Publications by authors named "Janne Koskimäki"

39 Publications

The protective role of PHB and its degradation products against stress situations in bacteria.

FEMS Microbiol Rev 2021 May;45(3)

Ecology and Genetics Research Unit, University of Oulu, Pentti Kaiteran katu 1, P.O. Box 3000, FI-90014 Oulu, Finland.

Many bacteria produce storage biopolymers that are mobilized under conditions of metabolic adaptation, for example, low nutrient availability and cellular stress. Polyhydroxyalkanoates are often found as carbon storage in Bacteria or Archaea, and of these polyhydroxybutyrate (PHB) is the most frequently occurring PHA type. Bacteria usually produce PHB upon availability of a carbon source and limitation of another essential nutrient. Therefore, it is widely believed that the function of PHB is to serve as a mobilizable carbon repository when bacteria face carbon limitation, supporting their survival. However, recent findings indicate that bacteria switch from PHB synthesis to mobilization under stress conditions such as thermal and oxidative shock. The mobilization products, 3-hydroxybutyrate and its oligomers, show a protective effect against protein aggregation and cellular damage caused by reactive oxygen species and heat shock. Thus, bacteria should have an environmental monitoring mechanism directly connected to the regulation of the PHB metabolism. Here, we review the current knowledge on PHB physiology together with a summary of recent findings on novel functions of PHB in stress resistance. Potential applications of these new functions are also presented.
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http://dx.doi.org/10.1093/femsre/fuaa058DOI Listing
May 2021

Biofertilizers and Biocontrol Agents for Agriculture: How to Identify and Develop New Potent Microbial Strains and Traits.

Microorganisms 2021 Apr 13;9(4). Epub 2021 Apr 13.

Ecology and Genetics, University of Oulu, FIN-90014 Oulu, Finland.

Microbiological tools, biofertilizers, and biocontrol agents, which are bacteria and fungi capable of providing beneficial outcomes in crop plant growth and health, have been developed for several decades. Currently we have a selection of strains available as products for agriculture, predominantly based on plant-growth-promoting rhizobacteria (PGPR), soil, epiphytic, and mycorrhizal fungi, each having specific challenges in their production and use, with the main one being inconsistency of field performance. With the growing global concern about pollution, greenhouse gas accumulation, and increased need for plant-based foods, the demand for biofertilizers and biocontrol agents is expected to grow. What are the prospects of finding solutions to the challenges on existing tools? The inconsistent field performance could be overcome by using combinations of several different types of microbial strains, consisting various members of the full plant microbiome. However, a thorough understanding of each microbiological tool, microbial communities, and their mechanisms of action must precede the product development. In this review, we offer a brief overview of the available tools and consider various techniques and approaches that can produce information on new beneficial traits in biofertilizer and biocontrol strains. We also discuss innovative ideas on how and where to identify efficient new members for the biofertilizer and biocontrol strain family.
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http://dx.doi.org/10.3390/microorganisms9040817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069042PMC
April 2021

Compensatory IgM to the Rescue: Patients with Selective IgA Deficiency Have Increased Natural IgM Antibodies to MAA-LDL and No Changes in Oral Microbiota.

Immunohorizons 2021 Apr 23;5(4):170-181. Epub 2021 Apr 23.

Medical Microbiology and Immunology, Research Unit of Biomedicine, University of Oulu, Oulu, Finland.

IgA is the most abundant Ab in the human body. However, most patients with selective IgA deficiency (SIgAD) are asymptomatic. IgM, and to lesser extent IgG Abs, are generally presumed to compensate for the lack of IgA in SIgAD by multiplying and adopting functions of IgA. We used data from the Northern Finland Birth Cohort 1966 to investigate whether SIgAD patients have differences in levels of natural Abs to oxidized epitopes compared with 20 randomly selected healthy controls. First, we screened the saliva and serum samples from the Northern Finland Birth Cohort 1966 cohort ( 1610) for IgA concentration. We detected five IgA-deficient subjects, yielding a prevalence of 0.3%, which is consistent with the general prevalence of 0.25% in the Finnish population. To detect natural Abs, we used malondialdehyde acetaldehyde-low-density lipoprotein (MAA-LDL), an Ag known to bind natural Abs. In this study, we show that natural secretory IgM and IgG Abs to MAA-DL were significantly increased in subjects with SIgAD. Given that secretory IgA is an important part of mucosal immune defense and that, in the gut microbiota, dysbiosis with SIgAD patients has been observed, we characterized the oral bacterial microbiota of the subjects with and without SIgAD using high-throughput 16S rRNA gene sequencing. We found no significant alterations in diversity and composition of the oral microbiota in subjects with SIgAD. Our data suggest that increased levels of secretory natural Abs in patients with SIgAD could be a compensatory mechanism, providing alternative first-line defense against infections and adjusting mucosal milieu to maintain a healthy oral microbiota.
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http://dx.doi.org/10.4049/immunohorizons.2100014DOI Listing
April 2021

The protective role of PHB and its degradation products against stress situations in bacteria.

FEMS Microbiol Rev 2021 May;45(3)

Ecology and Genetics Research Unit, University of Oulu, Pentti Kaiteran katu 1, P.O. Box 3000, FI-90014 Oulu, Finland.

Many bacteria produce storage biopolymers that are mobilized under conditions of metabolic adaptation, for example, low nutrient availability and cellular stress. Polyhydroxyalkanoates are often found as carbon storage in Bacteria or Archaea, and of these polyhydroxybutyrate (PHB) is the most frequently occurring PHA type. Bacteria usually produce PHB upon availability of a carbon source and limitation of another essential nutrient. Therefore, it is widely believed that the function of PHB is to serve as a mobilizable carbon repository when bacteria face carbon limitation, supporting their survival. However, recent findings indicate that bacteria switch from PHB synthesis to mobilization under stress conditions such as thermal and oxidative shock. The mobilization products, 3-hydroxybutyrate and its oligomers, show a protective effect against protein aggregation and cellular damage caused by reactive oxygen species and heat shock. Thus, bacteria should have an environmental monitoring mechanism directly connected to the regulation of the PHB metabolism. Here, we review the current knowledge on PHB physiology together with a summary of recent findings on novel functions of PHB in stress resistance. Potential applications of these new functions are also presented.
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http://dx.doi.org/10.1093/femsre/fuaa058DOI Listing
May 2021

A comprehensive p75 neurotrophin receptor gene network and pathway analyses identifying new target genes.

