Lipid responses to perfluorooctane sulfonate exposure for multiple rat organs.

Perfluorooctane sulfonate (PFOS) is a persistent chemical that has long been a threat to human health. However, the molecular effects of PFOS on various organs are not well studied. In this study, male Sprague-Dawley rats were treated with various doses of PFOS through gavage for 21 days. Subsequently, the liver, lung, heart, kidney, pancreas, testis, and serum of the rats were harvested for lipid analysis. We applied a focusing lipidomic analytical strategy to identify key lipid responses of phosphorylcholine-containing lipids, including phosphatidylcholines and sphingomyelins. Partial least squares discriminant analysis revealed that the organs most influenced by PFOS exposure were the liver, kidney, and testis. Changes in the lipid profiles of the rats indicated that after exposure, levels of diacyl-phosphatidylcholines and 22:6-containing phosphatidylcholines in the liver, kidney, and testis of the rats decreased, whereas the level of 20:3-containing phosphatidylcholines increased. Furthermore, levels of polyunsaturated fatty acids-containing plasmenylcholines decreased. Changes in sphingomyelin levels indicated organ-dependent responses. Decreased levels of sphingomyelins in the liver, nonmonotonic dose responses in the kidney, and irregular responses in the testis after PFOS exposure are observed. These lipid responses may be associated with alterations pertaining to phosphatidylcholine synthesis, fatty acid metabolism, membrane properties, and oxidative stress in the liver, kidney, and testis. Lipid responses in the liver could have contributed to the observed increase in liver to body weight ratios. The findings suggest potential toxicity and possible mechanisms associated with PFOS in multiple organs.

Predictive Scoring System for Spontaneous Closure of Infant Ventricular Septal Defect: The P-VSD Score.

Ventricular septal defect (VSD) is a common congenital heart disease. However, consensus on the utility of echocardiography in predicting spontaneous closure (SC) of VSD remains lacking. This study aimed to identify and validate significant predictors of SC through a predictive scoring system. This retrospective study included medical records of 712 echocardiography instances performed on 304 patients diagnosed with VSD from 2016 to 2020 in their first year of life. A novel scoring system for predicting the SC of VSD was developed and validated using another dataset from different hospitals. Of the 304 patients, 215 (70.7%) had perimembranous (PM) VSDs and 89 had muscular (29.3%) VSDs. The median follow-up periods were 36.2 (interquartile range [IQR], 13-59) months and 13.7 9 (IQR, 5-37.4) days for PM and muscular VSDs, respectively. The overall SC rate during follow-up was 29.3%. Pulmonary hypertension (HTN), concomitant left ventricle (LV)-right atrium (RA) shunt, VSD size to aortic valve (AV) annulus size ratio, and left ventricular end-diastolic dimension (LVEDD) z-score were significant risk factors affecting SC of VSD. The "P-VSD" score, a new scoring system, demonstrated an area under the curve for predictability of 0.769. Pulmonary HTN, concomitant LV-RA shunt, LVEDD z-score, and VSD size-to-AV annulus size ratio at diagnosis were significantly associated with non-SC VSD after infancy. The P-VSD score can predict the SC of VSD in clinical settings and simplify the identification and appropriate management of high-risk patients.

Peptide-Coated Bacteriorhodopsin-Based Photoelectric Biosensor for Detecting Rheumatoid Arthritis.

