| 1. |
- Cong, Goh Zheng, et al.
(author)
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Targeted pancreatic beta cell imaging for early diagnosis
- 2020
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In: European Journal of Cell Biology. - : Elsevier BV. - 0171-9335 .- 1618-1298. ; 99:7
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Research review (peer-reviewed)abstract
- Pancreatic beta cells are important in blood glucose level regulation. As type 1 and 2 diabetes are getting prevalent worldwide, we need to explore new methods for early detection of beta cell-related afflictions. Using bioimaging techniques to measure beta cell mass is crucial because a decrease in beta cell density is seen in diseases such as diabetes and thus can be a new way of diagnosis for such diseases. We also need to appraise beta cell purity in transplanted islets for type 1 diabetes patients. Sufficient amount of functional beta cells must also be determined before being transplanted to the patients. In this review, indirect imaging of beta cells will be discussed. This includes membrane protein on pancreatic beta cells whereby specific probes are designed for different imaging modalities mainly magnetic resonance imaging, positron emission tomography and fluorescence imaging. Direct imaging of insulin is also explored though probes synthesized for such function are relatively fewer. The path for successful pancreatic beta cell imaging is fraught with challenges like non-specific binding, lack of beta cell-restricted targets, the requirement of probes to cross multiple lipid layers to bind to intracellular insulin. Hence, there is an urgent need to develop new imaging techniques and innovative probing constructs in the entire imaging chain of bioengineering to provide early detection of beta cell-related pathology.
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| 2. |
- Gulyas, Miklos, et al.
(author)
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Use of cholesterol and soluble tumour markers CEA and syndecan-2 in pleural effusions in cases of inconclusive cytology
- 2019
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In: Journal of Clinical Pathology. - : BMJ PUBLISHING GROUP. - 0021-9746 .- 1472-4146. ; 72:8, s. 529-535
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Journal article (peer-reviewed)abstract
- Aims In order to improve diagnostics in pleural effusions, additional value of effusion cholesterol, carcinoembryonic antigen (CEA) and syndecan-2 assays to cytology was studied. Methods Biomarkers were measured in effusion supernatants from 247 patients, of whom 126 had malignant pleural involvement, and their additional diagnostic efficacy to cytology was assessed. Results Syndecan-2 measurement, although gave detectable concentrations in all effusions with highest median value in mesotheliomas, was non-discriminative between different pathological conditions. CEA concentrations exceeding 5 ng/mL cut-off point indicated carcinomas, regardless of pleural involvement, which gave a sensitivity of 62% and specificity of 100% for carcinoma. Cholesterol concentration over 1.21 mmol/L cut-off value indicated neoplastic pleural involvement with 99% sensitivity and 'merely' 69% specificity, the latter mainly due to raised levels being associated also with benign inflammatory effusions. Combined CEA and cholesterol determinations increased the sensitivity for diagnosing carcinomatosis from 70% with cytology alone to 84% and established the correct diagnosis in 16 of 31 carcinomatosis cases with inconclusive cytology. Cholesterol measurement alone, with elevated level, in combination with absence of substantial number of inflammatory cells in effusion sediment proved to be a magnificent marker for neoplastic pleural involvement with 99% efficacy, and recognised all 36 such cases with inconclusive cytology. Conclusions Simultaneous measurement of CEA and cholesterol concentrations in effusion, or at least cholesterol alone, in combination with non-inflammatory fluid cytology, provides additional specific information about neoplastic pleural involvement, and can therefore be used as an adjunct to cytology, above all, in inconclusive cases.
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| 3. |
- Musafargani, Sikkandhar, et al.
(author)
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Blood brain barrier : A tissue engineered microfluidic chip
- 2020
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In: Journal of Neuroscience Methods. - : Elsevier BV. - 0165-0270 .- 1872-678X. ; 331
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Research review (peer-reviewed)abstract
- With the increasing concern of neurological diseases, the improvised therapy for neurodegenerative disorders such as Alzheimer's disease is crucial. Yet, the efficacious delivery of drug across blood-brain barrier (BBB) remains a formidable challenge. BBB acts as a gate keeper to prevent the ingress of harmful foreign agents into the brain. It has built a great interest in designing BBB models to boost the field of neurotherapeutics. Recently, microfluidic systems are gaining ground in cell culture and bio-system analysis. It creates a new era of micro engineered laboratory onto a chip by combining the benefits of both in vitro and in vivo models. The high-fidelity microfluidic BBB-on-a-Chip possess the engineered physiological microenvironment for real time monitoring of barrier properties with human derived stem cells. These emerging models have intrinsic merits of regulating micro-scale fluid delivery and versatile fabrication. Moreover, the progress of 3D printing technology and versatility of stem cells assist in fabricating these robust and reproducible models. This review revolves around the various approaches of modelling microfluidic BBBs and emphasises on the limitations of existing models and technology. It contributes to the interdisciplinary engineering aspects of BBB research and its magnificent impact on drug development.