Sci Rep 2020 09 11;10(1):14984. Epub 2020 Sep 11.

Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital and University of Turku, Hämeentie 11, P.O. Box 52, 20521, Turku, Finland.

P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred, which makes p75NTR's related signaling networks an interesting and challenging initial point of investigation. We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years. Bioinformatic network and pathway analyses of identified genes (n = 235) were performed using ReactomeFIViz in Cytoscape based on the highly reliable Reactome functional interaction network algorithm. This approach merges interactions extracted from human curated pathways with predicted interactions from machine learning. Genome-wide pathway analysis showed total of 16 enriched hierarchical clusters. A total of 278 enriched single pathways were also identified (p < 0.05, false discovery rate corrected). Gene network analyses showed multiple known and new targets in the p75NTR gene network. This study provides a comprehensive analysis and investigation into the current knowledge of p75NTR signaling networks and pathways. These results also identify several genes and their respective protein products as involved in the p75NTR network, which have not previously been clearly studied in this pathway. These results can be used to generate novel hypotheses to gain a greater understanding of p75NTR in acute brain injuries, neurodegenerative diseases and general response to cellular damage.
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http://dx.doi.org/10.1038/s41598-020-72061-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486379PMC
September 2020

Does Intraspecific Variation in rDNA Copy Number Affect Analysis of Microbial Communities?

Trends Microbiol 2021 01 24;29(1):19-27. Epub 2020 Jun 24.

Department of Biological and Environmental Science, University of Jyväskylä, 40014 Jyväskylä, Finland. Electronic address:

Amplicon sequencing of partial regions of the ribosomal RNA loci (rDNA) is widely used to profile microbial communities. However, the rDNA is dynamic and can exhibit substantial interspecific and intraspecific variation in copy number in prokaryotes and, especially, in microbial eukaryotes. As change in rDNA copy number is a common response to environmental change, rDNA copy number is not necessarily a property of a species. Variation in rDNA copy number, especially the capacity for large intraspecific changes driven by external cues, complicates analyses of rDNA amplicon sequence data. We highlight the need to (i) interpret amplicon sequence data in light of possible interspecific and intraspecific variation, and (ii) examine the potential plasticity in rDNA copy number as an important ecological factor to better understand how microbial communities are structured in heterogeneous environments.
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http://dx.doi.org/10.1016/j.tim.2020.05.019DOI Listing
January 2021

Common transcriptome, plasma molecules, and imaging signatures in the aging brain and a Mendelian neurovascular disease, cerebral cavernous malformation.

Geroscience 2020 10 17;42(5):1351-1363. Epub 2020 Jun 17.

Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.

Brain senescence is associated with impaired endothelial barrier function, angiogenic and inflammatory activity, and propensity to brain hemorrhage. The same pathological changes occur in cerebral cavernous malformations (CCM), a genetic neurovascular anomaly. We hypothesized common transcriptomic and plasma cytokine signatures in the aging brain and CCM. We identified 320 genes [fold change ≥1.5; p < 0.05; false discovery rate (FDR) corrected] commonly dysregulated in the aging brain and CCM. Ontology and pathway analyses of the common differentially expressed genes were related to inflammation and extracellular matrix organization. Plasma levels of C-reactive protein and angiopoietin-2 were significantly greater in older compared to younger healthy non-CCM subjects and were also greater in CCM (Sporadic and Familial) subjects regardless of age (all: p < 0.05; FDR corrected). Plasma levels of vascular endothelial growth factor were significantly greater in older compared to younger subjects, in both healthy non-CCM and Sporadic-CCM groups (all: p < 0.05). Plasma levels of vascular endothelial growth factor were also significantly greater in Familial-CCM cases with germ line mutations regardless of age (all: p < 0.05) compared to both healthy non-CCM and Sporadic-CCM subjects. Brain white matter vascular permeability assessed by MRI followed the same pattern as vascular endothelial growth factor across all groups. In addition, quantitative susceptibility mapping of brain white matter, a measure of iron deposition, was increased in older compared to younger healthy non-CCM subjects. Genetic aberrations, plasma molecules, and imaging biomarkers in a well characterized Mendelian neurovascular disease may also be applicable in the aging brain. Graphical abstract.
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http://dx.doi.org/10.1007/s11357-020-00201-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525636PMC
October 2020

Permissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma.

Nat Commun 2020 05 27;11(1):2659. Epub 2020 May 27.

Section of Neurosurgery, Department of Surgery, The University of Chicago, 5841S. Maryland Avenue, Chicago, IL, 60637, USA.

Cavernous angiomas (CA) are common vascular anomalies causing brain hemorrhage. Based on mouse studies, roles of gram-negative bacteria and altered intestinal homeostasis have been implicated in CA pathogenesis, and pilot study had suggested potential microbiome differences between non-CA and CA individuals based on 16S rRNA gene sequencing. We here assess microbiome differences in a larger cohort of human subjects with and without CA, and among subjects with different clinical features, and conduct more definitive microbial analyses using metagenomic shotgun sequencing. Relative abundance of distinct bacterial species in CA patients is shown, consistent with postulated permissive microbiome driving CA lesion genesis via lipopolysaccharide signaling, in humans as in mice. Other microbiome differences are related to CA clinical behavior. Weighted combinations of microbiome signatures and plasma inflammatory biomarkers enhance associations with disease severity and hemorrhage. This is the first demonstration of a sensitive and specific diagnostic microbiome in a human neurovascular disease.
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http://dx.doi.org/10.1038/s41467-020-16436-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253448PMC
May 2020

Antibodies in cerebral cavernous malformations react with cytoskeleton autoantigens in the lesional milieu.

