Publications by authors named "Kenneth Nilsson"

64 Publications

Granulomatous mastitis caused by Rickettsia species.

Virchows Arch 2021 Apr 13. Epub 2021 Apr 13.

Pathology & Cytology Dalarna, Region Dalarna, Falun, Sweden.

Granulomatous mastitis is a rare inflammatory disease of varying etiology. Tuberculosis and cystic neutrophilic granulomatous mastitis caused by Corynebacterium are the best-established infectious examples. Despite the increasing incidence of Rickettsia-related diseases worldwide, granulomatous inflammation of breast parenchyma caused by Rickettsia has not yet been reported. We present a unique case of bilateral granulomatous mastitis documented with mammography, magnetic resonance imaging and core-needle biopsy. The rickettsial etiology of the disease was proved with specific immunohistochemistry and confirmed with DNA extraction, PCR and serology. The lesions completely resolved after a full-course tetracycline treatment. This case report widens the knowledge about the possible clinical manifestations of Rickettsia infection and adds a new bacterium to the list of etiological factors causing granulomatous mastitis.
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http://dx.doi.org/10.1007/s00428-021-03098-2DOI Listing
April 2021

A comprehensive clinical and laboratory evaluation of 224 patients with persistent symptoms attributed to presumed tick-bite exposure.

PLoS One 2021 18;16(3):e0247384. Epub 2021 Mar 18.

Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.

Background: Persistent symptoms attributed to presumed tick-bite exposure constitute an unresolved medical controversy. We evaluated whether Swedish adults who met the criteria for post-treatment Lyme disease syndrome (PTLDS) exhibited characteristics distinguishable from adults who did not, but who displayed similar symptoms and disease course after suspected previous tick-bite infection (TBI).

Methods And Findings: During 2015-2018, 255 patients-referred to the Centre for Vector-borne Infections, Uppsala University Hospital, Sweden with symptoms lasting longer than six months-were recruited. Of this group, 224 completed the study. Each patient was examined by an infectious disease specialist and, besides a full medical history, underwent a panel of blood and cerebrospinal fluid laboratory tests including hematological, biochemical, microbiological and immunological analyses, and the RAND-36 scale to measure quality of life. For analysis purposes, patients were divided into five subgroups, of which one represented PTLDS. According to serological results indicating TBI and documented/ reported objective signs of Lyme disease, 85 (38%) patients fulfilled the criteria for PTLDS and were compared with the other 139 (62%) serologically classified patients. In the PTLDS group, erythema chronicum migrans (ECM) was documented/reported in 86% of patients, previous neuroborreliosis in 15%, and acrodermatitis chronica atroficans (ACA) in 3.5%. However, there were no significant differences regarding symptoms, laboratory results or disease course between patients with PTLDS and those without laboratory evidence of Borrelia exposition. Most reported symptoms were fatigue-related (70%), musculoskeletal (79%), neurological (82%) and neurocognitive (57%). Tick bites were recalled by 74%. The RAND-36 score was significantly below that of the general Swedish population. Signs of immunological/inflammatory reactivity with myositis antibodies were detected in 20% of patients, fibrinogen levels were moderately increased in 21% and elevated rheumatoid factor in 6%.

Conclusions: The PTLDS group did not differ exclusively in any respect from the other subgroups, which either lacked previously documented/reported evidence of borreliosis or even lacked detectable serological signs of exposure to Lyme disease. The results suggest that symptoms often categorized as Chronic-Lyme-Disease (CLD) in the general debate, cannot be uniquely linked to Lyme disease. However, approximately 20% of the total group of patients showed signs of autoimmunity. Further studies are needed to elucidate the underlying causes and mechanisms of PTLDS and there is reason to consider a multifactorial approach.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247384PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971513PMC
March 2021

Characteristics of in vitro infection of human monocytes, by Rickettsia helvetica.

Microbes Infect 2021 Mar-Apr;23(2-3):104776. Epub 2020 Dec 1.

