and medical data from adult patients who receive routine care for melanoma. BioMEL is focused on primary and metastatic melanoma, but equivocal pigmented lesions such as clinically atypical nevi and melanoma in situ are also included. BioMEL data are gathered by questionnaires, blood sampling, tumour imaging, tissue sampling, medical records and histopathological reports. Ethics and dissemination The BioMEL biobank project is approved by the national Swedish Ethical Review Authority (Dnr. 2013/101, 2013/339, 2020/00469, 2021/01432 and 2022/02421-02). The datasets generated are not publicly available due to regulations related to the ethical review authority. Trial registration number NCT05446155.
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30.
  • Hobro, Sture, et al. (författare)
  • Dialysis as a Novel Adjuvant Treatment for Malignant Cancers
  • 2022
  • Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:20
  • Forskningsöversikt (refereegranskat)abstract
    • Cancer metabolism is characterized by an increased utilization of fermentable fuels, such as glucose and glutamine, which support cancer cell survival by increasing resistance to both oxidative stress and the inherent immune system in humans. Dialysis has the power to shift the patient from a state dependent on glucose and glutamine to a ketogenic condition (KC) combined with low glutamine levels—thereby forcing ATP production through the Krebs cycle. By the force of dialysis, the cancer cells will be deprived of their preferred fermentable fuels, disrupting major metabolic pathways important for the ability of the cancer cells to survive. Dialysis has the potential to reduce glucose levels below physiological levels, concurrently increase blood ketone body levels and reduce glutamine levels, which may further reinforce the impact of the KC. Importantly, ketones also induce epigenetic changes imposed by histone deacetylates (HDAC) activity (Class I and Class IIa) known to play an important role in cancer metabolism. Thus, dialysis could be an impactful and safe adjuvant treatment, sensitizing cancer cells to traditional cancer treatments (TCTs), potentially making these significantly more efficient.
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31.
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32.
  • Hortal, Joaquin, et al. (författare)
  • Perspectives on the use of lakes and ponds as model systems for macroecological research
  • 2014
  • Ingår i: Journal of limnology. - : Pagepress. - 1129-5767 .- 1723-8633. ; 73:Suppl. 1, s. 46-60
  • Tidskriftsartikel (refereegranskat)abstract
    • Macroecology studies large-scale patterns aiming to identify the effects of general ecological processes. Although lakes (and ponds) are particularly suited for macroecological research due to their discrete nature and non geographically-structured variability, the development of this discipline in lentic habitats is comparatively much smaller than for terrestrial environments. This is despite the interest of limnologists for large-scale phenomena, which results in the high level of development of some disciplines such as predictive limnology. Here we discuss how current state-of-the-art in macroecology may benefit from research in lentic habitats at five topics. First, by including an island biogeography analytical framework to incorporate the effects of lake origin and history on lentic biodiversity. Second, by studying local and regional effects on the latitudinal gradients of species richness. Third, by considering lakes and ponds altogether for the study of beta diversity and metacommunity structure, which is already common ground in limnological research. Fourth, by relating species traits with ecosystem structure and functioning; here we consider in particular the potential effects of body size-determined dispersal and competitive exclusion processes on lake-wide trophic organization. And fifth, by incorporating current research in functional (i.e., trait) and phylogenetic diversity to the study of community structure. We finally conclude that lentic habitats can be particularly important for the development of the most functional aspects of macroecology, due to the relative ease of studying the different biotic and abiotic components of the system separately, compared to most terrestrial systems. This can allow teasing apart many of the confounding factors that are characteristic of macroecological research, thus helping the development of future theoretical syntheses.
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33.
