Publications by authors named "Jenny Karlsson"

85 Publications

Differential Activation of Immune Effector Processes in Mature Compared to Immature Sacrococcygeal Teratomas.

Fetal Pediatr Pathol 2020 Oct 16:1-13. Epub 2020 Oct 16.

Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.

Objective: This study aims to characterize the molecular signatures of sacrococcygeal teratomas (SCTs). Three SCTs were analyzed with whole genome genotyping. RNA sequencing of 10 SCTs dominated by mature, immature and neuroglial elements was analyzed. Expression in SCT-samples with different elements were compared to each other and to a reference group of malignant pediatric tumors. Macrophages, T- and B-lymphocytes were detected by immunohistochemistry. : No chromosomal imbalances were detected. SCTs showed overexpression of genes involved in neurosignaling, DNA-binding molecules and pathways of early germ cells. Genes associated with immune effector processes were overexpressed in mature compared to immature SCTs, and immune cell infiltration was found predominantly around mature epithelial elements. The broad repertoire of histological elements in SCTs reflects differences in transcriptional regulation rather than differences in gene copy numbers. A paucity of immune response in immature SCTs may be a factor contributing to their uninhibited growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15513815.2020.1831661DOI Listing
October 2020

A Frequency-Multiplexed Coherent Electro-optic Memory in Rare Earth Doped Nanoparticles.

Nano Lett 2020 Oct 2;20(10):7087-7093. Epub 2020 Sep 2.

Chimie ParisTech, PSL University, CNRS, Institut de Recherche de Chimie Paris, F-75005 Paris, France.

Quantum memories for light are essential components in quantum technologies like long-distance quantum communication and distributed quantum computing. Recent studies have shown that long optical and spin coherence lifetimes can be observed in rare earth doped nanoparticles, opening exciting possibilities over bulk materials, e.g., for enhancing coupling to light and other quantum systems, and material design. Here, we report on coherent light storage in Eu:YO nanoparticles using the Stark echo modulation memory (SEMM) quantum protocol. We first measure a nearly constant Stark coefficient of 50 kHz/(V/cm) across a bandwidth of 15 GHz, which is promising for broadband operation. Storage of light is then demonstrated with an effective coherence lifetime of 5 μs. Pulses with two different frequencies are also stored, confirming frequency-multiplexing capability, and are used to demonstrate the memory high phase fidelity. These results open the way to nanoscale optical quantum memories with increased efficiency, bandwidth, and processing capabilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.nanolett.0c02200DOI Listing
October 2020

A dynamic mutational landscape associated with an inter-regionally diverse immune response in malignant rhabdoid tumour.

J Pathol 2020 09 22;252(1):22-28. Epub 2020 Jul 22.

Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.

Malignant rhabdoid tumour (MRT) is a childhood neoplasm of high malignancy characterised by biallelic mutation and/or loss of the epigenetic master regulator SMARCB1, accompanied by no or few other oncogenic drivers. In spite of their generally low mutational burden, an intratumoural T-cell response has been reported in a subset of MRTs, indicating that immune checkpoint inhibition may be considered a viable therapy option for some patients. We assess here the evolution over time and space of predicted neoantigens and indicators of immune checkpoint status in two MRT patients who progressed under treatment. Both patients showed an accumulation of novel clonal and subclonal mutations, including predicted neoantigens, in metastases compared to their inferred ancestral clones in the primary tumours. The first patient had peritoneal metastases from an MRT of the liver. Clonal deconvolution revealed polyclonal seeding from the primary tumour to a single metastatic site, followed by a local subclonal burst of mutations. The second patient had a renal MRT with multiple pulmonary metastases, each of which could be traced back to a single genetically unique founder cell, with formation of novel subclones in two metastases. Both patients showed a regionally heterogeneous landscape of predicted neoantigens and of tumour-infiltrating lymphocytes expressing CD8 and PD1. In both patients, some tumour regions fulfilled established criteria for PD-L1 positivity (> 1% of tumour cells), while others did not. This suggests that even in a tumour type like MRT, with a single driver mutation, there can be heterogeneity in neoantigen repertoire, immune response, and biomarkers for checkpoint blockade among sampled locations. This must be taken into account when assessing progressed MRT patients for checkpoint inhibition therapy. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.5490DOI Listing
September 2020

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy.

Cancer Biother Radiopharm 2020 Sep 7;35(7):497-510. Epub 2020 Apr 7.

Bayer AS, Oslo, Norway.