Department of Medical Sciences, Section of Clinical Microbiology, Uppsala University, SE-751 85 Uppsala, Sweden; Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, SE-751 85 Uppsala, Sweden. Electronic address:

Eighteen species of rickettsiae are reported to cause infections in humans. One of these is Rickettsia helvetica, which is endemic in European and Asian countries and transmitted by the tick Ixodes ricinus. Besides fever, it has been demonstrated to cause meningitis and is also associated with perimyocarditis. One of the initial targets for rickettsiae after inoculation by ticks is the macrophage/monocyte. How rickettsiae remain in the macrophages/monocytes before establishing their infection in vascular endothelial cells remains poorly understood. The main aim of the present study was to investigate the impact on and survival of R. helvetica in a human leukemic monocytic cell line, THP-1. Our results show that R. helvetica survives and propagates in the THP-1 cells. The infection in monocytes was followed for seven days by qPCR and for 30 days by TEM, where invasion of the nucleus was also observed as well as double membrane vacuoles containing rickettsiae, a finding suggesting that R. helvetica might induce autophagy at the early stage of infection. Infected monocytes induced TNF-α which may be important in host defence against rickettsial infections and promote cell survival and inhibiting cell death by apoptosis. The present findings illustrate the importance of monocytes to the pathogenesis of rickettsial disease.
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http://dx.doi.org/10.1016/j.micinf.2020.11.003DOI Listing
December 2020

Vasculitis due to Candidatus Neoehrlichia mikurensis: a cohort study of 40 Swedish patients.

Clin Infect Dis 2020 Aug 20. Epub 2020 Aug 20.

Department of Clinical Microbiology, Sahlgrenska University Hospital, Göteborg, Region Västra Götaland, Sweden.

Background: Candidatus (Ca.) Neoehrlichia (N.) mikurensis is an emerging tick-borne pathogen of humans that is closely related to Ehrlichia and Anaplasma species. This strict intracellular bacterium escapes detection by routine microbiologic diagnostic methods such as blood culture leading to considerable under-diagnosis of the infectious disease it causes, neoehrlichiosis.

Methods: Here, we describe the vascular and thromboembolic events afflicting a series of 40 patients diagnosed with neoehrlichiosis in Sweden during a 10-year period (2009-2019).

Results: The majority of the patients (60%) developed vascular events ranging from repeated thrombophlebitis, deep vein thrombosis, pulmonary embolism, transitory ischemic attacks to arteritis. Younger age was a risk factor for vascular complications. In contrast, there was no difference in the incidence of vascular events between immunosuppressed and immunocompetent patients. However, there were qualitative differences such that deep vein thrombosis exclusively afflicted the immunosuppressed patients whereas arteritis was restricted to the immunocompetent ones. We also present the case histories of two patients who developed vasculitis mimicking polyarteritis nodosa and giant cell arteritis. Both were cured by doxycycline treatment.

Conclusions: Ca. N. mikurensis infection should be considered in patients living in tick-endemic areas of Europe and northern Asia who present with atypical vascular and/or thromboembolic events. Early diagnosis and antibiotics targeting this emerging infectious agent can eradicate the infection and prevent the development of new vascular events.
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http://dx.doi.org/10.1093/cid/ciaa1217DOI Listing
August 2020

Willingness to pay for osteoporosis risk assessment in primary dental care.

Health Econ Rev 2019 May 24;9(1):14. Epub 2019 May 24.

Centre for Medical Technology Assessment, Department of Medical and Health Sciences, Linköping University, 581 83 Linköping, Linköping, Sweden.

Background: Fragility fracture related to osteoporosis among postmenopausal women is a significant cause of morbidity. The care and aftercare of these fractures are associated with substantial costs to society. A main problem is that many individuals suffer from osteoporosis without knowing it before a fracture happens. Dentists may have an important role in early identification of individuals with osteoporosis by assessment of dental radiographs already included in the dental examination. The aim of this study was therefore to investigate postmenopausal women's preferences for an osteoporosis risk assessment in primary dental care.

Results: Most respondents (129 of 144 (90%)) were willing to pay for an osteoporosis risk assessment in primary dental care. The overall mean willingness to pay (WTP) including respondents that denoted none or zero WTP was 44.60 € (CI 95% 38.46-50.74 €) (median 34.75 €). A majority (80.6%) of the respondents that denoted WTP also gave a motivation for their answer. The two most common reasons denoted for being willing to pay for osteoporosis risk assessment were the importance of early diagnosis and preventive care to avoid fractures (41.0%) and the importance of knowledge of a risk of osteoporosis (26.4%). A majority of respondents (67.8%) considered it valuable if dental clinics would offer osteoporosis risk assessment.

Conclusions: Postmenopausal women seem to find it valuable to be offered osteoporosis risk assessment in primary dental care and are willing to pay for such a risk assessment. From a societal perspective early diagnosis of osteoporosis by risk assessment in primary dental care could prevent osteoporotic related fractures and benefit women's health and quality of life, as well as have a major impact on the health-care budget in terms of cost-savings.
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http://dx.doi.org/10.1186/s13561-019-0232-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734228PMC
May 2019

Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease.