An effective early diagnosis is important for rheumatoid arthritis (RA) management. This study reveals a novel RA detection method using bacteriorhodopsin as a photoelectric transducer, a light-driven proton pump in purple membranes (PMs). It was devised by covalently conjugating a PM monolayer-coated electrode with a citrullinated-inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3)542-556 peptide that recognizes the serum RA-associated autoantibodies. The direct serum coating decreased the photocurrents in the biosensor, with the reduction in the photocurrent caused by coating with an RA-patient serum that is significantly larger than that with a healthy-control serum (38.1% vs. 20.2%). The difference in the reduction in the photocurrent between those two serum groups widened after the serum-coated biosensor was further labeled with gold nanoparticle (AuNP)-conjugated anti-IgA (anti-IgA-AuNP) (53.6% vs. 30.6%). Both atomic force microscopic (AFM) and Raman analyses confirmed the sequential peptide, serum, and anti-IgA-AuNP coatings on the PM-coated substrates. The reductions in the photocurrent measured in both the serum and anti-IgA-AuNPs coating steps correlated well with the results using commercial enzyme-linked immunosorbent assay kits (Spearman rho = 0.805 and 0.787, respectively), with both a sensitivity and specificity close to 100% in both steps. It was shown that an RA diagnosis can be performed in either a single- or two-step mode using the developed biosensor.

Identification of serum metabolic signatures of environmental-leveled phthalate in the Taiwanese child population using NMR-based metabolomics.

Phthalates have become important environmental pollutants due to their high exposure frequency in daily life; thus, phthalates are prevalent in humans. Although several epidemiologic surveys have linked phthalates with several adverse health effects in humans, the molecular events underlying phthalate exposure have not been fully elucidated. The purpose of this study was to reveal associations between phthalate exposure and the serum metabolome in Taiwanese children using a metabolomic approach. A total of 256 Taiwanese children (8-10 years old) from two cohorts were enrolled in this study. Twelve urinary phthalate metabolites were analyzed by high-performance liquid chromatography/tandem mass spectrometry, while a nuclear magnetic resonance-based metabolomic approach was used to record serum metabolic profiles. The associations between metabolic profiles and phthalate levels were assessed by partial least squares analysis coupled with multiple linear regression analysis. Our results revealed that unique phthalate exposures, such as mono-isobutyl phthalate, mono-n-butyl phthalate, and mono (2-ethyl-5-oxohexyl) phthalate, were associated with distinct serum metabolite profiles. These phthalate-mediated metabolite changes may be associated with perturbed energy mechanisms, increased oxidative stress, and lipid metabolism. In conclusion, this study suggests that metabolomics is a valid approach to examine the effects of environmental-level phthalate on the serum metabolome. This study also highlighted potentially important phthalates and their possible effects on children.

Autoantibodies to Oxidatively Modified Peptide: Potential Clinical Application in Coronary Artery Disease.

Coronary artery disease (CAD) is a global health issue. Lipid peroxidation produces various by-products that associate with CAD, such as 4-hydroxynonenal (HNE) and malondialdehyde (MDA). The autoantibodies against HNE and MDA-modified peptides may be useful in the diagnosis of CAD. This study included 41 healthy controls (HCs) and 159 CAD patients with stenosis rates of <30%, 30−70%, and >70%. The plasma level of autoantibodies against four different unmodified and HNE-modified peptides were measured in this study, including CFAH1211−1230, HPT78−108, IGKC2−19, and THRB328−345. Furthermore, feature ranking, feature selection, and machine learning models have been utilized to exploit the diagnostic performance. Also, we combined autoantibodies against MDA and HNE-modified peptides to improve the models' performance. The eXtreme Gradient Boosting (XGBoost) model received a sensitivity of 78.6% and a specificity of 90.4%. Our study demonstrated the combination of autoantibodies against oxidative modification may improve the model performance.

Using anti-malondialdehyde-modified peptide adduct autoantibodies in serum of taiwanese women to diagnose primary Sjogren's syndrome.