Targeted α therapy (TAT) offers the potential for the targeted delivery of potent α-particle-emitting radionuclides that emit high linear energy transfer radiation. This leads to a densely ionizing radiation track over a short path. Localized radiation induces cytotoxic, difficult-to-repair, clustered DNA double-strand breaks (DSBs). To date, radium-223 (Ra) is the only TAT approved for the treatment of patients with metastatic castration-resistant prostate cancer. Thorium-227 (Th), the progenitor nuclide of Ra, offers promise as a wider-ranging alternative due to the availability of efficient chelators, such as octadentate 3,2-hydroxypyridinone (3,2-HOPO). The 3,2-HOPO chelator can be readily conjugated to a range of targeting moieties, enabling the generation of new targeted thorium-227 conjugates (TTCs). This review provides a comprehensive overview of the advances in the preclinical development of TTCs for hematological cancers, including CD22-positive B cell cancers and CD33-positive leukemia, as well as for solid tumors overexpressing renal cell cancer antigen CD70, membrane-anchored glycoprotein mesothelin in mesothelioma, prostate-specific membrane antigen in prostate cancer, and fibroblast growth factor receptor 2. As the mechanism of action for TTCs is linked to the formation of DSBs, the authors also report data supporting combinations of TTCs with inhibitors of the DNA damage response pathways, including those of the ataxia telangiectasia and Rad3-related protein, and poly-ADP ribose polymerase. Finally, emerging evidence suggests that TTCs induce immunogenic cell death through the release of danger-associated molecular patterns. Based on encouraging preclinical data, clinical studies have been initiated to investigate the safety and tolerability of TTCs in patients with various cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/cbr.2020.3568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475103PMC
September 2020

Extensive Clonal Branching Shapes the Evolutionary History of High-Risk Pediatric Cancers.

Cancer Res 2020 04 10;80(7):1512-1523. Epub 2020 Feb 10.

Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.

Darwinian evolution of tumor cells remains underexplored in childhood cancer. We here reconstruct the evolutionary histories of 56 pediatric primary tumors, including 24 neuroblastomas, 24 Wilms tumors, and 8 rhabdomyosarcomas. Whole-genome copy-number and whole-exome mutational profiling of multiple regions per tumor were performed, followed by clonal deconvolution to reconstruct a phylogenetic tree for each tumor. Overall, 88% of the tumors exhibited genetic variation among primary tumor regions. This variability typically emerged through collateral phylogenetic branching, leading to spatial variability in the distribution of more than 50% (96/173) of detected diagnostically informative genetic aberrations. Single-cell sequencing of 547 individual cancer cells from eight solid pediatric tumors confirmed branching evolution to be a fundamental underlying principle of genetic variation in all cases. Strikingly, cell-to-cell genetic diversity was almost twice as high in aggressive compared with clinically favorable tumors (median Simpson index of diversity 0.45 vs. 0.88; = 0.029). Similarly, a comparison of multiregional sampling data from a total of 274 tumor regions showed that new phylogenetic branches emerge at a higher frequency per sample and carry a higher mutational load in high-risk than in low-risk tumors. Timelines based on spatial genetic variation showed that the mutations most influencing relapse risk occur at initiation of clonal expansion in neuroblastoma and rhabdomyosarcoma, whereas in Wilms tumor, they are late events. Thus, from an evolutionary standpoint, some high-risk childhood cancers are born bad, whereas others grow worse over time. SIGNIFICANCE: Different pediatric cancers with a high risk of relapse share a common generic pattern of extensively branching evolution of somatic mutations. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1512/F1.large.jpg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-3468DOI Listing
April 2020

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer.

Clin Cancer Res 2020 04 12;26(8):1985-1996. Epub 2019 Dec 12.

Bayer AG, Berlin, Germany.

Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody.

Experimental Design: PSMA-TTC was characterized for affinity, mode of action, and cytotoxic activity . Biodistribution, pharmacokinetics, and antitumor efficacy were investigated using cell line and patient-derived xenograft (PDX) models of prostate cancer.

Results: PSMA-TTC was selectively internalized into PSMA-positive cells and potently induced DNA damage, cell-cycle arrest, and apoptosis . Decrease in cell viability was observed dependent on the cellular PSMA expression levels. PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01 to 0.31 after a single injection at 300 to 500 kBq/kg in subcutaneous cell line and PDX models, including models resistant to standard-of-care drugs such as enzalutamide. Furthermore, inhibition of both cancer and cancer-induced abnormal bone growth was observed in a model mimicking prostate cancer metastasized to bone. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode of action for PSMA-TTC both and .

Conclusions: The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-2268DOI Listing
April 2020

Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with Olaparib in a BRCA2 Deficient Xenograft Model.

Pharmaceuticals (Basel) 2019 Oct 15;12(4). Epub 2019 Oct 15.

Thorium Conjugate Research, Bayer AS, Oslo 0283, Norway.

Targeted thorium-227 conjugates (TTCs) represent a novel class of therapeutic radiopharmaceuticals for the treatment of cancer. TTCs consist of the alpha particle emitter thorium-227 complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the alpha particles induce potent and selective anti-tumor activity driven by the induction of DNA damage in the target cell. Methods: The efficacy of human epidermal growth factor receptor 2 (HER2)-TTC was tested in combination in vitro and in vivo with the poly ADP ribose polymerase (PARP) inhibitor (PARPi), olaparib, in the human colorectal adenocarcinoma isogenic cell line pair DLD-1 and the knockout variant DLD-1 BRCA2 -/- Results: The in vitro combination effects were determined to be synergistic in DLD-1 BRCA2 -/- and additive in DLD-1 parental cell lines. Similarly, the in vivo efficacy of the combination was determined to be synergistic only in the DLD-1 BRCA2 -/- xenograft model, with statistically significant tumor growth inhibition at a single TTC dose of 120 kBq/kg body weight (bw) and 50 mg/kg bw olaparib (daily, i.p. for 4 weeks), demonstrating comparable tumor growth inhibition to a single TTC dose of 600 kBq/kg bw. Conclusions: This study supports the further investigation of DNA damage response inhibitors in combination with TTCs as a new strategy for the effective treatment of mutation-associated cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ph12040155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958469PMC
October 2019

Preclinical Combination Studies of an FGFR2 Targeted Thorium-227 Conjugate and the ATR Inhibitor BAY 1895344.