J Neuroimmunol 2019 07 25;332:31-36. Epub 2019 Mar 25.

Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden. Electronic address:

Background: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.

Methods: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.

Results: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.

Conclusions: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.
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http://dx.doi.org/10.1016/j.jneuroim.2019.03.015DOI Listing
July 2019

Serological reactivity to Anaplasma phagocytophilum in neoehrlichiosis patients.

Eur J Clin Microbiol Infect Dis 2018 Sep 14;37(9):1673-1678. Epub 2018 Jun 14.

Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.

The tick-borne bacterium Candidatus (Ca.) Neoehrlichia (N.) mikurensis is a cause of "fever of unknown origin" because this strict intracellular pathogen escapes detection by routine blood cultures. Case reports suggest that neoehrlichiosis patients may display serological reactivity to Anaplasma (A.) phagocytophilum. Since Anaplasma serology is part of the diagnostic work-up of undetermined fever in European tick-exposed patients, we wanted to investigate (1) the prevalence of A. phagocytophilum seropositivity among neoehrlichiosis patients, (2) the frequency of misdiagnosed neoehrlichiosis patients among A. phagocytophilum seropositive patients, and (3) the frequency of A. phagocytophilum and Ca. N. mikurensis co-infections. Neoehrlichiosis patients (n = 18) were analyzed for A. phagocytophilum IgM and IgG serum antibodies by indirect immunofluorescence assay. Serum samples from suspected anaplasmosis patients (n = 101) were analyzed for bacterial DNA contents by singleplex PCR specific for A. phagocytophilum and Ca. N. mikurensis, respectively. One fifth of the neoehrlichiosis patients (4/18) were seropositive for IgM and/or IgG to A. phagocytophilum at the time of diagnosis. Among the patients with suspected anaplasmosis, 2% (2/101) were positive for Ca. N. mikurensis by PCR whereas none (0/101) had detectable A. phagocytophilum DNA in the serum. To conclude, patients with suspected anaplasmosis may in fact have neoehrlichiosis. We found no evidence of A. phagocytophilum and Ca. N. mikurensis co-infections in humans with suspected anaplasmosis or confirmed neoehrlichiosis.
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http://dx.doi.org/10.1007/s10096-018-3298-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133046PMC
September 2018

Epidemiology of fungaemia in Sweden: A nationwide retrospective observational survey.

Mycoses 2018 Oct 18;61(10):777-785. Epub 2018 Jul 18.

Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

Objectives: To identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates to identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates in Sweden.

Methods: The study was a retrospective, observational nationwide laboratory-based surveillance for fungaemia and fungal meningitis and was conducted from September 2015 to August 2016.

Results: In total, 488 Candida blood culture isolates were obtained from 471 patients (58% males). Compared to our previous study, the incidence of candidaemia has increased from 4.2/100 000 (2005-2006) to 4.7/100 000 population/year (2015-2016). The three most common Candida spp. isolated from blood cultures were Candida albicans (54.7%), Candida glabrata (19.7%) and species in the Candida parapsilosis complex (9.4%). Candida resistance to fluconazole was 2% in C. albicans and between 0% and 100%, in non-albicans species other than C. glabrata and C. krusei. Resistance to voriconazole was rare, except for C. glabrata, C. krusei and C. tropicalis. Resistance to anidulafungin was 3.8% while no Candida isolate was resistant to amphotericin B.

Conclusions: We report an overall increase in candidaemia but a minor decrease of C. albicans while C. glabrata and C. parapsilosis remain constant over this 10-year period.
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http://dx.doi.org/10.1111/myc.12816DOI Listing
October 2018

Seroprevalence against and Species in Patients with Uveitis: A Prospective Survey.

J Ophthalmol 2017 26;2017:9247465. Epub 2017 Nov 26.

Department of Medical Sciences, Section of Clinical Microbiology, Uppsala University, Uppsala, Sweden.