BACKGROUND: Sjogren's syndrome (SS) is a systemic autoimmune disease featured with a dry mouth and dry eyes. Several autoantibodies, including anti-SSA, anti-SSB, antinuclear antibodies can be detected in patients with SS. Oxidation-specific epitopes (OSEs) can be formed from malondialdehyde (MDA)-modified protein adducts and trigger chronic inflammation. In this study, our purposes were used serum levels of anti-MDA-modified peptide adducts autoantibodies to evaluate predictive performance by machine learning algorithms in primary Sjögren's syndrome (pSS) and assess the association between pSS and healthy controls. METHODS: Three novel MDA-modified peptide adducts, including immunoglobulin (Ig) gamma heavy chain 1 (IGHG1)102-131, complement factor H (CFAH)1045-1062, and Ig heavy constant alpha 1 (IGHA1)307-327 were identified and validated. Serum levels of protein, MDA-modified protein adducts, MDA, and autoantibodies recognizing unmodified peptides and MDA-modified peptide adducts were measured. Statistically significance in correlations and odds ratios (ORs) were estimated. RESULTS: The random forest classifier utilized autoantibodies combination composed of IgM anti-IGHG1102-131, IgM anti-IGHG1102-131 MDA and IgM anti-IGHA1307-327 achieved predictive performance as an accuracy of 88.0%, a sensitivity of 93.7%, and a specificity of 84.4% which may be as potential diagnostic biomarkers to differentiate patients with pSS from rheumatoid arthritis (RA), and secondary SS in RA and HCs. CONCLUSIONS: Our findings imply that low levels of IgA anti-IGHG1102-131 MDA (OR = 2.646), IgA anti-IGHG1102-131 (OR = 2.408), IgA anti-CFAH1045-1062 (OR = 2.571), and IgA anti-IGHA1307-327 (OR = 2.905) may denote developing risks of pSS, respectively.

A Coronary Artery Disease Monitoring Model Built from Clinical Data and Alpha-1-Antichymotrypsin.

Coronary artery disease (CAD) is one of the most common subtypes of cardiovascular disease. The progression of CAD initiates from the plaque of atherosclerosis and coronary artery stenosis, and eventually turns into acute myocardial infarction (AMI) or stable CAD. Alpha-1-antichymotrypsin (AACT) has been highly associated with cardiac events. In this study, we proposed incorporating clinical data on AACT levels to establish a model for estimating the severity of CAD. Thirty-six healthy controls (HCs) and 162 CAD patients with stenosis rates of <30%, 30−70%, and >70% were included in this study. Plasma concentration of AACT was determined by enzyme-linked immunosorbent assay (ELISA). The receiver operating characteristic (ROC) curve analysis and associations were conducted. Further, five machine learning models, including decision tree, random forest, support vector machine, XGBoost, and lightGBM were implemented. The lightGBM model obtained a sensitivity of 81.4%, a specificity of 67.3%, and an area under the curve (AUC) of 0.822 for identifying CAD patients with a stenosis rate of <30% versus >30%. In this study, we provided a demonstration of a monitoring model with clinical data and AACT.

Distinct brain lipid signatures in response to low-level PM2.5 exposure in a 3xTg-Alzheimer's disease mouse inhalation model.

Fine particulate matter (PM2.5) poses a significant risk to human health. The molecular mechanisms underlying low-level PM2.5-induced neurotoxicity in the central nervous system remain unclear. In addition, changes in lipids in response to PM2.5 exposure have not yet been fully elucidated. In this study, 3xTg-Alzheimer's disease (AD) mice experienced continuous whole-body exposure to non-concentrated PM2.5 for three consecutive months, while control mice inhaled particulate matter-filtered air over the same time span. A liquid chromatography-mass spectrometry-based lipidomic platform was used to determine the distinct lipid profiles of various brain regions. The average PM2.5 concentration during the exposure was 11.38 µg/m3, which was close to the regulation limits of USA and Taiwan. The partial least squares discriminant analysis model showed distinct lipid profiles in the cortex, hippocampus, and olfactory bulb, but not the cerebellum, of mice in the exposure group. Increased levels of fatty acyls, glycerolipids, and sterol lipids, as well as the decreased levels of glycerophospholipids and sphingolipids in PM2.5-exposed mouse brains may be responsible for the increased energy demand, membrane conformation, neuronal loss, antioxidation, myelin function, and cellular signaling pathways associated with AD development. Our research suggests that subchronic exposure to low levels of PM2.5 may cause neurotoxicity by changing the lipid profiles in a susceptible model. Lipidomics is a powerful tool to study the early effects of PM2.5-induced AD toxicity.