Int J Radiat Oncol Biol Phys 2019 10 27;105(2):410-422. Epub 2019 Jun 27.

Bayer AS, Thorium Conjugate Research, Oslo, Norway.

Purpose: Fibroblast growth factor receptor 2 (FGFR2) has been previously reported to be overexpressed in several types of cancer, whereas the expression in normal tissue is considered to be moderate to low. Thus, FGFR2 is regarded as an attractive tumor antigen for targeted alpha therapy. This study reports the evaluation of an FGFR2-targeted thorium-227 conjugate (FGFR2-TTC, BAY 2304058) comprising an anti-FGFR2 antibody, a chelator moiety covalently conjugated to the antibody, and the alpha particle-emitting radionuclide thorium-227. FGFR2-TTC was assessed as a monotherapy and in combination with the DNA damage response inhibitor ATRi BAY 1895344.

Methods And Materials: The in vitro cytotoxicity and mechanism of action were evaluated by determining cell viability, the DNA damage response marker γH2A.X, and cell cycle analyses. The in vivo efficacy was determined using human tumor xenograft models in nude mice.

Results: In vitro mechanistic assays demonstrated upregulation of γH2A.X and induction of cell cycle arrest in several FGFR2-expressing cancer cell lines after treatment with FGFR2-TTC. In vivo, FGFR2-TTC significantly inhibited tumor growth at a dose of 500 kBq/kg in the xenograft models NCI-H716, SNU-16, and MFM-223. By combining FGFR2-TTC with the ATR inhibitor BAY 1895344, an increased potency was observed in vitro, as were elevated levels of γH2A.X and inhibition of FGFR2-TTC-mediated cell cycle arrest. In the MFM-223 tumor xenograft model, combination of the ATRi BAY 1895344 with FGFR2-TTC resulted in significant tumor growth inhibition at doses at which the single agents had no effect.

Conclusions: The data provide a mechanism-based rationale for combining the FGFR2-TTC with the ATRi BAY 1895344 as a new therapeutic approach for treatment of FGFR2-positive tumors from different cancer indications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2019.06.2508DOI Listing
October 2019

Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers.

Clin Cancer Res 2019 08 7;25(15):4723-4734. Epub 2019 May 7.

Bayer AS, Oslo, Norway.

Purpose: Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted alpha therapy (TAT). Covalent attachment of a 3,2-HOPO chelator to an antibody enables specific complexation and delivery of the alpha particle emitter thorium-227 to tumor cells. Because of the high energy and short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in the tumor cell with limited damage to the surrounding tissue. We present herein the preclinical evaluation of a mesothelin (MSLN)-targeted thorium-227 conjugate, BAY 2287411. MSLN is a GPI-anchored membrane glycoprotein overexpressed in mesothelioma, ovarian, pancreatic, lung, and breast cancers with limited expression in healthy tissue.

Experimental Design: The binding activity and radiostability of BAY 2287411 were confirmed bioanalytically. The mode-of-action and antitumor potency of BAY 2287411 were investigated and in cell line and patient-derived xenograft models of breast, colorectal, lung, ovarian, and pancreatic cancer.

Results: BAY 2287411 induced DSBs, apoptotic markers, and oxidative stress, leading to reduced cellular viability. Furthermore, upregulation of immunogenic cell death markers was observed. BAY 2287411 was well-tolerated and demonstrated significant antitumor efficacy when administered via single or multiple dosing regimens . In addition, significant survival benefit was observed in a disseminated lung cancer model. Biodistribution studies showed specific uptake and retention of BAY 2287411 in tumors and enabled the development of a mechanistic pharmacokinetic/pharmacodynamic model to describe the preclinical data.

Conclusions: These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and ovarian cancer patients (NCT03507452).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-3476DOI Listing
August 2019

Synergistic Effect of a Mesothelin-Targeted Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models.

J Nucl Med 2019 09 8;60(9):1293-1300. Epub 2019 Mar 8.

Thorium Conjugate Research, Bayer American Samoa, Oslo, Norway.

