Publications by authors named "Mattias Andersson"

54 Publications

Structured CT analysis can identify the majority of patients at risk of post-EVAR rupture.

Eur J Vasc Endovasc Surg 2022 May 10. Epub 2022 May 10.

Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Surgery, Ryhov Hospital, Jönköping, Sweden. Electronic address:

Objectives: The main objective was to report mechanisms and precursors for post-EVAR rupture. The second was to apply a structured protocol to explore if these factors were identifiable on follow-up CT prior to rupture. The third to study incidence, treatment and outcome of post-EVAR rupture.

Design: Multi-center, retrospective.

Materials: Patients treated with standard EVAR at five Swedish hospitals 2008-2018.

Methods: Patients were identified in the Swedvasc registry. Medical records were reviewed until 2020. Data of index EVAR and follow-up were recorded. The primary endpoint was post-EVAR rupture. CT at follow-up and at post-EVAR rupture were studied, using a structured protocol, to determine rupture mechanisms and identifiable precursors.

Results: In 1805 patients treated with EVAR, 45 post-EVAR ruptures occurred in 43 patients. The cumulative incidence was 2.5% over a mean follow-up of 5.2 years. The incidence rate was 4.5/1000 person years. Median time to post-EVAR rupture was 4.1 years. Another 6 cases of post-EVAR rupture in 5 patients found outside the main cohort were included in the analysis of rupture mechanisms only. The rupture mechanism was type IA in 20/51 cases (39%), IB in 20/51 (39%), and IIIA/B in 11/51 (22%). One of these had type IA+IB combined. One patient had aorto-duodenal fistula without other mechanism identified. Precursors had been noted on CT follow-up prior to post-EVAR rupture in 16/51 (31%). Retrospectively, using the structured protocol, precursors could be identified in 43/51 (84%). In 17/27 (63%) of cases missed on follow-up but retrospectively identifiable the mechanisms were type IB/III. Overall, 30-day mortality following post-EVAR rupture was 24/51 (47%) and post-operative mortality 7/33 (21%).

Conclusions: Most precursors of post-EVAR rupture are underdiagnosed, but identifiable before rupture using a structured follow-up CT protocol. Precursors of type IB and III failures caused the majority of post EVAR ruptures.
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http://dx.doi.org/10.1016/j.ejvs.2022.04.042DOI Listing
May 2022

The outcome of targeted NGS screening in patients with syndromic forms of sagittal and pansynostosis - IL11RA is an emerging core-gene for pansynostosis.

Eur J Med Genet 2022 May 21;65(5):104476. Epub 2022 Mar 21.

Department of Plastic Surgery, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden.

Here, we have studied the prevalence and spectrum of genetic alterations in syndromic forms of sagittal and pansynostosis. Eighteen patients with sagittal synostosis (isolated or combined with other synostoses, except coronal) or pansynostosis were phenotypically assessed by retrospective analysis of medical records, three-dimensional computed tomography skull reconstructions, and registered photos. Patient DNAs were analyzed using a targeted next-generation sequencing (NGS) panel including 63 craniosynostosis (CS) related genes. Pathogenic and likely pathogenic variants were found in 72% of the cases, mainly affecting FGFR2, TWIST1, IL11RA, and SKI. Two patients that were negative at NGS screening - one with a supernumerary marker chromosome with duplication of 15q25.2q26.3 and one with a pathogenic PHEX variant - were identified using microarray and single gene analysis, respectively. The overall diagnostic rate in the cohort was thus 83%. We identified two novel likely pathogenic variants in FGFR2 (NM_022970.3: c.811_812delGGinsCC, p.Gly271Pro) and TWIST1 (NM_000474.3: c.476T > A, p.Leu159His), and a novel variant of unclear phenotypic significance in RUNX2 (NM_001024630.3: c.340G > A, p.Val114Ile) which could suggest a modulatory effect. Notably, we also identified three new patients with pansynostosis and a Crouzon-like phenotype with IL11RA mutation. Targeted NGS using a broad panel of CS-related genes is a simple and powerful tool for detecting pathogenic mutations in patients with syndromic forms of CS and multiple suture involvement, in particular pansynostosis. Our results provide additional evidence of an association between pansynostosis and IL11RA, an emerging core gene for autosomal recessive CS.
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http://dx.doi.org/10.1016/j.ejmg.2022.104476DOI Listing
May 2022

Bcr-TMP, a Novel Nanomolar-Active Compound That Exhibits Both MYB- and Microtubule-Inhibitory Activity.

Cancers (Basel) 2021 Dec 23;14(1). Epub 2021 Dec 23.

Institute for Biochemistry, Westfälische-Wilhelms-Universität, 48149 Munster, Germany.

Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Here, we present the initial characterization of 2-amino-4-(3,4,5-trimethoxyphenyl)-4-naphtho[1,2-]pyran-3-carbonitrile (Bcr-TMP), a nanomolar-active MYB-inhibitory compound identified in a screen for novel MYB inhibitors. Bcr-TMP affects MYB function in a dual manner by inducing its degradation and suppressing its transactivation potential by disrupting its cooperation with co-activator p300. Bcr-TMP also interferes with the p300-dependent stimulation of C/EBPβ, a transcription factor co-operating with MYB in myeloid cells, indicating that Bcr-TMP is a p300-inhibitor. Bcr-TMP reduces the viability of AML cell lines at nanomolar concentrations and induces cell-death and expression of myeloid differentiation markers. It also down-regulates the expression of MYB target genes and exerts stronger anti-proliferative effects on MYB-addicted primary murine AML cells and patient-derived ACC cells than on their non-oncogenic counterparts. Surprisingly, we observed that Bcr-TMP also has microtubule-disrupting activity, pointing to a possible link between MYB-activity and microtubule stability. Overall, Bcr-TMP is a highly potent multifunctional MYB-inhibitory agent that warrants further investigation of its therapeutic potential and mechanism(s) of action.
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http://dx.doi.org/10.3390/cancers14010043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750090PMC
December 2021

Proteasome inhibitors suppress MYB oncogenic activity in a p300-dependent manner.

Cancer Lett 2021 11 10;520:132-142. Epub 2021 Jul 10.

Institute for Biochemistry, Westfälische-Wilhelms-Universität, Münster, Germany. Electronic address:

Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Although transcription factors are often considered un-druggable, recent work has demonstrated successful targeting of MYB by low molecular weight compounds. This has fueled the notion that inhibition of MYB has potential as a therapeutic approach against MYB-driven malignancies. Here, we have used a MYB reporter cell line to screen a library of FDA-approved drugs for novel MYB inhibitors. We demonstrate that proteasome inhibitors have significant MYB-inhibitory activity, prompting us to characterize the proteasome inhibitor oprozomib in more detail. Oprozomib was shown to interfere with the ability of the co-activator p300 to stimulate MYB activity and to exert anti-proliferative effects on human AML and ACC cells. Overall, our work demonstrated suppression of oncogenic MYB activity as a novel result of proteasome inhibition.
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http://dx.doi.org/10.1016/j.canlet.2021.07.010DOI Listing
November 2021

A population-based study of post-endovascular aortic repair rupture during 15 years.

