Biomarkers For Clinical Diagnosis Research Articles

Genetic Predisposition and Disease Expression of Bipolar Disorder Reflected in Shape Changes of the Anterior Limbic Network

Bipolar disorder (BD) is a genetically and phenotypically complex psychiatric disease. Although previous studies have suggested that the relatives of BD patients have an increased risk of experiencing affective disturbances, most relatives who have similar genotypes may not manifest the disorder. We aim to identify the neuroimaging alterations—specifically, the cortical folding structures of the anterior limbic network (ALN)—in BD patients and their siblings, compared to healthy controls. The shared alterations in patients and their siblings may indicate the hereditary predisposition of BD, and the altered cortical structures unique to BD patients may be a probe of BD expression. High-resolution, T1-weighted magnetic resonance images for 17 euthymic patients with BD, 17 unaffected siblings of BD patients, and 22 healthy controls were acquired. We categorized the cortical regions within the ALN into sulcal and gyral areas, based on the shape index, followed by the measurement of the folding degree, using the curvedness. Our results revealed that the changes in cortical folding in the orbitofrontal and temporal regions were associated with a hereditary predisposition to BD. Cortical folding structures in multiple regions of the ALN, particularly in the striatal–thalamic circuit and anterior cingulate cortex, could be used to differentiate BD patients from healthy controls and unaffected siblings. We concluded that the cortical folding structures of ALN can provide potential biomarkers for clinical diagnosis of BD and differentiation from the unaffected siblings.

Hepatocarcinoma Discrimination by Ratiometric Lipid Profiles Using Tip-Contact Sampling/Ionization Mass Spectrometry.

Precise diagnosis at the molecular level is essential for the improvement of surgery and treatment. High-throughput and spatial-resolved mass spectrometric (MS) methods for in situ detection of metabolites on tissue samples can reveal the dysregulation of metabolism in abnormal tissue and help identification of tumor. We here report a nondestructive MS method named as tip-contact sampling/ionization (TCSI)-MS technology which can quickly acquire lipidomic information from liver tissue and thereby realize tumor identification. Using this technology, fatty acids and lipids at the liver tissue surface can be rapidly imprinted onto a silicon nanowire tip attached with reduced graphene oxide (rGO) and sensitively detected by on-chip MS. With proper data pretreatment and statistical analysis, the clinical primary hepatocellular carcinoma (HCC) tissues can be discriminated from the nontumor parts. In addition, we found that a panel of adjacent dual peaks' ratio can be used to build a prediction model in artificial neural networks (ANN), resulting in high accuracy (91.7-98.3%) for tumor discrimination. Ratiometric TCSI-MS imaging using a selected dual peaks' ratio can greatly enhance the spatial resolution of tumor margin. The feature ratiometric data of lipid molecules may guide the study of metabolism pathways involved in hepatocarcinoma and ultimately become new metabolic biomarkers in clinical diagnosis. The present work demonstrated that the TCSI-MS technology may pave a novel way for surgery guidance and precision diagnosis in tissue biopsy.

Blocking-Free ELISA Using a Gold Nanoparticle Layer Coated Commercial Microwell Plate.

Enzyme-linked immunosorbent assays (ELISA) show extensive application in immunoassays, to detect and monitor protein biomarkers in clinical diagnosis. Nevertheless, the time required and its multiple steps limit its application. We take advantage of a polyethyleneimine (PEI) gold nanoparticle (GNP) coated microwell plate to perform blocking-free ELISA, in which no nonspecific protein adsorption appears on the GNP layer. If the PEI-GNP coated microwell plate and immobilization of captured antibodies on the plate are prepared in advance, such as using an ELISA kit, the whole ELISA process can be finished in less than 2 h. Meanwhile, we have ensured that the GNP layer can preserve the precision and good linearity of ELISA without causing negative effects on the plate.