J Autoimmun 2020 09 30;113:102469. Epub 2020 Apr 30.

Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, 5842 S. Maryland Ave, Chicago, IL, 60637, United States. Electronic address:

Previous studies have reported robust inflammatory cell infiltration, synthesis of IgG, B-cell clonal expansion, deposition of immune complexes and complement within cerebral cavernous malformation (CCM) lesions. B-cell depletion has also been shown to reduce the maturation of CCM in murine models. We hypothesize that antigen(s) within the lesional milieu perpetuate the pathogenetic immune responses in CCMs. This study aims to identify those putative antigen(s) using monoclonal antibodies (mAbs) derived from plasma cells found in surgically removed human CCM lesions. We produced human mAbs from laser capture micro-dissected plasma cells from four CCM patients, and also germline-reverted versions. CCM mAbs were assayed using immunofluorescence on central nervous system (CNS) tissues and immunocytochemistry on human primary cell lines. Antigen characterization was performed using a combination of confocal microscopy, immunoprecipitation and mass spectrometry. Affinity was determined by enzyme-linked immunosorbent assay, and specificity by multi-color confocal microscopy and quantitative co-localization. CCM mAbs bound CNS tissue, especially endothelial cells and astrocytes. Non-muscle myosin heavy chain IIA (NMMHCIIA), vimentin and tubulin are three cytoskeleton proteins that were commonly targeted. Selection of cytoskeleton proteins by plasma cells was supported by a high frequency of immunoglobulin variable region somatic hypermutations, high affinity and selectivity of mAbs in their affinity matured forms, and profoundly reduced affinity and selectivity in the germline reverted forms. Antibodies produced by plasma cells in CCM lesions commonly target cytoplasmic and cytoskeletal autoantigens including NMMHCIIA, vimentin and tubulin that are abundant in endothelial cells and astrocytes. Binding to, and selection on autoantigen(s) in the lesional milieu likely perpetuates the pathogenetic immune response in CCMs. Blocking this in situ autoimmune response may yield a novel treatment for CCM.
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http://dx.doi.org/10.1016/j.jaut.2020.102469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483292PMC
September 2020

Fungal Dysbiosis and Intestinal Inflammation in Children With Beta-Cell Autoimmunity.

Front Immunol 2020 19;11:468. Epub 2020 Mar 19.

Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Although gut bacterial dysbiosis is recognized as a regulator of beta-cell autoimmunity, no data is available on fungal dysbiosis in the children at the risk of type 1 diabetes (T1D). We hypothesized that the co-occurrence of fungal and bacterial dysbiosis contributes to the intestinal inflammation and autoimmune destruction of insulin-producing beta-cells in T1D. Fecal and blood samples were collected from 26 children tested positive for at least one diabetes-associated autoantibody (IAA, GADA, IA-2A or ICA) and matched autoantibody-negative children with HLA-conferred susceptibility to T1D (matched for HLA-DQB1 haplotype, age, gender and early childhood nutrition). Bacterial 16S and fungal ITS2 sequencing, and analyses of the markers of intestinal inflammation, namely fecal human beta-defensin-2 (HBD2), calprotectin and secretory total IgA, were performed. Anti-Saccharomyces cerevisiae antibodies (ASCA) and circulating cytokines, IFNG, IL-17 and IL-22, were studied. After these analyses, the children were followed for development of clinical T1D (median 8 years and 8 months). Nine autoantibody positive children were diagnosed with T1D, whereas none of the autoantibody negative children developed T1D during the follow-up. Fungal dysbiosis, characterized by high abundance of fecal and , was found in the progressors, i.e., children with beta-cell autoimmunity who during the follow-up progressed to clinical T1D. These children showed also bacterial dysbiosis, i.e., increased Bacteroidales and Clostridiales ratio, which was, however, found also in the non-progressors, and is thus a common nominator in the children with beta-cell autoimmunity. Furthermore, the progressors showed markers of intestinal inflammation detected as increased levels of fecal HBD2 and ASCA IgG to fungal antigens. We conclude that the fungal and bacterial dysbiosis, and intestinal inflammation are associated with the development of T1D in children with beta-cell autoimmunity.
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http://dx.doi.org/10.3389/fimmu.2020.00468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103650PMC
March 2021

Subclinical imaging changes in cerebral cavernous angiomas during prospective surveillance.

J Neurosurg 2020 Apr 3:1-8. Epub 2020 Apr 3.

Objective: The purpose of this study was to systematically assess asymptomatic changes (ACs), including subclinical hemorrhage, growth, or new lesion formation (NLF) during longitudinal follow-up of cerebral cavernous angiomas (CAs), and to correlate these with symptomatic hemorrhage (SH) during the same period and with clinical features of the disease.

Methods: One hundred ninety-two patients were included in this study, among 327 consecutive patients with CA, prospectively identified between September 2009 and February 2019. Included patients had undergone clinical and MRI follow-up, in conjunction with institutional review board-approved biomarker studies, and harbored ≥ 1 CA with a maximum diameter of ≥ 5 mm on T2-weighted MRI. Rates of AC and SH per lesion-year and patient-year were assessed using prospectively articulated criteria. In multifocal/familial cases, rates of NLF were also assessed.

