Multiple Disease Biomarkers Research Articles

MicroRNAs as Biomarkers for Nephrotic Syndrome.

Nephrotic syndrome represents the clinical situation characterized by presence of massive proteinuria and low serum protein caused by a variety of diseases, including minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephropathy. Differentiating between diagnoses requires invasive renal biopsies in general. Even with the biopsy, we encounter difficulties to differentiate MCNS and FSGS in some cases. There is no other better option currently available for the diagnosis other than renal biopsy. MicroRNAs (miRNAs) are no-coding RNAs of approximately 20 nucleotides in length, which regulate target genes in the post-transcriptional processes and have essential roles in many diseases. MiRNAs in serum and urine have been shown as non-invasive biomarkers in multiple diseases, including renal diseases. In this article, we summarize the current knowledge of miRNAs as the promising biomarkers for nephrotic syndrome.

Development of robust targeted proteomics assays for cerebrospinal fluid biomarkers in multiple sclerosis

BackgroundVerification of cerebrospinal fluid (CSF) biomarkers for multiple sclerosis and other neurological diseases is a major challenge due to a large number of candidates, limited sample material availability, disease and biological heterogeneity, and the lack of standardized assays. Furthermore, verification studies are often based on a low number of proteins from a single discovery experiment in medium-sized cohorts, where antibodies and surrogate peptides may differ, thus only providing an indication of proteins affected by the disease and not revealing the bigger picture or concluding on the validity of the markers. We here present a standard approach for locating promising biomarker candidates based on existing knowledge, resulting in high-quality assays covering the main biological processes affected by multiple sclerosis for comparable measurements over time.MethodsBiomarker candidates were located in CSF-PR (proteomics.uib.no/csf-pr), and further filtered based on estimated concentration in CSF and biological function. Peptide surrogates for internal standards were selected according to relevant criteria, parallel reaction monitoring (PRM) assays created, and extensive assay quality testing performed, i.e. intra- and inter-day variation, trypsin digestion status over time, and whether the peptides were able to separate multiple sclerosis patients and controls.ResultsAssays were developed for 25 proteins, represented by 72 peptides selected according to relevant guidelines and available literature and tested for assay peptide suitability. Stability testing revealed 64 peptides with low intra- and inter-day variations, with 44 also being stably digested after 16 h of trypsin digestion, and 37 furthermore showing a significant difference between multiple sclerosis and controls, thereby confirming literature findings. Calibration curves and the linear area of measurement have, so far, been determined for 17 of these peptides.ConclusionsWe present 37 high-quality PRM assays across 21 CSF-proteins found to be affected by multiple sclerosis, along with a recommended workflow for future development of new assays. The assays can directly be used by others, thus enabling better comparison between studies. Finally, the assays can robustly and stably monitor biological processes in multiple sclerosis patients over time, thus potentially aiding in diagnosis and prognosis, and ultimately in treatment decisions.

Current questions of multiple sclerosis: the secunder progressive form of the disease

Recent data suggest that long-term worsening is common in relapsing-remitting multiple sclerosis patients and is largely independent of relapses or new lesion formation on brain MRI. The current definition of secunder progressive multiple sclerosis is worsening of disability independent of relapses over at least 6-month interval. Early focal inflammatory disease activity and spinal cord lesion are predictors of very-long term disease outcomes in relapse - onset multiple sclerosis. The potential of PET imaging to visualize hidden inflammation in MS brain in vivo is an important contribution for better understanding the progression of the disease. Therefore, PET imaging is a promising tool in detecting the conversion from relapsing remitting multiple sclerosis to secunder progressive form of multiple sclerosis. Furthermore, neuro-axonal damage is the pathological substrate of permanent disability in different neurological disorders including multiple sclerosis. The neurofilament proteins have promise in this context because their levels rise upon neuro-axonal damage not only in the cerebrospinal fluid but also in blood. Patients with increased serum levels of neurofilament at baseline, independent of other clinical and MRI variables, experience significantly more brain and spinal cord volume loss over 2 years and 5 years of follow-up. The kynurenine-pathway abnormalities may be associated with the swich from early-mild stage multiple sclerosis to debilitating progressive forms of the disease. Analysis of these metabolites in serum may have application as multiple sclerosis disease biomarkers. Free radical action has been suggested as a causal factor in the illness. Increased free radical production and consumption of the scavenger molecules were found during the active phase of the disease. Based on the clinical findings (EXPAND Study) and pathomechanism of the disease siponimod is approved by the US Food and Drug Administration for the treatment of relapsing remitting forms of multiple sclerosis, to include secunder progressive multiple sclerosis with active disease, relapsing-remitting multiple sclerosis and clinically isolated syndrome.

