Biomarker composition for diagnosing radiation exposure, and kit and method for diagnosing radiation exposure using same

Abstract

A biomarker composition for diagnosing side effects upon radiation exposure to the lower abdomen according to an embodiment of the present invention is composed of 12 types of blood metabolites that change upon radiation exposure to a local radiation site, wherein the blood metabolites are obtained from a radiotherapy model for prostate cancer patients, diarrhea is diagnosed as a side effect of radiation upon local radiation exposure to the lower abdomen, substances that increase at least 1.5 fold among the blood metabolites are cinnamaldehyde, oleamide, guanidinosuccinic acid, or 2-tridecanone, and substances that decrease at least 2.0 fold among the blood metabolites are isatin, acetylcarnitine, 1-(1-ethyl-1H-pyrrol-2-yl)ethanone, 1-methylhistamine, ecgonine, hexanoylglycine, boschniakine, or 4-phenylpyridine.

Description

Biomarker composition for diagnosing radiation exposure, radiation exposure diagnostic kit using the same, and method

[0001] The present invention relates to a biomarker composition for diagnosing radiation exposure and a method for diagnosing radiation exposure using the same, and more specifically, to a plasma metabolite biomarker composition for diagnosing side effects of radiation exposure to the lower abdomen, a radiation exposure diagnostic kit and method that provide information for diagnosing radiation exposure using the same.

[0002] Since radiation is used industrially in various fields such as nuclear power generation, radiation therapy, and diagnosis, it is necessary to scientifically specify and quantify the risk of radiation exposure in order to clearly understand the human health effects on workers exposed to radiation or patients receiving radiation therapy.

[0003] Various biomarkers are being discovered as measures of the biological risk of radiation exposure, but most of them are biomarkers designed to diagnose the degree of whole-body exposure.

[0004] Local exposure to the lower abdomen during radiation therapy causes damage to the gastrointestinal tract, which may lead to side effects such as diarrhea in some cases.

[0005] Regarding the side effects of radiation therapy, namely diarrhea, some individuals may be asymptomatic, but many patients experience mild to severe diarrhea over several days.

[0006] However, to date, there are no biomarkers capable of rapidly diagnosing the potential for side effects, such as diarrhea induced by localized radiation exposure.

[0007] Furthermore, existing metabolite biomarkers for radiation exposure are applicable to whole-body exposure and are limited to the radiation dose; consequently, biomarkers regarding side effects induced by radiation exposure have not been presented.

[0008] The present invention was devised to solve these problems, and the objective of the present invention is to provide a biomarker composition for diagnosing radiation exposure capable of rapidly diagnosing the possibility of side effects such as diarrhea induced by localized radiation exposure, a radiation exposure diagnostic kit using the same, and a method.

[0009] The biomarker composition for diagnosing side effects upon lower abdominal radiation exposure according to one embodiment of the present invention is composed of 12 types of blood metabolites that change upon localized radiation exposure.

[0010] The above blood metabolites are obtained from a radiation therapy model of a prostate cancer patient, and diarrhea is diagnosed as a radiation side effect upon local radiation exposure to the lower abdomen, and the substances that increase by more than 1.5 times among the blood metabolites are Cinnamaldehyde, Oleamide, Guanidinosuccinic acid, or 2-Tridecanone, and the substances that decrease by less than 0.5 times among the blood metabolites are Isatin, Acetylcarnitine, 1-(1-Ethyl-1H-pyrrol-2-yl)ethanone, 1-Methylhistamine, Ecgonine, hexanoylglycine, Boschniakine, or 4-Phenylpyridine.

[0011] The present invention is characterized by a diagnostic method for diagnosing adverse effects upon radiation exposure to the lower abdomen according to another embodiment, comprising: a step of collecting a blood sample from a person whose local area has been exposed to radiation; a step of acquiring and analyzing information on compounds in the plasma of the collected blood sample; and a step of analyzing the information on plasma compounds of a blood sample collected from each patient after radiation exposure to determine whether four types of increasing substances, namely Cinnamaldehyde, Oleamide, Guanidinosuccinic acid, or 2-Tridecanone, have increased above a predetermined value, or eight types of decreasing substances, namely Isatin, Acetylcarnitine, 1-(1-Ethyl-1H-pyrrol-2-yl)ethenone, 1-Methylhistamine, Ecgonine, hexanoylglycine, Boschniakine, or 4-Phenylpyridine, have decreased below a predetermined value.

[0012] According to a biomarker composition for diagnosing radiation exposure, a radiation exposure diagnostic kit using the same, and a method according to one embodiment of the present invention, radiation side effects (diarrhea) can be rapidly diagnosed using blood in the event of local radiation exposure to the lower abdomen.

[0013] In addition, according to one embodiment of the present invention, the biomarker composition for diagnosing radiation exposure, the radiation exposure diagnostic kit and method using the same, can diagnose relatively quickly because it uses plasma metabolites rather than cells, such as genes, proteins, or mRNA of blood.