J Vasc Surg 2021 09 20;74(3):701-710.e3. Epub 2021 Feb 20.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden.

Objective: The devastating event of a ruptured abdominal aortic aneurysm (rAAA) in patients who have survived a previous AAA repair, either elective or urgent, is a feared and quite uncommon event. It has been suggested to partly explain the loss of the early survival benefit for endovascular aortic repair (EVAR) vs open surgical repair (OSR). The main objective of this study was to report the national incidence rate, risk factors and outcome of post-EVAR ruptures. Secondarily, the national incidence rate of ruptures after OSR (post-OSR ruptures) was investigated.

Methods: We conducted a nationwide, population-based, retrospective cohort study using the inpatient and outpatient entries for all patients >40 years of age, receiving their first (index) surgical procedure for AAA, from 2001 to 2015. Only patients surviving their index procedure were included. The primary outcome was rAAA, registered after discharge from the index procedure (EVAR or OSR), identified in the Swedish National Patient Registry and the Cause of Death Registry.

Results: In total, 14,859 patients survived their primary (index) AAA procedure. There were 6470 EVAR procedures, 5893 for intact AAA (iAAA) and 577 for rAAA. Of the 6470 EVAR patients, 86 cases of post-EVAR rupture were identified, corresponding with a cumulative incidence of 1.3% over a mean follow-up time of 3.9 years. The incidence rate was 3.4 (95% confidence interval [CI], 2.7-4.2)/1000 person-years. The independent risk factors identified for post-EVAR rupture were rAAA at index surgery HR 2.4 (95% CI, 1.4-4.1, p 0.002) and age (hazard ratio, 1.1; 95% CI, 1.0-1.1; P < .001). Freedom from post-EVAR rupture was 99%, 98%, and 96% at 3, 5, and 10 years, respectively. Total and postoperative mortality after post-EVAR rupture were 42% and 17% (30 days), 45% and 22% (90 days), and 53% and 33% (1 year). The incidence rate of post-OSR rupture was 0.9/1000 person-years (95% CI, 0.7-1.2).

Conclusions: Post-EVAR rupture is a rare complication that can occur at any time after the index EVAR procedure. This finding may have implications for the discussion of limited follow-up programs and for the choice of procedure in patients with an AAA with a long life expectancy. An rAAA as the indication for the index surgery and age were identified as risk factors for post-EVAR rupture. The mortality associated with post-EVAR rupture is high, but lower than that of primary rAAA. The much lower risk of post-OSR rupture was confirmed, but must not be neglected as a possible late complication.
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http://dx.doi.org/10.1016/j.jvs.2021.01.065DOI Listing
September 2021

Paperboard Coating Detection Based on Full-Stokes Imaging Polarimetry.

Sensors (Basel) 2020 Dec 31;21(1). Epub 2020 Dec 31.

Department of Design, Mid Sweden University, 831 25 Örnsköldsvik, Sweden.

The manufacturing of high-quality extruded low-density polyethylene (PE) paperboard intended for the food packaging industry relies on manual, intrusive, and destructive off-line inspection by the process operators to assess the overall quality and functionality of the product. Defects such as cracks, pinholes, and local thickness variations in the coating can occur at any location in the reel, affecting the sealable property of the product. To detect these defects locally, imaging systems must discriminate between the substrate and the coating. We propose an active full-Stokes imaging polarimetry for the classification of the PE-coated paperboard and its substrate (before applying the PE coating) from industrially manufactured samples. The optical system is based on vertically polarized illumination and a novel full-Stokes imaging polarimetry camera system. From the various parameters obtained by polarimetry measurements, we propose implementing feature selection based on the distance correlation statistical method and, subsequently, the implementation of a support vector machine algorithm that uses a nonlinear Gaussian kernel function. Our implementation achieves 99.74% classification accuracy. An imaging polarimetry system with high spatial resolution and pixel-wise metrological characteristics to provide polarization information, capable of material classification, can be used for in-process control of manufacturing coated paperboard.
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http://dx.doi.org/10.3390/s21010208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796269PMC
December 2020

Development and Evaluation of Drug Loaded Regenerated Bacterial Cellulose-Based Matrices as a Potential Dosage Form.

Front Bioeng Biotechnol 2020 3;8:579404. Epub 2020 Dec 3.

Department of Pharmacy, COMSATS University Islamabad, Abbottabad, Pakistan.

Bacterial cellulose (BC) is a highly pure form of cellulose and possesses superior physico-mechanical properties with wide range of applications. These properties of BC can further be improved by various modifications, including its regeneration from the BC solution. In the current research work, regenerated BC (R-BC) matrices were prepared using N-methyl-morpholine-oxide (NMMO; 50% w/w solution in water) and loaded with model drugs, i.e., famotidine or tizanidine. The characterization of drug loaded regenerated BC (R-BC-drug) matrices was carried out using Fourier transform infrared spectroscopy (FTIR), x-ray diffraction (XRD) analysis, scanning electron microscopy (SEM) and thermogravimetric analysis (TGA), which revealed the stability of matrices and successful drug loading. Results of dissolution studies showed immediate (i.e., >90%) drug release in 30 min. The drugs release data was found to best fit into first order kinetics model having values >0.99 for all the formulations. These results indicated that regenerated BC-based matrices had the ability to be used for delivery of orally administered drugs.
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http://dx.doi.org/10.3389/fbioe.2020.579404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744486PMC
December 2020

Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease.

N Engl J Med 2020 12 9;383(26):2538-2546. Epub 2020 Dec 9.