Functionalized helical fibre bundles of carbon nanotubes as electrochemical sensors for long-term in vivo monitoring of multiple disease biomarkers.

Mechanical mismatches between implanted electronics and biological tissues can lead to inaccurate readings and long-term tissue damage. Here, we show that functionalized multi-walled carbon nanotubes twisted into helical fibre bundles that mimic the hierarchical structure of muscle can monitor multiple disease biomarkers in vivo. The flexible fibre bundles are injectable, have a low bending stiffness and display ultralow stress under compression. As proof-of-concept evidence of the sensing capabilities of these fibre bundles, we show that the fibre bundles enable the spatially resolved and real-time monitoring of H2O2 when implanted in tumours in mice, and that they can be integrated with a wireless transmission system on an adhesive skin patch to monitor calcium ions and glucose in the venous blood of cats for 28 d. The versatility of the helical fibre bundles as chemically functionalized electrochemical sensors makes them suitable for multiple sensing applications in biomedicine and healthcare.

Universal Scaffold for an Activatable Photosensitizer with Completely Inhibited Photosensitivity

AbstractActivatable photosensitizers (aPSs) sensitive to specific stimuli hold potential for targeting multiple disease biomarkers and are desirable for photodynamic therapy (PDT). Presented herein is the design of aPSs that can be activated and fully recover from an inhibited state in the presence of specific biomarker. A designed long‐wavelength D‐π‐A photosensitizer, PSSe‐I, with highly efficient photosensitivity for generation of 1O2 was used. Caging of the phenolate donor of PSSe‐I with a biomarker‐sensitive group provided ALPPS, and the drastic activation of its photosensitivity was demonstrated intracellularly. To enhance the flexibility of the design strategy, a clickable azide group was introduced into the scaffold to allow integration of more functionality. Modularly derived mito‐PNPS, equipped with a mitochondria‐targeting group and a specific peroxynitrite‐reactive trigger, was synthesized and demonstrated superior performance in cells. This strategy could lead to customization of aPSs applicable to a specific PDT.

Universal Scaffold for an Activatable Photosensitizer with Completely Inhibited Photosensitivity.

Activatable photosensitizers (aPSs) sensitive to specific stimuli hold potential for targeting multiple disease biomarkers and are desirable for photodynamic therapy (PDT). Presented herein is the design of aPSs that can be activated and fully recover from an inhibited state in the presence of specific biomarker. A designed long-wavelength D-π-A photosensitizer, PSSe-I , with highly efficient photosensitivity for generation of 1 O2 was used. Caging of the phenolate donor of PSSe-I with a biomarker-sensitive group provided ALP PS, and the drastic activation of its photosensitivity was demonstrated intracellularly. To enhance the flexibility of the design strategy, a clickable azide group was introduced into the scaffold to allow integration of more functionality. Modularly derived mito-PN PS, equipped with a mitochondria-targeting group and a specific peroxynitrite-reactive trigger, was synthesized and demonstrated superior performance in cells. This strategy could lead to customization of aPSs applicable to a specific PDT.

CSF sAPPα and sAPPβ levels in Alzheimer's Disease and Multiple Other Neurodegenerative Diseases: A Network Meta-Analysis.

