CN114441701A - Application of detection reagent for nasopharyngeal carcinoma related serum marker - Google Patents
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Abstract
The invention belongs to the technical field of medical examination, and particularly relates to an application of a detection reagent of a nasopharyngeal carcinoma related serum marker, which is an application in preparation of products for diagnosing and/or prognosis of nasopharyngeal carcinoma, wherein the marker is Methyl (1- (cyclohexymethyl) -1h-indole-3-carbonyl) -l-valinate, and the CAS number is 1971007-94-9. By quantitatively detecting the marker in the serum of a subject, the onset of nasopharyngeal carcinoma can be well predicted, and a specific, rapid and noninvasive detection means is provided for the early diagnosis of nasopharyngeal carcinoma.
Description
Technical Field
The invention belongs to the technical field of medical examination, and particularly relates to an application of a detection reagent for nasopharyngeal carcinoma related serum markers.
Background
The main pathogenesis factors of nasopharyngeal carcinoma comprise genetic susceptibility, dietary factors and EBV (Epstein-Barr virus) infection, and the research on the pathogenesis of nasopharyngeal carcinoma comprises the aspects of gene mutation, metabonomics, proteomics, genomics and the like. Nevertheless, it is still difficult to fully understand the occurrence and development of nasopharyngeal carcinoma, which brings difficulties to the treatment.
Generally, nasopharyngeal carcinoma is mainly diagnosed by nasopharyngoscope examination, but the cost is high and the nasopharyngeal carcinoma is harmful to human bodies; further definite diagnosis of nasopharyngeal carcinoma still needs to rely on pathological diagnosis of tissues, but biopsy of the tissues is invasive, and patients suffer pain. Meanwhile, the occult nasopharyngeal carcinoma or submucosal nasopharyngeal carcinoma may need to be carried out for many times, so that the repeated tissue biopsy inevitably increases the economic burden and the psychological burden of a patient, and is also very unfavorable for large-scale screening. The plasma EBV DNA detection has great value in the aspects of nasopharyngeal carcinoma early diagnosis and screening, recurrence and metastasis diagnosis, prognosis judgment, individualized treatment and the like. It has been reported that there is a persistent positive EBV DNA in the plasma of nasopharyngeal carcinoma patients, whose copy number correlates with the staging of the tumor, decreases rapidly after effective treatment, and increases again upon recurrence and metastasis. However, the EB virus has high detection sensitivity and specificity. Therefore, how to find an effective, efficient, specific and noninvasive nasopharyngeal carcinoma tumor marker (Bio-marker) is crucial to improving the survival rate of patients.
Disclosure of Invention
In order to solve the technical problems, the invention screens out a marker capable of well distinguishing normal human control from early nasopharyngeal carcinoma in serum based on a metabonomics technology, and provides an application of a detection reagent of a nasopharyngeal carcinoma related serum marker in preparing a product for diagnosing and/or predicting nasopharyngeal carcinoma, wherein the marker is Methyl (1- (cyclohexymethyl) -1h-indole-3-carbonyl) -l-valinate, and the CAS number is 1971007-94-9.
Further, the amount of Methyl (1- (cyclohexymethyl) -1h-indole-3-carbonyl) -l-valinate in the serum of nasopharyngeal carcinoma patients was increased relative to that of normal healthy human controls.
Further, a method for detecting the marker using the reagent, comprising the steps of:
1) obtaining a serum sample from a subject;
2) separating the serum sample by using an ultra-high performance liquid chromatography system HILIC chromatographic column;
3) and (2) collecting primary and secondary spectrograms of the separated serum sample by using a mass spectrometer to obtain raw data in a Wiff format, converting the raw data into an mzXML format by Protewizard, and then performing peak alignment, retention time correction and peak area extraction by using XCMS software to obtain a quantitative result of Methyl (1- (cyclohexylmethyi) -1h-indole-3-carbonyl) -l-valenate in the serum sample of the subject.
Furthermore, in the step 1), after the serum sample is thawed in the environment of 4 ℃, a sample is added into the precooled sample according to the volume ratio of 2: 2: 1, mixing by vortex, carrying out low-temperature ultrasonic treatment for 30min, standing at-20 ℃ for 10min, 14000g, centrifuging at 4 ℃ for 20min, taking the supernatant, drying in vacuum, adding 100 mu L of acetonitrile aqueous solution during mass spectrometry, carrying out redissolution, carrying out vortex, 14000g, and centrifuging at 4 ℃ for 15min for later use.