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| 4. |
- Sridhar, Sriram, et al.
(author)
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An Overview of Multimodal Neuroimaging Using Nanoprobes
- 2017
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 18:2
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Research review (peer-reviewed)abstract
- Nanomaterials have gained tremendous significance as contrast agents for both anatomical and functional preclinical bio-imaging. Contrary to conventional medical practices, molecular imaging plays an important role in exploring the affected cells, thus providing precision medical solutions. It has been observed that incorporating nanoprobes improves the overall efficacy of the diagnosis and treatment processes. These nano-agents and tracers are therefore often incorporated into preclinical therapeutic and diagnostic applications. Multimodal imaging approaches are well equipped with nanoprobes to explore neurological disorders, as they can display more than one type of characteristic in molecular imaging. Multimodal imaging systems are explored by researchers as they can provide both anatomical and functional details of tumors and affected tissues. In this review, we present the state-of-the-art research concerning multimodal imaging systems and nanoprobes for neuroimaging applications.
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| 5. |
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| 6. |
- Backman, Max, et al.
(author)
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Infiltration of NK and plasma cells is associated with a distinct immune subset in non‐small cell lung cancer
- 2021
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In: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 255:3, s. 243-256
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Journal article (peer-reviewed)abstract
- Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and showed only poor association with specific mutations. The previously defined immune phenotypic patterns, desert, inflamed, and immune excluded, comprised 30, 13, and 57% of cases, respectively. Notably, mRNA immune activation and high estimated tumor mutational load were unique only for the inflamed pattern. However, in the unsupervised cluster analysis, including all immune cell markers, these conceptual patterns were only weakly reproduced. Instead, four immune classes were identified: (1) high immune cell infiltration, (2) high immune cell infiltration with abundance of CD20+ B cells, (3) low immune cell infiltration, and (4) a phenotype with an imprint of plasma cells and NK cells. This latter class was linked to better survival despite exhibiting low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, CTLA4). This compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC reveals two previously unrecognized immune classes. A refined immune classification, including traits of the humoral and innate immune response, is important to define the immunogenic potency of NSCLC in the era of immunotherapy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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| 7. |
- Backman, Max, 1987-, et al.
(author)
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Spatial immunophenotyping of the tumor microenvironment in non-small cell lung cancer
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Other publication (other academic/artistic)abstract
- Introduction: Immune cells in the tumor microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterize the spatial immune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC).Methods: We established a multiplexed fluorescence multispectral imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4 Eff), CD4 regulatory cells (CD4 Treg), CD8 effector cells (CD8 Eff), CD8 regulatory cells (CD8 Treg), B-cells, NK-cells, NKT-cells, M1 macrophages (M1), CD163+ myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs). Results: CD4 Eff cells, CD8 Eff cells, and M1 macrophages were the most abundant immune cells invading the tumor cell compartment and indicated a patient group with a favorable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4 Eff, CD4 Treg, CD8 Treg, and B-cells), as well as pDCs, were independently associated with longer survival. However, when these immune cells were located close to CD8 Treg cells, the favorable impact was attenuated. In the multivariate Cox regression model including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8 Treg–B-cells, CD8 Eff–cancer cells, and B-cells–CD4 Treg) demonstrated positive prognostic impact, while short M2–M1 distances were prognostically unfavorable.Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is also crucial for diagnostic use.
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| 8. |
- Backman, Max, 1987-, et al.
(author)
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Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer
- 2023
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In: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 185, s. 40-52
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Journal article (peer-reviewed)abstract
- Introduction: Immune cells in the tumour microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterise the spatial im-mune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC).Methods: We established a multiplexed fluorescence imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4-Eff), CD4 regulatory cells (CD4-Treg), CD8 effector cells (CD8-Eff), CD8 regulatory cells (CD8-Treg), B-cells, natural killer cells, natural killer T-cells, M1 macrophages (M1), CD163 thorn myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs).Results: CD4-Eff cells, CD8-Eff cells and M1 macrophages were the most abundant immune cells invading the tumour cell compartment and indicated a patient group with a favourable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4-Eff, CD4-Treg, CD8-Treg, B-cells and pDCs) were independently associated with longer survival. However, when these immune cells were located close to CD8-Treg cells, the favourable impact was attenuated. In the multivariable Cox regression model, including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8-Treg-B-cells, CD8-Eff-cancer cells and B-cells-CD4-Treg) demonstrated positive prognostic impact, whereas short M2-M1 distances were prognostically unfavourable.Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is crucial for diagnostic use.