The soluble amyloid protein procurer α (sAPPα) and β (sAPPβ) have been postulated as promising new cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) and multiple other neurodegenerative diseases, but have failed to meet expectations with their often discordant and even contradictory findings to date. The aim of the study was to systematically explore this issue. Cochrane Library, PubMed, and CNKI were systematically searched without language or date restrictions. This network meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and also adhered to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Twenty studies, comprising ten groups, were eligible and included. Overall, 19 eligible studies with 1634 patients contributed to the analysis of CSF sAPPα levels and 16 eligible studies with 1684 patients contributed to the analysis of CSF sAPPβ levels. CSF sAPPβ levels are significantly higher in AD than in corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP); higher in Control than in Depression, CBS and PSP; higher in Parkinson's disease dementia (PDD) than in CBS and PSP; higher in mild cognitive impairment progressed to AD dementia during the follow-up period (pMCI) than in Depression and PSP; higher in stable mild cognitive impairment (sMCI) than in Depression. With regard to CSF sAPPα levels, there were no significant difference among groups. However, surprisingly, the resultant rankings graphically showed that pMCI populations have the highest levels of CSF sAPPα and sAPPβ. Furthermore, it seemed there was a positive correlation between CSF sAPPα and sAPPβ levels. The measurement of CSF sAPPα and sAPPβ levels may provide an alternative method for the diagnosis of early-stage AD, pMCI, which is conducive to preventive therapy.

TGF-β1 and VCAM-1 Serum Concentrations as Diagnostic Biomarkers of Diabetic Kidney Disease Progression

Abstract Background and aims: Transforming growth factor-beta 1 (TGF-β1) and vascular adhesion molecule 1 (VCAM-1) have been proposed as promising biomarkers for multiple diseases. TGF-β1 and VCAM-1 are reported to be associated with diabetic kidney disease (DKD) and end stage renal disease in patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM). Material and methods: The aim of this study was to investigate the expression of circulating TGF-β1 and VCAM-1 and to assess their potential as a blood-based biomarker for DKD in T1DM and T2DM patients. Results:. The study included 124 participants: 66 patients with T1DM, 58 with T2DM and 20 healthy controls. The diabetic patients were classified according to the estimated glomerular filtration rate (eGFR). First group - eGFR ≥90ml/min/1.73 m2 (n=39), second group eGFR 89-60 ml/min/1.73m2 (n=45), and third group eGFR 59-45 ml/min/1.73m2 (n=40). Enzyme-linked immunosorbent assay for the quantitative detection of was used to evaluate blood TGF-β1 and VCAM-1 expression. It was found that there were higher TGF-β1 and VCAM-1 in all diabetic patients compared with healthy controls (P<0.05). TGF- β1 and VCAM-1 were higher in group with eGFR ≥90ml/min/1.73 m2 and gradually increased in the groups with eGFR89-60 ml/min/1.73m2 and eGFR 59-45 ml/min/1.73m2. TGF- β1 and VCAM-1 were less in T1DM, than T2DM in all study groups. Regression analysis revealed reverse associations between TGF- β1, VCAM-1 and eGFR (P<0.05). TGF- β1 and VCAM-1 correlated positively with albuminuria and negatively with renal function. Conclusion: In discriminating overall patients from healthy subjects, ROC analysis revealed areas under the curve (AUCs) of 1,0 for TGF- β1 for T1DM and T2DM, VCAM-1 0,866 for T1DM, 0,923 for T2DM (P<0.001). The results suggested that blood-based TGF- β1 and VCAM-1 may serve as potential biomarkers for early detection of DKD.

Chiral Plasmonic Nanostructures Enabled by Bottom-Up Approaches.