Further, in the step 2), an Agilent1290InfinityLC ultra-performance liquid chromatography system HILIC chromatographic column is adopted for separation; the column temperature is 25 ℃; the flow rate is 0.5 mL/min; the sample volume is 2 mu L; mobile phase composition A: water +25mM ammonium acetate +25mM ammonia, B: acetonitrile; the gradient elution procedure was as follows: 0-0.5min, 95% B; 0.5-7min, B changes from 95% to 65% linearly; 7-8min, B changes linearly from 65% to 40%; 8-9min, keeping B at 40%; 9-9.1min, B changes linearly from 40% to 95%; 9.1-12min, B is maintained at 95%; samples were placed in a 4 ℃ autosampler throughout the analysis.
Further, in the step 3), an ABTripleTOF6600 mass spectrometer is adopted to collect primary and secondary spectrograms of the sample, so as to obtain original data in an original Wiff format; after a sample is separated by an Agilent1290InfinityLC ultra-performance liquid chromatography system, mass spectrometry is carried out by a tripleTOF6600 mass spectrometer, and detection is carried out by adopting an electrospray ionization positive ion mode and a negative ion mode respectively, wherein the ESI source setting parameters are as follows: atomizing gas auxiliary heating gas 1: 60, auxiliary heating gas 2: 60, air curtain gas: 30psi, ion source temperature: spray voltage is +/-5500V at 600 ℃; first-order mass-to-charge ratio detection range: 60-1000Da, and the mass-to-charge ratio detection range of secondary ions: 25-1000Da, first mass spectrum scan accumulation time: 0.20s/spectra, and the second-order mass spectrum scanning accumulation time is 0.05 s/spectra; the secondary mass spectrum is obtained by adopting a data-dependent acquisition mode, and a peak intensity value screening mode is adopted to remove cluster voltage: ± 60V, collision energy: 35 ± 15eV, IDA set as follows: dynamic exclusion isotope ion range: 4Da, 10 fragment patterns per scan
The invention has the following beneficial effects:
the research of the invention firstly discovers that the amount of Methyl (1- (cyclohexymethyl) -1h-indole-3-carbonyl) -l-valenate in the serum of a nasopharyngeal carcinoma patient is obviously increased compared with the control of a normal healthy person, and ROC analysis discovers that the accuracy of the substance (AUC ═ 1) is 100 percent and the specificity is 100 percent, so that the onset of the nasopharyngeal carcinoma can be well predicted, and the result provides a specific, rapid and noninvasive detection means for the early diagnosis of the nasopharyngeal carcinoma.
Drawings
FIG. 1 shows PCA analysis of serum samples.
Fig. 2 shows the results of ROC analysis of 5 significantly different serum metabolites in the training set based on random forest (random forest) algorithm.
FIG. 3 shows the ROC analysis result of serum marker (Methyl (1- (cyclohexylmethyi) -1h-indole-3-carbonyl) -l-valenate) in the test group based on random forest (random forest) algorithm.
Detailed Description
The invention is described in detail below with reference to the figures and the specific embodiments, but the invention should not be construed as being limited thereto. The technical means used in the following examples are conventional means well known to those skilled in the art, and materials, reagents and the like used in the following examples can be commercially available unless otherwise specified.
Based on the ultra-high performance liquid chromatography-tandem time-of-flight mass spectrometry (UHPLC-Q-TOF MS) metabonomics technology, we studied the metabolic profile characteristics in serum and urine samples of 27 patients with nasopharyngeal carcinoma and 27 normal healthy people (table 1). Through database matching, data standardization, metrology, statistical analysis and the like, 181 metabolites in the serum of nasopharyngeal carcinoma patients are significantly changed (p is less than 0.05), and 179 metabolites in urine are significantly changed (p is less than 0.05) compared with normal healthy people. The intersection was then taken and the results showed that only 7 metabolites were changed in both serum and urine of nasopharyngeal carcinoma patients. According to VIP >1& Foldchange >1.5& p <0.05, 6 differential metabolites were co-screened, wherein the two groups of Dibucaine were opposite in the trend of up-regulation, and the trend of the other 5 metabolites (Decanoyl-l-carnitine, Methyl (1- (cyclohexylmethyl) -1h-indole-3-carbonyl) -l-valinate, octanylcarnitine, Stachydrine and Paraxanthin) was consistent. Finally, a serum marker (Methyl (1- (cyclohexylmethyi) -1h-indole-3-carbonyl) -l-valenate) is accurately screened out by using an algorithm of random forest (random forest), wherein the name of the serum marker is as follows: (1- (cyclohexylmethyl) -1h-indole-3-carbonyl) -1-valine methyl ester. CAS number: 1971007-94-9. ROC analysis found that the marker Methyl (1- (cyclohexymethyl) -1h-indole-3-carbonyl) -l-valinate had an AUC value of 1 and an accuracy of 100%.