  • Householder, John Ethan, et al. (författare)
  • One sixth of Amazonian tree diversity is dependent on river floodplains
  • 2024
  • Ingår i: NATURE ECOLOGY & EVOLUTION. - 2397-334X. ; 8, s. 901-911
  • Tidskriftsartikel (refereegranskat)abstract
    • Amazonia's floodplain system is the largest and most biodiverse on Earth. Although forests are crucial to the ecological integrity of floodplains, our understanding of their species composition and how this may differ from surrounding forest types is still far too limited, particularly as changing inundation regimes begin to reshape floodplain tree communities and the critical ecosystem functions they underpin. Here we address this gap by taking a spatially explicit look at Amazonia-wide patterns of tree-species turnover and ecological specialization of the region's floodplain forests. We show that the majority of Amazonian tree species can inhabit floodplains, and about a sixth of Amazonian tree diversity is ecologically specialized on floodplains. The degree of specialization in floodplain communities is driven by regional flood patterns, with the most compositionally differentiated floodplain forests located centrally within the fluvial network and contingent on the most extraordinary flood magnitudes regionally. Our results provide a spatially explicit view of ecological specialization of floodplain forest communities and expose the need for whole-basin hydrological integrity to protect the Amazon's tree diversity and its function.
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34.
  • Isaksson, Karolin, et al. (författare)
  • A Population-Based Comparison of the AJCC 7th and AJCC 8th Editions for Patients Diagnosed with Stage III Cutaneous Malignant Melanoma in Sweden.
  • 2019
  • Ingår i: Annals of surgical oncology. - : Springer Science and Business Media LLC. - 1534-4681 .- 1068-9265. ; 26:9, s. 2839-2845
  • Tidskriftsartikel (refereegranskat)abstract
    • Cutaneous melanoma is steadily increasing worldwide. The new AJCC 8th edition was recently launched and introduced several changes in melanoma staging, particularly for stage III. We conducted a population-based registry study with the purpose to evaluate the impact and prognostic accuracy of the new classification in Sweden.Consecutive patients diagnosed with stage III melanoma between January 2005 and September 2017 were identified by the Swedish Melanoma Registry (SMR) and included for analyses. Patients with multiple primary melanomas were excluded. Patients were classified according to the AJCC 7th as well as the 8th edition. Melanoma-specific survival (MSS) was retrieved from the Swedish Cause of Death Registry.A total of 2067 eligible patients were identified from the SMR; 1150 patients (57%) changed stage III subgroup when reclassified according to the AJCC 8th edition. The median 5- and 10-year MSS for the whole cohort of stage III melanoma patients was 59% and 51% respectively. The MSS for substage IIIA, B, and C were all improved when patients were reclassified by using to the AJCC 8th edition. The newly defined substage IIID had the worst prognosis with a 10-year MSS of 16%.A high proportion of patients diagnosed with stage III melanoma in Sweden between 2005 and 2017 was restaged to another subgroup, when they were reclassified according to the AJCC 8th of staging manual. We established an improved MSS for all substages compared with the former AJCC 7th edition. This may have implications on decisions about adjuvant treatment.
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35.
  • Jespersen, Henrik, et al. (författare)
  • Concomitant use of pembrolizumab and entinostat in adult patients with metastatic uveal melanoma (PEMDAC study): protocol for a multicenter phase II open label study.
  • 2019
  • Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 19:1
  • Tidskriftsartikel (refereegranskat)abstract
    • While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma. Thus, metastatic uveal melanoma remains a disease with an urgent unmet medical need. Reports of treatment with immune checkpoint inhibitors have thus far been disappointing. Based on animal experiments, it is reasonable to hypothesize that the effect of immunotherapy may be augmented by epigenetic therapy. Proposed mechanisms include enhanced expression of HLA class I and cancer antigens on cancer cells, as well as suppression of myeloid suppressor cells.The PEMDAC study is a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD1 inhibitor pembrolizumab and the class I HDAC inhibitor entinostat in adult patients with metastatic uveal melanoma. Primary endpoint is objective response rate. Eligible patients have histologically confirmed metastatic uveal melanoma, ECOG performance status 0-1, measurable disease as per RECIST 1.1 and may have received any number of prior therapies, with the exception of anticancer immunotherapy. Twenty nine patients will be enrolled. Patients receive pembrolizumab 200mg intravenously every third week in combination with entinostat 5mg orally once weekly. Treatment will continue until progression of disease or intolerable toxicity or for a maximum of 24months.The PEMDAC study is the first trial to assess whether the addition of an HDAC inhibitor to anti-PD1 therapy can yield objective anti-tumoral responses in metastatic UM.ClinicalTrials.gov registration number: NCT02697630 . (Registered 3 March 2016). EudraCT registration number: 2016-002114-50.