From the Department of Molecular and Clinical Medicine, Institute of Medicine (J.N., P.S.) and the Department of Radiology, Institute of Clinical Sciences (K.L., M.F.), Sahlgrenska Academy, Gothenburg University, Gothenburg, the Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University (S.J., H.R.), and the Department of Surgical Sciences, Vascular Surgery, Uppsala University (B.K., B.S., G.T.), Uppsala, the Department of Clinical and Experimental Medicine, Linköping University, Linköping (Manne Andersson), Sweden and County Hospital Ryhov, Region Jönköping County, Department of Surgery, Jönköping (Manne Andersson), the Department of Vascular Surgery, Sunderby Hospital, Luleå (Mattias Andersson), the Department of Vascular Surgery, Halland Hospital, Halmstad (P.D.), the Department of Clinical Science and Education, Karolinska Institute (P.G.), the Departments of Surgery (P.G.) and Radiology (N.N.), Södersjukhuset, the Department of Radiology, Unit of Peripheral Interventional Radiology, Karolinska University Hospital (M.D., J.E.), and the Department. of Vascular Surgery, Karolinska University Hospital and the Karolinska Institute, (C.-M.W.), Stockholm, the Vascular Center, Department of Thoracic and Vascular Surgery, Skåne University Hospital, Malmö (T.F.), the Department of Vascular Surgery, Skaraborgs Hospital, Skövde (M.H.), the Department of Surgery, Kristianstad Hospital, Kristianstad (A.H.), the Department of Vascular Surgery, Växjö Hospital, Växjö (P.J.), the Department of Surgery, Gävle Hospital, Gävle (L.K.), the Department of Clinical Sciences, Faculty of Medicine (H.L.), Lund University (H.L., J.S.), Lund, the Vascular Unit, Department of Surgery, Helsingborg Hospital, Helsingborg (H.L.), the Section of Vascular Surgery, Surgical and Ear Clinic, Södra Älvsborg Hospital, Borås (K.L.), the Vascular Unit, the Department of Surgery, NU-Hospital Group, Trollhättan/Uddevalla (S.M.), the Department of Vascular Surgery, Karlstad Central Hospital, Karlstad (B.S.), the Department of Surgery, Västervik Hospital, Västervik (J.S.), the Department of Cardiothoracic and Vascular Surgery, Örebro University Hospital, Örebro (A.T.), the Department of Radiation Sciences, Radiology, Umeå University, Umeå (M.T.), the Department of Surgery, Sundsvall District Hospital, Sundsvall (J.W.), and the Department of Vascular Surgery, Kalmar Hospital, Kalmar (A.Ö.) - all in Sweden.

Background: The results of a recent meta-analysis aroused concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease.

Methods: We conducted an unplanned interim analysis of data from a multicenter, randomized, open-label, registry-based clinical trial. At the time of the analysis, 2289 patients had been randomly assigned to treatment with drug-coated devices (the drug-coated-device group, 1149 patients) or treatment with uncoated devices (the uncoated-device group, 1140 patients). Randomization was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischemia (1480 patients) or intermittent claudication (809 patients). The single end point for this interim analysis was all-cause mortality.

Results: No patients were lost to follow-up. Paclitaxel was used as the coating agent for all the drug-coated devices. During a mean follow-up of 2.49 years, 574 patients died, including 293 patients (25.5%) in the drug-coated-device group and 281 patients (24.6%) in the uncoated-device group (hazard ratio, 1.06; 95% confidence interval, 0.92 to 1.22). At 1 year, all-cause mortality was 10.2% (117 patients) in the drug-coated-device group and 9.9% (113 patients) in the uncoated-device group. During the entire follow-up period, there was no significant difference in the incidence of death between the treatment groups among patients with chronic limb-threatening ischemia (33.4% [249 patients] in the drug-coated-device group and 33.1% [243 patients] in the uncoated-device group) or among those with intermittent claudication (10.9% [44 patients] and 9.4% [38 patients], respectively).

Conclusions: In this randomized trial in which patients with peripheral artery disease received treatment with paclitaxel-coated or uncoated endovascular devices, the results of an unplanned interim analysis of all-cause mortality did not show a difference between the groups in the incidence of death during 1 to 4 years of follow-up. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT02051088.).
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http://dx.doi.org/10.1056/NEJMoa2005206DOI Listing
December 2020

Activation of PLAG1 and HMGA2 by gene fusions involving the transcriptional regulator gene NFIB.

Genes Chromosomes Cancer 2020 11 5;59(11):652-660. Epub 2020 Aug 5.

Sahlgrenska Center for Cancer Research, Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

The pleomorphic adenoma (PA), which is the most common salivary gland neoplasm, is a benign tumor characterized by recurrent chromosome rearrangements involving 8q12 and 12q14-15. We have previously shown that the PLAG1 and HMGA2 oncogenes are the targets of these rearrangements. Here, we have identified previously unrecognized subsets of PAs with ins(9;8)/t(8;9) (n = 5) and ins(9;12)/t(9;12) (n = 8) and breakpoints located in the vicinity of the PLAG1 and HMGA2 loci. RNA-sequencing and reverse transcriptase (RT)-PCR analyses of a case with an ins(9;8) revealed a novel NFIB-PLAG1 fusion in which NFIB exon 4 is linked to PLAG1 exon 3. In contrast to the developmentally regulated PLAG1 gene, NFIB was highly expressed in normal salivary gland, indicating that PLAG1 in this case, as in other variant fusions, is activated by promoter swapping. RT-PCR analysis of three PAs with t(9;12) revealed two tumors with chimeric transcripts consisting of HMGA2 exon 4 linked to NFIB exons 9 or 3 and one case with a fusion linking HMGA2 exon 3 to NFIB exon 9. The NFIB fusion events resulted in potent activation of PLAG1 and HMGA2. Analysis of the chromatin landscape surrounding NFIB revealed several super-enhancers in the 5'- and 3'-parts of the NFIB locus and its flanking sequences. These findings indicate that PLAG1 and HMGA2, similar to MYB in adenoid cystic carcinoma, may be activated by enhancer-hijacking events, in which super-enhancers in NFIB are translocated upstream of PLAG1 or downstream of HMGA2. Our results further emphasize the role of NFIB as a fusion partner to multiple oncogenes in histopathologically different types of salivary gland tumors.
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http://dx.doi.org/10.1002/gcc.22885DOI Listing
November 2020

Monensin, a novel potent MYB inhibitor, suppresses proliferation of acute myeloid leukemia and adenoid cystic carcinoma cells.

Cancer Lett 2020 06 31;479:61-70. Epub 2020 Jan 31.

Institute for Biochemistry, Westfälische-Wilhelms-Universität, D-48149, Münster, Germany. Electronic address:

The master transcriptional regulator MYB is a key oncogenic driver in several human neoplasms, particularly in acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). MYB is therefore an attractive target for drug development in MYB-activated malignancies. Here, we employed a MYB-reporter cell line and identified the polyether ionophores monensin, salinomycin, and nigericin as novel inhibitors of MYB activity. As a proof of principle, we show that monensin affects the expression of a significant number of MYB-regulated genes in AML cells and causes down-regulation of MYB expression, loss of cell viability, and induction of differentiation and apoptosis. Furthermore, monensin significantly inhibits proliferation of primary murine AML cells but not of normal hematopoietic progenitors, reflecting a high MYB-dependence of leukemic cells and underscoring the efficacy of monensin in MYB-activated malignancies. Importantly, monensin also suppressed the viability and non-adherent growth of adenoid cystic carcinoma (ACC) cells expressing MYB-NFIB fusion oncoproteins. Our data show that a single compound with significant MYB-inhibitory activity is effective against malignant cells from two distinct MYB-driven human neoplasms. Hence, monensin and related compounds are promising molecular scaffolds for development of novel MYB inhibitors.
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http://dx.doi.org/10.1016/j.canlet.2020.01.039DOI Listing
June 2020

ATR is a MYB regulated gene and potential therapeutic target in adenoid cystic carcinoma.

