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Article ; Online: Transcriptional signatures measured in whole blood correlate with protection against tuberculosis in inbred and outbred mice.

Kurtz, Sherry L / Rydén, Patrik / Elkins, Karen L

2023 Volume 18, Issue 8, Page(s) e0289358

Abstract: Although BCG has been used for almost 100 years to immunize against Mycobacterium tuberculosis, TB remains a global public health threat. Numerous clinical trials are underway studying novel vaccine candidates and strategies to improve or replace BCG, ... ...

Abstract	Although BCG has been used for almost 100 years to immunize against Mycobacterium tuberculosis, TB remains a global public health threat. Numerous clinical trials are underway studying novel vaccine candidates and strategies to improve or replace BCG, but vaccine development still lacks a well-defined set of immune correlates to predict vaccine-induced protection against tuberculosis. This study aimed to address this gap by examining transcriptional responses to BCG vaccination in C57BL/6 inbred mice, coupled with protection studies using Diversity Outbred mice. We evaluated relative gene expression in blood obtained from vaccinated mice, because blood is easily accessible, and data can be translated to human studies. We first determined that the average peak time after vaccination is 14 days for gene expression of a small subset of immune-related genes in inbred mice. We then performed global transcriptomic analyses using whole blood samples obtained two weeks after mice were vaccinated with BCG. Using comparative bioinformatic analyses and qRT-PCR validation, we developed a working correlate panel of 18 genes that were highly correlated with administration of BCG but not heat-killed BCG. We then tested this gene panel using BCG-vaccinated Diversity Outbred mice and revealed associations between the expression of a subset of genes and disease outcomes after aerosol challenge with M. tuberculosis. These data therefore demonstrate that blood-based transcriptional immune correlates measured within a few weeks after vaccination can be derived to predict protection against M. tuberculosis, even in outbred populations.
MeSH term(s)	Animals ; Humans ; Mice ; BCG Vaccine ; Collaborative Cross Mice ; Mice, Inbred C57BL ; Tuberculosis/microbiology ; Mycobacterium tuberculosis/genetics ; Vaccination
Chemical Substances	BCG Vaccine
Language	English
Publishing date	2023-08-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0289358
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Comparison of Methods for Feature Selection in Clustering of High-Dimensional RNA-Sequencing Data to Identify Cancer Subtypes.

Källberg, David / Vidman, Linda / Rydén, Patrik

Frontiers in genetics

2021 Volume 12, Page(s) 632620

Abstract: Cancer subtype identification is important to facilitate cancer diagnosis and select effective treatments. Clustering of cancer patients based on high-dimensional RNA-sequencing data can be used to detect novel subtypes, but only a subset of the features ...

Abstract	Cancer subtype identification is important to facilitate cancer diagnosis and select effective treatments. Clustering of cancer patients based on high-dimensional RNA-sequencing data can be used to detect novel subtypes, but only a subset of the features (e.g., genes) contains information related to the cancer subtype. Therefore, it is reasonable to assume that the clustering should be based on a set of carefully selected features rather than all features. Several feature selection methods have been proposed, but how and when to use these methods are still poorly understood. Thirteen feature selection methods were evaluated on four human cancer data sets, all with known subtypes (gold standards), which were only used for evaluation. The methods were characterized by considering mean expression and standard deviation (SD) of the selected genes, the overlap with other methods and their clustering performance, obtained comparing the clustering result with the gold standard using the adjusted Rand index (ARI). The results were compared to a supervised approach as a positive control and two negative controls in which either a random selection of genes or all genes were included. For all data sets, the best feature selection approach outperformed the negative control and for two data sets the gain was substantial with ARI increasing from (-0.01, 0.39) to (0.66, 0.72), respectively. No feature selection method completely outperformed the others but using the dip-rest statistic to select 1000 genes was overall a good choice. The commonly used approach, where genes with the highest SDs are selected, did not perform well in our study.
Language	English
Publishing date	2021-02-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2021.632620
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Article: In Silico Identification of Potential Thyroid Hormone System Disruptors among Chemicals in Human Serum and Chemicals with a High Exposure Index

Dracheva, Elena / Norinder, Ulf / Rydén, Patrik / Engelhardt, Josefin / Weiss, Jana M. / Andersson, Patrik L.

Environmental science & technology. 2022 May 13, v. 56, no. 12

2022

Abstract: Data on toxic effects are at large missing the prevailing understanding of the risks of industrial chemicals. Thyroid hormone (TH) system disruption includes interferences of the life cycle of the thyroid hormones and may occur in various organs. In the ... ...