Targeted Th conjugates (TTCs) represent a new class of therapeutic radiopharmaceuticals for targeted α-therapy. They comprise the α-emitter Th complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the α-particles induce antitumor activity, driven by the induction of complex DNA double-strand breaks. We hypothesized that blocking the DNA damage response (DDR) pathway should further sensitize cancer cells by inhibiting DNA repair, thereby increasing the response to TTCs. This article reports the evaluation of the mesothelin (MSLN)-TTC conjugate (BAY 2287411) in combination with several DDR inhibitors, each of them blocking different DDR pathway enzymes. MSLN is a validated cancer target known to be overexpressed in mesothelioma, ovarian, lung, breast, and pancreatic cancer, with low expression in normal tissue. In vitro cytotoxicity experiments were performed on cancer cell lines by combining the MSLN-TTC with inhibitors of ataxia telangiectasia mutated, ataxia telangiectasia and Rad3-related (ATR), DNA-dependent protein kinase, and poly[adenosine diphosphate ribose] polymerase (PARP) 1/2. Further, we evaluated the antitumor efficacy of the MSLN-TTC in combination with DDR inhibitors in human ovarian cancer xenograft models. Synergistic activity was observed in vitro for all tested inhibitors (inhibitors are denoted herein by the suffix "i") when combined with MSLN-TTC. ATRi and PARPi appeared to induce the strongest increase in potency. Further, in vivo antitumor efficacy of the MSLN-TTC in combination with ATRi or PARPi was investigated in the OVCAR-3 and OVCAR-8 xenograft models in nude mice, demonstrating synergistic antitumor activity for the ATRi combination at doses demonstrated to be nonefficacious when administered as monotherapy. The presented data support the mechanism-based rationale for combining the MSLN-TTC with DDR inhibitors as new treatment strategies in MSLN-positive ovarian cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.118.223701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735281PMC
September 2019

Clonal evolution through genetic bottlenecks and telomere attrition: Potential threats to in vitro data reproducibility.

Genes Chromosomes Cancer 2019 07 29;58(7):452-461. Epub 2018 Nov 29.

Cell Biology, Research Institute of Oncology and Hematology, The Genomic Centre for Cancer Research and Diagnosis, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.

Tissue cultures of immortalized human cells, also known as established cell lines, are broadly accessible and cost-efficient tools for biomedical research. We here review potential genetic sources of systematic error in cell line experiments due to clonal evolution in vitro. In particular, the authors highlight alterations in telomere function over prolonged culture and population bottlenecks, respectively, as two commonly overlooked phenomena that can result in significant alterations in cell line genotypes over just one or a few passages in vitro. These alterations may include changes in mutation status of oncogenes and large scale chromosomal imbalances. We introduce a simple list of factors to be avoided in order to reduce the risk of data misinterpretation due to clonal evolution, including unacknowledged in vitro selection pressures, prolonged culture per se, harsh population size reductions, experiments at early phases after establishment, and the employment of cell lines not sufficiently analyzed by high resolution genetic techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22685DOI Listing
July 2019

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis.

J Pathol 2019 01 29;247(1):86-98. Epub 2018 Nov 29.

Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.

Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock-out Irx3 /Irx5 mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was already activated in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3 cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/β-catenin-signalling. In contrast, IRX5 cells displayed activation of Hippo and non-canonical WNT-signalling and generated small tumours with abundant tubulogenesis. Our findings suggest that promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.5171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588170PMC
January 2019

Patient-Derived Xenograft Models Reveal Intratumor Heterogeneity and Temporal Stability in Neuroblastoma.

Cancer Res 2018 10 28;78(20):5958-5969. Epub 2018 Aug 28.

Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University, Lund, Sweden.

Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research. These findings underpin the complexity of PDX modeling as a means to advance translational applications against neuroblastoma. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-0527DOI Listing
October 2018

Convergent evolution of 11p allelic loss in multifocal Wilms tumors arising in WT1 mutation carriers.

Pediatr Blood Cancer 2018 11 3;65(11):e27301. Epub 2018 Jul 3.

Divison of Clinical Genetics, Department of Laboratory Medicine, BMC C13, Lund University, Lund, Sweden.

Wilms tumors in patients with constitutional WT1 mutations are examples of Knudson's tumor suppressor paradigm, with somatic inactivation of the second allele occurring through 11p loss of heterozygosity. The time point of this second hit has remained unknown. We analyzed seven Wilms tumors from two patients with constitutional WT1 mutations by whole exome sequencing and genomic array. All tumors exhibited wild type WT1 loss through uniparental isodisomy. Each tumor had a unique genomic breakpoint in 11p, typically accompanied by a private activating mutation of CTNNB1. Hence, convergent evolution rather than field carcinogenesis underlies multifocal tumors in WT1 mutation carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27301DOI Listing
November 2018

Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer.

Nat Genet 2018 07 4;50(7):944-950. Epub 2018 Jun 4.

Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.

A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored. We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern consists of subclones with very few mutations confined to a single tumor region. The second most common is a stable coexistence, over vast areas, of clones characterized by changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a clone with driver mutations or structural chromosome rearrangements emerges through a clonal sweep to dominate an anatomical region. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53 inactivation. Death from disease was limited to tumors exhibiting the two last, most dynamic patterns.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0131-yDOI Listing
July 2018

Speech outcome in young children born with unilateral cleft lip and palate treated with one- or two-stage palatal repair and the impact of early intervention.