Oncogenesis 2020 Jan 30;9(1). Epub 2020 Jan 30.

Department of Life Sciences, Research Institute for the Environment, Health and Societies, Brunel University London, UB8 3PH, Uxbridge, UK.

Adenoid cystic carcinoma (ACC) is a rare cancer that preferentially occurs in the head and neck, breast, as well as in other sites. It is an aggressive cancer with high rates of recurrence and distant metastasis. Patients with advanced disease are generally incurable due to the lack of effective systemic therapies. Activation of the master transcriptional regulator MYB is the genomic hallmark of ACC. MYB activation occurs through chromosomal translocation, copy number gain or enhancer hijacking, and is the key driving event in the pathogenesis of ACC. However, the functional consequences of alternative mechanisms of MYB activation are still uncertain. Here, we show that overexpression of MYB or MYB-NFIB fusions leads to transformation of human glandular epithelial cells in vitro and results in analogous cellular and molecular consequences. MYB and MYB-NFIB expression led to increased cell proliferation and upregulation of genes involved in cell cycle control, DNA replication, and DNA repair. Notably, we identified the DNA-damage sensor kinase ATR, as a MYB downstream therapeutic target that is overexpressed in primary ACCs and ACC patient-derived xenografts (PDXs). Treatment with the clinical ATR kinase inhibitor VX-970 induced apoptosis in MYB-positive ACC cells and growth inhibition in ACC PDXs. To our knowledge, ATR is the first example of an actionable target downstream of MYB that could be further exploited for therapeutic opportunities in ACC patients. Our findings may also have implications for other types of neoplasms with activation of the MYB oncogene.
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http://dx.doi.org/10.1038/s41389-020-0194-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992744PMC
January 2020

NGS targeted screening of 100 Scandinavian patients with coronal synostosis.

Am J Med Genet A 2020 02 14;182(2):348-356. Epub 2019 Dec 14.

Department of Plastic Surgery, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Craniosynostosis (CS), the premature closure of one or more cranial sutures, occurs both as part of a syndrome or in isolation (nonsyndromic form). Here, we have studied the prevalence and spectrum of genetic alterations associated with coronal suture closure in 100 Scandinavian patients treated at a single craniofacial unit. All patients were phenotypically assessed and analyzed with a custom-designed 63 gene NGS-panel. Most cases (78%) were syndromic forms of CS. Pathogenic and likely pathogenic variants explaining the phenotype were found in 80% of the families with syndromic CS and in 14% of those with nonsyndromic CS. Sixty-five percent of the families had mutations in the CS core genes FGFR2, TWIST1, FGFR3, TCF12, EFNB1, FGFR1, and POR. Five novel pathogenic/likely pathogenic variants in TWIST1, TCF12, and EFNB1 were identified. We also found novel variants in SPECC1L, IGF1R, and CYP26B1 with a possible modulator phenotypic effect. Our findings demonstrate that NGS targeted sequencing is a powerful tool to detect pathogenic mutations in patients with coronal CS and further emphasize the importance of thorough assessment of the patient's phenotype for reliable interpretation of the molecular findings. This is particularly important in patients with complex phenotypes and rare forms of CS.
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http://dx.doi.org/10.1002/ajmg.a.61427DOI Listing
February 2020

Clinical and genomic features of adult and paediatric acute leukaemias with ophthalmic manifestations.

BMJ Open Ophthalmol 2019 3;4(1):e000362. Epub 2019 Oct 3.

Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Objective: To describe the clinicopathological and genomic features of nine patients with primary and secondary orbital/ocular manifestations of leukaemia.

Methods: All orbital/ocular leukaemic specimens from 1980 to 2009 were collected from the Danish Register of Pathology. In six cases, medical records and formalin-fixed, paraffin-embedded blocks were available. Three cases from the Department of Pathology, Royal Liverpool University Hospital, were also included. Immunophenotypes and MYB oncoprotein expression were ascertained by immunohistochemistry. Genomic imbalances were analysed with comparative genomic hybridisation arrays and oncogene rearrangements with fluorescence in situ hybridisation.

Results: Four patients had B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) and five had acute myeloid leukaemia (AML). Two patients with BCP-ALL and one with AML had primary orbital manifestations of leukaemia. Common symptoms were proptosis, displacement of the eye, and reduced eye mobility in patients with orbital leukaemias and pain, and reduced visual acuity in patients with ocular leukaemias. All patients with primary orbital lesions were alive up to 18 years after diagnosis. All but one patient with secondary ophthalmic manifestations died of relapse/disseminated disease. and were rearranged in BCP-ALL, and and in AML. Genomic profiling revealed quiet genomes (0-7 aberrations/case). The MYB oncoprotein was overexpressed in the majority of cases.

Conclusions: Leukaemias with and without ophthalmic manifestations have similar immunophenotypes, translocations/gene fusions and copy number alterations. Awareness of the clinical spectrum of leukaemic lesions of the eye or ocular region is important to quickly establish the correct diagnosis and commence prompt treatment.
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http://dx.doi.org/10.1136/bmjophth-2019-000362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797369PMC
October 2019

IGF2/IGF1R Signaling as a Therapeutic Target in MYB-Positive Adenoid Cystic Carcinomas and Other Fusion Gene-Driven Tumors.

Cells 2019 08 16;8(8). Epub 2019 Aug 16.

Sahlgrenska Cancer Center, Department of Pathology, University of Gothenburg, 405 30 Gothenburg, Sweden.

Chromosome rearrangements resulting in pathogenetically important gene fusions are a common feature of many cancers. They are often potent oncogenic drivers and have key functions in central cellular processes and pathways and encode transcription factors, transcriptional co-regulators, growth factor receptors, tyrosine kinases, and chromatin modifiers. In addition to being useful diagnostic biomarkers, they are also targets for development of new molecularly targeted therapies. Studies in recent decades have shown that several oncogenic gene fusions interact with the insulin-like growth factor (IGF) signaling pathway. For example, the MYB-NFIB fusion in adenoid cystic carcinoma is regulated by IGF1R through an autocrine loop, and IGF1R is a downstream target of the EWSR1-WT1 and PAX3-FKHR fusions in desmoplastic small round cell tumors and alveolar rhabdomyosarcoma, respectively. Here, we will discuss the mechanisms behind the interactions between oncogenic gene fusions and the IGF signaling pathway. We will also discuss the role of therapeutic inhibition of IGF1R in fusion gene driven malignancies.
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http://dx.doi.org/10.3390/cells8080913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721700PMC
August 2019

Clinical, genetic and experimental studies of the Brooke-Spiegler (CYLD) skin tumor syndrome.