Real-time monitoring of skin ethanol gas by a high-sensitivity gas phase biosensor (bio-sniffer) for the non-invasive evaluation of volatile blood compounds

In this study, a highly sensitive and selective biochemical gas sensor (bio-sniffer) and real-time monitoring system with skin gas cell was constructed for the determination of ethanol gas concentration on human skin. This bio-sniffer measured the concentration of ethanol according to the change in fluorescence intensity of nicotinamide adenine dinucleotide (NADH), which is produced in an enzymatic reaction by alcohol dehydrogenase (ADH). The NADH detection system used an ultraviolet light emitting diode (UV–LED) as the excitation light, and a highly sensitive photomultiplier tube as a fluorescence intensity detector. The calibration range of the ethanol bio-sniffer was validated from 25 ppb to 128 ppm. To measure the concentration of ethanol within skin gas, subjects ingested an alcohol beverage, and the sensor output was monitored. We chose the central part of the palm, a back of the hand, and a wrist as targets. The real-time concentration of skin ethanol gas at each target was measured after drinking. The maximum output values were reached at approximately 70 min after drinking and then gradually decreased. We showed that ethanol release kinetics were different depending on the part of the hand measured with the developed monitoring system. Accordingly, this highly sensitive and selective bio-sniffer with a skin gas cell could be used to measure ethanol on the skin surface and could be applied for breath and skin gas research, as well as investigation of volatile blood compounds used as biomarkers for clinical diagnosis.

Ultrasensitive analysis of heat shock protein 90α with antibodies orderly arrayed on a novel type of immunoprobe based on magnetic COFs

The early diagnosis of liver cancer by target biomarkers is of great significance for improving the survival rate of cancer patients. However, it is still a challenging task to sensitively detect circulating protein biomarkers due to decreased binding activity of antibodies originating from uncontrolled orientation of immobilization on the surface of a solid matrix. In this work, a novel immunoaffinity probe, Fe3O4@TpBD-DSS-Ab-MEG, based on magnetic COFs with ordered arrangement of anchored antibodies has been developed and applied for the first time to detection of a cancer biomarker, heat shock protein 90alpha (Hsp90α). The fabricated composites possess favorable features from magnetic cores and COF shells, including strong magnetic responses (7.96 emu g−1), ordered active groups, a large amount of immobilized antibodies (111.7 μg/mg), good solvent and thermal stability. Fe3O4@TpBD-DSS-Ab-MEG demonstrated low detection limit (50 pg/mL), high selectivity (Hsp90α:BSA = 1:1000), desirable repeatability and good stability for Hsp90α immunocapture. Compared with other immunoprobes, our materials showed higher selectivity and sensitivity, which were mainly attributed to regular arrays of surface antibodies. Furthermore, samples containing Hsp90α at the concentration of 1 µg/mL in human plasma were used to test our immunoprobe, and 2 peptides of Hsp90α were successfully observed. The proposed non-invasive immunoassay strategy offers enhanced ability to control the orientation of immobilized antibodies and great promise for accurate analysis of the liver cancer biomarker Hsp90α in a complicated biological matrix. In addition, the facile preparation of magnetic COFs support and the satisfactory analytical performance made the newly developed immunoprobe a potential tool for sensitive detection of other cancer biomarkers in clinical diagnosis.

A photoelectrochemical immunoassay for tumor necrosis factor-α using a GO-PTCNH2 nanohybrid as a probe

A simple photoelectrochemical (PEC) immunoassay based on an amino-terminated perylene derivative (PTCNH2) was developed for highly sensitive and specific detection of tumor necrosis factor-alpha (TNF-α). Simple grinding and sonication afforded a π-π stacked graphene oxide (GO)/PTCNH2 assembly exhibiting fast electron transfer kinetics and excellent photoelectric performance, and this assembly was applied as a PEC probe. The GO-PTCNH2 assembly provided not only a large surface area, fast electron transfer kinetics and abundant active sites for further biomolecule conjugation but also high PEC activity. A “signal-off” PEC immunoassay for TNF-α was developed by assembling GO-PTCNH2 on the electrode, followed by conjugation of anti-TNF-α with GO-PTCNH2 and subsequent capture of the target protein TNF-α. The linear detection range was from 10 pg/mL–100 ng/mL with a limit of detection (LOD) of 3.33 pg/mL. This method was also successfully applied for detecting TNF-α in human serum with recoveries ranging from 92.5% to 96.6% and a relative standard deviation of less than 9.99%. For the first time, this work reports a simple PEC immunoassay achieved by using PTC-NH2 as a photoelectrochemically active probe for the detection of a tumor biomarker. This assay could be applicable to the detection of other biomarkers for clinical diagnosis.