TEAD4 as an Oncogene and a Mitochondrial Modulator.

TEAD4 (TEA Domain Transcription Factor 4) is well recognized as the DNA-anchor protein of YAP transcription complex, which is modulated by Hippo, a highly conserved pathway in Metazoa that controls organ size through regulating cell proliferation and apoptosis. To acquire full transcriptional activity, TEAD4 requires co-activator, YAP (Yes-associated protein) or its homolog TAZ (transcriptional coactivator with PDZ-binding motif) the signaling hub that relays the extracellular stimuli to the transcription of target genes. Growing evidence suggests that TEAD4 also exerts its function in a YAP-independent manner through other signal pathways. Although TEAD4 plays an essential role in determining that differentiation fate of the blastocyst, it also promotes tumorigenesis by enhancing metastasis, cancer stemness, and drug resistance. Upregulation of TEAD4 has been reported in several cancers, including colon cancer, gastric cancer, breast cancer, and prostate cancer and serves as a valuable prognostic marker. Recent studies show that TEAD4, but not other members of the TEAD family, engages in regulating mitochondrial dynamics and cell metabolism by modulating the expression of mitochondrial- and nuclear-encoded electron transport chain genes. TEAD4's functions including oncogenic activities are tightly controlled by its subcellular localization. As a predominantly nuclear protein, its cytoplasmic translocation is triggered by several signals, such as osmotic stress, cell confluency, and arginine availability. Intriguingly, TEAD4 is also localized in mitochondria, although the translocation mechanism remains unclear. In this report, we describe the current understanding of TEAD4 as an oncogene, epigenetic regulator and mitochondrial modulator. The contributing mechanisms will be discussed.

Electrochemical biosensor with electrokinetics-assisted molecular trapping for enhancing C-reactive protein detection.

C-Reactive protein (CRP) is an essential biomarker relevant to various disease prognoses. Current biosensors require a significant amount of time for detecting CRP. To address this issue, this work proposes electrokinetic flow-assisted molecule trapping integrated with an impedance biosensor, where a driving signal in terms of a gated sine wave is provided to circularly arranged electrodes which detect proteins. To verify the biosensor's efficacy, protein aggregation on the electrode surface was evaluated through a fluorescence analysis and measurement of the electrochemical impedance spectrum (EIS). The fluorescence analysis with avidin showed that target samples largely accumulated on the electrode surface upon provision of the driving signal. The EIS measurement of CRP accumulation on the electrode surface further confirmed a significant electrokinetic phenomenon at the electrode/electrolyte interface. Even at the low CRP concentration of 10 pg/ml, the proposed device's sensitivity and reliability were as high as 3.92 pg/ml with a signal-to noise ratio (SNR) of ≥3, respectively. In addition, the protein detection time (without considering the preparation time) was minimized to as low as 90 s with the proposed device. This device's advantage is its minimal time consumption, and simple drop-analysis process flow; hence, it was used for monitoring clinical serum samples.

Lipid profiling differentiates the effect of ambient microenriched copper on a coral as an advanced tool for biomonitoring.

Copper can be beneficial or harmful to coral at environmentally relevant levels, making environmental monitoring a challenging. Membrane lipids make the cell a dynamic environment according to the circumstances; thus, the lipid profile should be indicative of an environmental/physiological state. To gain more insight into the copper effect on coral health and be a basis of biomonitoring, glycerophosphocholine profiling of coral exposed to microenriched copper levels was conducted in this study. The copper microenrichments resulted in a diacritical effect of decreasing carbonic anhydrase activity, following a supplementation effect, on coral lipid metabolism. Microdifferences in copper levels are critical to determine the coral metabolic state and were therefore included in this study. In addition, an excellent quantitative model correlating the coral lipid variation with the exposed copper levels or the induced physiological effect was obtained to demonstrate its performance for biomonitoring.