J Plast Surg Hand Surg 2019 Apr 24;53(2):71-75. Epub 2019 Jan 24.

a Sahlgrenska Cancer Center, Department of Pathology , University of Gothenburg , Gothenburg , Sweden.

Brooke-Spiegler syndrome (BSS; a.k.a. tuban tumor syndrome) is an autosomal dominant inherited skin disorder caused by germline mutations in the CYLD tumor suppressor gene. BSS is characterized by multiple skin adnexal tumors, mainly cylindromas and spiradenomas on the head and neck. The tumors are often severely disfiguring and require repeated surgical interventions. Here, we describe a four-generation BSS-family with a novel germline c.1613_1614delGC CYLD mutation that introduces a premature STOP codon predicted to result in a truncated, inactivated CYLD protein. In addition, we present a pilot study describing establishment of the first patient-derived xenografts (PDXs) from cutaneous CYLD-defective cylindromas. Fresh tumor tissues from cylindromas were transplanted into immunocompromised mice to generate PDXs. One xenograft showed progressive tumor growth after 3 months whereas the others remained unchanged in size during the 6 months study period. Histopathological and immunohistochemical analyses of the PDXs revealed that they recapitulate the histological and molecular features of their respective primary tumors, including expression of NTRK3 and the oncogenic driver MYB. In summary, we present the first preclinical BSS-model that morphologically and genetically recapitulates human CYLD-defective cylindromas. This model will be useful for preclinical therapeutic drug testing and for further studies of the molecular pathogenesis of inherited cylindromas.
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http://dx.doi.org/10.1080/2000656X.2018.1547736DOI Listing
April 2019

Estrous detection by continuous measurements of vaginal temperature and conductivity with supervised machine learning in cattle.

Theriogenology 2019 Jan 27;123:90-99. Epub 2018 Sep 27.

National Institute of Animal Health, National Agriculture and Food Research Organization, Tsukuba, Ibaraki, 305-0856, Japan. Electronic address:

This study aimed to evaluate the effectiveness of estrous detection technique based on continuous measurements of vaginal temperature (VT) and conductivity (VC) with supervised machine learning in cattle. The VT and VC of 17 cows in tie-stalls were measured using our developed wearable vaginal sensor from Day 11 (Day 0 = ovulation day) to Day 11 of the subsequent estrous cycle at 15-min interval. After the maximum VT and VC were extracted hourly, their changes were expressed as residual VT (rVT = actual VT - mean VT for the same time on the previous 3 days) and as VC ratio (VCr = actual VC/mean VC for the same time on Day 11-13), respectively, and were used for analysis. Trans-rectal ultrasonography was performed to monitor ovarian structure changes. The plasma concentrations of reproductive hormones (progesterone: P, estradiol-17β: E, and LH) were measured in the experimental period. Standing estrus was confirmed by testing with herd mates at 3-h interval. The rVT decreased transiently, which coincided with decreasing P a few days before estrus, and a sharp increase was associated with LH surge during estrus. The VCr increased as estrus approached, corresponding with decreasing P and increasing E and LH. After noise reduction, features, possible to follow-up estrus-associated changes in rVT and VCr, were extracted and used for developing estrous detection models; 9 models were developed with 3 feature sets (features extracted from rVT alone, VCr alone, and combination of rVT and VCr) and 3 machine learning algorithms (decision tree: DT, support vector machine: SVM, and artificial neural network: ANN). Cross-validation showed that models using the features from the combination of rVT and VCr showed better performance in terms of sensitivity and precision than those using features from VCr alone, and precision than those of using features from rVT alone. Within the models using the features from the combination of rVT and VCr, sensitivity and precision of the model generated by ANN were numerically, but not statistically, higher than those generated by DT and SVM. Of 17 estruses, 16 were detected, with one false positive, when the best model was used. Furthermore, both mean and variance of the interval from the beginning of the estrous detection alert to ovulation (27.3 ± 6.7 h, mean ± SD of 16 estruses) were not significantly different to those from the onset of standing estrus to ovulation (30.8 ± 5.8 h, n = 17), indicating that the estrus can be detected real-time by the present technique. Hence, the estrous detection technique based on continuous measurements of VT and VC with supervised machine learning has a potential for efficient and accurate estrous detection in cattle.
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http://dx.doi.org/10.1016/j.theriogenology.2018.09.038DOI Listing
January 2019

Targeting the Oncogenic Transcriptional Regulator MYB in Adenoid Cystic Carcinoma by Inhibition of IGF1R/AKT Signaling.

J Natl Cancer Inst 2017 09;109(9)

Sahlgrenska Cancer Center, Department of Pathology and Genetics, University of Gothenburg, Gothenburg, Sweden; Preclinical Research, South Texas Accelerated Research Therapeutics, San Antonio, TX.

Background: Adenoid cystic carcinoma (ACC) is an aggressive cancer with no curative treatment for patients with recurrent/metastatic disease. The MYB-NFIB gene fusion is the main genomic hallmark and a potential therapeutic target.

Methods: Oncogenic signaling pathways were studied in cultured cells and/or tumors from 15 ACC patients. Phospho-receptor tyrosine kinase (RTK) arrays were used to study the activity of RTKs. Effects of RTK inhibition on cell proliferation were analyzed with AlamarBlue, sphere assays, and two ACC xenograft models (n = 4-9 mice per group). The molecular effects of MYB-NFIB knockdown and IGF1R inhibition were studied with quantitative polymerase chain reaction, immunoblot, and gene expression microarrays. All statistical tests were two-sided.

Results: The MYB-NFIB fusion drives proliferation of ACC cells and is crucial for spherogenesis. Intriguingly, the fusion is regulated through AKT-dependent signaling induced by IGF1R overexpression and is downregulated upon IGF1R-inhibition (% expression of control ± SD = 27.2 ± 1.3, P < .001). MYB-NFIB regulates genes involved in cell cycle control, DNA replication/repair, and RNA processing. The transcriptional program induced by MYB-NFIB affects critical oncogenic mediators normally controlled by MYC and is reversed by pharmacological inhibition of IGF1R. Co-activation of epidermal growth factor receptor (EGFR) and MET promoted proliferation of ACC cells, and combined targeting of IGFR1/EGFR/MET induced differentiation and synergistically inhibited the growth of patient-derived xenografted ACCs (ACCX5M1, % growth of control ± SD = 34.9 ± 20.3, P = .006; ACCX6, % growth of control ± SD = 24.1 ± 17.5, P = .04).