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| 9. |
- Björner, Kajsa, et al.
(author)
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High iNOS and IL-1β immunoreactivity are features of colitis-associated colorectal cancer tumors, but fail to predict 5-year survival
- 2023
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In: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 128
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Journal article (peer-reviewed)abstract
- BACKGROUND: Inflammatory bowel disease (IBD; mainly ulcerative colitis and Crohn's disease) is associated with the development of colorectal cancer (CRC) referred to as colitis-associated colorectal cancer (CAC). In inflammatory flares of IBD, the production of luminal nitric oxide (NO) increases due to the increased inducible nitric oxide synthase (iNOS) activity in inflamed tissue. It is believed that iNOS parallels pro-inflammatory interleukin-1β (IL-1β). How these biomarkers relate to CAC pathogenesis or survival is unknown.AIM: The primary aim of this study was to investigate iNOS and IL-1β immunoreactivity in CAC tumors in comparison with CRC and normal colonic mucosa, and the secondary aim was to determine if immunoreactivity correlates with 5-year survival of CAC.METHODS: Immunohistochemistry was performed on tissue sections as follows: CAC (n = 59); sporadic CRC (sCRC) (n = 12); colonic mucosa >2 cm outside sCRC margin (normal mucosa) (n = 22); paracancerous IBD (pIBD) (n = 12). The expression of iNOS and IL-1β was quantified separately for epithelium and stroma. Data were evaluated using the Mann-Whitney U-test and the log-rank test for 5-year Kaplan-Meier survival curves. Results were compared with online mRNA databases.RESULTS: Immunoreactivity occurred predominantly in epithelial cells and to lesser extent in stroma. Compared with normal mucosa, immunoreactivity for iNOS (P < 0.01) and IL-1β (P < 0.005) was higher in CAC epithelium. In CAC stroma, iNOS immunoreactivity was lower than normal mucosa (P < 0.001), whereas IL-1β was higher (P < 0.05). Immunoreactivity differences of iNOS or IL-1β among CAC patients failed to correlate with 5-year survival. These findings were supported by online mRNA databases.CONCLUSION: Consistent with high NO production in IBD, there is more iNOS in CAC epithelium, albeit not in stroma. This immunoreactivity difference exists for IL-1β in both epithelium and stroma. The intervention of arginine or iNOS activity for CAC chemotherapy is not straightforward.
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| 10. |
- Braniste, Viorica, et al.
(author)
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The gut microbiota influences blood-brain barrier permeability in mice
- 2014
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In: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 6:263, s. 263ra158-
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Journal article (peer-reviewed)abstract
- Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota-BBB communication is initiated during gestation and propagated throughout life.
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| 11. |
- Brunnström, Hans, et al.
(author)
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PD-L1 immunohistochemistry in clinical diagnostics of lung cancer : inter-pathologist variability is higher than assay variability
- 2017
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In: Modern Pathology. - : NATURE PUBLISHING GROUP. - 0893-3952 .- 1530-0285. ; 30:10, s. 1411-1421
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Journal article (peer-reviewed)abstract
- Assessment of programmed cell death ligand 1 (PD-L1) immunohistochemical staining is used for decision on treatment with programmed cell death 1 and PD-L1 checkpoint inhibitors in lung adenocarcinomas and squamous cell carcinomas. This study aimed to compare the staining properties of tumor cells between the antibody clones 28-8, 22C3, SP142, and SP263 and investigate interrater variation between pathologists to see if these stainings can be safely evaluated in the clinical setting. Using consecutive sections from a tissue microarray with tumor tissue from 55 resected lung cancer cases, staining with five PD-L1 assays (28-8 from two different vendors, 22C3, SP142, and SP263) was performed. Seven pathologists individually evaluated the percentage of positive tumor cells, scoring each sample applying cutoff levels used in clinical studies: < 1% positive tumor cells (score 0), 1-4% (score 1), 5-9% (score 2), 10-24% (score 3), 25-49% (score 4), and > 50% positive tumor cells (score 5). Pairwise analysis of antibody clones showed weighted kappa values in the range of 0.45-0.91 with the highest values for comparisons with 22C3 and 28-8 and the lowest involving SP142. Excluding SP142 resulted in kappa 0.75-0.91. Weighted kappa for interobserver variation between pathologists was 0.71-0.96. Up to 20% of the cases were differently classified as positive or negative by any pathologist compared with consensus score using >= 1% positive tumor cells as cutoff. A significantly better agreement between pathologists was seen using >= 50% as cutoff (0-5% of cases). In conclusion, the concordance between the PD-L1 antibodies 22C3, 28-8 and SP263 is relatively good when evaluating lung cancers and suggests that any one of these assays may be sufficient as basis for decision on treatment with nivolumab, pembrolizumab, and durvalumab. The scoring of the pathologist presents an intrinsic source of error that should be considered especially at low PD-L1 scores.