Abstract	Data on toxic effects are at large missing the prevailing understanding of the risks of industrial chemicals. Thyroid hormone (TH) system disruption includes interferences of the life cycle of the thyroid hormones and may occur in various organs. In the current study, high-throughput screening data available for 14 putative molecular initiating events of adverse outcome pathways, related to disruption of the TH system, were used to develop 19 in silico models for identification of potential thyroid hormone system-disrupting chemicals. The conformal prediction framework with the underlying Random Forest was used as a wrapper for the models allowing for setting the desired confidence level and controlling the error rate of predictions. The trained models were then applied to two different databases: (i) an in-house database comprising xenobiotics identified in human blood and ii) currently used chemicals registered in the Swedish Product Register, which have been predicted to have a high exposure index to consumers. The application of these models showed that among currently used chemicals, fewer were overall predicted as active compared to chemicals identified in human blood. Chemicals of specific concern for TH disruption were identified from both databases based on their predicted activity.
Keywords	blood serum ; computer simulation ; databases ; environmental science ; humans ; prediction ; thyroid hormones ; toxicity ; xenobiotics
Language	English
Dates of publication	2022-0513
Size	p. 8363-8372.
Publishing place	American Chemical Society
Document type	Article
ISSN	1520-5851
DOI	10.1021/acs.est.1c07762
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: In Silico Identification of Potential Thyroid Hormone System Disruptors among Chemicals in Human Serum and Chemicals with a High Exposure Index.

Dracheva, Elena / Norinder, Ulf / Rydén, Patrik / Engelhardt, Josefin / Weiss, Jana M / Andersson, Patrik L

Environmental science & technology

2022 Volume 56, Issue 12, Page(s) 8363–8372

Abstract	Data on toxic effects are at large missing the prevailing understanding of the risks of industrial chemicals. Thyroid hormone (TH) system disruption includes interferences of the life cycle of the thyroid hormones and may occur in various organs. In the current study, high-throughput screening data available for 14 putative molecular initiating events of adverse outcome pathways, related to disruption of the TH system, were used to develop 19 in silico models for identification of potential thyroid hormone system-disrupting chemicals. The conformal prediction framework with the underlying Random Forest was used as a wrapper for the models allowing for setting the desired confidence level and controlling the error rate of predictions. The trained models were then applied to two different databases: (i) an in-house database comprising xenobiotics identified in human blood and ii) currently used chemicals registered in the Swedish Product Register, which have been predicted to have a high exposure index to consumers. The application of these models showed that among currently used chemicals, fewer were overall predicted as active compared to chemicals identified in human blood. Chemicals of specific concern for TH disruption were identified from both databases based on their predicted activity.
MeSH term(s)	Computer Simulation ; Endocrine Disruptors/toxicity ; High-Throughput Screening Assays ; Humans ; Thyroid Hormones/metabolism ; Xenobiotics
Chemical Substances	Endocrine Disruptors ; Thyroid Hormones ; Xenobiotics
Language	English
Publishing date	2022-05-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1520-5851
ISSN (online)	1520-5851
DOI	10.1021/acs.est.1c07762
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A genome-wide test for paternal indirect genetic effects on lifespan in

Shenoi, Vinesh Naresh / Brengdahl, Martin I / Grace, Jaime L / Eriksson, Björn / Rydén, Patrik / Friberg, Urban

Proceedings. Biological sciences

2022 Volume 289, Issue 1974, Page(s) 20212707

Abstract: Exposing sires to various environmental manipulations has demonstrated that paternal effects can be non-trivial also in species where male investment in offspring is almost exclusively limited to sperm. Whether paternal effects also have a genetic ... ...

Abstract	Exposing sires to various environmental manipulations has demonstrated that paternal effects can be non-trivial also in species where male investment in offspring is almost exclusively limited to sperm. Whether paternal effects also have a genetic component (i.e. paternal indirect genetic effects (PIGEs)) in such species is however largely unknown, primarily because of methodological difficulties separating indirect from direct effects of genes. PIGEs may nevertheless be important since they have the capacity to contribute to evolutionary change. Here we use
MeSH term(s)	Animals ; Biological Evolution ; Drosophila melanogaster/genetics ; Genome ; Longevity ; Male ; Paternal Inheritance
Language	English
Publishing date	2022-05-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209242-6
ISSN	1471-2954 ; 0080-4649 ; 0962-8452 ; 0950-1193
ISSN (online)	1471-2954
ISSN	0080-4649 ; 0962-8452 ; 0950-1193
DOI	10.1098/rspb.2021.2707
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Article ; Online: Cluster analysis on high dimensional RNA-seq data with applications to cancer research - An evaluation study.