Conclusions: MYB-NFIB is an oncogenic driver and a key therapeutic target in ACC that is regulated by AKT-dependent IGF1R signaling. Our studies uncover a new strategy to target an oncogenic transcriptional master regulator and provide new important insights into the biology and treatment of ACC.
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http://dx.doi.org/10.1093/jnci/djx017DOI Listing
September 2017

Genomic imbalances and fusion in synchronous bilateral adenoid cystic carcinoma and invasive lobular carcinoma of the breast.

Mol Clin Oncol 2017 Sep 18;7(3):322-326. Epub 2017 Jul 18.

Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.

The incidence of synchronous bilateral breast carcinomas (BBCs) has increased with a more frequent use of magnetic resonance imaging screening of the contralateral breast in women with newly diagnosed breast cancer. A total of 30% of all BBCs occur synchronously. In the present study, we describe a unique case of synchronous BBC in a 59-year-old previously healthy woman with no known family history of breast or ovarian cancer. At the time of diagnosis the patient had an invasive lobular carcinoma (ILC) in the right breast and an adenoid cystic carcinoma (ACC) in the left breast. To the best of our knowledge, this is the first published case of bilateral, simultaneously occurring ACC and ILC of the breast. Genome-wide genomic profiling of the tumors revealed that they had distinctly different genomic imbalances. The ACC had a 5.7 Mb interstitial 6q deletion with a breakpoint located in the 3'-part of , resulting in loss of the last coding exon of and its 3'-UTR. RT-PCR analysis confirmed that the tumor expressed an ACC-specific fusion transcript. In contrast, the ILC had no rearrangements of 6q or gene fusion but showed instead gain of 1q21.1-qter, loss of 16q11.2-qter, and 22q12.2-q12.3 as the sole genomic imbalances. Notably, concurrent gains of 1q and losses of 16q are characteristic features of ILC. Collectively, our findings indicate that the ACC and ILC had originated independently of each other and that the fusion is a specific biomarker for breast ACC.
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http://dx.doi.org/10.3892/mco.2017.1330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582535PMC
September 2017

Forage plants of an Arctic-nesting herbivore show larger warming response in breeding than wintering grounds, potentially disrupting migration phenology.

Ecol Evol 2017 04 19;7(8):2652-2660. Epub 2017 Mar 19.

Department of Animal Ecology Netherlands Institute of Ecology (NIOO) Wageningen The Netherlands.

During spring migration, herbivorous waterfowl breeding in the Arctic depend on peaks in the supply of nitrogen-rich forage plants, following a "green wave" of grass growth along their flyway to fuel migration and reproduction. The effects of climate warming on forage plant growth are expected to be larger at the Arctic breeding grounds than in temperate wintering grounds, potentially disrupting this green wave and causing waterfowl to mistime their arrival on the breeding grounds. We studied the potential effect of climate warming on timing of food peaks along the migratory flyway of the Russian population of barnacle geese using a warming experiment with open-top chambers. We measured the effect of 1.0-1.7°C experimental warming on forage plant biomass and nitrogen concentration at three sites along the migratory flyway (temperate wintering site, temperate spring stopover site, and Arctic breeding site) during 2 months for two consecutive years. We found that experimental warming increased biomass accumulation and sped up the decline in nitrogen concentration of forage plants at the Arctic breeding site but not at temperate wintering and stop-over sites. Increasing spring temperatures in the Arctic will thus shorten the food peak of nitrogen-rich forage at the breeding grounds. Our results further suggest an advance of the local food peak in the Arctic under 1-2°C climate warming, which will likely cause migrating geese to mistime their arrival at the breeding grounds, particularly considering the Arctic warms faster than the temperate regions. The combination of a shorter food peak and mistimed arrival is likely to decrease goose reproductive success under climate warming by reducing growth and survival of goslings after hatching.
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http://dx.doi.org/10.1002/ece3.2859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395431PMC
April 2017

Exfoliated MoS2 in Water without Additives.

PLoS One 2016 27;11(4):e0154522. Epub 2016 Apr 27.

Department of Natural Sciences, Mid Sweden University, Sundsvall, Sweden.

Many solution processing methods of exfoliation of layered materials have been studied during the last few years; most of them are based on organic solvents or rely on surfactants and other funtionalization agents. Pure water should be an ideal solvent, however, it is generally believed, based on solubility theories that stable dispersions of water could not be achieved and systematic studies are lacking. Here we describe the use of water as a solvent and the stabilization process involved therein. We introduce an exfoliation method of molybdenum disulfide (MoS2) in pure water at high concentration (i.e., 0.14 ± 0.01 g L-1). This was achieved by thinning the bulk MoS2 by mechanical exfoliation between sand papers and dispersing it by liquid exfoliation through probe sonication in water. We observed thin MoS2 nanosheets in water characterized by TEM, AFM and SEM images. The dimensions of the nanosheets were around 200 nm, the same range obtained in organic solvents. Electrophoretic mobility measurements indicated that electrical charges may be responsible for the stabilization of the dispersions. A probability decay equation was proposed to compare the stability of these dispersions with the ones reported in the literature. Water can be used as a solvent to disperse nanosheets and although the stability of the dispersions may not be as high as in organic solvents, the present method could be employed for a number of applications where the dispersions can be produced on site and organic solvents are not desirable.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154522PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847868PMC
March 2017

The landscape of gene fusions and somatic mutations in salivary gland neoplasms - Implications for diagnosis and therapy.

Oral Oncol 2016 06 18;57:63-9. Epub 2016 Apr 18.

Sahlgrenska Cancer Center, Department of Pathology, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.

Recent studies of the genomic landscape of salivary gland tumors have provided important insights into the molecular pathogenesis of these tumors. The most consistent alterations identified include a translocation-generated gene fusion network involving transcription factors, transcriptional coactivators, tyrosine kinase receptors, and other kinases. In addition, next-generation sequencing studies of a few subtypes of salivary neoplasms have revealed hotspot mutations in individual genes and mutations clustering to specific pathways frequently altered in cancer. Although limited, these studies have opened up new avenues for improved classification and targeted therapies of salivary gland cancers. In this review, we summarize the latest developments in this field, focusing on tumor types for which clinically important molecular data are available.
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http://dx.doi.org/10.1016/j.oraloncology.2016.04.002DOI Listing
June 2016

Overexpression of MYB drives proliferation of CYLD-defective cylindroma cells.

J Pathol 2016 06 21;239(2):197-205. Epub 2016 Apr 21.