Vector-borne diseases such as Lyme borreliosis and rickettsioses have been associated with ocular inflammation. Our aim was to study patients with diagnosed uveitis to evaluate serological signs of infection or exposure to these tick-borne agents. Forty-eight patients were prospectively examined with serology together with medical records and a questionnaire concerning previous exposure, diseases, and treatments. Seven patients (14.6%) showed seroconversion to spp. between acute and convalescent phase sera, which provides support for a positive diagnosis according to guidelines. The specificity was confirmed by Western blot. Additional 28 patients had stationary titres of which eight (16.6%) had 1 : 256 or higher titre in the first serum, and another 13 patients were seronegative. No epidemiological risk factor or marker could be identified. For , only three patients showed moderate IgG titres. A control group of 100 blood donors, 60 patients with rheumatic disease, and 56 patients seeking medical care were tested of which 2.0-7.1% showed low anti- titres and 3.0-8.3% anti- titres. The findings are indicative for an association between infection or exposure to spp. and uveitis with a seropositivity among patients with recurrent uveitis in concordance with the spread of rickettsial exposure in a tick-exposed population.
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http://dx.doi.org/10.1155/2017/9247465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727782PMC
November 2017

The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomains.

Oncotarget 2017 Nov 20;8(61):103731-103743. Epub 2017 Oct 20.

Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.
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http://dx.doi.org/10.18632/oncotarget.21909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732762PMC
November 2017

African tick bite fever in returning Swedish travellers. Report of two cases and aspects of diagnostics.

Infect Ecol Epidemiol 2017 2;7(1):1343081. Epub 2017 Aug 2.

Department of Medical Sciences, Section of Clinical Microbiology, Uppsala University, Uppsala, Sweden.

: African tick-bite fever, caused by , is endemic in rural areas of sub-Saharan Africa and a possible cause of fever in returning Swedish travellers. Two patients are presented, and the advantages and disadvantages of different diagnostic methods are discussed. : Two middle-aged men fell ill with fever after returning home from South Africa. Both had single eschars and one also presented with a lymph node swelling. Samples were taken for serology, general bacterial culture from the wound (Patient 1) using a swab and additionally for Patient 2 PCR of a skin biopsy from the eschar. : Both patients seroconverted one month after onset. Real-time PCR of the biopsy was positive, where sequencing of the gene was 99-100% consistent with . A drop of fluid from the biopsy contained a sufficient number of bacteria to also allow for isolation of rickettsiae in Vero cell culture. Direct molecular detection by PCR from a swab used for bacteria culture from the eschar from Patient 1 also yielded a positive result. In conclusion, the findings highlight the usefulness of swabs for early non-invasive diagnosis of African tick-bite fever in febrile travellers.
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http://dx.doi.org/10.1080/20008686.2017.1343081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549825PMC
August 2017

EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.

Oncotarget 2017 Feb;8(6):10213-10224

Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.
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http://dx.doi.org/10.18632/oncotarget.14378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354653PMC
February 2017

Prevalence of Rickettsia spp. in Ticks and Serological and Clinical Outcomes in Tick-Bitten Individuals in Sweden and on the Åland Islands.

PLoS One 2016 15;11(11):e0166653. Epub 2016 Nov 15.

Unit of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Tick-transmitted diseases are an emerging health problem, and the hard tick Ixodes ricinus is the main vector for Borrelia spp., tick-borne encephalitis virus and most of the spotted fever Rickettsiae in Europe. The aim of the present study was to examine the incidence of rickettsial infection in the southernmost and south central parts of Sweden and the Åland Islands in Finland, the risk of infection in humans and its correlation with a bite of a Rickettsia-infected tick, the self-reported symptoms of rickettsial disease, and the prevalence of co-infection between Rickettsia spp. and Borrelia spp. Persons with a recent tick bite were enrolled through public media and asked to answer a questionnaire, provide a blood sample and bring detached ticks at enlistment and at follow-up three months later. Blood samples were previously analysed for Borrelia spp. antibodies and, for this report, analysed for antibodies to Rickettsia spp. by immunofluorescence and in 16 cases also using Western Blot. Ninety-six (44.0%) of the 218 participants were seropositive for IgG antibodies to Rickettsia spp. Forty (18.3%) of the seropositive participants had increased titres at the follow-up, indicating recent/current infection, while four (1.8%) had titres indicating probable recent/current infection (≥1:256). Of 472 ticks, 39 (8.3%) were Rickettsia sp. positive. Five (31.3%) of 16 participants bitten by a Rickettsia-infected tick seroconverted. Experience of the self-reported symptoms nausea (p = 0.006) and radiating pain (p = 0.041) was more common among those with recent, current or probable infection compared to those who did not seroconvert. Participants who showed seroreactivity or seroconversion to Rickettsia spp. had more symptoms than those who were seronegative. Seven (3.2%) participants showed seroconversion to Borrelia spp., and three (1.4%) of these showed seroconversion to both Rickettsia spp. and Borrelia spp., in accordance with previous studies in Sweden. Symptoms of rickettsial disease were in most of the cases vague and general that were difficult to differentiate from other tick-borne diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166653PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113005PMC
June 2017

Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.