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36.
  • Jönsson, Jenny-Maria, et al. (författare)
  • Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome.
  • 2014
  • Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 13:4, s. 537-545
  • Tidskriftsartikel (refereegranskat)abstract
    • Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to alternative preferred tumorigenic routes and suggest that genetic discriminators may be relevant for molecular diagnostics and targeted therapeutics.
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37.
  • Kirik, Ufuk, et al. (författare)
  • Discovery-based Protein Expression Profiling Identifies Distinct Subgroups and Pathways in Leiomyosarcomas.
  • 2014
  • Ingår i: Molecular Cancer Research. - 1557-3125. ; 12:12, s. 1729-1739
  • Tidskriftsartikel (refereegranskat)abstract
    • Soft tissue sarcomas (STS) are malignant tumors of mesenchymal origin. A substantial portion of these tumors exhibits complex karyotypes and lack characterized chromosomal aberrations. Owing to such properties, both histopathological and molecular classification of these tumors has been a significant challenge. This study examines the protein expression of a large number of human softtissue sarcomas, including subtype heterogeneity, using 2D-gel proteomics. In addition, detailed proteome profiles of a subset of pleomorphic STS specimens using an in-depth mass-spectrometry approach and identified subgroups within the leiomyosarcomas with distinct protein expression patterns. Pathways analysis indicates that key biological nodes like apoptosis, cytoskeleton remodeling and telomere regulation are differentially regulated among these subgroups. Finally, investigating the Kirik et al. Protein profiling of leiomyosarcoma Page 2 of 24 similarities between protein expression of leiomyosarcomas and undifferentiated pleomorphic sarcomas (UPS) revealed similar protein expression profiles for these tumors, in comparison to pleomorphic leiomyosarcomas. Implications: These results suggest that UPS tumors share a similar lineage as leiomyosarcomas, and are likely to originate from different stages of differentiation from mesenchymal stem cells to smooth muscle cells.
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38.
  • Lauss, Martin, et al. (författare)
  • Molecular patterns of resistance to immune checkpoint blockade in melanoma
  • 2024
  • Ingår i: Nature Communications. - 2041-1723. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collect biopsies from a cohort of 44 patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways are observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions have a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and T cell receptor (TCR) clonality analyses. One anti-PD1 resistant lesion harbors a distinct immune cell niche, however, anti-PD1 resistant tumors are generally immune poor with non-expanded TCR clones. Such immune poor microenvironments are associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors have reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.
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39.
  • Luize, Bruno Garcia, et al. (författare)
  • Geography and ecology shape the phylogenetic composition of Amazonian tree communities
  • 2024
  • Ingår i: JOURNAL OF BIOGEOGRAPHY. - 0305-0270 .- 1365-2699. ; 51:7, s. 1163-1184
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: Amazonia hosts more tree species from numerous evolutionary lineages, both young and ancient, than any other biogeographic region. Previous studies have shown that tree lineages colonized multiple edaphic environments and dispersed widely across Amazonia, leading to a hypothesis, which we test, that lineages should not be strongly associated with either geographic regions or edaphic forest types. Location: Amazonia. Taxon: Angiosperms (Magnoliids; Monocots; Eudicots). Methods: Data for the abundance of 5082 tree species in 1989 plots were combined with a mega-phylogeny. We applied evolutionary ordination to assess how phylogenetic composition varies across Amazonia. We used variation partitioning and Moran's eigenvector maps (MEM) to test and quantify the separate and joint contributions of spatial and environmental variables to explain the phylogenetic composition of plots. We tested the indicator value of lineages for geographic regions and edaphic forest types and mapped associations onto the phylogeny. Results: In the terra firme and v & aacute;rzea forest types, the phylogenetic composition varies by geographic region, but the igap & oacute; and white-sand forest types retain a unique evolutionary signature regardless of region. Overall, we find that soil chemistry, climate and topography explain 24% of the variation in phylogenetic composition, with 79% of that variation being spatially structured (R-2 = 19% overall for combined spatial/environmental effects). The phylogenetic composition also shows substantial spatial patterns not related to the environmental variables we quantified (R-2 = 28%). A greater number of lineages were significant indicators of geographic regions than forest types. Main Conclusion: Numerous tree lineages, including some ancient ones (>66 Ma), show strong associations with geographic regions and edaphic forest types of Amazonia. This shows that specialization in specific edaphic environments has played a long-standing role in the evolutionary assembly of Amazonian forests. Furthermore, many lineages, even those that have dispersed across Amazonia, dominate within a specific region, likely because of phylogenetically conserved niches for environmental conditions that are prevalent within regions.