Combination treatment of docetaxel with caffeic acid phenethyl ester suppresses the survival and the proliferation of docetaxel-resistant prostate cancer cells via induction of apoptosis and metabolism interference.

BACKGROUND: Docetaxel has been approved by USFDA as a first-line treatment for castration-resistant prostate cancer (CRPC) patients. Patients receiving androgen deprivation therapy along with docetaxel result in superior survival, lower serum prostate specific antigen (PSA) level, and better quality of life. However, a significant proportion of these patients ultimately develop resistance to docetaxel within months. Caffeic acid phenethyl ester (CAPE), one of the main bioactive components extracted from the propolis, has been reported to be effective for repressing the tumor growth, the migration and invasion of prostate cancer (PCa) cells, as well as the downstream signaling and stability of androgen receptor (AR). We hence determined if combination treatment of docetaxel with CAPE can suppress the proliferation and the survival of docetaxel-resistant PCa cells. METHODS: We established docetaxel-resistant PC/DX25 and DU/DX50 CRPC cell lines from PC-3 and DU-145 human PCa cells, respectively. Proliferation assay, MTT assay, flow cytometry with Annexin V staining, Comet Assay, and nude mice xenograft model were applied to determine the effects of combination treatment on cell proliferation and survival of the docetaxel-resistant PCa cells. Micro-Western Array (MWA) and qRT-PCR were used to investigate the molecular mechanism lying underneath. RESULTS: Combination treatment effectively suppressed the proliferation, survival and tumor growth of docetaxel-resistant PCa cells both in vitro and in nude mice. Comet assay and flow cytometry indicated that combination treatment induced apoptosis in docetaxel-resistant PCa cells. MWA and Western blotting assay revealed that combination treatment suppressed protein expression of Bcl-2, AKT2, c-Myc, apoptosis and caspase activation inhibitor (AVEN), pyruvate kinase M2 (PKM2) but increased protein expression of Bax, caspase 3, cytochrome c, glucose-6-phosphate dehydrogenase (G6PD) and acylglycerol kinase (AGK). Overexpression of Bcl-2 in the docetaxel-resistant PCa cells enhanced cell proliferation of docetaxel-resistant PCa cells under combination treatment. Analysis with qRT-PCR suggested that combination treatment decreased cholesterol biosynthesis genes DHCR24 (24-dehydrocholesterol reductase) and LSS (lanosterol synthase) but increased genes involved in glycolysis and TCA cycle. CONCLUSIONS: Combination treatment of docetaxel with CAPE effectively suppressed the proliferation and survival of docetaxel-resistant PCa cells via inhibition of Bcl-2 and c-Myc as well as induction of metabolism interference. Combination treatment can be beneficial for patients with docetaxel-resistant PCa.

Machine Learning in Prediction of Bladder Cancer on Clinical Laboratory Data.

Bladder cancer has been increasing globally. Urinary cytology is considered a major screening method for bladder cancer, but it has poor sensitivity. This study aimed to utilize clinical laboratory data and machine learning methods to build predictive models of bladder cancer. A total of 1336 patients with cystitis, bladder cancer, kidney cancer, uterus cancer, and prostate cancer were enrolled in this study. Two-step feature selection combined with WEKA and forward selection was performed. Furthermore, five machine learning models, including decision tree, random forest, support vector machine, extreme gradient boosting (XGBoost), and light gradient boosting machine (GBM) were applied. Features, including calcium, alkaline phosphatase (ALP), albumin, urine ketone, urine occult blood, creatinine, alanine aminotransferase (ALT), and diabetes were selected. The lightGBM model obtained an accuracy of 84.8% to 86.9%, a sensitivity 84% to 87.8%, a specificity of 82.9% to 86.7%, and an area under the curve (AUC) of 0.88 to 0.92 in discriminating bladder cancer from cystitis and other cancers. Our study provides a demonstration of utilizing clinical laboratory data to predict bladder cancer.