Results: There were no differences in demographic or disease features among cases included or excluded in the study cohort, except for a higher proportion of included patients with CCM3 mutation. Follow-up was 411 patient-years (2503 lesion-years). The rate of AC was higher than the rate of SH (12.9% vs 7.5% per patient-year, and 2.1% vs 1.2% per lesion-year, both p = 0.02). Patients presenting with a prior history of SH had a higher rate of AC than those with other forms of presentation (19.7% and 8.2% per patient-year, respectively; p = 0.003). A higher rate of NLF on T2-weighted MRI (p = 0.03) was observed in patients with prior SH. Three of 6 solitary/sporadic and 2 of 28 multifocal/familial patients underwent resection of the lesion after AC.

Conclusions: Rates of AC are greater than SH during prospective follow-up of CAs, and greater in cases with prior SH. AC may be a more sensitive biomarker of lesional activity, and a more efficient surrogate outcome in clinical trials than SH. Patients experiencing an AC are more likely to undergo a surgical intervention when CAs are solitary/sporadic than when they are multifocal/familial.
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http://dx.doi.org/10.3171/2020.1.JNS193479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541547PMC
April 2020

Editorial for "Ensemble Learning for Early-Response Prediction of Antidepressant Treatment in Major Depressive Disorder".

J Magn Reson Imaging 2020 07 8;52(1):172-173. Epub 2020 Feb 8.

Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.

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http://dx.doi.org/10.1002/jmri.27081DOI Listing
July 2020

Symptomatic Brain Hemorrhages from Cavernous Angioma After Botulinum Toxin Injections, a Role of TLR/MEKK3 Mechanism? Case Report and Review of the Literature.

World Neurosurg 2020 Apr 7;136:7-11. Epub 2020 Jan 7.

Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA. Electronic address:

Background: Cavernous angiomas (CAs) are vascular malformations that may result in stroke.

Case Description: Herein, we evaluate a CA patient with chronic migraine who experienced 2 documented symptomatic hemorrhages after receiving respective high doses of botulinum toxin (Btx).

Conclusions: Recently, bacterial lipopolysaccharide has been reported to contribute to CA development through Toll-like receptor signaling, causing hemorrhagic angiogenic proliferation. Lipopolysaccharide and Btx share a common intracellular signaling pathway driving CA development and hemorrhage. Significance of these observations is demonstrated by previous works on plasma molecules showing prognostic associations with symptomatic hemorrhages in human CA, related to the same canonical pathways. Authors suggest careful tracking of the association of Btx and hemorrhage in CA patients.
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http://dx.doi.org/10.1016/j.wneu.2019.12.172DOI Listing
April 2020

Phantom validation of quantitative susceptibility and dynamic contrast-enhanced permeability MR sequences across instruments and sites.

J Magn Reson Imaging 2020 04 12;51(4):1192-1199. Epub 2019 Sep 12.

Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.

Background: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative permeability (DCEQP) on magnetic resonance (MR) have been shown to correlate with neurovascular disease progression as markers of vascular leakage and hemosiderin deposition. Applying these techniques as monitoring biomarkers in clinical trials will be necessary; however, their validation across multiple MR platforms and institutions has not been rigorously verified.

Purpose: To validate quantitative measurement of MR biomarkers on multiple instruments at different institutions.

Study Type: Phantom validation between platforms and institutions.

Phantom Model: T /susceptibility phantom, two-compartment dynamic flow phantom.

Field Strength/sequence: 3T/QSM, T mapping, dynamic 2D SPGR.

Assessment: Philips Ingenia, Siemens Prisma, and Siemens Skyra at three different institutions were assessed. A QSM phantom with concentrations of gadolinium, corresponding to magnetic susceptibilities of 0, 0.1, 0.2, 0.4, and 0.8 ppm was assayed. DCEQP was assessed by measuring a MultiHance bolus as the consistency of the width ratio of the curves at the input and outputs over a range of flow ratios between outputs.

Statistical Tests: Each biomarker was assessed by measures of accuracy (Pearson correlation), precision (paired t-test between repeated measurements), and reproducibility (analysis of covariance [ANCOVA] between instruments).

Results: QSM accuracy of r  > 0.997 on all three platforms was measured. Precision (P = 0.66 Achieva, P = 0.76 Prisma, P = 0.69 Skyra) and reproducibility (P = 0.89) were good. T mapping of accuracy was r  > 0.98. No significant difference between width ratio regression slopes at site 2 (P = 0.669) or site 3 (P = 0.305), and no significant difference between width ratio regression slopes between sites was detected by ANCOVA (P = 0.48).

Data Conclusion: The phantom performed as expected and determined that MR measures of QSM and DCEQP are accurate and consistent across repeated measurements and between platforms.

Level Of Evidence: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1192-1199.
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http://dx.doi.org/10.1002/jmri.26927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065930PMC
April 2020

A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma Disease.

Transl Stroke Res 2020 06 24;11(3):365-376. Epub 2019 Aug 24.

Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine, Chicago, IL, USA.

Cavernous angioma (CA) is a vascular pathology caused by loss of function in one of the 3 CA genes (CCM1, CCM2, and CCM3) that result in rho kinase (ROCK) activation. We investigated a novel ROCK2 selective inhibitor for the ability to reduce brain lesion formation, growth, and maturation. We used genetic methods to explore the use of a ROCK2-selective kinase inhibitor to reduce growth and hemorrhage of CAs. The role of ROCK2 in CA was investigated by crossing Rock1 or Rock2 hemizygous mice with Ccm1 or Ccm3 hemizygous mice, and we found reduced lesions in the Rock2 hemizygous mice. A ROCK2-selective inhibitor, BA-1049 was used to investigate efficacy in reducing CA lesions after oral administration to Ccm1 and Ccm3 mice that were bred into a mutator background. After assessing the dose range effective to target brain endothelial cells in an ischemic brain model, Ccm1 and Ccm3 transgenic mice were treated for 3 (Ccm3) or 4 months (Ccm1), concurrently, randomized to receive one of three doses of BA-1049 in drinking water, or placebo. Lesion volumes were assessed by micro-computed tomography. BA-1049 reduced activation of ROCK2 in Ccm3Trp53 lesions. Ccm1Msh2 (n=68) and Ccm3Trp53 (n=71) mice treated with BA-1049 or placebo showed a significant dose-dependent reduction in lesion volume after treatment with BA-1049, and a reduction in hemorrhage (iron deposition) near lesions at all doses. These translational studies show that BA-1049 is a promising therapeutic agent for the treatment of CA, a disease with no current treatment except surgical removal of the brain lesions.
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http://dx.doi.org/10.1007/s12975-019-00725-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036327PMC
June 2020

Transcriptome clarifies mechanisms of lesion genesis versus progression in models of Ccm3 cerebral cavernous malformations.