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40.
  • Manning, Alisa, et al. (författare)
  • A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
  • 2017
  • Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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41.
  • Mehmeti-Ajradini, Meliha, et al. (författare)
  • Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer
  • 2020
  • Ingår i: Life Science Alliance. - 2575-1077. ; 3:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients cotransplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.
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42.
  • Mehmeti-Ajradini, Meliha, et al. (författare)
  • Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer
  • 2020
  • Ingår i: Life Science Alliance. - : LIFE SCIENCE ALLIANCE LLC. - 2575-1077. ; 3:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.
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43.
  • Mitra, Shamik, et al. (författare)
  • Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma
  • 2020
  • Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 14:5, s. 933-950
  • Tidskriftsartikel (refereegranskat)abstract
    • The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type-specific genes extracted from genome-wide methylation arrays. Unsupervised clustering identified three immune-methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss-of-function events for melanomas unresponsive to immunotherapies (immune-low). To understand if melanoma tumors resemble other solid tumors in terms of immune-methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low-dimensional projection based on immune cell type-specific methylation revealed grouping of the solid tumors in line with melanoma immune-methylation clusters rather than tumor types. Association of survival outcome with immune cell type-specific methylation differed across tumor and cell types. However, in melanomas immune-cell type-specific methylation was associated with inferior patient survival. Exploration of the immune-methylation patterns in a pan-cancer context suggested that specific immune-microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.
  •  
44.
  • Ny, Lars, 1967, et al. (författare)
  • The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma
  • 2021
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The authors report the results of the phase II PEMDAC clinical study testing the combination of the HDAC inhibitor entinostat with the anti- PD-1 antibody pembrolizumab in uveal melanoma. Low tumor burden, a wildtype BAP1 gene in the tumor or iris melanoma correlates with response and longer survival. Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. We report the results of the PEMDAC phase 2 clinical trial (n = 29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM). The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM.
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45.
  • Nyström, Helena, et al. (författare)
  • Immune-cell infiltration in high-grade soft tissue sarcomas; prognostic implications of tumor-associated macrophages and B-cells
  • 2023
  • Ingår i: Acta Oncologica. - 0284-186X. ; 62:1, s. 33-39
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Soft tissue sarcomas are rare, morphologically, and genetically heterogenous. Though the tumors display abundant tumor stroma with infiltrating immune cells, the prognostic impact of various immunologic markers in sarcoma remains poorly defined. We aimed to characterize the immune landscape of a treatment-naïve cohort of soft tissue sarcoma of the extremities and the trunk wall with correlations to metastasis-free survival. Materials and Methods: We surveyed immunohistochemical expression patterns for CD163, CD20, CD3, CD8, and FOXP3 in 134 adult high-grade leiomyosarcomas, liposarcomas, and synovial sarcomas. Results: Macrophages outnumbered tumor-infiltrating lymphocytes. High CD163 infiltration was identified in 49% of the tumors and was overrepresented (66%) in leiomyosarcoma compared to liposarcoma (46%) and synovial sarcoma (9%). Tumor-grade also correlated with CD163 positivity with high expression in 53% of the high-grade lesions and 28% in low-grade tumors. Infiltrating CD3, CD8 and FOXP3-positive T-cells were significantly more prevalent in leiomyosarcomas than in liposarcomas/synovial sarcomas. CD20+ B-cells were identified only in 14% of the STS. Correlation to established prognostic factors revealed a correlation between CD163+ macrophages and necrosis and predicted an increased risk of metastases. No correlation between CD20+ B-cells and known prognostic factors could be established, though CD20+ B-cells infiltration predicted improved overall survival. Conclusion: We confirm that tumor-infiltrating macrophages outnumber tumor-infiltrating lymphocytes in soft tissue sarcoma and signify an increased risk of metastasis. CD20+ B-cells are scarce in STS and correlate to improved survival. To date, immunotherapeutic strategies directed against T-cells have shown limited effect in soft tissue sarcoma. Our observations suggest that immunomodulatory agents focusing on macrophages may be worthwhile for further investigations in this tumor type. Further studies exploring the prognostic and predictive significance of CD20+ B cells are warranted.