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| 12. |
- Cedervall, Jessica, et al.
(author)
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Species-specific in vivo engraftment of the human BL melanoma cell line results in an invasive dedifferentiated phenotype not present in xenografts
- 2009
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In: Cancer Research. - 0008-5472 .- 1538-7445. ; 69:9, s. 3746-3754
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Journal article (peer-reviewed)abstract
- For clinically relevant studies on melanoma progression and invasiveness, in vivo experimental systems with a human cellular microenvironment would be advantageous. We have compared tumor formation from a human cutaneous malignant melanoma cell line (BL), after injection as conventional xenografts in the mouse, or when injected into a predominantly species-specific environment of human embryonic stem cell-derived teratoma induced in the mouse (the hEST model). The resulting melanoma histology was generally analogous, both systems showing delimited densely packed areas with pleomorphic cells of malignant appearance. A specificity of the integration process into the human embryonic teratoma tissues was indicated by the melanoma exclusively being found in areas compatible with condensed mesenchyme, similar to neural crest development. Here, also enhanced neovascularization was seen within the human mesenchymal tissues facing the BL melanoma growth. Furthermore, in the hEST model an additional melanoma cell phenotype occurred, located at the border of, or infiltrating into, the surrounding human loose mesenchymal fibrous stroma. This BL population had a desmoplastic spindle-like appearance, with markers indicative of dedifferentiation and migration. The appearance of this apparently more aggressive phenotype, as well as the induction of human angiogenesis, shows specific interactions with the human embryonic microenvironment in the hEST model. In conclusion, these data provide exciting options for using the hEST model in molecular in vivo studies on differentiation, invasiveness, and malignancy of human melanoma, while analyzing species-specific reactions in vivo.
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| 13. |
- Elfving, Hedvig, et al.
(author)
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Spatial distribution of tertiary lymphoid structures in the molecular and clinical context of non-small cell lung cancer.
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Other publication (other academic/artistic)abstract
- Tertiary lymphoid structures (TLS) are lymphocyte aggregates resembling secondary lymphoid organs and are pivotal in cancer immunity. The ambiguous morphological definition of TLS makes it challenging to ascertain their clinical impact on patient survival and response to immunotherapy. This study aimed to characterize TLS in hematoxylin-eosin tissue sections from lung cancer patients, assessing their occurrence in relation to the local immune environment, mutational background, and patient outcome.Two pathologists evaluated one whole tissue section from each resection specimen of 680 NSCLC patients. TLS were spatially quantified within the tumor area or periphery and further categorized based on the presence of germinal centers (mature TLS). Metrics were integrated with immune cell counts, genomic and transcriptomic data, and correlated with clinical parameters.Out of 536 evaluable cases, TLS were present in 86% of tumor samples, predominantly in the tumor periphery, with a median of eight TLS per case. TLS with germinal centers were found in 24% of cases. TLS presence correlated positively with increased plasma cell (CD138+) and lymphocytic cell (CD3+, CD8+, FOXP3+) infiltration. Tumors with higher tumor mutational burden (TMB) exhibited higher periphery TLS numbers. The overall TLS quantity was associated with improved patient survival, irrespective of TLS maturation status. This prognostic association held true for periphery TLS but not for tumor TLS.In conclusion, TLS occurrence in NSCLC is common and its correlation with a specific immune phenotype suggests biological relevance in the local immune reaction. The prognostic significance of this scoring system on routine hematoxylin-eosin sections has the potential to augment diagnostic algorithms for NSCLC patients.
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| 14. |
- Ericson Lindquist, Kajsa, et al.