Oncotarget 2016 Feb;7(6):6809-23

Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.
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http://dx.doi.org/10.18632/oncotarget.6843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872750PMC
February 2016

Serologic and Molecular Prevalence of Rickettsia helvetica and Anaplasma phagocytophilum in Wild Cervids and Domestic Mammals in the Central Parts of Sweden.

Vector Borne Zoonotic Dis 2015 Sep;15(9):529-34

1 Department of Medical Sciences, Unit of Clinical Bacteriology, Uppsala University , Uppsala, Sweden .

Both Rickettsia helvetica and Anaplasma phagocytophilum are common in Ixodes ricinus ticks in Sweden. Knowledge is limited regarding different animal species' competence to act as reservoirs for these organism. For this reason, blood samples were collected from wild cervids (roe deer, moose) and domestic mammals (horse, cat, dog) in central Sweden, and sera were tested using immunofluorescence assay to detect antibodies against spotted fever rickettsiae using Rickettsia helvetica as antigen. Sera with a titer ≥1:64 were considered as positive, and 23.1% (104/450) of the animals scored positive. The prevalence of seropositivity was 21.5% (23/107) in roe deer, 23.3% (21/90) in moose, 36.5% (23/63) in horses, 22.1% (19/90) in cats, and 17.0% (17/100) in dogs. PCR analysis of 113 spleen samples from moose and sheep from the corresponding areas were all negative for rickettsial DNA. In roe deer, 85% (91/107) also tested seropositive for A. phagocytophilum with a titer cutoff of 1:128. The findings indicate that the surveyed animal species are commonly exposed to rickettsiae and roe deer also to A. phagocytophilum.
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http://dx.doi.org/10.1089/vbz.2015.1768DOI Listing
September 2015

The transcriptomic and proteomic landscapes of bone marrow and secondary lymphoid tissues.

PLoS One 2014 26;9(12):e115911. Epub 2014 Dec 26.

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Background: The sequencing of the human genome has opened doors for global gene expression profiling, and the immense amount of data will lay an important ground for future studies of normal and diseased tissues. The Human Protein Atlas project aims to systematically map the human gene and protein expression landscape in a multitude of normal healthy tissues as well as cancers, enabling the characterization of both housekeeping genes and genes that display a tissue-specific expression pattern. This article focuses on identifying and describing genes with an elevated expression in four lymphohematopoietic tissue types (bone marrow, lymph node, spleen and appendix), based on the Human Protein Atlas-strategy that combines high throughput transcriptomics with affinity-based proteomics.

Results: An enriched or enhanced expression in one or more of the lymphohematopoietic tissues, compared to other tissue-types, was seen for 693 out of 20,050 genes, and the highest levels of expression were found in bone marrow for neutrophilic and erythrocytic genes. A majority of these genes were found to constitute well-characterized genes with known functions in lymphatic or hematopoietic cells, while others are not previously studied, as exemplified by C19ORF59.

Conclusions: In this paper we present a strategy of combining next generation RNA-sequencing with in situ affinity-based proteomics in order to identify and describe new gene targets for further research on lymphatic or hematopoietic cells and tissues. The results constitute lists of genes with enriched or enhanced expression in the four lymphohematopoietic tissues, exemplified also on protein level with immunohistochemical images.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115911PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277406PMC
November 2015

Spotted fever Rickettsia species in Hyalomma and Ixodes ticks infesting migratory birds in the European Mediterranean area.

Parasit Vectors 2014 Jul 10;7:318. Epub 2014 Jul 10.

Department of Medical Sciences, Section of Clinical Microbiology, Uppsala University, Uppsala, Sweden.

Background: A few billion birds migrate annually between their breeding grounds in Europe and their wintering grounds in Africa. Many bird species are tick-infested, and as a result of their innate migratory behavior, they contribute significantly to the geographic distribution of pathogens, including spotted fever rickettsiae. The aim of the present study was to characterize, in samples from two consecutive years, the potential role of migrant birds captured in Europe as disseminators of Rickettsia-infected ticks.

Methods: Ticks were collected from a total of 14,789 birds during their seasonal migration northwards in spring 2009 and 2010 at bird observatories on two Mediterranean islands: Capri and Antikythira. All ticks were subjected to RNA extraction followed by cDNA synthesis and individually assayed with a real-time PCR targeting the citrate synthase (gltA) gene. For species identification of Rickettsia, multiple genes were sequenced.