We present a comprehensive review of recent developments in the field of chiral plasmonics. Significant advances have been made recently in understanding the working principles of chiral plasmonic structures. With advances in micro- and nanofabrication techniques, a variety of chiral plasmonic nanostructures have been experimentally realized; these tailored chiroptical properties vastly outperform those of their molecular counterparts. We focus on chiral plasmonic nanostructures created using bottom-up approaches, which not only allow for rational design and fabrication but most intriguingly in many cases also enable dynamic manipulation and tuning of chiroptical responses. We first discuss plasmon-induced chirality, resulting from the interaction of chiral molecules with plasmonic excitations. Subsequently, we discuss intrinsically chiral colloids, which give rise to optical chirality owing to their chiral shapes. Finally, we discuss plasmonic chirality, achieved by arranging achiral plasmonic particles into handed configurations on static or active templates. Chiral plasmonic nanostructures are very promising candidates for real-life applications owing to their significantly larger optical chirality than natural molecules. In addition, chiral plasmonic nanostructures offer engineerable and dynamic chiroptical responses, which are formidable to achieve in molecular systems. We thus anticipate that the field of chiral plasmonics will attract further widespread attention in applications ranging from enantioselective analysis to chiral sensing, structural determination, and in situ ultrasensitive detection of multiple disease biomarkers, as well as optical monitoring of transmembrane transport and intracellular metabolism.

Hybrid PET/MR Kernelised Expectation Maximisation Reconstruction for Improved Image-Derived Estimation of the Input Function from the Aorta of Rabbits.

Positron emission tomography (PET) provides simple noninvasive imaging biomarkers for multiple human diseases which can be used to produce quantitative information from single static images or to monitor dynamic processes. Such kinetic studies often require the tracer input function (IF) to be measured but, in contrast to direct blood sampling, the image-derived input function (IDIF) provides a noninvasive alternative technique to estimate the IF. Accurate estimation can, in general, be challenging due to the partial volume effect (PVE), which is particularly important in preclinical work on small animals. The recently proposed hybrid kernelised ordered subsets expectation maximisation (HKEM) method has been shown to improve accuracy and contrast across a range of different datasets and count levels and can be used on PET/MR or PET/CT data. In this work, we apply the method with the purpose of providing accurate estimates of the aorta IDIF for rabbit PET studies. In addition, we proposed a method for the extraction of the aorta region of interest (ROI) using the MR and the HKEM image, to minimise the PVE within the rabbit aortic region—a method which can be directly transferred to the clinical setting. A realistic simulation study was performed with ten independent noise realisations while two, real data, rabbit datasets, acquired with the Biograph Siemens mMR PET/MR scanner, were also considered. For reference and comparison, the data were reconstructed using OSEM, OSEM with Gaussian postfilter and KEM, as well as HKEM. The results across the simulated datasets and different time frames show reduced PVE and accurate IDIF values for the proposed method, with 5% average bias (0.8% minimum and 16% maximum bias). Consistent results were obtained with the real datasets. The results of this study demonstrate that HKEM can be used to accurately estimate the IDIF in preclinical PET/MR studies, such as rabbit mMR data, as well as in clinical human studies. The proposed algorithm is made available as part of an open software library, and it can be used equally successfully on human or animal data acquired from a variety of PET/MR or PET/CT scanners.

A Hand-Held Point-of-Care Biosensor Device for Detection of Multiple Cancer and Cardiac Disease Biomarkers Using Interdigitated Capacitive Arrays.

This paper presents a hand-held point-of-care device that incorporates a lab-on-a-chip module with interdigitated capacitive biosensors for label-free detection of multiple cancer and cardiovascular disease biomarkers. The developed prototype is comprised of a cartridge incorporating capacitive biodetection sensors, a sensitive capacitive readout electronics enclosed in a hand-held unit, and data analysis software calculating the concentration of biomarkers using previously stored reference database. The capacitive biodetection sensors are made of interdigitated circular electrodes, which are preactivated with single (for detecting one biomarker) or multiple specific antibodies (for detecting multiple disease biomarkers). Detection principle of capacitive biosensor is based on measuring the level of capacitance change between interdigitated electrode pairs induced by the change in dielectric constant due to affinity-based electron exchange in between antibodies/antigens and electrodes. The more antibody-antigens binding occurs, the more capacitance change is measured due to the change in dielectric constant of the capacitance media. The device uses preactivated ready-to-use cartridges embedded with capacitive biosensors with shelf-life of three months under optimal conditions, and is capable of onsite diagnosis and can report the result in less than 30 min. The device is verified with real patient blood samples for six different disease biomarkers.

