scholarly journals Multidimensional Data Integration Identifies Tumor Necrosis Factor Activation in Nephrotic Syndrome: A Model for Precision Nephrology

2021 ◽  
Author(s):  
Laura H Mariani ◽  
Sean Eddy ◽  
Fadhl M Alakwaa ◽  
Phillip J. McCown ◽  
Jennifer L Harder ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Underlying Disease ◽  
Functional Enrichment ◽  
Multidimensional Data ◽  
Molecular Profile ◽  
Protein Levels ◽  
Non Invasive ◽  
Pathway Activation ◽  
Observed Score ◽  
Necrosis Factor

Background: Classification of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies. This approach does not reflect underlying disease biology, limiting the ability to predict progression or treatment response. Methods: Systems biology approaches were used to categorize patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) based on kidney biopsy tissue transcriptomics across three cohorts and assessed association with clinical outcomes. Patient- level tissue pathway activation scores were generated using differential gene expression. Then, functional enrichment and non-invasive urine biomarker candidates were identified. Biomarkers were validated in kidney organoid models and single nucleus RNA-seq (snRNAseq) from kidney biopsies. Results: Transcriptome-based categorization identified three subgroups of patients with shared molecular signatures across independent North American, European and African cohorts. One subgroup demonstrated worse longterm outcomes (HR 5.2, p = 0.001) which persisted after adjusting for diagnosis and clinical measures (HR 3.8, p = 0.035) at time of biopsy. The molecular profile of this subgroup was largely (48%) driven by tissue necrosis factor (TNF) activation and could be predicted based on levels of TNF pathway urinary biomarkers TIMP-1 and MCP-1 and clinical features (correlation 0.63, p <0.001 for predicted vs observed score). Kidney organoids confirmed TNF-dependent increase in transcript and protein levels of these markers in kidney cells, as did snRNAseq from NEPTUNE biopsy samples. Conclusions: Molecular profiling identified a patient subgroup within nephrotic syndrome with poor outcome and kidney TNF pathway activation. Clinical trials using non-invasive biomarkers of pathway activation to target therapies are currently being evaluated.

scholarly journals Cold-induction of afadin in brown fat supports its thermogenic capacity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Morten Lundh ◽  
Ali Altıntaş ◽  
Marco Tozzi ◽  
Odile Fabre ◽  
Tao Ma ◽  
...  
Keyword(s):  
Cold Exposure ◽  
Functional Enrichment ◽  
Activation Process ◽  
Target Tissue ◽  
Cold Stimulation ◽  
Brown Adipocytes ◽  
Protein Levels ◽  
Mrna Induction ◽  
Metabolic Functions ◽  
Brown Adipose

AbstractThe profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders. While cold exposure is the strongest inducer of BAT activity, the temporal mechanisms tuning BAT adaptation during this activation process are incompletely understood. Here we show that the scaffold protein Afadin is dynamically regulated by cold in BAT, and participates in cold acclimation. Cold exposure acutely increases Afadin protein levels and its phosphorylation in BAT. Knockdown of Afadin in brown pre-adipocytes does not alter adipogenesis but restricts β3-adrenegic induction of thermogenic genes expression and HSL phosphorylation in mature brown adipocytes. Consistent with a defect in thermogenesis, an impaired cold tolerance was observed in fat-specific Afadin knockout mice. However, while Afadin depletion led to reduced Ucp1 mRNA induction by cold, stimulation of Ucp1 protein was conserved. Transcriptomic analysis revealed that fat-specific ablation of Afadin led to decreased functional enrichment of gene sets controlling essential metabolic functions at thermoneutrality in BAT, whereas it led to an altered reprogramming in response to cold, with enhanced enrichment of different pathways related to metabolism and remodeling. Collectively, we demonstrate a role for Afadin in supporting the adrenergic response in brown adipocytes and BAT function.

scholarly journals Integration of Urinary EN2 Protein & Cell-Free RNA Data in the Development of a Multivariable Risk Model for the Detection of Prostate Cancer Prior to Biopsy

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2102
Author(s):  
Shea Connell ◽  
Robert Mills ◽  
Hardev Pandha ◽  
Richard Morgan ◽  
Colin Cooper ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Model ◽  
Action Plan ◽  
Digital Rectal Examination ◽  
Standards Of Care ◽  
Net Benefit ◽  
Protein Levels ◽  
Non Invasive ◽  
Trus Biopsy ◽  
Diagnostic Potential