Lipid profiling of coral symbiosomes in response to copper-induced carbon limitation: A metabolic effect of algal symbionts on the host immune status.

Copper micropollutants are known to constrain coral's assimilation of carbonate, affecting the carbon available to algal symbionts and thus inducing a light stress. However, little is known regarding the physiological relevance of lipid metabolism in coral symbiotic algae in a carbon-limited state. Membrane lipids exhibit multiple physicochemical properties that are collectively responsible for the dynamic structure of cells depending on the physiological demands of the circumstances. To gain insight into lipid metabolism's importance in this regard, glycerophosphocholine (GPC) profiling of symbiosomes in coral (Seriatopora caliendrum) exposed to environmentally relevant copper levels (2.2-7.5 µg/L) for 4 days was performed in this study. Notably, reducing the number of 22:6-processing GPCs and increasing that of lyso-GPCs likely addressed the demands of metabolizing excess light energy, such as affecting the membrane dynamics to promote mitochondrial uncoupling. The decrease in 22:6-processing GPCs additionally protected cellular membranes from elevated oxidative stress, reducing their susceptibility to peroxidation and offsetting oxidized lipid-induced effects on membrane dynamics. The change in plasmanylcholines specifically localized within the symbiosome membrane also met the membrane requirements for responding to oxidative stress conditions. Moreover, increasing the 20:4-possessing plasmanylcholines and lysoplasmanylcholines and reducing the 22:6-possessing plasmanylcholines likely resulted in an imbalance of the immune reaction, influencing the coral-algae symbiosis given the role of such plasmanylcholines in cell signaling. In summary, carbon limitations induced by copper enrichment lead to a shift in the membrane lipid profile of coral symbiosomes, accommodating themselves to light stress conditions while compromising the symbiosis's stability.

Serum levels of 4-hydroxynonenal adducts and responding autoantibodies correlate with the pathogenesis from hyperglycemia to Alzheimer's disease.

OBJECTIVE: Hyperglycemia leads to lipid peroxidation, producing 4-hydroxynonenal (HNE) adducts which correlate with the production of amyloid-beta (Aß), one of the hallmarks of Alzheimer's disease (AD). This study is to investigate the interactions of Aß, HNE adducts and responding autoantibodies during the pathogenesis from hyperglycemia to AD. METHODS: A total of 239 Taiwanese serum samples from a healthy control group and patients with hyperglycemia, and AD with and without hyperglycemia were analyzed. Aß was immunoprecipitated from randomly pooled serum in each group and immunoblotted. Synthetic Aß1-16 and Aß17-28 peptides were modified with HNE in vitro and verified with LC-MS/MS. The levels of Aß, HNE adducts, and autoantibody isotypes IgG and IgM against either native or HNE-modified Aß were determined with ELISA. The diagnostic power of potential biomarkers was evaluated. RESULTS: Increased fasting glucose and decreased high-density-lipoprotein cholesterol in AD groups indicated abnormal metabolism in the pathogenesis progression from hyperglycemia to AD. Indeed, serum Aß, HNE adducts and most of the autoantibodies recognizing either native or HNE-modified Aß were increased in the diseased groups. However, HNE adducts had better diagnostic performances than Aß for both hyperglycemia and AD. Additionally, HNE-Aß peptide levels were increased, and the responding autoantibodies (most notably IgM) were decreased in hyperglycemic AD group compared to the hyperglycemia only group, suggesting an immunity disturbance in the pathogenesis progression from hyperglycemia to AD. CONCLUSION: Hyperglycemia increases the level of HNE adducts which may be neutralized by responding autoantibodies. Depletion of these autoantibodies promotes AD-like pathogenesis. Thus, levels of a patient's HNE adducts and associated responding autoantibodies are potential biomarkers for AD with diabetes.