Applications of Nanomaterials for Immunosensing.

In biomedical science among several other growing fields, the detection of specific biological agents or biomolecular markers, from biological samples is crucial for early diagnosis and decision-making in terms of appropriate treatment, influencing survival rates. In this regard, immunosensors are based on specific antibody-antigen interactions, forming a stable immune complex. The antigen-specific detection antibodies (i.e., biomolecular recognition element) are generally immobilized on the nanomaterial surfaces and their interaction with the biomolecular markers or antigens produces a physico-chemical response that modulates the signal readout. Lowering the detection limits for particular biomolecules is one of the key parameters when designing immunosensors. Thus, their design by combining the specificity and versatility of antibodies with the intrinsic properties of nanomaterials offers a plethora of opportunities for clinical diagnosis. In this review, we show a comprehensive set of recent developments in the field of nanoimmunosensors and how they are progressing the detection and validation for a wide range of different biomarkers in multiple diseases and what are some drawbacks and considerations of the uses of such devices and their expansion.

Array testing for multiplex assays.

Group testing involves pooling individual specimens (e.g., blood, urine, swabs, etc.) and testing the pools for the presence of disease. When the proportion of diseased individuals is small, group testing can greatly reduce the number of tests needed to screen a population. Statistical research in group testing has traditionally focused on applications for a single disease. However, blood service organizations and large-scale disease surveillance programs are increasingly moving towards the use of multiplex assays, which measure multiple disease biomarkers at once. Tebbs and others (2013, Two-stage hierarchical group testing for multiple infections with application to the Infertility Prevention Project. Biometrics69, 1064-1073) and Hou and others (2017, Hierarchical group testing for multiple infections. Biometrics73, 656-665) were the first to examine hierarchical group testing case identification procedures for multiple diseases. In this article, we propose new non-hierarchical procedures which utilize two-dimensional arrays. We derive closed-form expressions for the expected number of tests per individual and classification accuracy probabilities and show that array testing can be more efficient than hierarchical procedures when screening individuals for multiple diseases at once. We illustrate the potential of using array testing in the detection of chlamydia and gonorrhea for a statewide screening program in Iowa. Finally, we describe an R/Shiny application that will help practitioners identify the best multiple-disease case identification algorithm.

"Mix-to-Go" Silver Colloidal Strategy for Prostate Cancer Molecular Profiling and Risk Prediction.

Molecular profiling via analysis of multiple disease biomarkers is a powerful tool for disease diagnosis and risk prediction. Due to simplicity and minimal instrumentation requirement, colloidal-based colorimetric DNA/RNA assays are attractive for driving molecular profiling toward widespread clinical usage. Still, the reliability and speed of current colorimetric assays need to be further improved upon for eventual clinical use. Herein, we propose a "mix-to-go" colloidal strategy that utilizes the electrostatic attraction between negatively charged target sequences and positively charged silver nanoparticles (AgNPs) to induce aggregation of AgNPs to profile a panel of clinically validated urinary prostate cancer (PCa) RNA biomarkers ( TMPRSS2:ERG, T2:ERG; prostate cancer antigen 3, PCA3; and kallikrein-related peptidase 2, KLK2). Our strategy is unique in inducing a rapid (10 s), unambiguous solution color change in the presence of target sequences, without the additional NP aggregation agents that are used in existing electrostatic-mediated aggregation assays. Our strategy is analytically specific and sensitive for the detection of 105 and 104 target copies by the naked eye and UV-vis spectrophotometry, respectively. Analytical accuracies of our strategy in detecting T2:ERG, PCA3, and KLK2 RNA biomarkers were 95.9%, 97.3%, and 100%, respectively, as validated by quantitative reverse transcription-polymerase chain reaction. To further evaluate clinical molecular profiling performance beyond conventional proof-of-concept demonstration, we tested our colloidal strategy for noninvasive PCa risk prediction of 73 patients, using the urinary RNA biomarker panel comprising of T2:ERG, PCA3, and KLK2. We found that elevated T2:ERG and PCA3 levels were positively associated with high-risk PCa and obtained a corresponding area-under-the-curve values of 0.790 and 0.833 for predicting PCa and high-risk PCa on biopsy, respectively. We believe our "mix-to-go" strategy may serve as a reliable and accessible Ag colloidal-based molecular profiling approach for clinical applications.