  •  
46.
  • Pereira, Carla, et al. (författare)
  • Comparison of East‐Asia and West‐Europe cohorts explains disparities in survival outcomes and highlights predictive biomarkers of early gastric cancer aggressiveness
  • 2021
  • Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 150:5, s. 868-880
  • Tidskriftsartikel (refereegranskat)abstract
    • Surgical resection with lymphadenectomy and perioperative chemotherapy is the universal mainstay for curative treatment of gastric cancer (GC) patients with locoregional disease. However, GC survival remains asymmetric in West- and East-world regions. We hypothesize that this asymmetry derives from differential clinical management. Therefore, we collected chemo-naïve GC patients from Portugal and South Korea to explore specific immunophenotypic profiles related to disease aggressiveness and clinicopathological factors potentially explaining associated overall survival (OS) differences. Clinicopathological and survival data were collected from chemo-naïve surgical cohorts from Portugal (West-Europe cohort [WE-C]; n = 170) and South Korea (East-Asia cohort [EA-C]; n = 367) and correlated with immunohistochemical expression profiles of E-cadherin and CD44v6 obtained from consecutive tissue microarrays sections. Survival analysis revealed a subset of 12.4% of WE-C patients, whose tumors concomitantly express E-cadherin_abnormal and CD44v6_very high, displaying extremely poor OS, even at TNM stages I and II. These WE-C stage-I and -II patients tumors were particularly aggressive compared to all others, invading deeper into the gastric wall (P = .032) and more often permeating the vasculature (P = .018) and nerves (P = .009). A similar immunophenotypic profile was found in 11.9% of EA-C patients, but unrelated to survival. Tumours, from stage-I and -II EA-C patients, that display both biomarkers, also permeated more lymphatic vessels (P = .003), promoting lymph node (LN) metastasis (P = .019), being diagnosed on average 8 years earlier and submitted to more extensive LN dissection than WE-C. Concomitant E-cadherin_abnormal/CD44v6_very-high expression predicts aggressiveness and poor survival of stage-I and -II GC submitted to conservative lymphadenectomy.
  •  
47.
  • Sah, Vasu R., et al. (författare)
  • Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy
  • 2023
  • Ingår i: Cancer Research Communications. - : American Association For Cancer Research (AACR). - 2767-9764. ; 3:5, s. 884-895
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed.Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tu-mor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival.Results: Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of respond-ing patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling ter -tiar y lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival.Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients.Significance: The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomark-ers needing validation and become hypothesis generating for experimental research.
  •  
48.