Vidman, Linda / Källberg, David / Rydén, Patrik

PloS one

2019 Volume 14, Issue 12, Page(s) e0219102

Abstract: Background: Clustering of gene expression data is widely used to identify novel subtypes of cancer. Plenty of clustering approaches have been proposed, but there is a lack of knowledge regarding their relative merits and how data characteristics ... ...

Abstract	Background: Clustering of gene expression data is widely used to identify novel subtypes of cancer. Plenty of clustering approaches have been proposed, but there is a lack of knowledge regarding their relative merits and how data characteristics influence the performance. We evaluate how cluster analysis choices affect the performance by studying four publicly available human cancer data sets: breast, brain, kidney and stomach cancer. In particular, we focus on how the sample size, distribution of subtypes and sample heterogeneity affect the performance. Results: In general, increasing the sample size had limited effect on the clustering performance, e.g. for the breast cancer data similar performance was obtained for n = 40 as for n = 330. The relative distribution of the subtypes had a noticeable effect on the ability to identify the disease subtypes and data with disproportionate cluster sizes turned out to be difficult to cluster. Both the choice of clustering method and selection method affected the ability to identify the subtypes, but the relative performance varied between data sets, making it difficult to rank the approaches. For some data sets, the performance was substantially higher when the clustering was based on data from only one sex compared to data from a mixed population. This suggests that homogeneous data are easier to cluster than heterogeneous data and that clustering males and females individually may be beneficial and increase the chance to detect novel subtypes. It was also observed that the performance often differed substantially between females and males. Conclusions: The number of samples seems to have a limited effect on the performance while the heterogeneity, at least with respect to sex, is important for the performance. Hence, by analyzing the genders separately, the possible loss caused by having fewer samples could be outweighed by the benefit of a more homogeneous data.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Algorithms ; Cluster Analysis ; Data Analysis ; Datasets as Topic ; Female ; Genetic Research ; Humans ; Male ; Middle Aged ; Neoplasms/genetics ; RNA, Neoplasm ; RNA-Seq ; Sample Size ; Sex Factors ; Young Adult
Chemical Substances	RNA, Neoplasm
Language	English
Publishing date	2019-12-05
Publishing country	United States
Document type	Comparative Study ; Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0219102
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Article: Vaccine-Mediated Mechanisms Controlling <i>Francisella tularensis</i> SCHU S4 Growth in a Rat Co-Culture System

Lindgren, Helena / Eneslätt, Kjell / Golovliov, Igor / Gelhaus, Carl / Rydén, Patrik / Wu, Terry / Sjöstedt, Anders

Pathogens. 2020 Apr. 30, v. 9, no. 5

2020

Abstract: ... Francisella tularensis ... causes the severe disease tularemia. In the present study, the aim was to identify correlates of protection in the rat co-culture model by investigating the immune responses using two vaccine candidates conferring distinct ... ...

Abstract	Francisella tularensis causes the severe disease tularemia. In the present study, the aim was to identify correlates of protection in the rat co-culture model by investigating the immune responses using two vaccine candidates conferring distinct degrees of protection in rat and mouse models. The immune responses were characterized by use of splenocytes from naïve or Live vaccine strain- (LVS) or ∆clpB/∆wbtC-immunized Fischer 344 rats as effectors and bone marrow-derived macrophages infected with the highly virulent strain SCHU S4. A complex immune response was elicited, resulting in cytokine secretion, nitric oxide production, and efficient control of the intracellular bacterial growth. Addition of LVS-immune splenocytes elicited a significantly better control of bacterial growth than ∆clpB/∆wbtC splenocytes. This mirrored the efficacy of the vaccine candidates in the rat model. Lower levels of IFN-γ, TNF, fractalkine, IL-2, and nitrite were present in the co-cultures with ∆clpB/∆wbtC splenocytes than in those with splenocytes from LVS-immunized rats. Nitric oxide was found to be a correlate of protection, since the levels inversely correlated to the degree of protection and inhibition of nitric oxide production completely reversed the growth inhibition of SCHU S4. Overall, the results demonstrate that the co-culture assay with rat-derived cells is a suitable model to identify correlates of protection against highly virulent strains of F. tularensis
Keywords	Francisella tularensis ; animal models ; assays ; bacterial growth ; chemokine CX3CL1 ; coculture ; disease severity ; growth retardation ; immune response ; interleukin-2 ; live vaccines ; macrophages ; nitric oxide ; nitrites ; pathogens ; rats ; secretion ; splenocytes ; tularemia ; virulent strains
Language	English
Dates of publication	2020-0430
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
Note	NAL-light
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens9050338
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Vaccine-Mediated Mechanisms Controlling Replication of

Eneslätt, Kjell / Golovliov, Igor / Rydén, Patrik / Sjöstedt, Anders

Frontiers in cellular and infection microbiology

2018 Volume 8, Page(s) 27

Abstract: Cell-mediated immunity (CMI) is normally required for efficient protection against intracellular infections, however, identification of correlates is challenging and they are generally lacking. ...