Peptide-based electrochemical sensor with nanogold enhancement for detecting rheumatoid arthritis.

Rheumatoid arthritis (RA), an autoimmune and chronic inflammatory disorder, is an incurable disease. We developed a peptide-based electrochemical sensor using electrochemical impedance spectroscopy that can be used to detect autoantibodies for RA diagnostics. We first validated that the developed peptide showed high sensitivity and could compliment the current gold standard method of an anti-cyclic citrullinated peptide antibody (anti-CCP) ELISA. The developed peptide can be modified on the nanogold surface of the working electrode of sensing chips through the method of a self-assembling monolayer. The sensing process was first optimized using a positive control cohort and a healthy control cohort. Subsequently, 10 clinically confirmed samples from RA patients and five healthy control samples were used to find the threshold value of the impedance between RA and healthy subjects. Furthermore, 10 clinically confirmed samples but with low values of anti-CCP autoantibodies were used to evaluate the sensitivity of the present method compared to the conventional method. The proposed method showed better sensitivity than the current conventional anti-CCP ELISA method.

Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers.

Increasing evidence suggests that tumor development requires not only oncogene/tumor suppressor mutations to drive the growth, survival, and metastasis but also metabolic adaptations to meet the increasing energy demand for rapid cellular expansion and to cope with the often nutritional and oxygen-deprived microenvironment. One well-recognized strategy is to shift the metabolic flow from oxidative phosphorylation (OXPHOS) or respiration in mitochondria to glycolysis or fermentation in cytosol, known as Warburg effects. However, not all cancer cells follow this paradigm. In the development of prostate cancer, OXPHOS actually increases as compared to normal prostate tissue. This is because normal prostate epithelial cells divert citrate in mitochondria for the TCA cycle to the cytosol for secretion into seminal fluid. The sustained level of OXPHOS in primary tumors persists in progression to an advanced stage. As such, targeting OXPHOS and mitochondrial activities in general present therapeutic opportunities. In this review, we summarize the recent findings of the key regulators of the OXPHOS pathway in prostate cancer, ranging from transcriptional regulation, metabolic regulation to genetic regulation. Moreover, we provided a comprehensive update of the current status of OXPHOS inhibitors for prostate cancer therapy. A challenge of developing OXPHOS inhibitors is to selectively target cancer mitochondria and spare normal counterparts, which is also discussed.

Clinical Assay for the Early Detection of Colorectal Cancer Using Mass Spectrometric Wheat Germ Agglutinin Multiple Reaction Monitoring.

Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality in the world. U.S. Food and Drug Administration-approved circulating tumor markers, including carcinoembryonic antigen, carbohydrate antigen (CA) 19-9 and CA125 were used as prognostic biomarkers of CRC that attributed to low sensitivity in diagnosis of CRC. Therefore, our purpose is to develop a novel strategy for novel clinical biomarkers for early CRC diagnosis. We used mass spectrometry (MS) methods such as nanoLC-MS/MS, targeted LC-MS/MS, and stable isotope-labeled multiple reaction monitoring (MRM) MS coupled to test machine learning algorithms and logistic regression to analyze plasma samples from patients with early-stage CRC, late-stage CRC, and healthy controls (HCs). On the basis of our methods, 356 peptides were identified, 6 differential expressed peptides were verified, and finally three peptides corresponding wheat germ agglutinin (WGA)-captured proteins were semi-quantitated in 286 plasma samples (80 HCs and 206 CRCs). The novel peptide biomarkers combination of PF454-62, ITIH4429-438, and APOE198-207 achieved sensitivity 84.5%, specificity 97.5% and an AUC of 0.96 in CRC diagnosis. In conclusion, our study demonstrated that WGA-captured plasma PF454-62, ITIH4429-438, and APOE198-207 levels in combination may serve as highly effective early diagnostic biomarkers for patients with CRC.