(author)
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Difficulties in diagnostics of lung tumours in biopsies : an interpathologist concordance study evaluating the international diagnostic guidelines
- 2022
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In: Journal of Clinical Pathology. - : BMJ Publishing Group Ltd. - 0021-9746 .- 1472-4146. ; 75:5, s. 302-309
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Journal article (peer-reviewed)abstract
- AIMS: Accurate and reliable diagnosis is essential for lung cancer treatment. The study aim was to investigate interpathologist diagnostic concordance for pulmonary tumours according to WHO diagnostic criteria.METHODS: Fifty-two unselected lung and bronchial biopsies were diagnosed by a thoracic pathologist based on a broad spectrum of immunohistochemical (IHC) stainings, molecular data and clinical/radiological information. Slides stained with H&E, thyroid transcription factor-1 (TTF-1) clone SPT24 and p40 were scanned and provided digitally to 20 pathologists unaware of reference diagnoses. The pathologists independently diagnosed the cases and stated if further diagnostic markers were deemed necessary.RESULTS: In 31 (60%) of the cases, ≥80% of the pathologists agreed with each other and with the reference diagnosis. Lower agreement was seen in non-small cell neuroendocrine tumours and in squamous cell carcinoma with diffuse TTF-1 positivity. Agreement with the reference diagnosis ranged from 26 to 45 (50%-87%) for the individual pathologists. The pathologists requested additional IHC staining in 15-44 (29%-85%) of the 52 cases. In nearly half (17 of 36) of the malignant cases, one or more pathologist advocated for a different final diagnosis than the reference without need of additional IHC markers, potentially leading to different clinical treatment.CONCLUSIONS: Interpathologist diagnostic agreement is moderate for small unselected bronchial and lung biopsies based on a minimal panel of markers. Neuroendocrine morphology is sometimes missed and TTF-1 clone SPT24 should be interpreted with caution. Our results suggest an intensified education need for thoracic pathologists and a more generous use of diagnostic IHC markers.
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| 15. |
- Gertow, Karin, et al.
(author)
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Early Events in Xenograft Development from the Human Embryonic Stem Cell Line HS181-Resemblance with an Initial Multiple Epiblast Formation
- 2011
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:11, s. e27741-
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Journal article (peer-reviewed)abstract
- Xenografting is widely used for assessing in vivo pluripotency of human stem cell populations. Here, we report on early to late events in the development of mature experimental teratoma from a well-characterized human embryonic stem cell (HESC) line, HS181. The results show an embryonic process, increasingly chaotic. Active proliferation of the stem cell derived cellular progeny was detected already at day 5, and characterized by the appearance of multiple sites of engraftment, with structures of single or pseudostratified columnar epithelium surrounding small cavities. The striking histological resemblance to developing embryonic ectoderm, and the formation of epiblast-like structures was supported by the expression of the markers OCT4, NANOG, SSEA-4 and KLF4, but a lack of REX1. The early neural marker NESTIN was uniformly expressed, while markers linked to gastrulation, such as BMP-4, NODAL or BRACHYURY were not detected. Thus, observations on day 5 indicated differentiation comparable to the most early transient cell populations in human post implantation development. Confirming and expanding on previous findings from HS181 xenografts, these early events were followed by an increasingly chaotic development, incorporated in the formation of a benign teratoma with complex embryonic components. In the mature HS181 teratomas not all types of organs/tissues were detected, indicating a restricted differentiation, and a lack of adequate spatial developmental cues during the further teratoma formation. Uniquely, a kinetic alignment of rare complex structures was made to human embryos at diagnosed gestation stages, showing minor kinetic deviations between HS181 teratoma and the human counterpart.
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| 16. |
- Gulyas, Miklos, et al.
(author)
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COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.
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Journal article (peer-reviewed)abstract
- Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyse COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition.Methods: In the multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells.Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95%CI 0.81-1.27 and HR 1.12; 95%CI 0.78-1.61, respectively). Similarly, in patients with high COX-2 expression in tumor cells (n=71) or stromal cells (n=55), survival did not differ significantly between patients who received celecoxib or placebo (HR 1.07; 95%CI 0.74-1.54 and HR 0.80; 95%CI 0.56-1.15). No significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p=0.48 and 0.25, respectively).Conclusion: In this subgroup analysis of patients with advanced NSCLC, we could not detect any significant interaction between COX-2 expression in tumor or stromal cells and outcome of celecoxib treatment in addition to standard chemotherapy.
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| 17. |
- Gulyas, Miklos, et al.
(author)
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COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.