Abstract	Cell-mediated immunity (CMI) is normally required for efficient protection against intracellular infections, however, identification of correlates is challenging and they are generally lacking.
MeSH term(s)	Antigens, Bacterial/immunology ; Bacterial Vaccines/administration & dosage ; Bacterial Vaccines/immunology ; Biomarkers ; Cells, Cultured ; Coculture Techniques ; Cytokines/metabolism ; Francisella tularensis/physiology ; Host-Pathogen Interactions/immunology ; Humans ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/metabolism ; Leukocytes, Mononuclear/microbiology ; Lymphocyte Activation/immunology ; Lymphocytes/immunology ; Lymphocytes/metabolism ; Tularemia/immunology ; Tularemia/microbiology ; Tularemia/prevention & control
Chemical Substances	Antigens, Bacterial ; Bacterial Vaccines ; Biomarkers ; Cytokines
Language	English
Publishing date	2018-02-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2018.00027
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Flow cytometry analysis using sysmex UF-1000i classifies uropathogens based on bacterial, leukocyte, and erythrocyte counts in urine specimens among patients with urinary tract infections.

Monsen, Tor / Rydén, Patrik

Journal of clinical microbiology

2015 Volume 53, Issue 2, Page(s) 539–545

Abstract: Urinary tract infections (UTIs) are the second most common bacterial infection. Urine culture is the gold standard for diagnosis, but new techniques, such as flow cytometry analysis (FCA), have been introduced. The aim of the present study was to ... ...

Abstract	Urinary tract infections (UTIs) are the second most common bacterial infection. Urine culture is the gold standard for diagnosis, but new techniques, such as flow cytometry analysis (FCA), have been introduced. The aim of the present study was to evaluate FCA characteristics regarding bacteriuria, leukocyturia, and erythrocyturia in relation to cultured uropathogens in specimens from patients with a suspected UTI. We also wanted to evaluate whether the FCA characteristics can identify uropathogens prior to culture. From a prospective study, 1,587 consecutive urine specimens underwent FCA prior to culture during January and February 2012. Outpatients and inpatients (79.6% and 19.4%, respectively) were included, of whom women represented 67.5%. In total, 620 specimens yielded growth, of which Escherichia coli represented 65%, Enterococcus spp. 8%, Klebsiella spp. 7%, and Staphylococcus spp. 5%. For the uropathogens, the outcome of FCA was compared against the results for specimens with E. coli and those with a negative culture. E. coli had high bacterial (median, 17,914/μl), leukocyte (median, 348/μl), and erythrocyte (median, 23/μl) counts. With the exception of Klebsiella spp., the majority of the uropathogens had considerable or significantly lower bacterial counts than that of E. coli. High leukocyte counts were found in specimens with Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, and group C streptococci. Elevated erythrocyte counts were found for P. vulgaris, P. aeruginosa, and group C streptococci, as well as for Staphylococcus saprophyticus. In essence, FCA adds new information about the bacterial, leukocyte, and erythrocyte counts in urine specimens for different uropathogens. Based on FCA characteristics, uropathogens can be classified and identified prior to culture. E. coli and Klebsiella spp. have similar FCA characteristics.
MeSH term(s)	Adult ; Aged ; Bacterial Infections/diagnosis ; Bacterial Infections/microbiology ; Bacterial Infections/pathology ; Bacterial Load/methods ; Erythrocyte Count/methods ; Female ; Flow Cytometry/methods ; Humans ; Leukocyte Count/methods ; Male ; Middle Aged ; Prospective Studies ; Urinary Tract Infections/diagnosis ; Urinary Tract Infections/microbiology ; Urinary Tract Infections/pathology ; Urine/cytology ; Urine/microbiology
Language	English
Publishing date	2015-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	390499-4
ISSN	1098-660X ; 0095-1137
ISSN (online)	1098-660X
ISSN	0095-1137
DOI	10.1128/JCM.01974-14
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Vaccine-Mediated Mechanisms Controlling

Lindgren, Helena / Eneslätt, Kjell / Golovliov, Igor / Gelhaus, Carl / Rydén, Patrik / Wu, Terry / Sjöstedt, Anders

Pathogens (Basel, Switzerland)

2020 Volume 9, Issue 5

Abstract: Francisella ... ...

Abstract	Francisella tularensis
Language	English
Publishing date	2020-04-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens9050338
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