Blood Gene Expression Signatures Predict Invasive Candidiasis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE20524 | GEO | 2010/02/25
SECONDARY ACCESSION(S): PRJNA125135
REPOSITORIES: GEO
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Project description:Focusing on host response to infection, we utilized a murine model to develop a blood gene expression signature that accurately classified mice with candidemia and distinguished candidemia from S. aureus bacteremia. Validation of the signature was achieved in an independent cohort of mice. BALB/c male mice were injected with either normal saline, C.albicans, or S.aureus and sacrificed at pre-set time points of 24, 48, 72-96 hrs (Infection Duration). Blood was placed in RNA Later (R) for RNA expression analysis and the right kidney collected for analysis of pathogen burden.
2010-03-09 | E-GEOD-20524 | biostudies-arrayexpress
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Project description:Invasive candidiasis (IC) is a leading cause of morbidity and mortality in preterm infants. Even if successfully treated, IC can cause significant neurodevelopmental impairment. Preterm infants are at increased risk for hematogenous Candida meningoencephalitis owing to increased permeability of the blood-brain barrier, so antifungal treatment should have adequate central nervous system penetration. Amphotericin B deoxycholate, lipid preparations of amphotericin B, fluconazole, and micafungin are first-line treatments of IC. Fluconazole prophylaxis reduces the incidence of IC in extremely premature infants, but its safety has not been established for this indication, and as yet, the product has not been shown to reduce mortality in neonates. Targeted prophylaxis may have a role in reducing the burden of disease in this vulnerable population.
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Project description:Multiplexed proteomics of S. aureus bacteremia patient serum samples.
2020-03-12 | MSV000085090 | MassIVE
Project description:Multiplexed proteomics of S. aureus bacteremia patient serum samples including PTM-inclusive analyses.
2020-03-12 | MSV000085091 | MassIVE
Project description:The opportunistic pathogen Staphylococcus aureus is carried asymptomatically by about one-third of the human population. Body sites known to be colonized by S. aureus are the skin, nasopharynx and gut. In particular, the mechanisms that allow S. aureus to pass the gut epithelial barrier and to invade the bloodstream are poorly understood. Therefore, our present study was aimed at investigating possible differences between gut-colonizing and bacteremia isolates of S. aureus. To this end, 74 gut-colonizing isolates from healthy individuals and 144 blood-culture isolates were characterized by whole-genome sequencing. Subsequently, the cellular and extracellular proteomes of six representative isolates were examined by mass spectrometry. Lastly, the virulence potential of these isolates was evaluated using infection models based on human gut epithelial cells, blood cells, and a small animal infection model. Intriguingly, our results show that gut-colonizing and bacteremia isolates with the same sequence type (ST1 or ST5) are very similar at the genomic and proteomic levels. Nonetheless, they display differences in virulence, but gut-colonizing isolates may be more virulent than bacteremia isolates and vice versa. Importantly, we show that the main decisive factor preventing infection of gut epithelial cells in vitro is the presence of a tight barrier. Based on our present observations, we propose that the integrity of the gut epithelial layer, rather than the pathogenic potential of a gut-colonizing S. aureus strain, is the main decisive factor that determines whether this colonizer will become an invasive pathogen.