- 2018
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In: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 244-250
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Journal article (peer-reviewed)abstract
- Aim: Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyze COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition.Methods: In a multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells. For each compartment, COX-2 expression was graded as high or low, based on a product score of extension and intensity of positively stained cells.Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95% CI 0.81–1.27 and HR 1.12; 95% CI 0.78–1.61, respectively). High COX-2 scores in tumor (n = 71) or stromal cells (n = 55) was not associated with a superior survival outcome with celecoxib vs. placebo (HR =0.96, 95% CI 0.60–1.54; and HR =1.51; 95% CI 0.86–2.66), and no significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p = .48 and .25, respectively).Conclusions: In this subgroup analysis of patients with advanced NSCLC treated within the context of a randomized trial, we could not detect any interaction effect of COX-2 expression in tumor or stromal cells and the outcome of celecoxib treatment in addition to standard chemotherapy.
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| 18. |
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| 19. |
- Gulyás, Miklós
(author)
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Mesothelial differentiation, mesothelioma and tumor markers in serous cavities
- 2003
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Doctoral thesis (other academic/artistic)abstract
- Mesothelial cells covering the serous membranes are of mesodermal origin although they acquire several characteristics of epithelial cells. The cytological and histological diagnosis of malignant tumors in serous cavities is sometimes a major challenge: the main diagnostic alternatives are reactive benign mesothelium, mesothelioma and adenocarcinoma. The aims of this thesis were to improve the differential diagnosis of these conditions and to study mechanisms related to mesothelial differentiation. None of the antibodies recommended for distinguishing between mesothelioma and adenocarcinoma are entirely specific. Using logistic regression analysis the tissue immunoreactivities of 10 antibodies were ranked, 2 rejected and a panel of the best 8 retained. The optimized panel should preferably be applied in two steps, starting with the 4 diagnostically most valuable parameters. The additional diagnostic value of two biochemical assays in ascitic fluid was assessed in cases having inconclusive effusion cytology. An increased concentration of CEA indicated a carcinoma. A higher cholesterol level indicated carcinomatosis, but was not entirely specific for this condition. These two chemical assays measure different effects of tumors (CEA production versus cell disintegration), and when they were combined, increases in both parameters were specific for carcinomatosis and improved the sensitivity of "single" effusion cytology. Mesothelial cells obtained from benign effusions are not terminally differentiated and grow uniformly with a fibroblastic or epithelioid morphology in vitro. To investigate how this differentiation correlated with Wilms' tumor susceptibility gene I (WTI) and proteoglycans (PGs), their expressions were studied by semiquantitative RT-PCR. mRNAs for WTI and cell surface PGs syndecans-1, -2, -4 and glypican-1 were more abundant in epithelioid cells, while fibroblastic cells expressed more of the matrix PGs biglycan and versican. To assess the involvement of other molecules in mesothelial differentiation, suppression subtractive hybridization was used. This showed a pattern of genes coordinately regulated during this process. The genes overexpressed in fibroblastic cells were either matrix-associated or related to proliferation, while those upregulated in the epithelioid phenotype were related to a more differentiated cell type. Immunohistochemistry with available antibodies confirmed that the differences were also present in vivo at sites of mild mesothelial activation and regeneration. Since PGs and WTI were related to phenotypic differentiation in benign mesothelial cells, their expression was also studied in adenocarcinomas and mesotheliomas. Adenocarcinoma cells produced more mRNA for syndecan-1, but mesothelially derived cells expressed WTI, biglycan and larger amounts of syndecan-2. Syndecan-4 was highly expressed in all malignant cell lines, as compared to benign mesothelial ones. Versican expression was associated with a high rate of proliferation. Pilot experiments suggest that the reciprocal appearance of syndecan-1 and syndecan-2 may be a useful diagnostic marker with dominance of syndecan-2 reactivity in mesothelial tissues. In summary, these data show the role of PGs in mesothelial differentiation, and suggest that they can be used as markers to distinguish malignant mesothelioma from other conditions. The findings also indicate that epithelioid mesothelial cells may be derived from subserosal fibroblastic cells, which would then correspond to a less differentiated mesothelial phenotype.
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| 20. |
- Hashemi, Helya, et al.
(author)
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Localized IgG4-related disease manifested on the tongue : a case report
- 2021
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In: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 126:1
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Journal article (peer-reviewed)abstract
- Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect multiple organs. IgG4-RD may show a variety of initial symptoms. In the oral mucosa, lesions present as inflammatory fibrosis with a large number of IgG4-positive plasma cells. Evaluating treatment is a well-known problem in IgG4-RD due to the absence of an established assessment system. There are difficulties in defining the severity of the disease, which is why treatment is primarily based on its clinical manifestations. We present a case report of localized IgG4-RD with ulcerative and proliferative manifestations on the tongue, which clinically mimicked oral squamous cell carcinoma. A tumor-like lesion on the tongue can indicate something else other than the malignant or reactive changes commonly found in the oral mucosa. Multiple differential diagnoses of these atypical oral lesions, including localized IgG4-RD, should be considered.