Results: Three hundred and ninety-eight (2.7%) of all captured birds were tick-infested; some birds carried more than one tick. A total number of 734 ticks were analysed of which 353 ± 1 (48%) were Rickettsia-positive; 96% were infected with Rickettsia aeschlimannii and 4% with Rickettsia africae or unidentified Rickettsia species. The predominant tick taxon, Hyalomma marginatum sensu lato constituted 90% (n = 658) of the ticks collected. The remaining ticks were Ixodes frontalis, Amblyomma sp., Haemaphysalis sp., Rhipicephalus sp. and unidentified ixodids. Most ticks were nymphs (66%) followed by larvae (27%) and adult female ticks (0.5%). The majority (65%) of ticks was engorged and nearly all ticks contained visible blood.

Conclusions: Migratory birds appear to have a great impact on the dissemination of Rickettsia-infected ticks, some of which may originate from distant locations. The potential ecological, medical and veterinary implications of such Rickettsia infections need further examination.
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http://dx.doi.org/10.1186/1756-3305-7-318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230250PMC
July 2014

Effects of smoking, gender and occupational exposure on the risk of severe pulmonary fibrosis: a population-based case-control study.

BMJ Open 2014 Jan 9;4(1):e004018. Epub 2014 Jan 9.

Department of Clinical Sciences, Division of Respiratory Medicine & Allergology, Lund University, Lund, Sweden.

Objectives: To estimate the effects of smoking, gender and occupational exposure on the risk of developing severe pulmonary fibrosis (PF), including dose-response and interaction effects.

Methods: National case-control study of 171 patients (cases) who had started a long-term oxygen therapy for PF in Sweden between February 1997 and April 2000, and 719 random control participants from the general population. Of these cases, 137 had probable idiopathic PF (IPF). The ORs for smoking, gender and occupational exposure were estimated using Mantel-Haenszel analysis and conditional logistic regression, controlling for age and year of diagnosis.

Results: The adverse effect of smoking was amplified by male gender and occupational exposure, OR 4.6 (95% CI 2.1 to 10.3) for PF, and OR 3.0 (1.3 to 6.5) for IPF, compared with in non-exposed women. Higher cumulative smoking exposure was linearly associated with increased risks. Compared with smoking less than 10 pack-years, smoking ≥20 pack-years was associated with increased risk of PF and IPF, OR 2.6 (1.4 to 4.9) and OR 2.5 (1.3 to 5.0), respectively.

Conclusions: Smoking has a dose-related association with increased risk of severe PF. Men with a history of smoking and occupational exposure is a particular risk group for developing severe PF.
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http://dx.doi.org/10.1136/bmjopen-2013-004018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902328PMC
January 2014

Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia.

Leuk Lymphoma 2013 Aug 25;54(8):1769-79. Epub 2013 Feb 25.

Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of authentic Abs and DNA.
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http://dx.doi.org/10.3109/10428194.2013.764418DOI Listing
August 2013

Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma.

BMC Cancer 2012 Jul 28;12:318. Epub 2012 Jul 28.

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, S- 751 85, Sweden.

Background: Multiple myeloma (MM) is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN) treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat)1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM.

Methods: To delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS).

Results: To explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA), geldanamycin (17-AAG), doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered.

Conclusion: We conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro-apoptotic genes. However, this shift alone is not sufficient to alter apoptosis sensitivity in MM cells, suggesting that Stat1 independent pathways are operative in IFN mediated apoptosis sensitization.
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http://dx.doi.org/10.1186/1471-2407-12-318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488543PMC
July 2012

Prevalence of Rickettsia spp., Anaplasma phagocytophilum, and Coxiella burnetii in adult Ixodes ricinus ticks from 29 study areas in central and southern Sweden.

Ticks Tick Borne Dis 2012 Apr 9;3(2):100-6. Epub 2012 Jan 9.

Unit of Clinical Bacteriology, Dept. of Medical Sciences, Uppsala University, Uppsala, Sweden.

A total of 887 adult Ixodes ricinus ticks (469 females and 418 males) from 29 different localities in Sweden were screened for Rickettsia, Anaplasma, and Coxiella DNA using PCR and then subjected to gene sequencing. Rickettsial DNA was detected in 9.5-9.6% of the ticks. Most of the positive ticks were infected with Rickettsia helvetica. One tick harbored another spotted fever rickettsia, closely related to or identical with R. sibirica not previously found in I. ricinus nor in Sweden. Six of the ticks (0.7%) were infected with an Anaplasma sp., presumably A. phagocytophilum. Coxiella burnetii DNA was not detected in any of the ticks. The detection of R. helvetica and A. phagocytophilum in several of the localities sampled suggests that these potentially human-pathogenic agents are common in Sweden.
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http://dx.doi.org/10.1016/j.ttbdis.2011.11.003DOI Listing
April 2012

Targeting the IGF-1R signaling and mechanisms for epigenetic gene silencing in human multiple myeloma.