The objective is to develop a multivariable risk model for the non-invasive detection of prostate cancer prior to biopsy by integrating information from clinically available parameters, Engrailed-2 (EN2) whole-urine protein levels and data from urinary cell-free RNA. Post-digital-rectal examination urine samples collected as part of the Movember Global Action Plan 1 study which has been analysed for both cell-free-RNA and EN2 protein levels were chosen to be integrated with clinical parameters (n = 207). A previously described robust feature selection framework incorporating bootstrap resampling and permutation was applied to the data to generate an optimal feature set for use in Random Forest models for prediction. The fully integrated model was named ExoGrail, and the out-of-bag predictions were used to evaluate the diagnostic potential of the risk model. ExoGrail risk (range 0–1) was able to determine the outcome of an initial trans-rectal ultrasound guided (TRUS) biopsy more accurately than clinical standards of care, predicting the presence of any cancer with an area under the receiver operator curve (AUC) = 0.89 (95% confidence interval(CI): 0.85–0.94), and discriminating more aggressive Gleason ≥ 3 + 4 disease returning an AUC = 0.84 (95% CI: 0.78–0.89). The likelihood of more aggressive disease being detected significantly increased as ExoGrail risk score increased (Odds Ratio (OR) = 2.21 per 0.1 ExoGrail increase, 95% CI: 1.91–2.59). Decision curve analysis of the net benefit of ExoGrail showed the potential to reduce the numbers of unnecessary biopsies by 35% when compared to current standards of care. Integration of information from multiple, non-invasive biomarker sources has the potential to greatly improve how patients with a clinical suspicion of prostate cancer are risk-assessed prior to an invasive biopsy.

Markers of steroid resistance of the primary nephrotic syndrome in children

2021 ◽  
Vol 19 (1) ◽  
pp. 15-21
Author(s):  
S. L. Morozov ◽  
◽  
V. V. Dlin ◽  
Keyword(s):  
Nephrotic Syndrome ◽  
Steroid Therapy ◽  
Molecular Genetic ◽  
Clinical Importance ◽  
Recent Decade ◽  
Immunosuppressive Drugs ◽  
Steroid Resistance ◽  
Primary Nephrotic Syndrome ◽  
Non Invasive ◽  
The Common

The global task of the recent decade is to search for clinical and laboratory markers accurately showing a patient’s reaction to steroid therapy and other immunosuppressive drugs. It is important the applied methods and tests to be non-invasive and simple to use. The article considers various biomarkers used to verify the type of nephrotic syndrome depending on the sensitivity to steroid therapy. Besides the common markers, which are used in clinical practice or have shown a significant result, the work highlights the molecular- genetic markers of resistance to steroid therapy, which are of special clinical importance today. Also, the article presents authors’ own results in diagnosing the steroid resistance of the primary nephrotic syndrome.

Personalized mathematical model of endotoxin-induced inflammatory responses in young men and associated changes in heart rate variability

2018 ◽  
Vol 13 (5) ◽  
pp. 42 ◽  
Author(s):  
R. Brady ◽  
D.O. Frank-Ito ◽  
H.T. Tran ◽  
S. Janum ◽  
K. Møller ◽  
...  
Keyword(s):  
Heart Rate ◽  
Heart Rate Variability ◽  
Inflammatory Responses ◽  
Interleukin 10 ◽  
Tnf Alpha ◽  
Non Invasive ◽  
Estimated Parameters ◽  
Subject Specific ◽  
The Subject ◽  
Necrosis Factor

The objective of this study was to develop a personalized inflammatory model and estimate subject-specific parameters that could be related to changes in heart rate variability (HRV), a measure that can be obtained non-invasively in real time. An inflammatory model was developed and calibrated to measurements of interleukin-6 (IL-6), tumor necrosis factor (TNF-alpha), interleukin-8 (IL-8) and interleukin-10 (IL-10) over 8 hours in 20 subjects administered a low dose of lipopolysaccharide. For this model, we estimated 11 subject-specific parameters for all 20 subjects. Estimated parameters were correlated with changes in HRV, computed from ECG measurements using a built-in HRV module available in Labchart. Results revealed that patients could be separated into two groups expressing normal and abnormal responses to endotoxin. Abnormal responders exhibited increased HRV, most likely as a result of increased vagal firing. The observed correlation between the inflammatory response and HRV brings us a step further towards understanding if HRV predictions can be used as a marker for inflammation. Analyzing HRV parameters provides an easy, non-invasively obtained measure that can be used to assess the state of the subject, potentially translating to identifying a non-invasive marker that can be used to detect the onset of sepsis.