Logoped Phoniatr Vocol 2019 Jul 25;44(2):58-66. Epub 2017 Oct 25.

a Functional Area Speech and Language Pathology , Karolinska University Hospital , Stockholm , Sweden.

Objectives: The aim of this study was to describe speech at 1, 1;6 and 3 years of age in children born with unilateral cleft lip and palate (UCLP) and relate the findings to operation method and amount of early intervention received.

Methods: A prospective trial of children born with UCLP operated with a one-stage (OS) palatal repair at 12 months or a two-stage repair (TS) with soft palate closure at 3-4 months and hard palate closure at 12 months was undertaken (Scandcleft). At 1 and 1;6 years the place and manner of articulation and number of different consonants produced in babbling were reported in 33 children. At three years of age percentage consonants correct adjusted for age (PCC-A) and cleft speech errors were assessed in 26 of the 33 children. Early intervention was not provided as part of the trial but according to the clinical routine and was extracted from patient records.

Results: At age 3, the mean PCC-A was 68% and 46% of the children produced articulation errors with no significant difference between the two groups. At one year there was a significantly higher occurrence of oral stops and anterior place consonants in the TS group. There were significant correlations between the consonant production between one and three years of age, but not with amount of early intervention received.

Conclusions: The TS method was beneficial for consonant production at age 1, but not shown at 1;6 or 3 years. Behaviourally based early intervention still needs to be evaluated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14015439.2017.1390606DOI Listing
July 2019

Targeted alpha therapy using a novel CD70 targeted thorium-227 conjugate in and models of renal cell carcinoma.

Oncotarget 2017 Aug 7;8(34):56311-56326. Epub 2017 Apr 7.

Thorium Conjugate Research, Bayer AS, Oslo, Norway.

The cell surface receptor CD70 has been previously reported as a promising target for B-cell lymphomas and several solid cancers including renal cell carcinoma. We describe herein the characterization and efficacy of a novel CD70 targeted thorium-227 conjugate (CD70-TTC) comprising the combination of the three components, a CD70 targeting antibody, a chelator moiety and the short-range, high-energy alpha-emitting radionuclide thorium-227 (Th). analysis demonstrated that the CD70-TTC retained binding affinity to its target and displayed potent and specific cytotoxicity compared to an isotype control-TTC. A biodistribution study in subcutaneous tumor-bearing nude mice using the human renal cell carcinoma cell line 786-O demonstrated significant uptake and retention with 122 ± 42% of the injected dose of Th per gram (% ID/g) remaining in the tumor seven days post dose administration compared to only 3% ID/g for the isotype control-TTC. Tumor accumulation correlated with a dose dependent and statistically significant inhibition in tumor growth compared to vehicle and isotype control-TTC groups at radioactivity doses as low as 50 kBq/kg. The CD70-TTC was well tolerated as evidenced by only modest changes in hematology and normal gain in body weight of the mice. To our knowledge, this is the first report describing molecular targeting of CD70 expressing tumors using a targeted alpha-therapy (TAT).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.16910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593563PMC
August 2017

The extracellular matrix - the under-recognized element in lung disease?

J Pathol 2016 12 28;240(4):397-409. Epub 2016 Oct 28.

Lung Biology, Department of Experimental Medical Sciences, Medical Faculty, Lund University, Lund, Sweden.

The lung is composed of airways and lung parenchyma, and the extracellular matrix (ECM) contains the main building blocks of both components. The ECM provides physical support and stability to the lung, and as such it has in the past been regarded as an inert structure. More recent research has provided novel insights revealing that the ECM is also a bioactive environment that orchestrates the cellular responses in its environs. Changes in the ECM in the airway or parenchymal tissues are now recognized in the pathological profiles of many respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Only recently have we begun to investigate whether these ECM changes result from the disease process, or whether they constitute a driving factor that orchestrates the pathological outcomes. This review summarizes our current knowledge of the alterations in the ECM in asthma, COPD, and IPF, and the contributions of these alterations to the pathologies. Emerging data suggest that alterations in the composition, folding or rigidity of ECM proteins may alter the functional responses of cells within their environs, and in so doing change the pathological outcomes. These characteristics highlight potential avenues for targeting lung pathologies in the future. This may ultimately contribute to a better understanding of chronic lung diseases, and novel approaches for finding therapeutic solutions. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.4808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129494PMC
December 2016

In Vitro and In Vivo Efficacy of a Novel CD33-Targeted Thorium-227 Conjugate for the Treatment of Acute Myeloid Leukemia.

Mol Cancer Ther 2016 10 17;15(10):2422-2431. Epub 2016 Aug 17.

Thorium Conjugate Research, Bayer AS, Oslo, Norway.