Sahlgrenska Cancer Centre, Department of Pathology, University of Gothenburg, Sweden.

Cutaneous cylindroma is an adnexal tumour with apocrine differentiation. A predisposition to multiple cylindromas is seen in patients with Brooke-Spiegler syndrome, who carry germline mutations in the tumour suppressor gene CYLD. Previous studies of inherited cylindromas have highlighted the frequent presence of bi-allelic truncating CYLD mutations as a recurrent driver mutation. We have previously shown that sporadic cylindromas express either MYB-NFIB fusion transcripts or show evidence of MYB activation in the absence of such fusions. Here, we investigated inherited cylindromas from several families with germline CYLD mutations for the presence of MYB activation. Strikingly, none of the inherited CYLD-defective (n = 23) tumours expressed MYB-NFIB fusion transcripts. However, MYB expression was increased in the majority of tumours (69%) and global gene expression analysis revealed that well-established MYB target genes were up-regulated in CYLD-defective tumours. Moreover, knock-down of MYB expression caused a significant reduction in cylindroma cell proliferation, suggesting that MYB is also a key player and oncogenic driver in inherited cylindromas. Taken together, our findings suggest molecular heterogeneity in the pathogenesis of sporadic and inherited cutaneous cylindromas, with convergence on MYB activation. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.4717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869681PMC
June 2016

The Effect of Processing Additives on Energetic Disorder in Highly Efficient Organic Photovoltaics: A Case Study on PBDTTT-C-T:PC71 BM.

Adv Mater 2015 Jul 27;27(26):3868-73. Epub 2015 May 27.

Biomolecular and Organic Electronics, IFM, Linköping University, Linköping, 58183, Sweden.

Energetic disorder, an important parameter affecting the performance of organic photovoltaics, is significantly decreased upon the addition of processing additives in a highly efficient benzodithiophene-based copolymer blend (PBDTTT-C-T:PC71 BM). Wide-angle and small-angle X-ray scattering measurements suggest that the origin of this reduced energetic disorder is due to increased aggregation and a larger average fullerene domain size together with purer phases.
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http://dx.doi.org/10.1002/adma.201405913DOI Listing
July 2015

Thermally reduced kaolin-graphene oxide nanocomposites for gas sensing.

Sci Rep 2015 Jan 8;5:7676. Epub 2015 Jan 8.

Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden.

Highly sensitive graphene-based gas sensors can be made using large-area single layer graphene, but the cost of large-area pure graphene is high, making the simpler reduced graphene oxide (rGO) an attractive alternative. To use rGO for gas sensing, however, require a high active surface area and slightly different approach is needed. Here, we report on a simple method to produce kaolin-graphene oxide (GO) nanocomposites and an application of this nanocomposite as a gas sensor. The nanocomposite was made by binding the GO flakes to kaolin with the help of 3-Aminopropyltriethoxysilane (APTES). The GO flakes in the nanocomposite were contacting neighboring GO flakes as observed by electron microscopy. After thermal annealing, the nanocomposite become conductive as showed by sheet resistance measurements. Based on the conductance changes of the nanocomposite films, electrical gas sensing devices were made for detecting NH3 and HNO3. These devices had a higher sensitivity than thermally annealed multilayer GO films. This kaolin-GO nanocomposite might be useful in applications that require a low-cost material with large conductive surface area including the demonstrated gas sensors.
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http://dx.doi.org/10.1038/srep07676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378989PMC
January 2015

Squamous/epidermoid differentiation in normal breast and salivary gland tissues and their corresponding tumors originate from p63/K5/14-positive progenitor cells.

Virchows Arch 2015 Jan 26;466(1):21-36. Epub 2014 Oct 26.

Institute for Hematopathology, Fangdieckstr. 75A, 22547, Hamburg, Germany,

A small group of tumors of breast and salivary glands contains squamous/epidermoid elements as a constitutive feature (e.g., squamous carcinoma, syringomatous tumors, and mucoepidermoid carcinoma). Other tumors (e.g., pleomorphic adenoma, adenomyoepithelial tumors, and adenoid cystic carcinoma) may show occasionally squamous differentiation. Furthermore, squamous metaplasia may be observed in non-neoplastic breast and salivary tissues. However, the histogenesis of these squamous differentiations is far from being understood. Based on our earlier in situ triple immunofluorescence and quantitative reverse transcription (RT)-PCR experiments for basal keratins K5/14 and p63 as well as for glandular keratins (K7/K8/18), squamous keratins (K10 and K13), and myoepithelial lineage markers (smooth muscle actin, SMA), we here traced the squamous/epidermoid differentiation lineage of 60 tumors of the breast and/or salivary glands, cultured tumor cells of 2 tumors, and of 7 squamous metaplasias of non-neoplastic breast and salivary tissues. Our results indicate that both the neoplastic lesions as well as the non-neoplastic squamous metaplasia contain p63/K5/14+ cells that differentiate toward K10/13+ squamous cells. Thus, cells with squamous/epidermoid differentiation undergo a transition from its original p63/K5/14+ precursor state to K10/13+ squamous lineage state, which can be pictured by triple-immunofluorescence experiments. Given the immunophenotypic similarity of p63/K5/14+ tumor cells to their physiological p63/K5/14+ counterparts in normal breast and salivary duct epithelium, we suggest that these cells provide an important histogenetic key to understanding the pathogenesis of squamous differentiation both in normal breast/salivary gland tissues and their corresponding tumors.
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http://dx.doi.org/10.1007/s00428-014-1671-xDOI Listing
January 2015

Diagnostic and therapeutic implications of new molecular biomarkers in salivary gland cancers.

Oral Oncol 2014 Aug 21;50(8):683-90. Epub 2014 May 21.

Sahlgrenska Cancer Center, Department of Pathology, University of Gothenburg, Gothenburg, Sweden.

Salivary gland carcinomas (SGCs) are uncommon tumors, constituting approximately 5% of all cancers of the head and neck. They are a heterogeneous group of diseases that pose significant diagnostic and therapeutic challenges. The treatment of patients with SGCs is mainly restricted to surgery and/or radiation therapy and there is only limited data available on the role of conventional systemic and targeted therapies in the management of patients with advanced disease. There is thus a great need to develop new molecular biomarkers to improve the diagnosis, prognostication, and therapeutic options for these patients. In this review, we will discuss the most recent developments in this field, with focus on pathognomonic gene fusions and other driver mutations of clinical significance. Comprehensive cytogenetic and molecular genetic analyses of SGCs have revealed a translocation-generated network of fusion oncogenes. The molecular targets of these fusions are transcription factors, transcriptional coactivators, and tyrosine kinase receptors. Prominent examples of clinically significant fusions are the MYB-NFIB fusion in adenoid cystic carcinoma and the CRTC1-MAML2 fusion in mucoepidermoid carcinoma. The fusions are key events in the molecular pathogenesis of these tumor types and contribute as new diagnostic, prognostic, and therapeutic biomarkers. Moreover, next-generation sequencing analysis of SGCs have revealed new druggable driver mutations, pinpointing alternative therapeutic options for subsets of patients. Continued molecular characterization of these fusions and their down-stream targets will ultimately lead to the identification of novel driver genes in SGCs and will form the basis for development of new therapeutic strategies for these patients.
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http://dx.doi.org/10.1016/j.oraloncology.2014.04.008DOI Listing
August 2014

Influence of finite-sized detection solid angle on bidirectional reflectance distribution function measurements.