[0014] Figure 1 is a table showing metabolite information and patient side effect information for each patient after radiation therapy,

[0015] FIG. 2 is a table and corresponding graph showing compositions that increase or decrease in the Severe group compared to the None group based on metabolite information,

[0016] Figure 3 is a graph showing increased metabolites,

[0017] Figure 4 is a graph showing reduced metabolites.

[0018] FIG. 5 is a biomarker composition for diagnosing radiation exposure according to one embodiment of the present invention.

[0019] With reference to the drawings below, a biomarker composition for diagnosing radiation exposure according to one embodiment of the present invention, a radiation exposure diagnostic kit using the same, and a method will be described in detail.

[0020] A biomarker composition for diagnosing radiation exposure according to one embodiment of the present invention is composed of 12 types of blood metabolites that change upon localized radiation exposure, and since it diagnoses radiation exposure using plasma without using cells such as blood genes, proteins, or mRNA, it can diagnose quickly.

[0021] The above blood metabolites are obtained from a radiation therapy model of a prostate cancer patient, and blood metabolites can be identified by utilizing the presence or absence of diarrhea as a radiation side effect upon localized radiation exposure to the lower abdomen.

[0022] Among the above blood metabolites, the substance that significantly increases by 1.5 times or more is Cinnamaldehyde, Oleamide, Guanidinosuccinic acid, or 2-Tridecanone, and among the above blood metabolites, the substance that significantly decreases by 0.5 times or less may be Isatin, Acetylcarnitine, 1-(1-Ethyl-1H-pyrrol-2-yl)ethanone, 1-Methylhistamine, Ecgonine, hexanoylglycine, Boschniakine, or 4-Phenylpyridine.

[0023] According to one embodiment of the present invention, a diagnostic kit and a diagnostic method for diagnosing side effects of radiation exposure to the lower abdomen can be provided by increasing or decreasing the fold change of four types of increasing substances and eight types of decreasing substances as a biomarker composition for diagnosing radiation exposure.

[0024] As radiation has become an integral part of daily life and localized human exposure increases with the rise in radiation use, promptly diagnosing localized radiation exposure to proceed with patient treatment can lead to high therapeutic efficacy; therefore, this device was developed to rapidly diagnose radiation side effects (diarrhea) using blood in cases of localized lower abdominal radiation exposure.

[0025] The "biomarker" of the present invention is a substance that can diagnose localized radiation exposure side effects by distinguishing it from the plasma or blood of a normal control group as a substance or blood metabolite that has been altered in the blood or plasma of a subject suspected of radiation exposure, and includes organic biomolecules such as proteins or nucleic acids, lipids, glycolipids, glycoproteins, etc. that show an increasing or decreasing pattern in the blood or plasma of a subject exposed to radiation compared to a normal control group.

[0026] In a broad sense, the term "diagnosis" in the present invention means judging the actual condition of a patient's disease in all aspects. The content of the judgment includes the name of the disease, the cause of the disease, the type of disease, the severity, the detailed aspects of the condition, and the presence or absence of complications.

[0027] The following experimental examples were used to discover a biomarker composition capable of rapidly diagnosing radiation side effects (diarrhea) using blood upon localized radiation exposure to the lower abdomen according to one embodiment of the present invention, as well as a radiation exposure diagnostic kit and a diagnostic method using the same.

[0028] <Experimental Example>

[0029] To identify metabolites that change upon localized radiation exposure, a radiation therapy model of prostate cancer patients was utilized.

[0030] 1. Radiation irradiation

[0031] For radiation therapy of prostate cancer patients (10 people), an experiment was conducted by irradiating the prostate area with local radiation (total 44 Gy x-ray, 2 Gy / fraction (22 fraction)).

[0032] 2. Collection of blood sample

[0033] Blood samples were collected from each patient after radiation exposure (after a 44 Gy dose).

[0034] 3. Acquisition and Analysis of Plasma Compound Information

[0035] Information on compounds in plasma is obtained by performing LC-MS / MS (positive mode) analysis using UPLC / Q-Exactive equipment.

[0036] Here, UPLC / Q-Exactive equipment refers to a mass spectrometer equipped with a programmable logic controller and an automation and control system, meaning a high-resolution precision mass spectrometer, and LC-MS / MS (positive mode) (liquid chromatography mass spectrometer) analysis is used for targeted and non-target screening, characterization, compound discovery, and quantitative analysis.

[0037] 4. Analysis and identification of composition types using Compound Discoverer 3.3 (ThermoFisher) program

[0038] The plasma compound information of blood samples collected from each patient after radiation was analyzed using the Compound Discoverer 3.3 (ThermoFisher) program to identify the types of composition.

[0039] As shown in Figure 1, using the blood metabolite information (metabolite name and amount) and the patient's adverse effect information for each patient, metabolite analysis was performed by dividing the patients into a group of 3 patients who had no diarrhea or had a relatively short duration of diarrhea (None) and a group of 3 patients who had relatively severe or long duration of diarrhea (Severe).