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| 21. |
- Kasim, Ihsan, et al.
(author)
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A recruitment breath manoeuvre directly after endotracheal suction improves lung function : an experimental study in pigs
- 2009
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In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 114:3, s. 129-135
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Journal article (peer-reviewed)abstract
- BACKGROUND: Atelectasis occurs after a well performed endotracheal suction. Clinical studies have shown that recruitment manoeuvres added after endotracheal suction during mechanical ventilation restore lung function. Repetitive lung over-distension is, however, harmful for the lung, and the effects of adding a larger breath, recruitment breath, directly after repeated endotracheal suction were therefore investigated.METHODS: Twelve healthy anaesthetized pigs were randomized into two groups: one without and one with a recruitment breath manoeuvre (RBM), i.e. a breath 15 cmH(2)O above inspiratory pressure for 10 s during pressure-controlled ventilation. The pigs were suctioned every hour for 4 hours with an open suction system.RESULTS: At the end of the study there was a statistically significant difference between the group given RBM and that without with respect to PaCO(2), tidal volume (V(T)), and compliance (Crs). Without RBM, the PaCO(2) increased from 4.6+/-0.4 to 6.1+/-1.5 kPa, V(T) decreased from 345+/-39 to 247+/-71 mL, and Crs decreased from 28+/-6 to 18+/-5 mL/cmH(2)O. There was no change in PaCO(2) or Crs when a RBM was given. Morphological analysis revealed no differences in aeration of apical and central lung parenchyma. In the basal lung parenchyma there were, however, greater areas with normal lung parenchyma and less atelectasis after RBM.CONCLUSIONS: Atelectasis created by endotracheal suction can be opened by inflating the lung for a short duration with low pressure, without over-distension, immediately after suction.
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| 22. |
- Mattsson, Johanna Sofia Margareta, 1985-, et al.
(author)
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Prognostic impact of COX-2 in non-small cell lung cancer : a comprehensive compartment-specific evaluation of tumor and stromal cell expression
- 2015
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In: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 356:2, s. 837-845
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Journal article (peer-reviewed)abstract
- Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n = 1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n = 616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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| 23. |
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| 24. |
- Milosevic, Jelena, et al.
(author)
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High Expression of PPM1D Induces Tumors Phenotypically Similar to TP53 Loss-of-Function Mutations in Mice
- 2021
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In: Cancers. - : MDPI. - 2072-6694. ; 13:21
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Journal article (peer-reviewed)abstract
- PPM1D is a negative regulator of p53 and genomic aberrations resulting in increased activity of PPM1D have been observed in cancers of different origins, indicating that PPM1D has oncogenic properties. We established a transgenic mouse model overexpressing PPM1D and showed that these mice developed a wide variety of cancers. PPM1D-expressing mice developed tumors phenotypically and genetically similar to tumors in mice with dysfunctional p53. T-cell lymphoblastic lymphoma was the most frequent cancer observed in these mice (55%) followed by adenocarcinomas (24%), leukemia (12%) and other solid tumors including neuroblastoma. Characterization of T-cell lymphomas in mice overexpressing PPM1D demonstrates Pten-deletion and p53-accumulation similar to mice with p53 loss-of-function. Also, Notch1 mutations which are recurrently observed in T-cell acute lymphoblastic lymphoma (T-ALL) were frequently detected in PPM1D-transgenic mice. Hence, PPM1D acts as an oncogenic driver in connection with cellular stress, suggesting that the PPM1D gene status and expression levels should be investigated in TP53 wild-type tumors.
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| 25. |
- Milosevic, Jelena, et al.
(author)
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PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors
- 2020
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Other publication (other academic/artistic)abstract
- Majority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms.Here we show that p53-regulating PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. We identified that WIP1-phosphatase encoded by PPM1D, is activated by frequent segmental 17q-gain further accumulated during clonal evolution, gene-amplifications, gene-fusions or gain-of-function somatic and germline mutations. Pharmacological and genetic manipulation established WIP1 as a druggable target in neuroblastoma. Genome-scale CRISPR-Cas9 screening demonstrated PPM1D genetic dependency in TP53 wild-type neuroblastoma cell lines, and shRNA PPM1D knockdown significantly delayed in vivo tumor formation. Establishing a transgenic mouse model overexpressing PPM1D showed that these mice develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1-mutations, Pten-deletions and p53-accumulation, adenocarcinomas and PHOX2B-expressing neuroblastomas establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors.