Table 127 nasopharyngeal carcinoma patients and 27 normal healthy people basic information
The following is a further description of the invention:
first, serum metabonomics analysis
1) After the serum sample was slowly thawed at 4 ℃, an appropriate amount of the sample was taken and added to a pre-chilled methanol/acetonitrile/water solution (2: 2: 1, v/v), vortex mixing, low-temperature ultrasonic treatment for 30min, standing at-20 ℃ for 10min, centrifuging at 14000g and 4 ℃ for 20min, vacuum drying the supernatant, and adding 100 μ L of acetonitrile aqueous solution (acetonitrile: water 1:1, v/v), vortexed, centrifuged at 14000g 4 ℃ for 15min, and the supernatant was sampled for analysis.
2) Chromatographic conditions are as follows: separating the sample by adopting an Agilent1290Infinity LC ultra-high performance liquid chromatography system (UHPLC) HILIC chromatographic column; the column temperature is 25 ℃; the flow rate is 0.5 mL/min; the sample volume is 2 mu L; mobile phase composition A: water +25mM ammonium acetate +25mM ammonia, B: acetonitrile; the gradient elution procedure was as follows: 0-0.5min, 95% B; 0.5-7min, B is changed from 95% to 65% linearly; 7-8min, B changes linearly from 65% to 40%; 8-9min, keeping B at 40%; 9-9.1min, B changes linearly from 40% to 95%; 9.1-12min, B is maintained at 95%; samples were placed in a 4 ℃ autosampler throughout the analysis. In order to avoid the influence caused by the fluctuation of the detection signal of the instrument, the continuous analysis of the samples is carried out by adopting a random sequence. QC samples are inserted into the sample queue and used for monitoring and evaluating the stability of the system and the reliability of experimental data.
3) Q-TOF mass spectrum conditions: and (3) collecting primary and secondary spectrograms of the sample by adopting an AB Triple TOF6600 mass spectrometer. After being separated by Agilent1290Infinity LC ultra-high performance liquid chromatography (UHPLC), the sample is subjected to mass spectrometry by a Triple TOF6600 mass spectrometer (AB SCIEX), and is respectively detected by electrospray ionization (ESI) positive ion mode and negative ion mode. The ESI source set-up parameters are as follows: atomizing Gas assisted heating Gas 1(Gas 1): auxiliary heating Gas 2(Gas 2): 60, air curtain gas (CUR): 30psi, ion source temperature: spraying Voltage (ISVF) +/-5500V (positive and negative modes) at 600 ℃; first-order mass-to-charge ratio detection range: 60-1000Da, and the mass-to-charge ratio detection range of secondary ions: 25-1000Da, first mass spectrum scan accumulation time: 0.20s/spectra, and the secondary mass spectrum scanning accumulation time is 0.05 s/spectra; secondary mass spectra were acquired using a data-dependent acquisition mode (IDA), and using a peak intensity value screening mode, declustering voltage (DP): ± 60V (positive and negative modes), collision energy: 35 + -15 eV, IDA is set as follows: 4Da, 10 fragment patterns per scan were acquired.
4) Data analysis flow: raw data in the Wiff format is converted into the mzXML format through the proteo wizard, and then the XCMS software is adopted to perform peak alignment, retention time correction and peak area extraction. The data extracted by XCMS is subjected to metabolite structure identification and data preprocessing, experimental data quality evaluation and data analysis. The data analysis content comprises the contents of univariate statistical analysis, multidimensional statistical analysis, differential metabolite screening, differential metabolite correlation analysis, KEGG channel analysis and the like.