The clinical efficacy of the first approved alpha pharmaceutical, Xofigo (radium-223 dichloride, RaCl), has stimulated significant interest in the development of new alpha-particle emitting drugs in oncology. Unlike radium-223 (Ra), the parent radionuclide thorium-227 (Th) is able to form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. We describe the preparation and use of a CD33-targeted thorium-227 conjugate (CD33-TTC), which binds to the sialic acid receptor CD33 for the treatment of acute myeloid leukemia (AML). A chelator was conjugated to the CD33-targeting antibody lintuzumab via amide bonds, enabling radiolabeling with the alpha-emitter Th. The CD33-TTC induced in vitro cytotoxicity on CD33-positive cells, independent of multiple drug resistance (MDR) phenotype. After exposure to CD33-TTC, cells accumulated DNA double-strand breaks and were arrested in the G phase of the cell cycle. In vivo, the CD33-TTC demonstrated antitumor activity in a subcutaneous xenograft mouse model using HL-60 cells at a single dose regimen. Dose-dependent significant survival benefit was further demonstrated in a disseminated mouse tumor model after single dose injection or administered as a fractionated dose. The data presented support the further development of the CD33-TTC as a novel alpha pharmaceutical for the treatment of AML. Mol Cancer Ther; 15(10); 2422-31. ©2016 AACR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-16-0251DOI Listing
October 2016

A confocal optical microscope for detection of single impurities in a bulk crystal at cryogenic temperatures.

Rev Sci Instrum 2016 Mar;87(3):033701

Department of Physics, Lund University, P.O. Box 118, SE-22100 Lund, Sweden.

A compact sample-scanning confocal optical microscope for detection of single impurities below the surface of a bulk crystal at cryogenic temperatures is described. The sample, lens, and scanners are mounted inside a helium bath cryostat and have a footprint of only 19 × 19 mm. Wide field imaging and confocal imaging using a Blu-ray lens immersed in liquid helium are demonstrated with excitation at 370 nm. A spatial resolution of 300 nm and a detection efficiency of 1.6% were achieved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1063/1.4942906DOI Listing
March 2016

Aberrant epigenetic regulation in clear cell sarcoma of the kidney featuring distinct DNA hypermethylation and EZH2 overexpression.

Oncotarget 2016 Mar;7(10):11127-36

Department of Clinical Genetics, Lund University, University and Regional Laboratories, Lund, Sweden.

The global methylation profile and the mutational status of 633 specific epigenetic regulators were analyzed in the pediatric tumor clear cell sarcoma of the kidney (CCSK). Methylation array analyses of 30 CCSKs revealed CCSK tumor DNA to be globally hypermethylated compared to Wilms tumor, normal fetal kidney, and adult kidney. The aberrant methylation pattern of CCSKs was associated with activation of genes involved in embryonic processes and with silencing of genes linked to normal kidney function. No epigenetic regulator was recurrently mutated in our cohort, but a mutation in the key epigenetic regulator EZH2 was discovered in one case. EZH2 mRNA was significantly higher in CCSK compared to Wilms tumor and normal kidney, and the EZH2 protein was strongly expressed in more than 90 % of CCSK tumor cells in 9/9 tumors analyzed. This was in striking contrast to the lack of EZH2 protein expression in Wilms tumor stromal elements, indicating that EZH2 could be explored further as a diagnostic marker and a potential drug target for CCSK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.7152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905462PMC
March 2016

BCOR internal tandem duplication and YWHAE-NUTM2B/E fusion are mutually exclusive events in clear cell sarcoma of the kidney.

Genes Chromosomes Cancer 2016 Feb 23;55(2):120-3. Epub 2015 Oct 23.

Department of Clinical Genetics, Lund University, Lund, Sweden.

Clear cell sarcoma of the kidney (CCSK) is the second most common pediatric renal tumor. Two recurrent genetic aberrations have been described in CCSK. One is a fusion of YWHAE and NUTM2B/E, the other is an internal tandem duplication (ITD) in the BCOR gene. Here it is shown that YWHAE-NUTM2B/E fusion and the BCOR ITD are mutually exclusive events and activated different downstream signaling systems. This has important diagnostic implications and opens up for further mechanistic studies of CCSK pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22316DOI Listing
February 2016

ROS-induced endothelial stress contributes to pulmonary fibrosis through pericytes and Wnt signaling.

Lab Invest 2016 Feb 14;96(2):206-17. Epub 2015 Sep 14.

Unit of Lung Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden.

Pulmonary fibrosis is a grave diagnosis with insidious progression, generally considered as a consequence of aberrant epithelial wound healing and excessive scarring. This process is commonly modeled in animals by local bleomycin administration, resulting in peribronchial inflammation and subsequent fibrosis. We have previously described initiation and early development of distal pulmonary fibrosis following repeated subcutaneous bleomycin injections (systemic administration). The aim of this study was to identify mechanisms for the development of pulmonary fibrosis, which we hypothesize is related to endothelial stress and activation. Bleomycin was administered subcutaneously 3 times/week during 0.33-4w, and parenchymal alterations were studied. In addition, we used microvascular endothelial cells to investigate effects of bleomycin in vitro. Our results confirmed that systemic administration of bleomycin exerts oxidative stress indicated by an increase in Sod1 at 0.33, 1, and 4w (P<0.05). Endothelial cells were activated (increased CD106 expression) from 1w and onwards (P<0.05), and p21 expression was increased 2-3 times throughout the study (P<0.05) as were the number of β-catenin-positive nuclei (P<0.001). Wnt3a was increased at 0.33, 1, and 4w (P<0.01) and Wnt5a from 1w and onwards (P<0.001). The present study suggests that bleomycin-induced reactive oxygen species (ROS) causes DNA stress affecting the endothelial niche, initiating repair processes including Wnt signaling. The repeated systemic administrations disrupt a normally fine-tuned balance in the Wnt signaling. In addition, pericyte differentiation was affected, which may have significant effects on fibrosis due to their ability to differentiate into myofibroblasts. We conclude that the endothelial niche may have an important role in the development of pulmonary fibrosis and warrants further investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/labinvest.2015.100DOI Listing
February 2016

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.