Label-free fluorescent and electrochemical biosensors based on defective G-quadruplexes

Abnormal levels of guanine closely associated with plenty of diseases are usually used as a biomarker for clinical diagnosis. In order to detect guanine and its derivatives accurately, in this paper, a defective G-quadruplex (DGQ) containing a G-vacancy at one of its G-quartet layers, and two kinds of G-quadruplex specific indicators including thioflavine T (ThT) and hemin were used for constructing a fluorescent and an electrochemical biosensor, respectively. In brief, a G-rich DNA probe is designed to form either hairpin or DGQ structure. In the absence of guanine, G-rich probes prefer to maintain hairpin structure and nearly have no interaction with ThT or hemin, leading to almost negligible signals. Upon addition of guanine, the G-rich probe fold into DGQ structure and then the G-vacancy in it is filled up immediately by guanine via Hoogsteen hydrogen bonds, resulting canonical G-quadruplex formation. Accordingly, ThT or hemin can selectively combine with G-quadruplex, giving rise to distinct fluorescent or current signal changes for label-free detection of guanine. Benefiting from the perfect discriminative ability of guanine towards DGQ and ThT/hemin against standard G-quadruplex, the fluorescent and electrochemical biosensors present better sensitivity and selectivity for guanine detection with the limit of detection (LOD) as low as 18.26 and 0.36 nM, respectively. Successful attempts were also made in applying the proposed electrochemical biosensor to detect guanine in drugs and urine, obtaining satisfactory recovery rates of 99~104% and 96~106%, respectively.

Frontal analysis capillary electrophoresis: recent advances and future perspectives.

The developments on frontal analysis capillary electrophoresis (FACE) from 2012 to 2017 to study interactions of simple and complex systems are reviewed. Most research papers focused on therapeutic drug-related studies; however, other studies include chemical sensing, drug delivery, inhibitor screening and capillary coating. New ligand-substrate systems such as template-molecularly imprinted polymer systems were reported. Comparison of FACE with other analytical techniques used to investigate binding interaction, and the determination of binding parameters using different isotherm models are also covered. In 2017, eight research papers were reported including new detection by ESI-MS. Future research direction of FACE may include high sensitivity detection and throughput screening of drugs, natural products and biomarkers for clinical diagnosis.

An ultrasensitive and simple method for alkaline phosphatase assay and targeted natural compound screening in vitro.

As an essential phosphate group hydrolase, alkaline phosphatase (ALP), whose level in serum is correlated with bone disease, liver dysfunction, and cancer, could be used as a biomarker for clinical diagnosis and biomedical studies. Hence, developing a convenient and sensitive method for ALP assay has importance in disease diagnosis, drug treatment, and prognosis assessment. In this work, using a hairpin DNA strand as the substrate, we developed an ultrasensitive and simple fluorescence method for quantitative ALP assay based on the binding difference of reduced graphene oxide (rGO) with different DNA strands coupled with λ exonuclease (λ exo) cleavage. Under the optimal conditions, the limit of detection (LOD) of ALP is estimated to be 0.01U/L with the linear region from 0.5U/L to 70U/L. Furthermore, the proposed assay was used to detect ALP in complicated cell-free extracts and evaluate the inhibitory effects of two well-known inhibitors of ALP activity. Finally, the method was used to investigate the effect of natural compounds on ALP activity and five compounds with different inhibitory capability were screened. In summary, we propose that the new method for ALP assay can be applied for therapeutic drug monitoring (TDM) and high-throughput compound screening in combination with multiwell plate technology.