As a result: in all 54 serum samples, the positive and negative ion patterns were combined to identify 1230 metabolites. The 27 nasopharyngeal carcinoma serum samples were clearly distinguished from the 27 normal healthy population serum samples in positive and negative ion mode by Principal Component Analysis (PCA) (fig. 1). Further, orthogonal partial least squares discriminant analysis (OPLS-DA) shows that the model can also distinguish the two groups of samples, and 181 metabolites in serum of patients with nasopharyngeal carcinoma are found to have significant changes by taking strict VIP >1 and p value <0.05 as screening standards. The results of the KEGG pathway enrichment analysis indicate that these differential metabolites are significantly enriched (p value <0.05) on 16 pathways, specifically including Aminoacyl-tRNA biosyntheses, Biosynthesis of unsautrated Fatty acids, Fatty acid biosyntheses, Aldoster synthesis and precipitation, Glutamergic synthesis, Argine biosyntheses, Ovarian oleogenesis, Long-term depression, GABAergic synthesis, Cholesterol metabolic syndrome, basic cell carbonate, Biosynthesis of amino acids, oligo metabolic in cell, Feopolysises, D-Glutamine D-glutamic acid and Centamycin.
Second, urine metabonomics analysis
The extraction of metabolites from urine samples, chromatographic conditions, Q-TOF mass spectrometry conditions, and data analysis procedures were the same as those of serum.
In all 54 urine samples, 2509 metabolites were identified after the positive and negative ion patterns were combined. The Analysis of Principal Component Analysis (PCA) shows that urine samples of 27 patients with nasopharyngeal carcinoma in positive ion mode and negative ion mode are mixed with urine samples of 27 normal healthy people. Further, orthogonal partial least squares discriminant analysis (OPLS-DA) shows that the model can distinguish the two groups of samples, and 179 metabolites in the urine of patients with nasopharyngeal carcinoma are found to have significant changes by taking strict VIP >1 and p value <0.05 as screening standards. The results of the KEGG pathway enrichment analysis show that these differential metabolites are significantly enriched (p value <0.05) on 8 pathways, specifically including Caffeine metabolism, Citrate cycle (TCA cycle), ABC transporters, Glucagon signaling pathway, Nicotinate and nicotinamide metabolism, Central carbon metabolism in the cancer, Butanoate metabolism and Alanine, aspartate and glutamate metabolism.
Thirdly, establishing and evaluating a prediction model
The results of combined serum and urine metabolomics found that only 7 metabolites (table 2) were significantly changed in serum and urine simultaneously in patients with nasopharyngeal carcinoma. On the other hand, the Central carbon metabolism in cancer pathway is also significantly enriched in serum and urine of patients with nasopharyngeal carcinoma. According to the screening criteria of Foldchange >1.5 or Foldchange <0.67, 5 metabolites are finally shown to have consistent trend in serum and urine of patients with nasopharyngeal carcinoma, which specifically includes: decanoyl-l-carnitine, Methyl (1- (cyclohexylmethyl) -1h-indole-3-carbonyl) -l-valinate, octavinylcyanidine, Stachydrine and Paraxanthin. And then, discovering biomarkers by using a random forest (random forest) algorithm, and randomly dividing all original serum samples into a training set and a testing set, wherein the training set is used for establishing a prediction model, and the verifying set is used for testing the accuracy of the model. The results show that the importance of the above 5 different serum metabolites in the training group is Methyl (1- (cyclohexymethyl) -1h-indole-3-carbonyl) -l-valinate, octanylcarbonitine, Stachydrine, Decanoyl-l-carbonitine and Paraxanthin in sequence from high to low. The AUC value of Methyl (1- (cyclohexymethyl) -1h-indole-3-carbonyl) -l-valinate was directly 1 (FIG. 2). Therefore, Methyl (1- (cyclohexymethyl) -1h-indole-3-carbonyl) -l-valinate was chosen as the only serum marker. ROC analysis in the test group found that the AUC value of the marker was 1, and both accuracy and specificity were 100% (fig. 3).
TABLE 27 metabolites that undergo significant changes simultaneously in serum and urine of nasopharyngeal carcinoma patients
Foldchange*Representing the ratio of nasopharyngeal carcinoma patient group to normal healthy human group.