Nat Commun 2015 Jan 27;6:6125. Epub 2015 Jan 27.

1] Department of Clinical Genetics, Lund University, Biomedical Center C13, SE22184 Lund, Sweden [2] Department of Pathology, Skåne Regional and University Laboratories, SE22185 Lund, Sweden.

Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P=0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms7125DOI Listing
January 2015

Activation of human telomerase reverse transcriptase through gene fusion in clear cell sarcoma of the kidney.

Cancer Lett 2015 Feb 3;357(2):498-501. Epub 2014 Dec 3.

Department of Clinical Genetics, BMC C13, Lund University, Lund SE 221 84, Sweden; Department of Pathology, Skåne Regional and University Laboratories, Lund SE 221 85, Sweden.

Clear cell sarcoma of the kidney (CCSK) is a rare tumor type affecting infants and young children. Most CCSKs display few genomic aberrations, and no general underlying mechanism for tumor initiation has yet been identified, although a YWHAE-NUTM2B/NUTM2E fusion gene has been observed in a minority of cases. We performed RNA-sequencing of 22 CCSKs to investigate the presence of additional fusion transcripts. The presence of the YWHAE-NUTM2B/NUTM2E fusion was confirmed in two cases. In addition, a novel IRX2-TERT fusion transcript was identified in one case. SNP-array analyses revealed the underlying event to be an interstitial deletion in the short arm of chromosome 5 (5p15.33). TERT was dramatically upregulated under the influence of the IRX2 promoter. In line with TERT expression being driven by active IRX2 regulatory elements, we found a high expression of IRX2 in CCSKs irrespective of fusion gene status. IRX2 was also expressed in human fetal kidney - the presumed tissue of origin for CCSK. We conclude that in addition to promoter mutations and epigenetic events, TERT can also be activated in tumors via formation of fusion transcripts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2014.11.057DOI Listing
February 2015

Versican in inflammation and tissue remodeling: the impact on lung disorders.

Glycobiology 2015 Mar 3;25(3):243-51. Epub 2014 Nov 3.

Lung Biology.

Versican is a proteoglycan that has many different roles in tissue homeostasis and inflammation. The biochemical structure comprises four different types of the core protein with attached glycosaminoglycans (GAGs) that can be sulfated to various extents and has the capacity to regulate differentiation of different cell types, migration, cell adhesion, proliferation, tissue stabilization and inflammation. Versican's regulatory properties are of importance during both homeostasis and changes that lead to disease progression. The GAGs that are attached to the core protein are of the chondroitin sulfate/dermatan sulfate type and are known to be important in inflammation through interactions with cytokines and growth factors. For a more complex understanding of versican, it is of importance to study the tissue niche, where the wound healing process in both healthy and diseased conditions take place. In previous studies, our group has identified changes in the amount of the multifaceted versican in chronic lung disorders such as asthma, chronic obstructive pulmonary disease, and bronchiolitis obliterans syndrome, which could be a result of pathologic, transforming growth factor β driven, on-going remodeling processes. Reversely, the context of versican in its niche is of great importance since versican has been reported to have a beneficial role in other contexts, e.g. emphysema. Here we explore the vast mechanisms of versican in healthy lung and in lung disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/glycob/cwu120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310351PMC
March 2015

Specific subsets of mesenchymal stroma cells to treat lung disorders--finding the Holy Grail.

Pulm Pharmacol Ther 2014 Dec 16;29(2):93-5. Epub 2014 Sep 16.

Lung Biology, Department of Experimental Medical Sciences, BMC D12, Lund University, Lund 221 84, Sweden.

Accumulating studies, both in animals and human clinical trials with mesenchymal stroma cells (MSC) support the hypothesis of therapeutic effects of these cells in various disorders. However, despite success in immune-mediated disorders such as Crohns' disease, lung disorders such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary disease (IPF) treated with MSC have so far not yielded a revolutionary effect on clinical symptoms. Promising data on immunomodulatory effects in COPD have kept nourishing the research into finding specific traits of MSC beneficial in disease. A heterogeneous population of injected cells might drown a potential therapeutic role of a specific group of MSC. Thus careful analysis of MSC regarding their molecular capabilities such as delivering specific therapeutic vesicles to the environment, or plain cytokine/chemokine fingerprinting might prove useful in augmenting therapies against lung diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pupt.2014.08.001DOI Listing
December 2014

Hindering and buffering factors for parental sleep in neonatal care. A phenomenographic study.