scholarly journals cdc37 is essential for JNK pathway activation and wound closure in Drosophila

2019 ◽  
Vol 30 (21) ◽  
pp. 2651-2658
Author(s):  
Chan-wool Lee ◽  
Young-Chang Kwon ◽  
Youngbin Lee ◽  
Min-Yoon Park ◽  
Kwang-Min Choe
Keyword(s):  
Cell Growth ◽  
Wound Closure ◽  
Cell Growth And Migration ◽  
Jnk Pathway ◽  
Protein Levels ◽  
Pathway Activation ◽  
And Migration ◽  
The Stability ◽  
Jnk Activation

Wound closure in the Drosophila larval epidermis mainly involves nonproliferative, endocyling epithelial cells. Consequently, it is largely mediated by cell growth and migration. We discovered that both cell growth and migration in Drosophila require the cochaperone-encoding gene cdc37. Larvae lacking cdc37 in the epidermis failed to close wounds, and the cells of the epidermis failed to change cell shape and polarize. Likewise, wound-induced cell growth was significantly reduced, and correlated with a reduction in the size of the cell nucleus. The c-Jun N-terminal kinase (JNK) pathway, which is essential for wound closure, was not typically activated in injured cdc37 knockdown larvae. In addition, JNK, Hep, Mkk4, and Tak1 protein levels were reduced, consistent with previous reports showing that Cdc37 is important for the stability of various client kinases. Protein levels of the integrin β subunit and its wound-induced protein expression were also reduced, reflecting the disruption of JNK activation, which is crucial for expression of integrin β during wound closure. These results are consistent with a role of Cdc37 in maintaining the stability of the JNK pathway kinases, thus mediating cell growth and migration during Drosophila wound healing.

Protein biomarkers for multiple sclerosis: semi-quantitative analysis of cerebrospinal fluid candidate protein biomarkers in different forms of multiple sclerosis

2012 ◽  
Vol 18 (8) ◽  
pp. 1081-1091 ◽  
Author(s):  
Timucin Avsar ◽  
Didem Korkmaz ◽  
Melih Tütüncü ◽  
N Onat Demirci ◽  
Sabahattin Saip ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Disease Process ◽  
Underlying Disease ◽  
Protein Biomarkers ◽  
Serum Samples ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Protein Levels ◽  
Clinical Subtype

Background: The complex pathogenesis of multiple sclerosis, combined with an unpredictable prognosis, requires identification of disease-specific diagnostic and prognostic biomarkers. Objective: To determine whether inflammatory proteins, such as neurofilament light chain, myelin oligodendrocyte glycoprotein and myelin basic protein, and neurodegenerative proteins, such as tau and glial fibrillary acidic protein, can serve as biomarkers for predicting the clinical subtype and prognosis of MS. Methods: Cerebrospinal fluid and serum samples were collected from patients with a diagnosis of clinically isolated syndrome ( n = 46), relapsing–remitting MS ( n = 67) or primary-progressive MS ( n = 22) along with controls having other non-inflammatory neurological disease ( n = 22). Western blot analyses were performed for the listed proteins. Protein levels were compared among different clinical subtypes using one-way analysis of variance analysis. The k-nearest neighbour algorithm was further used to assess the predictive use of these proteins for clinical subtype classification. Results: The results showed that each of tau, GFAP, MOG and NFL protein concentrations differed significantly ( p < 0.001) in multiple sclerosis clinical subtypes compared with the controls. Levels of the proteins also differed between the multiple sclerosis clinical subtypes, which may be associated with the underlying disease process. Classification studies revealed that these proteins might be useful for identifying multiple sclerosis clinical subtypes. Conclusions: We showed that select biomarkers may have potential in identifying multiple sclerosis clinical subtypes. We also showed that the predictive value of the prognosis increased when using a combination of the proteins versus using them individually.

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