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| 26. |
- Sun, Xiaojuan, et al.
(author)
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Proteasome inhibitor PSI induces apoptosis in human mesothelioma cells
- 2006
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In: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 232:2, s. 161-169
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Journal article (peer-reviewed)abstract
- Malignant mesothelioma is an increasingly common tumor with an almost 100% mortality rate. It is refractory to conventional treatment. We have previously shown with SSH and microarray that the mRNA expression level of proteasome is higher in epithelioid mesothelioma cell lines than in sarcomatoid ones. This study evaluates the differential apoptotic effect of proteasome inhibitors on both of these mesothelioma sub-lines. Proteasome inhibitors show substantial anti-tumor activity in some tumor cells in vitro and in vivo, but the effects on mesothelioma cells has not been studied. The viability of mesothelioma cells was reduced in a dose- and time-dependent manner by the proteasome inhibitors tested; PSI was effective with a low dose, but higher concentrations were needed for calpain inhibitor I. The epithelioid mesothelioma cells are more sensitive to the inhibitors than the sarcomatoid ones, their IC50 after 24 h of treatment with PSI being 4 and 16 microm, respectively. Other mesothelioma cell lines show similar sensitivity. PSI seemed to decrease mesothelioma viability by inducing apoptosis, as verified by cell morphology, Western blotting analysis of caspase 3 cleavage, and flow-cytometric analysis. In conclusion, PSI, a representative agent that reduces viability and induces apoptosis of mesothelioma cells, might be useful in the treatment of patients with mesothelioma, especially of epithelioid phenotype.
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| 27. |
- Thurfjell, Viktoria, et al.
(author)
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Comparison of ROS1-rearrangement detection methods in a cohort of surgically resected non-small cell lung carcinomas
- 2022
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In: Translational Lung Cancer Research (TLCR). - : AME Publishing. - 2218-6751 .- 2226-4477. ; 11:12, s. 2477-2494
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Journal article (peer-reviewed)abstract
- Background: Patients with non-small cell lung cancer (NSCLC) harboring a ROS proto-oncogene 1 (ROS1)-rearrangement respond to treatment with ROS1 inhibitors. To distinguish these rare cases, screening with immunohistochemistry (IHC) for ROS1 protein expression has been suggested. However, the reliability of such an assay and the comparability of the antibody clones has been debated. Therefore we evaluated the diagnostic performance of current detection strategies for ROS1-rearrangement in two NSCLC-patient cohorts.Methods: Resected tissue samples, retrospectively collected from consecutive NSCLC-patients surgically treated at Uppsala University Hospital were incorporated into tissue microarrays [all n=676, adenocarcinomas (AC) n=40 1, squamous cell carcinomas (SCC) n=2 13, other NSCLC n=62]. ROS1rearrangements were detected using fluorescence in situ hybridization (FISH) (Abbott Molecular; ZytoVision). In parallel, ROS1 protein expression was detected using IHC with three antibody clones (D4D6, SP384, EPMGHR2) and accuracy, sensitivity, and specificity were determined. Gene expression microarray data (Affymetrix) and RNA-sequencing data were available for a subset of patients. NanoString analyses were performed for samples with positive or ambiguous results (n=21).Results: Using FISH, 2/630 (0.3% all NSCLC; 0.5% non-squamous NSCLC) cases were positive for ROS1 fusion. Additionally, nine cases demonstrated ambiguous FISH results. Using IHC, ROS1 protein expression was detected in 24/665 (3.6% all NSCLC; 5.1% non-squamous NSCLC) cases with clone D4D6, in 18/639 (2.8% all NSCLC; 3.9% non-squamous NSCLC) cases with clone SP384, and in 1/593 (0.2% all NSCLC; 0.3% non-squamous NSCLC) case with clone EPMGHR2. Elevated RNA-levels were seen in 19/369 (5.1%) cases (Affymetrix and RNA-sequencing combined). The overlap of positive results between the assays was poor. Only one of the FISH-positive cases was positive with all antibodies and demonstrated high RNA-expression. This rearrangement was confirmed in the NanoString-assay and also in the RNA sequencing data. Other cases with high protein/RNA-expression or ambiguous FISH were negative in the NanoString-assay.Conclusions: The occurrence of ROS1 fusions is low in our cohorts. The IHC assays detected the fusions, but the accuracy varied depending on the clone. The presumably false-positive and uncertain FISH results questions this method for detection of ROS1-rearrangements. Thus, when IHC is used for screening, transcript-based assays are preferable for validation in clinical diagnostics.
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