A dry immersion model of microgravity modulates platelet phenotype, miRNA signature, and circulating plasma protein biomarker profile

Ground based research modalities of microgravity have been proposed as innovative methods to investigate the aetiology of chronic age-related conditions such as cardiovascular disease. Dry Immersion (DI), has been effectively used to interrogate the sequelae of physical inactivity (PI) and microgravity on multiple physiological systems. Herein we look at the causa et effectus of 3-day DI on platelet phenotype, and correlate with both miRomic and circulating biomarker expression. The miRomic profile of platelets is reflective of phenotype, which itself is sensitive and malleable to the exposome, undergoing responsive transitions in order to fulfil platelets role in thrombosis and haemostasis. Heterogeneous platelet subpopulations circulate at any given time, with varying degrees of sensitivity to activation. Employing a DI model, we investigate the effect of acute PI on platelet function in 12 healthy males. 3-day DI resulted in a significant increase in platelet count, plateletcrit, platelet adhesion, aggregation, and a modest elevation of platelet reactivity index (PRI). We identified 15 protein biomarkers and 22 miRNA whose expression levels were altered after DI. A 3-day DI model of microgravity/physical inactivity induced a prothrombotic platelet phenotype with an unique platelet miRNA signature, increased platelet count and plateletcrit. This correlated with a unique circulating protein biomarker signature. Taken together, these findings highlight platelets as sensitive adaptive sentinels and functional biomarkers of epigenetic drift within the cardiovascular compartment.

An Initial Evaluation of Human Plasma cMLC-1 as a Potential Protein Biomarker for Trastuzumab-Induced Cardiotoxicity, Breast Cancer Screening and Progression

Background Trastuzumab is a targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, trastuzumab-induced cardiotoxicity (TIC) has been reported as a single agent or combined with anthracycline. Methods such as biomarkers for early TIC detection is not available. Blood-based protein biomarker prostate-specific antigen (PSA) for diagnosis, screening, prediction of response to therapy, and disease progression has revolutionized management and outcome of prostate cancer. Nevertheless, no blood biomarkers exist for breast cancer diagnosis or screening. Methods We evaluated for the first time the potentials of cardiac myosin light chain 1(cMLC-1) as a biomarker to predict TIC, screen breast cancer and monitor breast cancer progression. Plasma cMCL-1 was measured quantitatively using enzyme-linked immunosorbent assays (ELISA). Archived paired plasma samples collected before and after trastuzumab treatment from 15 HER2 + patients with or without cardiotoxicity, recently collected unpaired plasma samples from 79 breast cancer patients (40 HER2+, 39 HER2- ) and 46 healthy donors were tested for cMLC-1 levels. Results We found that elevated plasma level of cMLC-1 is associated with cardiotoxicity in 43% of trastuzumab-treated patients. In addition, we demonstrated that elevated plasma cMCL-1 is associated with breast cancer. The cutoff cMLC-1 concentration is estimated to be 44.99 ng/mL with a sensitivity of 59.49% (95%CI: 48.47%-69.63%) and specificity of 71.74% (95%CI: 57.45% -82.68%). We also found that plasma cMCL-1 is more elevated in HER2- than in HER2 + breast cancer patients. As a result, improved sensitivity of 79.49% (95%CI: 64.47%-89.22%) with the specificity of 63.04% (95%CI:48.60%-75.48%) were obtained for cMLC-1 to predict HER2- breast cancer with the cutoff at 37.17 ng/mL. Moreover, we determined that cMLC-1 level was significantly higher in patients with metastatic breast cancer than in patients with non-metastatic breast cancer. Conclusions Here we report the first exploratory human study on the potential of cMLC-1 as a blood protein biomarker for predicting TIC. Additionally, we show our findings which shed light on and filled, to some extent, the gap of knowledge of the potential of cMLC-1 as a blood protein biomarker for screening breast cancer, especially for HER2- breast cancer, and disease progression of breast cancer.

CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice

More humans have died of tuberculosis (TB) than any other infectious disease and millions still die each year. Experts advocate for blood-based, serum protein biomarkers to help diagnose TB, which afflicts millions of people in high-burden countries. However, the protein biomarker pipeline is small. Here, we used the Diversity Outbred (DO) mouse population to address this gap, identifying five protein biomarker candidates. One protein biomarker, serum CXCL1, met the World Health Organization’s Targeted Product Profile for a triage test to diagnose active TB from latent M.tb infection (LTBI), non-TB lung disease, and normal sera in HIV-negative, adults from South Africa and Vietnam. To find the biomarker candidates, we quantified seven immune cytokines and four inflammatory proteins corresponding to highly expressed genes unique to progressor DO mice. Next, we applied statistical and machine learning methods to the data, i.e., 11 proteins in lungs from 453 infected and 29 non-infected mice. After searching all combinations of five algorithms and 239 protein subsets, validating, and testing the findings on independent data, two combinations accurately diagnosed progressor DO mice: Logistic Regression using MMP8; and Gradient Tree Boosting using a panel of 4: CXCL1, CXCL2, TNF, IL-10. Of those five protein biomarker candidates, two (MMP8 and CXCL1) were crucial for classifying DO mice; were above the limit of detection in most human serum samples; and had not been widely assessed for diagnostic performance in humans before. In patient sera, CXCL1 exceeded the triage diagnostic test criteria (>90% sensitivity; >70% specificity), while MMP8 did not. Using Area Under the Curve analyses, CXCL1 averaged 94.5% sensitivity and 88.8% specificity for active pulmonary TB (ATB) vs LTBI; 90.9% sensitivity and 71.4% specificity for ATB vs non-TB; and 100.0% sensitivity and 98.4% specificity for ATB vs normal sera. Our findings overall show that the DO mouse population can discover diagnostic-quality, serum protein biomarkers of human TB.

Multiplexed Prostate Cancer Companion Diagnostic Devices

Prostate cancer (PCa) remains one of the most prominent forms of cancer for men. Since the early 1990s, Prostate-Specific Antigen (PSA) has been a commonly recognized PCa-associated protein biomarker. However, PSA testing has been shown to lack in specificity and sensitivity when needed to diagnose, monitor and/or treat PCa patients successfully. One enhancement could include the simultaneous detection of multiple PCa-associated protein biomarkers alongside PSA, also known as multiplexing. If conventional methods such as the enzyme-linked immunosorbent assay (ELISA) are used, multiplexed detection of such protein biomarkers can result in an increase in the required sample volume, in the complexity of the analytical procedures, and in adding to the cost. Using companion diagnostic devices such as biosensors, which can be portable and cost-effective with multiplexing capacities, may address these limitations. This review explores recent research for multiplexed PCa protein biomarker detection using optical and electrochemical biosensor platforms. Some of the novel and potential serum-based PCa protein biomarkers will be discussed in this review. In addition, this review discusses the importance of converting research protocols into multiplex point-of-care testing (xPOCT) devices to be used in near-patient settings, providing a more personalized approach to PCa patients’ diagnostic, surveillance and treatment management.