Ups J Med Sci 2012 May 21;117(2):166-77. Epub 2012 Feb 21.

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Multiple myeloma (MM) is a B cell malignancy characterized by the expansion of clonal plasmablast/plasma cells within the bone-marrow. It is well established that the bone-marrow microenvironment has a pivotal role in providing critical cytokines and cell-cell interactions to support the growth and survival of the MM tumor clone. The pathogenesis of MM is, however, only fragmentarily understood. Detailed genomic analysis reveals a heterogeneous and complex pattern of structural and numerical chromosomal aberrations. In this review we will discuss some of the recent results on the functional role and potential clinical use of the IGF-1R, one of the major mediators of growth and survival for MM. We will also describe some of our results on epigenetic gene silencing in MM, as it may indeed constitute a novel basis for the understanding of tumor initiation and maintenance in MM and thus may change the current view on treatment strategies for MM.
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http://dx.doi.org/10.3109/03009734.2012.659293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339548PMC
May 2012

Life cycle, growth characteristics and host cell response of Rickettsia helvetica in a Vero cell line.

Exp Appl Acarol 2012 Feb 25;56(2):179-87. Epub 2011 Nov 25.

Department of Medical Sciences, Unit of Clinical Bacteriology, Uppsala University, Uppsala, Sweden.

Rickettsia helvetica, a spotted fever rickettsia and emerging pathogen with Ixodes ricinus ticks as the main vector, is an agent of human disease and may cause febrile illness as well as meningitis. In three parallel series the isolated standard type of R. helvetica, obtained from a PCR-positive I. ricinus tick, was high-passaged and propagated in a Vero cell line. By using quantitative real-time PCR, the generation time from inoculation to stationary phase of growth was calculated to 20-22 h. In the static cultivation system the stationary phase was observed from the seventh day after inoculation, and there was no observed degradation of R. helvetica DNA during the 14 days studied. Microscopy showed that the organisms invaded the host cells rapidly and were primarily found free in the cytoplasm and only occasionally located in the nucleus. Four days after inoculation some of the host cells were broken and many indifferent stages of cytoplasmic organic decomposition were seen. However the R. helvetica organism did not show any morphologic alterations and the number of organisms was stable after the replication peak which may indicate that R. helvetica is adapted to growth in a Vero cell line and/or that the phase of degradation occurs later than the 14 days studied. The findings differ from what has been reported for other rickettsiae of the spotted fever group and may be of importance for invasiveness and virulence of R. helvetica.
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http://dx.doi.org/10.1007/s10493-011-9508-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253991PMC
February 2012

Large-scale protein profiling in human cell lines using antibody-based proteomics.

J Proteome Res 2011 Sep 22;10(9):4066-75. Epub 2011 Jul 22.

Department of Proteomics, School of Biotechnology, AlbaNova University Center, KTH-Royal Institute of Technology, SE-10691 Stockholm, Sweden.

Human cancer cell lines grown in vitro are frequently used to decipher basic cell biological phenomena and to also specifically study different forms of cancer. Here we present the first large-scale study of protein expression patterns in cell lines using an antibody-based proteomics approach. We analyzed the expression pattern of 5436 proteins in 45 different cell lines using hierarchical clustering, principal component analysis, and two-group comparisons for the identification of differentially expressed proteins. Our results show that immunohistochemically determined protein profiles can categorize cell lines into groups that overall reflect the tumor tissue of origin and that hematological cell lines appear to retain their protein profiles to a higher degree than cell lines established from solid tumors. The two-group comparisons reveal well-characterized proteins as well as previously unstudied proteins that could be of potential interest for further investigations. Moreover, multiple myeloma cells and cells of myeloid origin were found to share a protein profile, relative to the protein profile of lymphoid leukemia and lymphoma cells, possibly reflecting their common dependency of bone marrow microenvironment. This work also provides an extensive list of antibodies, for which high-resolution images as well as validation data are available on the Human Protein Atlas ( www.proteinatlas.org ), that are of potential use in cell line studies.
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http://dx.doi.org/10.1021/pr200259vDOI Listing
September 2011

Trypanosoma spp. in Swedish game animals.