Appl Opt 2014 Feb;53(6):1212-20

This paper deals with limitations and often overlooked sources of error introduced in compact double-beam goniophotometers. It is shown that relative errors in measured radiance factor, comparable to the total measurement uncertainty, can be introduced if recommended corrections are not carried out. Two different error sources are investigated, both related to the size of the detection solid angle. The first is a geometrical error that occurs when the size of the illuminated area and detector aperture are comparable to the distance between them. The second is a convolution error due to variations in radiant flux over the detector aperture, which is quantified by simulating the full 3D bidirectional reflectance distribution function (BRDF) of a set of samples with different degrees of anisotropic reflectance. The evaluation is performed for a compact double-beam goniophotometer using different detection solid angles, and it is shown that both error sources introduce relative errors of 1%-3%, depending on viewing angle and optical properties of the sample. Commercially available compact goniophotometers, capable of absolute measurements, are becoming more and more common, and the findings in this paper are therefore important for anyone using or planning to use this type of instrument.
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http://dx.doi.org/10.1364/AO.53.001212DOI Listing
February 2014

Differentiation and histogenesis of syringomatous tumour of the nipple and low-grade adenosquamous carcinoma: evidence for a common origin.

Histopathology 2014 Jul 9;65(1):9-23. Epub 2014 Apr 9.

Institute for Hematopathology, Reference Centre for Gynaeco- and Breast Pathology, Hamburg, Germany; Gerhard-Domagk-Institute of Pathology, University of Muenster, Münster, Germany.

Aims: Syringomatous tumour of the nipple and low-grade adenosquamous carcinoma (LGAdSC) of the breast are regarded as distinct entities. To clarify the nature of these two lesions, we compared the expression of different lineage/differentiation markers in 12 syringomatous tumours of the nipple, nine LGAdSCs, and normal breast epithelium.

Methods And Results: Using triple immunofluorescence labelling and quantitative RT-PCR for keratins, p63, and smooth muscle actin, we demonstrated that syringomatous tumour and LGAdSC contain p63+/K5/14+ tumour cells, K10+ squamous cells, and K8/18+ glandular cells, with intermediary cells being found in both lineages. Identical p63+/K5/14+ cells were also found in the normal breast duct epithelium.

Conclusions: Our data provide evidence that syringomatous tumour of the nipple and LGAdSC are identical or nearly identical lesions. They contain p63+/K5/14+ cells as the key cells from which the K10+ squamous lineage and the K8/18+ glandular lineage arise. On the basis of our findings in normal breast tissue and associated benign lesions, we suggest that p63+/K5/14+ cells of the normal breast duct epithelium or early related cells might play a key role in the neoplastic transformation of both syringomatous tumour and LGAdSC. We propose that the differentiation patterns found in both lesions reflect the early ontogenetic stages of the normal breast epithelium.
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http://dx.doi.org/10.1111/his.12358DOI Listing
July 2014

The role of arginine and arginine-metabolizing enzymes during Giardia - host cell interactions in vitro.

BMC Microbiol 2013 Nov 14;13:256. Epub 2013 Nov 14.

Department of Cell- and Molecular Biology, Uppsala University, BMC, Box 596, Uppsala SE-751 24, Sweden.

Background: Arginine is a conditionally essential amino acid important in growing individuals and under non-homeostatic conditions/disease. Many pathogens interfere with arginine-utilization in host cells, especially nitric oxide (NO) production, by changing the expression of host enzymes involved in arginine metabolism. Here we used human intestinal epithelial cells (IEC) and three different isolates of the protozoan parasite Giardia intestinalis to investigate the role of arginine and arginine-metabolizing enzymes during intestinal protozoan infections.

Results: RNA expression analyses of major arginine-metabolizing enzymes revealed the arginine-utilizing pathways in human IECs (differentiated Caco-2 cells) grown in vitro. Most genes were constant or down-regulated (e.g. arginase 1 and 2) upon interaction with Giardia, whereas inducible NO synthase (iNOS) and ornithine decarboxylase (ODC) were up-regulated within 6 h of infection. Giardia was shown to suppress cytokine-induced iNOS expression, thus the parasite has both iNOS inducing and suppressive activities. Giardial arginine consumption suppresses NO production and the NO-degrading parasite protein flavohemoglobin is up-regulated in response to host NO. In addition, the secreted, arginine-consuming giardial enzyme arginine deiminase (GiADI) actively reduces T-cell proliferation in vitro. Interestingly, the effects on NO production and T cell proliferation could be reversed by addition of external arginine or citrulline.

Conclusions: Giardia affects the host's arginine metabolism on many different levels. Many of the effects can be reversed by addition of arginine or citrulline, which could be a beneficial supplement in oral rehydration therapy.
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http://dx.doi.org/10.1186/1471-2180-13-256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225669PMC
November 2013

Separation of surface and bulk reflectance by absorption of bulk scattered light.

Appl Opt 2013 Jul;52(19):4749-54

Department of Natural Sciences, Digital Printing Center, Mid Sweden University, Örnsköldsvik SE-891 18, Sweden.

A method is proposed for separating light reflected from turbid media with a rough surface into a bulk and a surface component. Dye is added to the sample, thereby increasing absorption and canceling bulk scattering. The remaining reflected light is surface reflectance, which can be subtracted from the total reflectance of an undyed sample to obtain the bulk component. The method is applied to paper where the addition of dye is accomplished by inkjet printing. The results show that the bulk scattered light is efficiently canceled, and that both the spectrally neutral surface reflectance and the surface topography of the undyed paper is maintained. The proposed method is particularly suitable for characterization of dielectric, highly randomized materials with significant bulk reflectance and rough surfaces, which are difficult to analyze with existing methods. A reliable separation method opens up for new ways of analyzing, e.g., biological tissues and optical coatings, and is also a valuable tool in the development of more comprehensive reflectance models.
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http://dx.doi.org/10.1364/AO.52.004749DOI Listing
July 2013
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