J Clin Nurs 2015 Mar 8;24(5-6):717-27. Epub 2014 Jul 8.

Department of Medicine and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.

Aims And Objectives: To explore and describe how parents of preterm and/or sick infants in neonatal care perceive their sleep.

Background: Parents experience many stressful situations when their newborn infant is preterm and/or sick. This affects bonding. By developing more family-centred care units with single-family rooms, parents are given the opportunity to stay and care for their newborn infant(s) 24 hours a day. Lack of sleep may affect new parents' ability to cope with the many challenges they face on a daily basis.

Design: A phenomenographic study with an inductive and exploratory design.

Methods: Semi-structured interviews were conducted with twelve parents of infants in neonatal care between January-March 2012. To describe variations in perception of the phenomenon, data were analysed using phenomenography.

Findings: Four descriptive categories were identified within the phenomenon sleep in parents of preterm and/or sick infants in neonatal care: impact of stress on sleep; how the environment affects sleep; keeping the family together improves sleep; and, how parents manage and prevent tiredness.

Conclusion: Anxiety, uncertainty and powerlessness have a negative influence on sleep. This can be decreased by continuous information, guidance and practical support. Skin-to-skin care was perceived as a stress-reducing factor that improved relaxation and sleep and should be encouraged by the nurse. The parents also mentioned the importance of being together. Having a private place where they could relax and take care of themselves and their newborn infant improved sleep. It was also desirable to involve older siblings in order to decrease feelings of loneliness, sadness and isolation.

Relevance For Clinical Practice: Improved parental sleep in neonatal care may help the families cope with the situation and facilitate problem-solving, emotional regulation and the transition to parenthood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jocn.12654DOI Listing
March 2015

Automated functional characterization of radiolabeled antibodies: a time-resolved approach.

Nucl Med Commun 2014 Jul;35(7):767-76

aAlgeta ASA, Oslo, Norway bBiomedical Radiation Sciences, Uppsala University cRidgeview Instruments AB, Vänge dRidgeview Diagnostics AB, Uppsala, Sweden.

Background: The number of radiolabeled monoclonal antibodies (mAbs) used for medical imaging and cancer therapy is increasing. The required chemical modification for attaching a radioactive label and all associated treatment may lead to a damaged mAb subpopulation. This paper describes a novel method, concentration through kinetics (CTK), for rapid assessment of the concentration of immunoreactive mAb and the specific radioactivity, based on monitoring binding kinetics.

Methods: The interaction of radiolabeled mAb with either the antigen or a general mAb binder such as Protein A was monitored in real time using the instrument LigandTracer. As the curvature of the binding trace has a distinct shape based on the interaction kinetics and concentration of the functional mAb, the immunoreactive mAb concentration could be calculated through reverse kinetic fitting of the binding curves, using software developed for this project. The specific activity, describing the degree of radioactive labeling, was determined through the use of calibrated signal intensities.

Results: The performance of the CTK assay was evaluated on the basis of various mAb-based interaction systems and assay formats, and it was shown that the assay can provide accurate and repeatable results for immunoreactive concentration and specific activity, with both accuracy and relative SD values below 15%.

Conclusion: By applying reverse kinetics on real-time binding traces it is possible to estimate the functional concentration and specific activity of radiolabeled mAb. The CTK assay may in the future be included as a complement to current quality assessment methods of radiolabeled mAbs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MNM.0000000000000117DOI Listing
July 2014

Clear cell sarcoma of the kidney demonstrates an embryonic signature indicative of a primitive nephrogenic origin.

Genes Chromosomes Cancer 2014 May 1;53(5):381-91. Epub 2014 Feb 1.

Department of Clinical Genetics, Lund University, University and Regional Laboratories, Lund, Sweden.

Clear cell sarcoma of the kidney (CCSK) is a tumor affecting children with a median age of 3 years at diagnosis. The cell of origin of CCSK is unknown and data on the molecular changes giving rise to CCSK is scarce. This has hindered the identification of positive diagnostic markers and development of molecularly targeted treatment protocols for CCSK. We have characterized a panel of CCSK to gain information regarding its molecular profile and possible origin. High-resolution genomic analysis with single nucleotide polymorphism array of 37 tumors did not reveal any clues to the mechanisms behind tumor development as remarkably few genetic imbalances were found. Gene expression analysis revealed a highly characteristic gene signature, enriched for pathways involved in embryonic development, including kidney formation. The presence of markers for two different developmental lineages in the embryonic kidney was therefore investigated in the tumor cells. FOXD1 which identifies cells giving rise to stromal elements, and CITED1, a marker for cells primed for nephrogenic epithelial differentiation, were both highly expressed in CCSK. In addition, the early embryonic marker OSR1 was expressed at higher levels in CCSK than in Wilms tumor, normal fetal kidney or adult kidney. As this marker discriminates the intermediate mesoderm from other mesodermal structures, our study could suggest that CCSK arises from a mesodermal cell type that retains the capacity to initiate differentiation towards both nephrons and stroma, but remains locked in a primitive state.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334316PMC
May 2014