2023-03-11 | PXD030971 | Pride
Project description:Chronic lymphocytic leukemia (CLL) is a heterogeneous malignancy, characterized by a variable clinical course. While clinical and laboratory parameters are increasingly being used to refine prognosis, they do not accurately predict response to commonly used therapy. We used gene expression profiling to generate and further refine prognostic and predictive markers. Genomic signatures that reflect progressive disease and responses to chemotherapy or chemo-immunotherapy were created using cancer cell lines and patient leukemia samples. We validated these signatures using independent clinical data from four separate cohorts representing a total of 301 CLL patients. A prognostic genomic signature created from patient leukemic cell gene expression data coupled with clinical parameters could statistically differentiate patients with stable or progressive disease in the training dataset. The progression signature was then validated in two independent datasets, demonstrating a capacity to accurately identify patients at risk for progressive disease. In addition, two distinct genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were also generated and were shown to accurately distinguish responding and non-responding CLL patients. Microarray analysis of CLL patientsâ lymphocytes can be used to refine prognosis and predict response to different therapies. These results have direct implications for standard and investigational therapeutics in CLL patients. Experiment Overall Design: For the predictive genomic signature or response to pentostatin, cyclophosphamide, and rituximab, 20 CLL leukemia samples were used in the training set, and 20 CLL leukemia samples were used in the validation set
2009-11-11 | E-GEOD-10137 | biostudies-arrayexpress
Project description:Invasive candidiasis occurs frequently in hospitalized patients, and is associated with high mortality rates due to delays in recognition and initiation of appropriate antifungals. Management of invasive candidiasis must take into account multiple host, pathogen, and drug-related factors, including the site of infection, host immune status, severity of sepsis, resistance and tolerance to antifungal agents, biofilm formation, and pharmacokinetic/pharmacodynamic considerations. Recent treatment directives have been shaped by the widespread introduction of echinocandins, highly potent and safe antifungals, into clinical use, as well as important changes in drug susceptibility patterns and the emergence of known and novel drug-resistant Candida species. Advances in molecular diagnostics have the potential to guide early targeted treatment of high-risk patients.
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Project description:For Candida species, a bimodal wild-type MIC distribution for echinocandins exists, but resistance to echinocandins is rare. We characterized isolates from patients with invasive candidiasis (IC) breaking through >or=3 doses of micafungin therapy during the first 28 months of its use at our center: MICs were determined and hot-spot regions within FKS genes were sequenced. Eleven of 12 breakthrough IC cases identified were in transplant recipients. The median duration of micafungin exposure prior to breakthrough was 33 days (range, 5 to 165). Seventeen breakthrough isolates were recovered: FKS hot-spot mutations were found in 5 C. glabrata and 2 C. tropicalis isolates; of these, 5 (including all C. glabrata isolates) had micafungin MICs of >2 microg/ml, but all demonstrated caspofungin MICs of >2 microg/ml. Five C. parapsilosis isolates had wild-type FKS sequences and caspofungin MICs of 0.5 to 1 microg/ml, but 4/5 had micafungin MICs of >2 microg/ml. The remaining isolates retained echinocandin MICs of <or=2 microg/ml and wild-type FKS gene sequences. Breakthrough IC on micafungin treatment occurred predominantly in severely immunosuppressed patients with heavy prior micafungin exposure. The majority of cases were due to C. glabrata with an FKS mutation or wild-type C. parapsilosis with elevated micafungin MICs. MIC testing with caspofungin identified all mutant strains. Whether the naturally occurring polymorphism within the C. parapsilosis FKS1 gene responsible for the bimodal wild-type MIC distribution is also responsible for micafungin MICs of >2 microg/ml and clinical breakthrough or an alternative mechanism contributes to the nonsusceptible echinocandin MICs in C. parapsilosis requires further study.
| S-EPMC2897493 | biostudies-literature
Project description:BackgroundInvasive candidiasis (IC) is a severe and often fatal fungal infection that affects critically ill patients. The development of animal models that mimic human disease is essential for advancing our understanding of IC pathophysiology and testing experimental or novel treatments. We aimed to develop a large animal model of IC that could provide a much-needed addition to the widely used murine models.ResultsA total of 25 pigs (including one control), aged between 9 and 12 weeks, with a median weight of 25.1 kg (IQR 24.1-26.2), were used to develop the porcine IC model. We present the setup, the results of the experiments, and the justification for the changes made to the model. The experiments were conducted in an intensive care setting, using clinically relevant anaesthesia, monitoring and interventions. The final model used corticosteroids, repeated Candida inoculation, and continuous endotoxin. The model consistently demonstrated quantifiable growth of Candida in blood and organs. The registered physiological data supported the development of the sepsis-induced circulatory distress observed in IC patients in the ICU.ConclusionsOur proposed porcine model of IC offers a potential new tool in the research of IC.
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