EDL Gated FET Biosensor Array for the Investigation of Ion Channels and Bioelectric Signals of Circulating Tumor Cells

This paper demonstrates the applications of novel high sensitive electrical double layer (EDL) gated FET biosensor array in detecting and counting cells, and analyzing their bioelectric signals in different test conditions. We focused on extremely rare cell type such as Circulating Tumor Cells (CTCs) (HCT-8 cell line) derived from Colorectal Cancer (CRC) cell line. CRC is one of the major forms of cancer that affects human population and CTCs have emerged as a clinical biomarker for diagnosis and prognosis of metastatic CRC. Previously, we had shown that our methodology can detect and count CTCs with very high sensitivity, with up to single cell resolution. Simultaneously, we discovered our sensor platform can be used to dynamically monitor the changes in transmembrane potential (Vm) of the cell, which is an important fundamental bioelectric signal of cell. Studies have shown Vm may be useful as a primary parameter in understanding disease progression, cell signaling mechanism and ion channel gating. We demonstrated that the EDL gated FET sensor can dynamically monitor the changes in Vm induced by high concentrations of extracellular KCl. It was also shown that the sensor response changes as extracellular divalent cation concentrations are dynamically increased towards physiological concentrations. The results display the ability of the sensing platform to monitor the cellular response to dynamically changing, very low ion concentrations as well. Furthermore, an interesting application of bioelectric signal study is demonstrated using cadmium ions to block the calcium channels present in the cell. As shown in figure, in low micro molar concentrations, cadmium acts as a permeant channel blocker (electrically, the cell is depolarized and as the Cd2+ concentration increases, it re-polarizes) and in higher concentrations, it accumulates in the intracellular region (the cell is depolarized again), causing induction of apoptotic signals. The sensor response closely follows the cellular response to permeant channel blockers such as cadmium. These results demonstrate that our sensing methodology can replace the conventional electrophysiological methods or optical potentiometric probes to study fundamental cellular mechanisms such as ion channel gating. Our method offers non-invasive means to monitor changes in Vm, with very high sensitivity for individual cells. The cell based studies can be carried out directly in physiological media with high ionic strength, without the use of extensive pre-treatments or additional reagents. Figure 1

Homogeneous Immunosorbent Assay Based on Single-Particle Enumeration Using Upconversion Nanoparticles for the Sensitive Detection of Cancer Biomarkers

Prostate-specific antigen (PSA) is an intercellular glycoprotein produced primarily by the prostate gland, which is commonly chosen as the initial target for the early diagnosis of prostate cancer. In this work, we demonstrate a simple yet sensitive sandwich-type single-particle enumeration (SPE) immunoassay for the quantitative detection of PSA in a flow chamber. The design is based on the luminescence resonance energy transfer (LRET) between upconversion nanoparticles (UCNPs) and gold nanoparticles (GNPs). The carboxyl group-functionalized UCNPs are conjugated with anti-PSA detection antibodies (Ab1) and serve as the luminescence energy donor, while GNPs are modified with anti-PSA capture antibodies (Ab2) and act as the energy acceptor. In the presence of target antigen (i.e., PSA), the specific immnuoreaction brings the donor and acceptor into close proximity, resulting in quenched luminescence. Through statistical counting of the target-dependent fluorescent particles on the glass slide surface, the quantity of antigens in the solution is accurately determined. The dynamic range for PSA detection in Tris-buffered saline (TBS) is 0-500 pM and the limit-of-detection (LOD) is 1.0 pM, which is much lower than the cutoff level in patients' serum samples. In the serum sample assay, comparable LOD was also achieved (i.e., 2.3 pM). As a consequence, this method will find promising applications for the selective detection of cancer biomarkers in clinical diagnosis.