Acta Neuropathol Commun 2019 08 19;7(1):132. Epub 2019 Aug 19.

Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.

Cerebral cavernous malformations (CCMs) are dilated capillaries causing epilepsy and stroke. Inheritance of a heterozygous mutation in CCM3/PDCD10 is responsible for the most aggressive familial form of the disease. Here we studied the differences and commonalities between the transcriptomes of microdissected lesional neurovascular units (NVUs) from acute and chronic in vivo Ccm3/Pdcd10 mice, and cultured brain microvascular endothelial cells (BMECs) Ccm3/Pdcd10.We identified 2409 differentially expressed genes (DEGs) in acute and 2962 in chronic in vivo NVUs compared to microdissected brain capillaries, as well as 121 in in vitro BMECs with and without Ccm3/Pdcd10 loss (fold change ≥ |2.0|; p < 0.05, false discovery rate corrected). A functional clustered dendrogram generated using the Euclidean distance showed that the DEGs identified only in acute in vivo NVUs were clustered in cellular proliferation gene ontology functions. The DEGs only identified in chronic in vivo NVUs were clustered in inflammation and immune response, permeability, and adhesion functions. In addition, 1225 DEGs were only identified in the in vivo NVUs but not in vitro BMECs, and these clustered within neuronal and glial functions. One miRNA mmu-miR-3472a was differentially expressed (FC = - 5.98; p = 0.07, FDR corrected) in the serum of Ccm3/Pdcd10 when compared to wild type mice, and this was functionally related as a putative target to Cand2 (cullin associated and neddylation dissociated 2), a DEG in acute and chronic lesional NVUs and in vitro BMECs. Our results suggest that the acute model is characterized by cell proliferation, while the chronic model showed inflammatory, adhesion and permeability processes. In addition, we highlight the importance of extra-endothelial structures in CCM disease, and potential role of circulating miRNAs as biomarkers of disease, interacting with DEGs. The extensive DEGs library of each model will serve as a validation tool for potential mechanistic, biomarker, and therapeutic targets.
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http://dx.doi.org/10.1186/s40478-019-0789-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699077PMC
August 2019

Biomarkers of cavernous angioma with symptomatic hemorrhage.

JCI Insight 2019 06 20;4(12). Epub 2019 Jun 20.

Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.

BACKGROUNDCerebral cavernous angiomas (CAs) with a symptomatic hemorrhage (CASH) have a high risk of recurrent hemorrhage and serious morbidity.METHODSEighteen plasma molecules with mechanistic roles in CA pathobiology were investigated in 114 patients and 12 healthy subjects. The diagnostic biomarker of a CASH in the prior year was derived as that minimizing the Akaike information criterion and validated using machine learning, and was compared with the prognostic CASH biomarker predicting bleeding in the subsequent year. Biomarkers were longitudinally followed in a subset of cases. The biomarkers were queried in the lesional neurovascular unit (NVU) transcriptome and in plasma miRNAs from CASH and non-CASH patients.RESULTSThe diagnostic CASH biomarker included a weighted combination of soluble CD14 (sCD14), VEGF, C-reactive protein (CRP), and IL-10 distinguishing CASH patients with 76% sensitivity and 80% specificity (P = 0.0003). The prognostic CASH biomarker (sCD14, VEGF, IL-1β, and sROBO-4) was confirmed to predict a bleed in the subsequent year with 83% sensitivity and 93% specificity (P = 0.001). Genes associated with diagnostic and prognostic CASH biomarkers were differentially expressed in CASH lesional NVUs. Thirteen plasma miRNAs were differentially expressed between CASH and non-CASH patients.CONCLUSIONShared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in CA are mechanistically linked to lesional transcriptome and miRNA. The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice.FUNDINGNIH, William and Judith Davis Fund in Neurovascular Surgery Research, Be Brave for Life Foundation, Safadi Translational Fellowship, Pritzker School of Medicine, and Sigrid Jusélius Foundation.
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http://dx.doi.org/10.1172/jci.insight.128577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629090PMC
June 2019

Corpse management of the invasive Argentine ant inhibits growth of pathogenic fungi.

Sci Rep 2019 05 20;9(1):7593. Epub 2019 May 20.

Ecology and Genetics Research Unit, University of Oulu, FI-90014, Oulu, Finland.

A dead conspecific poses a potential pathogen risk for social animals. We have discovered that Argentine ants (Linepithema humile) prevent spread of pathogenic fungi from corpses by depositing the dead to combined toilet and refuse areas and applying pygidial gland secretion on them. The presence of a corpse in a nest increases this secretion behaviour. We identified three fungi growing on Argentine ant corpses. Growth of the Argentine ant pathogen Aspergillus nomius and the plant pathogen Fusarium solani on corpses was inhibited as long as the ants were constantly attending them as the ant anal secretion only delayed germination of their spores. In contrast, the effect of the ant anal secretion on the human pathogen Aspergillus fumigatus was much stronger: it prevented spore germination and, accordingly, the fungus no longer grew on the treated corpses. The Argentine ants are one of the world's worst invasive alien species as they cause ecological and economical damage in their new habitats. Our discovery points at a novel method to limit Argentine ant colonies through their natural fungal pathogens.
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http://dx.doi.org/10.1038/s41598-019-44144-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527551PMC
May 2019

A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis.