LncRNA HOXA11-AS drives cisplatin resistance of human LUAD cells via modulating miR-454-3p/Stat3.

Over the past several years, long non‐coding RNAs (lncRNAs) have attracted more and more attention due to their special functions. They are vital biomarkers in multiple diseases. LncRNA HOMEOBOX A11 (HOXA11) has been found to be aberrantly expressed in some kinds of malignant tumors. In this study, we mainly discuss the oncogenic role of it in promoting malignant progression and chemoresistance in lung adenocarcinoma (LUAD) cells. The expression of HOXA11‐AS was much stronger in cisplatin‐resistant LUAD cells. Based on The Cancer Genome Atlas database, patients with high expression of HOXA11‐AS had shorter survival time. Additionally, knockdown of HOXA11‐AS caused positive changes in cell activities of LUAD. For example, cell proliferation and migration were weakened, the epithelial mesenchymal transition process was reversed, and apoptosis was induced. These changes were more obvious in cells treated with cisplatin. Next, the HOXA11‐AS/miR‐454‐3p/Stat3 (signal transducer and activator of transcription 3) pathway was found to influence the cisplatin resistance of LUAD cells. HOXA11‐AS specifically acted as a competing endogenous RNA (ceRNA) in LUAD cells. The combinations among these three genes were demonstrated. Finally, rescue assays were applied to demonstrate the ceRNA pattern consisting of HOXA11‐AS, miR‐454‐3p and Stat3. In conclusion, lncRNA HOXA11‐AS acted as a ceRNA to promote cisplatin resistance of human LUAD cells via the miR‐454‐3p/Stat3 axis.

Circulating transcriptome as a signature for the diagnosis of pulmonary arterial hypertension.

IntroductionPulmonary Arterial hypertension (PAH) is a rare disease that progressively leads to right heart failure and risk of mortality. However, the diagnosis of PAH in clinic largely depends on hemodynamic data. Circulating transcriptomic profiles have been developed as biomarkers in multiple cardiovascular diseases and thus can be potentially used to detect the signature of PAH. Here we aim to develop a robust approach for the diagnosis and prediction of PAH and its severity by integrate genotype, phenotype, and gene expression data.MethodsWe analyzed 96 peripheral blood mononuclear cell transcriptomes from PAH patients and control cohort. Gene expression analysis was performed using Rsubread, limma, and EdgeR package in R. Variation calling, filtering. The comparison was performed between PAH, idiopathic PAH with control, and different PAH severity groups. GWAS was performed using Samtools, Vcftools, and PLINK.ResultsA total of 72 genes with significant differential expression and 150 genes associated with PAH severity were identified. In addition, 405 of the 4.1 million identified SNPs are associated with PAH.ConclusionCirculating transcriptome can be used to identify genetic signatures for the diagnosis of pulmonary arterial hypertension based on our preliminary results. Once validated in a larger cohort, the identified genes and SNPs can provide a molecular marker system for the PAH diagnosis in addition to hemodynamic data.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Identification of microRNAs in human circulating monocytes of postmenopausal osteoporotic Mexican-Mestizo women: A pilot study.