MiR-217 is involved in the carcinogenesis of gastric cancer by down-regulating CDH1 expression

GC is one of the most leading malignancies all over the world, and is also the leading cause of cancer-related mortalities. At present, GC remains difficult to diagnose at an early stage. In this study, we first detected the expression of 9 selected miRNAs in the exosomes from 67 GC patients’ circular exosomes and found 4 miRNAs level was significantly altered. Meanwhile, one out of 4 candidate miRNAs also had a higher expression in the GC tissue samples, and negative correlated with CDH1 expression. Predicted by bioinformatics tools, confirmed by dual luciferase assay and immunoblotting, we identified that CDH1 is a direct target of miR-217. MiR-217 overexpression enhanced gastric cancer cells proliferation, and reduced exosomal CDH1 level which can be delivered into microenvironment. In conclusion, we constructed the negative correlation between miR-217 and CDH1 level in GC patients and cells; unveiled part of the miR-217 function during the pathogenesis of GC. These findings may give insight into understanding the mechanism of GC pathogenesis and provide new biomarkers for clinical diagnosis.

Combination of Multifocal Electroretinogram and Spectral-Domain OCT Can Increase Diagnostic Efficacy of Parkinson’s Disease

Background The retinal changes have been identified in morphology and function in Parkinson's disease (PD). However, the controversial results suggest that it is incredible that only using a single method for testing retinal change to evaluate Parkinson's disease. The aim of this study was to assess retinal changes and increase the diagnostic efficacy of Parkinson's disease with a combination of multifocal electroretinogram (mf-ERG) and spectral domain optical coherence tomography (SD-OCT) examinations. Method Fifty-three PD patients and forty-one healthy controls were enrolled. Subjects were assessed for retinal function using mf-ERG and retinal structure using SD-OCT. Results The PD patients had a significantly decreased amplitude density of P1 and a delayed implicit time of P1 in some regions. The macular retinal thickness, macular volume, and average RNFL thickness were decreased in PD. The AUC of a single parameter of either retinal function or structure was low. Both of them were higher in diagnostic value to discriminate PD patients. Conclusion The amplitude density of P1 combined with macular volume can get a high diagnostic efficacy to discriminate between participants with or without PD. It indicates that a combination of mf-ERG and SD-OCT provides a good clinical biomarker for diagnosis of PD.

FOXC1 in cancer development and therapy: deciphering its emerging and divergent roles.

Forkhead box C1 (FOXC1) is an essential member of the forkhead box transcription factors and has been highlighted as an important transcriptional regulator of crucial proteins associated with a wide variety of carcinomas. FOXC1 regulates tumor-associated genes and is regulated by multiple pathways that control its mRNA expression and protein activity. Aberrant FOXC1 expression is involved in diverse tumorigenic processes, such as abnormal cell proliferation, cancer stem cell maintenance, cancer migration, and angiogenesis. Herein, we review the correlation between the expression of FOXC1 and tumor behaviors. We also summarize the mechanisms of the regulation of FOXC1 expression and activity in physiological and pathological conditions. In particular, we focus on the pathological processes of cancer targeted by FOXC1 and discuss whether FOXC1 is good or detrimental during tumor progression. Moreover, FOXC1 is highlighted as a clinical biomarker for diagnosis or prognosis in various human cancers. The information reviewed here should assist in experimental designs and emphasize the potential of FOXC1 as a therapeutic target for cancer.

Current Role for Biomarkers in Clinical Diagnosis of Alzheimer Disease and Frontotemporal Dementia.