  • Sanna, Adriana, et al. (författare)
  • DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype
  • 2022
  • Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 7:19
  • Tidskriftsartikel (refereegranskat)abstract
    • Cellular stress contributes to the capacity of melanoma cells to undergo phenotype switching into highly migratory and drug tolerant dedifferentiated states. Such dedifferentiated melanoma cell states are marked by loss of melanocyte specific gene expression and increase of mesenchymal markers. Two crucial transcription factors, MITF and SOX10, important in melanoma development and progression have been implicated in this process. In this study we describe that loss of MITF is associated with a distinct transcriptional program, MITF promoter hypermethylation and poor patient survival in metastatic melanoma. From a comprehensive collection of melanoma cell lines, we observed that MITF methylated cultures were subdivided in two distinct subtypes. Examining mRNA levels of neural crest associated genes we found that one subtype had lost the expression of several lineage genes including SOX10. Intriguingly, SOX10 loss was associated with SOX10 gene promoter hypermethylation and distinct phenotypic and metastatic properties. Depletion of SOX10 in MITF methylated melanoma cells using CRISPR/Cas9 confirmed these findings. In conclusion, this study describes the significance of melanoma state and the underlying functional properties explaining the aggressiveness of such states.
  •  
49.
  • Sanna, Adriana, et al. (författare)
  • DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype.
  • 2022
  • Ingår i: JCI insight. - : The American Society for Clinical Investigation. - 2379-3708. ; 7:19
  • Tidskriftsartikel (refereegranskat)abstract
    • Cellular stress contributes to the capacity of melanoma cells to undergo phenotype switching into highly migratory and drug-tolerant dedifferentiated states. Such dedifferentiated melanoma cell states are marked by loss of melanocyte-specific gene expression and increase of mesenchymal markers. Two crucial transcription factors, microphthalmia-associated transcription factor (MITF) and SRY-box transcription factor 10 (SOX10), important in melanoma development and progression, have been implicated in this process. In this study we describe that loss of MITF is associated with a distinct transcriptional program, MITF promoter hypermethylation, and poor patient survival in metastatic melanoma. From a comprehensive collection of melanoma cell lines, we observed that MITF-methylated cultures were subdivided in 2 distinct subtypes. Examining mRNA levels of neural crest-associated genes, we found that 1 subtype had lost the expression of several lineage genes, including SOX10. Intriguingly, SOX10 loss was associated with SOX10 gene promoter hypermethylation and distinct phenotypic and metastatic properties. Depletion of SOX10 in MITF-methylated melanoma cells using CRISPR/Cas9 supported these findings. In conclusion, this study describes the significance of melanoma state and the underlying functional properties explaining the aggressiveness of such states.
  •  
50.
  • Seinen, Jojanneke M, et al. (författare)
  • Prognostic value of proliferation in pleomorphic soft tissue sarcomas: a new look at an old measure.
  • 2012
  • Ingår i: Human Pathology. - : Elsevier BV. - 1532-8392 .- 0046-8177.
  • Tidskriftsartikel (refereegranskat)abstract
    • Though proliferation has repeatedly shown a prognostic role in sarcomas, it has not reached clinical application. We performed a comprehensive evaluation of the prognostic role of 5 proliferation measures in a large series of soft tissue sarcomas of the extremities and the trunk wall. One hundred ninety-six primary soft tissue sarcomas of the extremities and the trunk wall were subjected to DNA flow cytometry for quantification of S-phase fraction and to immunohistochemical evaluation of Ki-67, Top2a, p21, and p27Kip1. In univariate analysis, positive expression of Ki-67 (hazard ratio = 4.5, CI = 1.6-12.1), Top2a (hazard ratio = 2.2, CI = 1.2-3.5) and high S-phase fraction (hazard ratio = 1.8, CI = 1.2-3.7) significantly correlated with risk for metastasis. When combined with currently used prognostic factors, Ki-67, S-phase fraction and Top2a fraction contributed to refined identification of prognostic risk groups. Proliferation, as assessed by expression of Ki-67 and Top2a and evaluation of S-phase fraction and applied to statistical decision-tree models, provides prognostic information in soft tissue sarcomas of the extremity and trunk wall. Though proliferation contributes independently to currently applied prognosticators, its role is particularly strong when few other factors are available, which suggests a role in preoperative decision-making related to identification of high-risk individuals who would benefit from neoadjuvant therapy.
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