MicroRNAs (miRNAs or miRs) are a class of short non-coding RNAs that serve an important regulatory role in living organisms. These molecules are associated with multiple biological processes and are potential biomarkers in multiple diseases. The present study aimed to further identify miRNAs that are differentially expressed in circulating monocytes (CMCs) from postmenopausal Mexican-Mestizo women. Microarray analyses of monocytes using Affymetrix miRNA 4.0 and Human Genome U133 Plus 2.0 arrays were performed in 6 normal and 6 osteoporotic women, followed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) validation. The overexpression of miR-1270, miR-548×-3p and miR-8084 were detected in the osteoporosis compared with the normal group according to the microarray analysis; miR-1270, a miRNA with several target genes associated with bone remodeling, was validated by RT-qPCR. Bioinformatics analysis identified that interferon regulatory factor 8 (IRF8) is the most likely target gene of miR-1270, which is associated with osteoclastogenesis. Furthermore, the findings of the present study demonstrate that an upregulation of miR-1270 may reduce the gene expression of IRF8 in CMCs (osteoclast precursors), implicating its potential role in leading to low bone mineral density and contributing to osteoporosis development in postmenopausal women.

MicroRNAs: Biomarkers, Diagnostics, and Therapeutics.

MicroRNAs (miRNAs) are small noncoding RNAs (21-23 nucleotides in length) that regulate gene expression at translational or posttranslational levels. The major regulatory mechanisms include translational repression or mRNA degradation (Filipowicz et al., Curr Opin Struct Biol 15:331-341, 2005).Aberrant expression of miRNAs has been found to be associated with a variety of human diseases such as cancers/tumors, diabetes, viral infections, cardiovascular diseases, neurodegenerative diseases, and other diseases (Wang et al., J Cell Physiol 23:25-30, 2016; Lawrie, MicroRNAs in medicine, 2013). The expression of miRNAs is tissue specific and can be used to identify tumor type and its origin (Mishra and Merlino, J Clin Invest 119:2119-2123, 2009). Many investigations suggest that the miRNA-expression profiles are novel diagnostic and prognostic biomarkers for multiple human diseases. Manipulating relevant miRNA expression or function may serve as potential therapeutic strategies for different diseases.

Group-based multi-trajectory modeling.

Identifying and monitoring multiple disease biomarkers and other clinically important factors affecting the course of a disease, behavior or health status is of great clinical relevance. Yet conventional statistical practice generally falls far short of taking full advantage of the information available in multivariate longitudinal data for tracking the course of the outcome of interest. We demonstrate a method called multi-trajectory modeling that is designed to overcome this limitation. The method is a generalization of group-based trajectory modeling. Group-based trajectory modeling is designed to identify clusters of individuals who are following similar trajectories of a single indicator of interest such as post-operative fever or body mass index. Multi-trajectory modeling identifies latent clusters of individuals following similar trajectories across multiple indicators of an outcome of interest (e.g., the health status of chronic kidney disease patients as measured by their eGFR, hemoglobin, blood CO2 levels). Multi-trajectory modeling is an application of finite mixture modeling. We lay out the underlying likelihood function of the multi-trajectory model and demonstrate its use with two examples.

The electrophotonic silicon biosensor.

The emergence of personalized and stratified medicine requires label-free, low-cost diagnostic technology capable of monitoring multiple disease biomarkers in parallel. Silicon photonic biosensors combine high-sensitivity analysis with scalable, low-cost manufacturing, but they tend to measure only a single biomarker and provide no information about their (bio)chemical activity. Here we introduce an electrochemical silicon photonic sensor capable of highly sensitive and multiparameter profiling of biomarkers. Our electrophotonic technology consists of microring resonators optimally n-doped to support high Q resonances alongside electrochemical processes in situ. The inclusion of electrochemical control enables site-selective immobilization of different biomolecules on individual microrings within a sensor array. The combination of photonic and electrochemical characterization also provides additional quantitative information and unique insight into chemical reactivity that is unavailable with photonic detection alone. By exploiting both the photonic and the electrical properties of silicon, the sensor opens new modalities for sensing on the microscale.