The above results show that: methyl (1- (cyclohexymethyl) -1h-indole-3-carbonyl) -l-valinate can be used as a serum diagnosis marker of early nasopharyngeal carcinoma, and a specific, rapid and noninvasive detection means is provided for the early diagnosis of the nasopharyngeal carcinoma.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (6)
1. The application of the detection reagent of the nasopharyngeal carcinoma related serum marker in preparing products for diagnosing and/or prognosis of the nasopharyngeal carcinoma is characterized in that the marker is Methyl (1- (cyclohexymethyl) -1 h-indele-3-carbonyl) -1-valinate, and the CAS number is 1971007-94-9.
2. The use according to claim 1, wherein the amount of Methyl (1- (cyclohexymethyl) -1h-indole-3-carbonyl) -l-valenate in the serum of a patient with nasopharyngeal carcinoma is increased relative to a normal healthy human control.
3. The use according to claim 2, wherein the method of detecting the marker using the reagent comprises the steps of:
1) obtaining a serum sample from a subject;
2) separating the serum sample by using an ultra-high performance liquid chromatography system HILIC chromatographic column;
3) and (2) collecting primary and secondary spectrograms of the separated serum sample by using a mass spectrometer to obtain raw data in a Wiff format, converting the raw data into an mzXML format by Protewizard, and then performing peak alignment, retention time correction and peak area extraction by using XCMS software to obtain a quantitative result of Methyl (1- (cyclohexylmethyi) -1h-indole-3-carbonyl) -l-valenate in the serum sample of the subject.
4. The use according to claim 3, wherein in step 1), after the serum sample is thawed at 4 ℃, the sample is added to the precooled serum sample in a volume ratio of 2: 2: 1, mixing by vortex, carrying out low-temperature ultrasonic treatment for 30min, standing at-20 ℃ for 10min, 14000g, centrifuging at 4 ℃ for 20min, taking the supernatant, drying in vacuum, adding 100 mu L of acetonitrile aqueous solution during mass spectrometry, carrying out redissolution, carrying out vortex, 14000g, and centrifuging at 4 ℃ for 15min for later use.
5. The use of claim 4, wherein in step 2), the separation is performed using an Agilent1290InfinityLC ultra high performance liquid chromatography system HILIC chromatography column; the column temperature is 25 ℃; the flow rate is 0.5 mL/min; the sample volume is 2 mu L; mobile phase composition A: water +25mM ammonium acetate +25mM ammonia, B: acetonitrile; the gradient elution procedure was as follows: 0-0.5min, 95% B; 0.5-7min, B changes from 95% to 65% linearly; 7-8min, B changes linearly from 65% to 40%; 8-9min, keeping B at 40%; 9-9.1min, B changes linearly from 40% to 95%; 9.1-12min, B is maintained at 95%; samples were placed in a 4 ℃ autosampler throughout the analysis.
6. The use of claim 5, wherein in step 3), the ABTripl eTOF6600 mass spectrometer is used to collect the primary and secondary spectrograms of the sample, so as to obtain the raw data in the raw Wiff format; after a sample is separated by an Agilent1290InfinityLC ultra-performance liquid chromatography system, mass spectrometry is carried out by a triple OF6600 mass spectrometer, detection is carried out by adopting an electrospray ionization positive ion mode and a negative ion mode respectively, and the ESI source setting parameters are as follows: atomizing gas auxiliary heating gas 1: 60, auxiliary heating gas 2: 60, air curtain gas: 30psi, ion source temperature: spray voltage is +/-5500V at 600 ℃; first-order mass-to-charge ratio detection range: 60-1000Da, and the mass-to-charge ratio detection range of secondary ions: 25-1000Da, first mass spectrum scan accumulation time: 0.20s/spectra, and the second-order mass spectrum scanning accumulation time is 0.05 s/spectra; the secondary mass spectrum is obtained by adopting a data-dependent acquisition mode, and a peak intensity value screening mode is adopted to remove cluster voltage: ± 60V, collision energy: 35 + -15 eV, IDA is set as follows: 4Da, 10 fragment patterns per scan were acquired.
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| 公安部 国家卫生健康委员会 国家药品监督管理局: "关于将合成大麻素类物质和氟胺酮等18种物质列入《非药用类麻醉药品和精神药品管制品种增补目录》的公告", 《HTTPS://WWW.MPS.GOV.CN/N6557558/C7881251/CONTENT.HTML》 * |
| 宣宇等: "新型毒品"小树枝"成分的结构确证", 《刑事技术》 * |
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