Parasitol Res 2012 Jan 26;110(1):135-9. Epub 2011 May 26.

Department of Biology and Chemical Engineering, Mälardalen University, Box 883, 72123, Västerås, Sweden.

Serum and blood samples from 36 game animals, shot during the hunting seasons 2007-2009, were collected and analyzed for the presence of Trypanosoma spp. by three methods: isolation, polymerase chain reaction (PCR), and serology. Only fissiped animals were included, four different ruminants and wild boar. Trypanosomes could be isolated from two of the animals, and eight had detectable parasite DNA. Seven animals had high titers of anti-trypanosoma IgG antibodies. The two isolated strains, one from roe dear and one from European elk, were determined to Trypanosoma theileri by partial DNA sequencing of the 18S ribosomal gene. In the seven boars, no Trypanosoma were detected, but four out of seven strongly positive serological samples came from this group. This is the first study in Scandinavia on the presence of Trypanosoma in game animals. The results indicate that trypanosomiasis is frequently occurring among Swedish game animals.
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http://dx.doi.org/10.1007/s00436-011-2462-9DOI Listing
January 2012

Coinfection with Rickettsia helvetica and Herpes Simplex Virus 2 in a Young Woman with Meningoencephalitis.

Case Rep Infect Dis 2011 19;2011:469194. Epub 2011 Oct 19.

Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden.

Herpes virus type 2 DNA was detected by PCR in the cerebrospinal fluid in a young woman presenting with headache, stiff neck and pleocytosis, and serological findings consistent with reactivation. Since she was exposed to ticks, Lyme disease and tick-borne encephalitis were excluded. Further investigation in an ongoing project, using PCR and sequencing of the amplified products, showed the presence of Rickettsia helvetica in the cerebrospinal fluid. The bacteria were also isolated in Vero cell culture, and microimmunofluorescence confirmed the development of antibodies against Rickettsia spp. with predominance of IgM reactivity consistent with recent infection. She was treated with antibiotics and improved rapidly. The patient could easily have been judged to have isolated herpes meningitis. Because Sweden and other European countries are endemic areas for rickettsioses, the paper reaffirms the importance of investigating for the presence of rickettsial infections in endemic areas in cases of meningitis of uncertain aetiology.
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http://dx.doi.org/10.1155/2011/469194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336230PMC
August 2012

Rickettsia felis infection in Sweden: report of two cases with subacute meningitis and review of the literature.

Scand J Infect Dis 2010 Dec 25;42(11-12):906-9. Epub 2010 Aug 25.

Unit of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Two patients with headache and pleocytosis were diagnosed with Rickettsia felis infection using a polymerase chain reaction of cerebrospinal fluid and serological testing. Sequencing of the amplified products showed that they were 99-100% homologous to R. felis. These cases add to our knowledge of the clinical manifestations, as well as the geographical distribution, of this spotted fever agent.
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http://dx.doi.org/10.3109/00365548.2010.508466DOI Listing
December 2010

Detection and prevalence of Anaplasma phagocytophilum and Rickettsia helvetica in Ixodes ricinus ticks in seven study areas in Sweden.

Parasit Vectors 2010 Aug 4;3:66. Epub 2010 Aug 4.

Department of Medical Sciences, Clinical Bacteriology, Uppsala University, Uppsala, Sweden.

Background: Tick-borne Anaplasma phagocytophilum and Rickettsia spp. are considered to be emerging human pathogens, but only limited data are available on their occurrence in Sweden. Two real-time PCR assays followed by nested PCR and sequence analysis were carried out to investigate the prevalence of A. phagocytophilum and spotted fever rickettsiae in ticks from seven areas in Sweden.

Results: In 139 pooled samples, representing a total of 1245 Ixodes ricinus ticks (204 larvae, 963 nymphs, 38 males, 40 females), the overall positive mean infection prevalence was 1.3-15.0% for A. phagocytophilum and 1.5-17.3% for R. helvetica. A. phagocytophilum was only detected in nymphs (1.7-19.4%), whereas R. helvetica was detected in all three tick stages. Support for vertical and transstadial transmission was only obtained for R. helvetica. Both agents showed similar infection rates across study areas, although infection rates were greater in coastal areas.

Conclusions: The results show that both pathogens occurred in all seven locations, indicating that they are prevalent in Sweden and should be considered etiological agents in patients recently bitten by ticks.
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http://dx.doi.org/10.1186/1756-3305-3-66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923137PMC
August 2010