Androgen Receptor Pathway Activity Assay for Sepsis Diagnosis and Prediction of Favorable Prognosis

Introduction: Sepsis is a life-threatening complication of a bacterial infection. It is hard to predict which patients with a bacterial infection will develop sepsis, and accurate and timely diagnosis as well as assessment of prognosis is difficult. Aside from antibiotics-based treatment of the causative infection and supportive measures, treatment options have remained limited. Better understanding of the immuno-pathophysiology of sepsis is expected to lead to improved diagnostic and therapeutic solutions.Functional activity of the innate (inflammatory) and adaptive immune response is controlled by a dedicated set of cellular signal transduction pathways, that are active in the various immune cell types. To develop an immune response-based diagnostic assay for sepsis and provide novel therapeutic targets, signal transduction pathway activities have been analyzed in whole blood samples from patients with sepsis.Methods: A validated and previously published set of signal transduction pathway (STP) assays, enabling determination of immune cell function, was used to analyze public Affymetrix expression microarray data from clinical studies containing data from pediatric and adult patients with sepsis. STP assays enable quantitative measurement of STP activity on individual patient sample data, and were used to calculate activity of androgen receptor (AR), estrogen receptor (ER), JAK-STAT1/2, JAK-STAT3, Notch, Hedgehog, TGFβ, FOXO-PI3K, MAPK-AP1, and NFκB signal transduction pathways.Results: Activity of AR and TGFβ pathways was increased in children and adults with sepsis. Using the mean plus two standard deviations of normal pathway activity (in healthy individuals) as threshold for abnormal STP activity, diagnostic assay parameters were determined. For diagnosis of pediatric sepsis, the AR pathway assay showed high sensitivity (77%) and specificity (97%), with a positive prediction value (PPV) of 99% and negative prediction value (NPV) of 50%. For prediction of favorable prognosis (survival), PPV was 95%, NPV was 21%. The TGFβ pathway activity assay performed slightly less for diagnosing sepsis, with a sensitivity of 64% and specificity of 98% (PPV 99%, NPV 39%).Conclusion: The AR and TGFβ pathways have an immunosuppressive role, suggesting a causal relation between increased pathway activity and sepsis immunopathology. STP assays have been converted to qPCR assays for further evaluation of clinical utility for sepsis diagnosis and prediction of prognosis, as well as for prediction of risk at developing sepsis in patients with a bacterial infection. STPs may present novel therapeutic targets in sepsis.

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Androgen receptor pathway activity assay for sepsis diagnosis and prediction of favorable prognosis.

10.1101/2021.07.07.21259768 ◽

2021 ◽

Author(s):

Wilbert Bouwman ◽

Wim Verhaegh ◽

Anja van de Stolpe

Keyword(s):

Signal Transduction ◽

Androgen Receptor ◽

Bacterial Infection ◽

Signal Transduction Pathway ◽

Transduction Pathway ◽

Activity Assay ◽

Pathway Activity ◽

Sepsis Diagnosis ◽

Favorable Prognosis ◽

Tgfβ Pathway

Introduction Sepsis is a life-threatening complication of a bacterial infection. Accurate and timely diagnosis, as well as prognosis-prediction, is difficult. It is hard to predict which patients with a bacterial infection will develop sepsis. Aside from antibiotics-based treatment of the causative infection and circulation-supportive measures, treatment options remain very limited. Better understanding of the immuno-pathophysiology of sepsis may lead to improved diagnostic and therapeutic solutions. Functional activity of the innate (inflammatory) and adaptive immune response is controlled by a dedicated set of cellular signal transduction pathways in the various immune cell types. To develop an immune response-based assay for sepsis for diagnostic, prognostic and therapeutic purposes, signaling pathway activities were analyzed in whole blood samples from patients with sepsis. Methods A prevalidated and previously published set of signal transduction pathway (STP) assays was used to analyze public Affymetrix expression microarray data from multiple clinical studies with pediatric and adult patients with sepsis. STP activity measurement is based on computational interpretation of a preselected set of target gene mRNA expression levels. STP assays were used to calculate androgen receptor, estrogen receptor, JAK-STAT1/2, JAK-STAT3, Notch, Hedgehog, TGFβ, FOXO-PI3K, MAPK-AP1, and NFκB signal transduction pathway activity scores for individual patient samples. Results Activity of both AR and TGFβ pathways was increased in both children and adults with sepsis. Using the upper threshold of normal pathway activity range as threshold diagnostic assay parameters were determined. For pediatric sepsis diagnosis, the AR pathway assay showed high sensitivity (77%) and specificity (97%), with a PPV of 99% and NPV of 50%. For prediction of favorable prognosis (survival), PPV was 95%, NPV was 21%. The TGFβ pathway activity assay performed slightly less for diagnosing sepsis, with a sensitivity of 64% and specificity of 98% (PPV 99%, NPV 39%) Conclusion We have demonstrated potential clinical use of measuring AR and TGFβ pathway activity in sepsis patients. Both androgen receptor and TGFβ pathways have been described as immunosuppressive pathways, and increased activity in patients with sepsis suggests a causal relation with the immunopathology in sepsis. The AR pathway assay has been converted to a qPCR test for further testing of clinical utility for sepsis diagnosis and prediction of prognosis, as well as for prediction of risk at developing sepsis in patients with a bacterial infection. In view of their putative role in sepsis pathophysiology, both the AR and TGFβ pathways may present novel drug targets in sepsis.

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Signal Transduction Pathway Activity in High-Grade, Serous Ovarian Carcinoma Reveals a More Favorable Prognosis in Tumors with Low PI3K and High NF-κB Pathway Activity: A Novel Approach to a Long-Standing Enigma

Cancers ◽

10.3390/cancers12092660 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2660

Author(s):

Laura van Lieshout ◽

Anja van de Stolpe ◽

Phyllis van der Ploeg ◽

David Bowtell ◽

Joanne de Hullu ◽

...

Keyword(s):

Signal Transduction ◽

Ovarian Carcinoma ◽

Transforming Growth Factor ◽

Signal Transduction Pathway ◽

Cancer Tissue ◽

High Grade ◽

Transduction Pathway ◽

Pathway Activity ◽

Favorable Prognosis ◽

Serous Ovarian Carcinoma

We investigated signal transduction pathway (STP) activity in high-grade serous ovarian carcinoma (HGSC) in relation to progression-free survival (PFS) and overall survival (OS). We made use of signal transduction pathway activity analysis (STA analysis), a novel method to quantify functional STP activity. Activity of the following pathways was measured: androgen receptor (AR), estrogen receptor (ER), phosphoinositide 3-kinase (PI3K), Hedgehog (Hh), Notch, nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGF-β), and Wnt. We selected HGSC samples from publicly available datasets of ovarian cancer tissue, and used repeated k-means clustering to identify pathway activity clusters. PFS and OS of the clusters were analyzed. We used a subset of publicly available dataset GSE9891 (n = 140), where repeated k-means clustering based on PI3K and NF-κB pathway activity in HGSC samples resulted in two stable clusters. The cluster with low PI3K and high NF-κB pathway activity (n = 72) had a more favorable prognosis for both PFS (p = 0.004) and OS (p = 0.001) compared to the high-PI3K and low-NF-κB pathway activity cluster (n = 68). The low PI3K and high NF-κB pathway activity of the favorable prognosis cluster may indicate a more active immune response, while the high PI3K and low NF-κB pathway activity of the unfavorable prognosis cluster may indicate high cell division.

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