Nat Commun 2019 04 17;10(1):1791. Epub 2019 Apr 17.

Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, ON, Canada.

Apoptotic death of cells damaged by genotoxic stress requires regulatory input from surrounding tissues. The C. elegans scaffold protein KRI-1, ortholog of mammalian KRIT1/CCM1, permits DNA damage-induced apoptosis of cells in the germline by an unknown cell non-autonomous mechanism. We reveal that KRI-1 exists in a complex with CCM-2 in the intestine to negatively regulate the ERK-5/MAPK pathway. This allows the KLF-3 transcription factor to facilitate expression of the SLC39 zinc transporter gene zipt-2.3, which functions to sequester zinc in the intestine. Ablation of KRI-1 results in reduced zinc sequestration in the intestine, inhibition of IR-induced MPK-1/ERK1 activation, and apoptosis in the germline. Zinc localization is also perturbed in the vasculature of krit1 zebrafish, and SLC39 zinc transporters are mis-expressed in Cerebral Cavernous Malformations (CCM) patient tissues. This study provides new insights into the regulation of apoptosis by cross-tissue communication, and suggests a link between zinc localization and CCM disease.
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http://dx.doi.org/10.1038/s41467-019-09829-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470173PMC
April 2019

Surgical Performance Determines Functional Outcome Benefit in the Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation (MISTIE) Procedure.

Neurosurgery 2019 06;84(6):1157-1168

Division of Brain Injury Outcomes, Department of Neurology, Johns Hopkins University Medical Institutions, Baltimore, Maryland.

Background: Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr).

Objective: To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes.

Methods: Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial.

Results: Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation.

Conclusion: This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal.
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http://dx.doi.org/10.1093/neuros/nyz077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537634PMC
June 2019

Rho Kinase Inhibition Blunts Lesion Development and Hemorrhage in Murine Models of Aggressive Pdcd10/Ccm3 Disease.

Stroke 2019 03;50(3):738-744

From the Section of Neurosurgery (R.S., T.M., R.L., R.G., N.H., S.P.P., J.K., D.Z., S.B.L., Y.C., K.C., L.S., I.A.A.), Biological Sciences Division, University of Chicago, IL.

Background and Purpose- Previously, murine models Krit1 Msh2 and Ccm2 Trp53 showed a reduction or no effect on cerebral cavernous malformation (CCM) burden and favorable effects on lesional hemorrhage by the robust Rock (Rho-associated protein kinase) inhibitor fasudil and by simvastatin (a weak pleiotropic inhibitor of Rock). Herein, we concurrently investigated treatment of the more aggressive Pdcd10/Ccm3 model with fasudil, simvastatin, and higher dose atorvastatin to determined effectiveness of Rock inhibition. Methods- The murine models, Pdcd10 Trp53 and Pdcd10 Msh2 , were contemporaneously treated from weaning to 5 months of age with fasudil (100 mg/kg per day in drinking water, n=9), simvastatin (40 mg/kg per day in chow, n=11), atorvastatin (80 mg/kg per day in chow, n=10), or with placebo (n=16). We assessed CCM volume in mouse brains by microcomputed tomography. Lesion burden was calculated as lesion volume normalized to total brain volume. We analyzed chronic hemorrhage in CCM lesions by quantitative intensity of Perls staining in brain sections. Results- The Pdcd10 Trp53 /Msh2 models showed a mean CCM lesion burden per mouse reduction from 0.0091 in placebos to 0.0042 ( P=0.027) by fasudil, and to 0.0047 ( P=0.025) by atorvastatin treatment, but was not changed significantly by simvastatin. Hemorrhage intensity per brain was commensurately decreased by Rock inhibition. Conclusions- These results support the exploration of proof of concept effect of high-dose atorvastatin on human CCM disease for potential therapeutic testing.
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http://dx.doi.org/10.1161/STROKEAHA.118.024058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389370PMC
March 2019

Comprehensive transcriptome analysis of cerebral cavernous malformation across multiple species and genotypes.

JCI Insight 2019 Feb 7;4(3). Epub 2019 Feb 7.

Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.

The purpose of this study was to determine important genes, functions, and networks contributing to the pathobiology of cerebral cavernous malformation (CCM) from transcriptomic analyses across 3 species and 2 disease genotypes. Sequencing of RNA from laser microdissected neurovascular units of 5 human surgically resected CCM lesions, mouse brain microvascular endothelial cells, Caenorhabditis elegans with induced Ccm gene loss, and their respective controls provided differentially expressed genes (DEGs). DEGs from mouse and C. elegans were annotated into human homologous genes. Cross-comparisons of DEGs between species and genotypes, as well as network and gene ontology (GO) enrichment analyses, were performed. Among hundreds of DEGs identified in each model, common genes and 1 GO term (GO:0051656, establishment of organelle localization) were commonly identified across the different species and genotypes. In addition, 24 GO functions were present in 4 of 5 models and were related to cell-to-cell adhesion, neutrophil-mediated immunity, ion transmembrane transporter activity, and responses to oxidative stress. We have provided a comprehensive transcriptome library of CCM disease across species and for the first time to our knowledge in Ccm1/Krit1 versus Ccm3/Pdcd10 genotypes. We have provided examples of how results can be used in hypothesis generation or mechanistic confirmatory studies.
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http://dx.doi.org/10.1172/jci.insight.126167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413775PMC
February 2019

Risk Factors for Recurrent Hematoma After Surgery for Acute Traumatic Subdural Hematoma.

World Neurosurg 2019 Jan 10. Epub 2019 Jan 10.

Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital and University of Turku, Turku, Finland; Neurovascular Surgery Program, Section of Neurosurgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA. Electronic address:

Objective: The development of postcraniotomy hematoma (PCH) after surgery for acute traumatic subdural hematoma (aSDH) has been associated with an increased risk of a poor outcome. The risk factors contributing to PCH remain poorly understood. Our aim was to study the potential risk factors for PCH in a consecutive series of surgically evacuated patients with aSDH.

Methods: A total of 132 patients with aSDH treated at Turku University Hospital (Turku, Finland) from 2008 to 2012 were enrolled in the present retrospective cohort study. The demographic, clinical, laboratory, and imaging data were collected from the medical records. A comprehensive analysis of the data using 6 different univariate methods, including machine learning and multivariate analyses, was conducted to identify the factors related to PCH.

Results: The incidence of PCH after primary surgery for traumatic aSDH was 10.6%. The patients experiencing PCH were younger (P = 0.04). No difference was found in the use of anticoagulant or antiplatelet medication for the patients with and without PCH. Multivariate analyses identified alcohol inebriation at the time of injury (odds ratio [OR], 12.67; P = 0.041) and hypocapnia (OR, 26.09; P = 0.003) as independent risk factors for PCH. The patients with PCH had had hyponatremia (OR, 0.08; P = 0.018) less often, and their maximal systolic blood pressure was lower (OR, 0.94; P = 0.009). The area under the curve for the multivariate model was 0.96 (P = 0.049), with a Youden index of 0.88.

Conclusions: The results suggest that alcohol inebriation at the time of injury and hypocapnia during hospitalization are risk factors for the development of PCH.
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http://dx.doi.org/10.1016/j.wneu.2018.12.155DOI Listing
January 2019

Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial.

Neurosurgery 2019 12;85(6):843-853

Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois.

Background: More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit.

Objective: To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups.

Methods: The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint.

Expected Outcomes: The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug.

Discussion: With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.
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http://dx.doi.org/10.1093/neuros/nyy539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054711PMC
December 2019

Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice.

Blood 2019 01 15;133(3):193-204. Epub 2018 Nov 15.

Department of Medicine, University of California, San Diego, La Jolla, CA.

Cerebral cavernous malformations (CCMs) are common brain vascular dysplasias that are prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here, we show that central nervous system hemorrhage in CCMs is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions, as well as in the plasma of patients with CCMs. In mice, endothelial-specific genetic inactivation of ( ) or ( ), which cause CCM formation, results in increased levels of vascular TM and EPCR, as well as in enhanced generation of activated protein C (APC) on endothelial cells. Increased TM expression is due to upregulation of transcription factors KLF2 and KLF4 consequent to the loss of or Increased TM expression contributes to CCM hemorrhage, because genetic inactivation of 1 or 2 copies of the gene decreases brain hemorrhage in mice. Moreover, administration of blocking antibodies against TM and EPCR significantly reduced CCM hemorrhage in mice. Thus, a local increase in the endothelial cofactors that generate anticoagulant APC can contribute to bleeding in CCMs, and plasma soluble TM may represent a biomarker for hemorrhagic risk in CCMs.
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http://dx.doi.org/10.1182/blood-2018-06-856062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337879PMC
January 2019

Phenotypic characterization of murine models of cerebral cavernous malformations.

Lab Invest 2019 03 26;99(3):319-330. Epub 2018 Jun 26.

Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.

Cerebral cavernous malformations (CCMs) are clusters of dilated capillaries that affect around 0.5% of the population. CCMs exist in two forms, sporadic and familial. Mutations in three documented genes, KRIT1(CCM1), CCM2, and PDCD10(CCM3), cause the autosomal dominant form of the disease, and somatic mutations in these same genes underlie lesion development in the brain. Murine models with constitutive or induced loss of respective genes have been applied to study disease pathobiology and therapeutic manipulations. We aimed to analyze the phenotypic characteristic of two main groups of models, the chronic heterozygous models with sensitizers promoting genetic instability, and the acute neonatal induced homozygous knockout model. Acute model mice harbored a higher lesion burden than chronic models, more localized in the hindbrain, and largely lacking iron deposition and inflammatory cell infiltrate. The chronic model mice showed a lower lesion burden localized throughout the brain, with significantly greater perilesional iron deposition, immune B- and T-cell infiltration, and less frequent junctional protein immunopositive endothelial cells. Lesional endothelial cells in both models expressed similar phosphorylated myosin light chain immunopositivity indicating Rho-associated protein kinase activity. These data suggest that acute models are better suited to study the initial formation of the lesion, while the chronic models better reflect lesion maturation, hemorrhage, and inflammatory response, relevant pathobiologic features of the human disease.
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http://dx.doi.org/10.1038/s41374-018-0030-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309944PMC
March 2019

Plasma Biomarkers of Inflammation and Angiogenesis Predict Cerebral Cavernous Malformation Symptomatic Hemorrhage or Lesional Growth.

Circ Res 2018 06 2;122(12):1716-1721. Epub 2018 May 2.

From the Section of Neurosurgery, Department of Surgery, University of Chicago Medicine and Biological Sciences, IL (R.G., H.A.Z., J.K., M.D.F., Y.C., C.S., T.M., R.L., A.S., K.C., S.P., R.S., I.A.A.)

Rationale: The clinical course of cerebral cavernous malformations is highly unpredictable, with few cross-sectional studies correlating proinflammatory genotypes and plasma biomarkers with prior disease severity.

Objective: We hypothesize that a panel of 24 candidate plasma biomarkers, with a reported role in the physiopathology of cerebral cavernous malformations, may predict subsequent clinically relevant disease activity.