Purpose of review Alzheimer's disease (AD) and frontotemporal dementia can often be diagnosed accurately with careful clinical history, cognitive testing, neurological examination, and structural brain MRI. However, there are certain circumstances wherein detection of specific biomarkers of neurodegeneration or underlying AD pathology will impact the clinical diagnosis or treatment plan. We will review the currently available biomarkers for AD and frontotemporal dementia (FTD) and discuss their clinical importance. Recent findings With the advent of 18F-labeled tracers that bind amyloid plaques, amyloid PET is now clinically available for the detection of amyloid pathology and to aid in a biomarker-supported diagnosis of AD or mild cognitive impairment (MCI) due to AD. It is not yet possible to test for the specific FTD pathologies (tau or TDP-43); however, a diagnosis of FTD may be "imaging supported" based upon specific MRI or FDG-PET findings. Cerebrospinal fluid measures of amyloid-beta, total-tau, and phospho-tau are clinically available and allow detection of both of the cardinal pathologies of AD: amyloid and tau pathology. Summary It is appropriate to pursue biomarker testing in cases of MCI and dementia when there remains diagnostic uncertainty and the result will impact diagnosis or treatment. Practically speaking, due to the rising prevalence of amyloid positivity with advancing age, measurement of biomarkers in cases of MCI and dementia is most helpful in early-onset patients, patients with atypical clinical presentations, or when considering referral for AD clinical trials.

ATF1 and RAS in exosomes are potential clinical diagnostic markers for cervical cancer.

Cervical cancer is one of the most common cancers among women worldwide. It is highly lethal yet can be treated when found in early stage. Thus, early detection is of significant important for early diagnosis of cervical cancer. Exosomes have been used as biomarkers in clinical diagnosis. It is unknown that whether blood exosomes associated with cervical cancer can be detected and if these exosomes can accurately represent the developmental stage of cervical cancer. Mouse models were made out of a relapsed cervical cancer patient's tumour sample for original and recurrent cervical cancer, and gene analysis in both tumours and exosomes in these mouse models were performed. We found that activating transcription factor 1 (ATF1) and RAS genes were significantly up-regulated in tumours of both primary and recurrent cervical cancer mouse model, and they can also be detected in the blood exosomes of the mouse model. Our results indicated that ATF1 and RAS could be potential candidate biomarkers for cervical cancer in early diagnosis. ATF1 and RAS genes were found significantly elevated in tumours of primary and recurrent cervical cancer mouse model, and they were also detected in the blood exosomes. Therefore, ATF1 and RAS could be used as a diagnostic marker for cervical cancer in the future.

Identification of M. tuberculosis antigens in the sera of tuberculosis patients using biomimetic affinity chromatography in conjunction with ESI-CID-MS/MS.

The profiling of abnormally-expressed proteins in host cells using mass spectrometry (MS) analysis is a classical approach for screening disease-associated biomarkers in clinical diagnosis. However, few pathogen-specific antigens can currently be detected in serum using this proteomic approach, since these are very low-abundant proteins that are easily masked by host high-abundant proteins. Identification of pathogen-specific antigens in the sera of tuberculosis patients is crucial for the clinical diagnosis of this infectious disease, especially in immune-compromised patients. In the present study, two biomimetic affinity chromatography (BiAC) media, At-23 and A115-94, were selected from a library of BiAC media and used to selectively fractionate Albumin and Immunoglobulin from sera, respectively, prior to MS analyses. Each fraction was collected and screened against the proteomic database of M. tuberculosis complex. Three antigens, FbpA, FbpB and BfrB, were identified with two distinct peptides in BiAC-fractionated sera from tuberculosis patients, which were confirmed by Western blotting. Moreover, the identification of pathogen-specific antigens in sera by BiAC in conjunction with ESI-CID-MS/MS represents a promising strategy for the discovery of disease-associated biomarkers in other diseases.

Comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer's disease

The recent development of tau-specific positron emission tomography (PET) tracers enables in vivo quantification of regional tau pathology, one of the key lesions in Alzheimer's disease (AD). Tau PET imaging may become a useful biomarker for clinical diagnosis and tracking of disease progression but there is no consensus yet on how tau PET signal is best quantified. The goal of the current study was to evaluate multiple whole-brain and region-specific approaches to detect clinically relevant tau PET signal. Two independent cohorts of cognitively normal adults and amyloid-positive (Aβ+) patients with mild cognitive impairment (MCI) or AD-dementia underwent [18F]AV-1451 PET. Methods for tau tracer quantification included: (i) in vivo Braak staging, (ii) regional uptake in Braak composite regions, (iii) several whole-brain measures of tracer uptake, (iv) regional uptake in AD-vulnerable voxels, and (v) uptake in a priori defined regions. Receiver operating curves characterized accuracy in distinguishing Aβ- controls from AD/MCI patients and yielded tau positivity cutoffs. Clinical relevance of tau PET measures was assessed by regressions against cognition and MR imaging measures. Key tracer uptake patterns were identified by a factor analysis and voxel-wise contrasts. Braak staging, global and region-specific tau measures yielded similar diagnostic accuracies, which differed between cohorts. While all tau measures were related to amyloid and global cognition, memory and hippocampal/entorhinal volume/thickness were associated with regional tracer retention in the medial temporal lobe. Key regions of tau accumulation included medial temporal and inferior/middle temporal regions, retrosplenial cortex, and banks of the superior temporal sulcus. Our data indicate that whole-brain tau PET measures might be adequate biomarkers to detect AD-related tau pathology. However, regional measures covering AD-vulnerable regions may increase sensitivity to early tau PET signal, atrophy and memory decline.

Identification of urine tauro-β-muricholic acid as a promising biomarker in Polygoni Multiflori Radix-induced hepatotoxicity by targeted metabolomics of bile acids

Polygoni Multiflori Radix (PMR) has been widely used as a tonic for centuries. However, hepatotoxicity cases linked to PMR have been frequently reported and appropriate biomarkers for clinical diagnosis are currently lacking. Here, an approach using UPLC-QqQ/MS-based targeted metabolomics of bile acids (BAs) complemented with biochemistry and histopathology was applied to characterize the development and recovery processes of PMR-induced hepatotoxicity in rats and to identify biomarkers. The expression of bile salt export pump (Bsep) and sodium taurocholate cotransporting polypeptide (Ntcp) were evaluated to investigate the underlying mechanism. Steatosis and inflammatory cell infiltration were observed in PMR-treated rats, which were accompanied by the elevation of serum biochemistry. The metabolic profiles of BAs were analyzed by Principal Component Analysis, hyodeoxycholic acid (HDCA) in serum and tauro-β-muricholic acid (TβMCA) in urine were identified as potential biomarkers for PMR-induced hepatotoxicity. The elevated expression of Bsep and decreased expression of Ntcp in the liver of PMRtreated rats indicated that hepatotoxicity was related to the disorders of BAs metabolism. Our study demonstrated that BAs may be used for clinical diagnosis of PMR-induced hepatotoxicity. Urine TβMCA was identified as a promising biomarker to facilitate the clinical monitoring of PMR-induced hepatotoxicity and may serve as potential therapeutic target.

MiR-9 regulates the multidrug resistance of chronic myelogenous leukemia by targeting ABCB1.

Multidrug resistance(MDR) is commonly correlated with the poor prognosis of chronic myelogenous leukemia. Aberrant expression of microRNAs (miRNAs) plays an important role in the MDR of various types of cancers. MicroRNA-9 (miR-9) has been confirmed to be dysregulated in many types of cancers. However, the relationship between miR-9 and MDR in chronic myelogenous leukemia (CML) remains largely unknown. In the present study, we showed that miR‑9-3p (miR-9) was downregulated in adriamycin (ADR)‑resistant K562/ADR cells and CML/MDR patients. Overexpression of miR-9 was sufficient to reverse cancer cell resistance to multiple chemotherapeutics invitro and sensitized tumors to chemotherapy invivo. Furthermore, we found that ABCB1 is a direct target of miR-9. These findings suggest that miR-9 plays a critical role in MDR in CML by targeting ABCB1. These results provide new evidence of miR-9 as a biomarker for clinical diagnosis and as a potential therapeutic target for CML.