Methods And Results: Plasma biomarkers were assessed in nonfasting peripheral venous blood collected from consecutive cerebral cavernous malformation subjects followed for 1 year after initial sample collection. A first cohort (N=49) was used to define the best model of biomarker level combinations to predict a subsequent symptomatic lesional hemorrhagic expansion within a year after the blood sample. We generated the receiver operating characteristic curves and area under the curve for each biomarker individually and each weighted linear combination of relevant biomarkers. The best model to predict lesional activity was selected as that minimizing the Akaike information criterion. In this cohort, 11 subjects experienced symptomatic lesional hemorrhagic expansion (5 bleeds and 10 lesional growths) within a year after the blood draw. Subjects had lower soluble CD14 (cluster of differentiation 14; =0.05), IL (interleukin)-6 (=0.04), and VEGF (vascular endothelial growth factor; =0.0003) levels along with higher plasma levels of IL-1β (=0.008) and soluble ROBO4 (roundabout guidance receptor 4; =0.03). Among the 31 weighted linear combinations of these 5 biomarkers, the best model (with the lowest Akaike information criterion value, 25.3) was the weighted linear combination including soluble CD14, IL-1β, VEGF, and soluble ROBO4, predicting a symptomatic hemorrhagic expansion with a sensitivity of 86% and specificity of 88% (area under the curve, 0.90; <0.0001). We then validated our best model in the second sequential independent cohort (N=28).

Conclusions: This is the first study reporting a predictive association between plasma biomarkers and subsequent cerebral cavernous malformation disease clinical activity. This may be applied in clinical prognostication and stratification of cases in clinical trials.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.312680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993629PMC
June 2018

Trial Readiness in Cavernous Angiomas With Symptomatic Hemorrhage (CASH).

Neurosurgery 2019 04;84(4):954-964

Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois.

Background: Brain cavernous angiomas with symptomatic hemorrhage (CASH) are uncommon but exact a heavy burden of neurological disability from recurrent bleeding, for which there is no proven therapy. Candidate drugs to stabilize the CASH lesion and prevent rebleeding will ultimately require testing of safety and efficacy in multisite clinical trials. Much progress has been made in understanding the epidemiology of CASH, and novel biomarkers have been linked to the biological mechanisms and clinical activity in lesions. Yet, the ability to enroll and risk-stratify CASH subjects has never been assessed prospectively at multiple sites. Biomarkers and other outcomes have not been evaluated for their sensitivity and reliability, nor have they been harmonized across sites.

Objective: To address knowledge gaps and establish a research network as infrastructure for future clinical trials, through the Trial Readiness grant mechanism, funded by National Institute of Neurological Disorders and Stroke/National Institutes of Health.

Methods: This project includes an observational cohort study to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization, and follow-up of CASH using common data elements at multiple sites, (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures that have been shown to correlate with lesion activity, and (3) the rates of recurrent hemorrhage and change in functional status and biomarker measurements during prospective follow-up.

Expected Outcomes: We propose a harmonized multisite assessment of enrollment rates of CASH, baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes in relation to clinical bleeds. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic foundations, which have been linked to clinical disease activity. We shall test their reliability and validity at multiple sites, and assess their changes over time, with and without clinical rebleeds, hence their fitness as outcome instruments in clinical trials.

Discussion: The timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.
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http://dx.doi.org/10.1093/neuros/nyy108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500884PMC
April 2019

Different endophyte communities colonize buds of sprouts compared with mature trees of mountain birch recovered from moth herbivory.

Tree Physiol 2018 09;38(9):1437-1444

Ecology and Genetics, University of Oulu, Oulu, Finland.

Plant meristems were previously thought to be sterile. Today, meristem-associated shoot endophytes are mainly reported as contaminants from plant tissue cultures, the number of observed species being very low. However, the few strains characterized have the capacity for infecting host cells and affecting plant growth and development. Here we studied the communities of endophytic bacteria in the buds of mountain birch (Betula pubescens ssp. czerepanovii (N. I. Orlova) Hämet-Ahti) exposed to winter moth (Operophtera brumata L.) herbivory, to identify differences between sprouts and branches of mature birch trees. Mountain birch of the high subarctic is cyclically exposed to winter moth and produces sprouts to generate new trees as a survival mechanism. The majority (54%) of operational taxonomic units belonged to Xanthomonadaceae and Pseudomonales of Proteobacteria. Most of the observed species were classified as Xanthomonas (28%). Sprout buds had the highest diversity, containing approximately three times more species, and significantly more (43%) Pseudomonas species than the mature trees (14%). Our results demonstrate that endophytic communities of buds are richer than previously thought. We suggest that the meristem-associated endophytes should be studied further for a possible role in sprouting and aiding regeneration of trees.
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http://dx.doi.org/10.1093/treephys/tpy012DOI Listing
September 2018

Methyl-esterified 3-hydroxybutyrate oligomers protect bacteria from hydroxyl radicals.

Nat Chem Biol 2016 May 14;12(5):332-8. Epub 2016 Mar 14.

Genetics and Physiology, University of Oulu, Oulu, Finland.

Bacteria rely mainly on enzymes, glutathione and other low-molecular weight thiols to overcome oxidative stress. However, hydroxyl radicals are the most cytotoxic reactive oxygen species, and no known enzymatic system exists for their detoxification. We now show that methyl-esterified dimers and trimers of 3-hydroxybutyrate (ME-3HB), produced by bacteria capable of polyhydroxybutyrate biosynthesis, have 3-fold greater hydroxyl radical-scavenging activity than glutathione and 11-fold higher activity than vitamin C or the monomer 3-hydroxybutyric acid. We found that ME-3HB oligomers protect hypersensitive yeast deletion mutants lacking oxidative stress-response genes from hydroxyl radical stress. Our results show that phaC and phaZ, encoding polymerase and depolymerase, respectively, are activated and polyhydroxybutyrate reserves are degraded for production of ME-3HB oligomers in bacteria infecting plant cells and exposed to hydroxyl radical stress. We found that ME-3HB oligomer production is widespread, especially in bacteria adapted to stressful environments. We discuss how ME-3HB oligomers could provide opportunities for numerous applications in human health.
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http://dx.doi.org/10.1038/nchembio.2043DOI Listing
May 2016