[0040] In Figure 1, the duration of side effects after radiation therapy for each patient refers to the duration of diarrhea, which is a side effect of the patient. It can be seen that the patient numbers for the three patients in the group with no diarrhea or relatively short duration of diarrhea (None) are #2, 8, and 10, and the patient numbers for the three patients in the group with relatively severe or long duration of diarrhea (Severe) are #1, 4, and 9.

[0041] Here, D-factor is the sum of the duration of diarrhea grade 1 and (duration of diarrhea grade 2 x 2), where diarrhea grade 1 refers to mild diarrhea and diarrhea grade 2 refers to severe diarrhea.

[0042] Figure 2 is a table showing the results of metabolite analysis, indicating the metabolite, change amount (FC: fold change), log2FC, p-value (an indicator for accurately determining statistical significance), and whether it is an increasing or decreasing substance using UP / DOWN.

[0043] 5. Discovery of plasma metabolites increasing or decreasing in the Severe group compared to None

[0044] Figures 3 and 4 show tables of increased and decreased metabolites in the group Severe, in which diarrhea was relatively severe or prolonged, compared to the group None, in which diarrhea was not present or the duration of diarrhea was relatively short, for each patient after radiation therapy.

[0045] As shown in Figure 3, when looking at the fold change of metabolites in the group Severe (where diarrhea was relatively severe or long) compared to the group None (where diarrhea was absent or had a relatively short duration of diarrhea) after radiation therapy for each patient, it can be seen that Cinnamaldehyde is 5, Oleamide is 4, Guanidinosuccinic acid is 4, and 2-Tridecanone is 2, and that the four substances among the metabolites that increased significantly by more than 1.5 times are Cinnamaldehyde, Oleamide, Guanidinosuccinic acid, and 2-Tridecanone.

[0046] As shown in Figure 4, when looking at the fold change of metabolites in the group Severe (where diarrhea was relatively severe or long) compared to the group None (where diarrhea was not present or the duration of diarrhea was relatively short) after radiation therapy for each patient, it can be seen that the eight substances that decreased to less than 0.5 times are Isatin, Acetylcarnitine, 1-(1-Ethyl-1H-pyrrol-2-yl)ethenone, 1-Methylhistamine, Ecgonine, hexanoylglycine, Boschniakine, and 4-Phenylpyridine.

[0047] Now, a diagnostic kit for diagnosing side effects of lower abdominal radiation exposure according to one embodiment of the present invention will be briefly described.

[0048] A diagnostic kit for diagnosing side effects of lower abdominal radiation exposure according to one embodiment of the present invention is configured to detect at least one of four substances that increase fold change in metabolites—Cinnamaldehyde, Oleamide, Guanidinosuccinic acid, and 2-Tridecanone—and substances that decrease fold change—Isatin, Acetylcarnitine, 1-(1-Ethyl-1H-pyrrol-2-yl)ethenone, 1-Methylhistamine, Ecgonine, hexanoylglycine, Boschniakine, and 4-Phenylpyridine—in the group Severe, in which diarrhea is relatively severe or long, compared to the group None, in which diarrhea does not occur or the duration of diarrhea is relatively short after radiation therapy for each patient, and to diagnose through the increase or decrease thereof.

[0049] Now, with reference to FIG. 5, a diagnostic method for diagnosing side effects upon lower abdominal radiation exposure according to one embodiment of the present invention will be briefly described.

[0050] As illustrated in FIG. 5, a method for diagnosing adverse effects of radiation exposure to the lower abdomen according to one embodiment of the present invention comprises the steps of: collecting a blood sample from a person whose local area has been exposed to radiation (S110); obtaining and analyzing information on compounds in the plasma of the collected blood sample (S120); and analyzing the information on plasma compounds of a blood sample collected from each patient after radiation exposure to determine whether four types of increasing substances, such as Cinnamaldehyde, Oleamide, Guanidinosuccinic acid, or 2-Tridecanone, have increased by more than 1.5 times compared to a normal group, or eight types of decreasing substances, such as Isatin, Acetylcarnitine, 1-(1-Ethyl-1H-pyrrol-2-yl)ethenone, 1-Methylhistamine, Ecgonine, hexanoylglycine, Boschniakine, or 4-Phenylpyridine, have decreased by less than 0.5 times.

[0051] The method for collecting blood samples can be the conventional method, and the method for obtaining and analyzing information on compounds in plasma can be performed by conducting LC-MS / MS (positive mode) analysis using UPLC / Q-Exactive equipment to obtain information on compounds in plasma.

[0052] The method for obtaining and analyzing information on compounds in plasma can be analyzed and the type of composition identified using the Compound Discoverer 3.3 (ThermoFisher) program.

[0053] A method for diagnosing side effects upon lower abdominal radiation exposure according to one embodiment of the present invention can detect a biomarker composition for diagnosing side effects upon lower abdominal radiation exposure and diagnose side effects upon lower abdominal radiation exposure through an increase or decrease thereof.

[0054] Foregoing, specific parts of the present invention have been described in detail. It will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the actual scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A biomarker composition for diagnosing side effects of lower abdominal radiation exposure, composed of 12 types of blood metabolites that change upon localized radiation exposure.

2. In Paragraph 1, The above blood metabolite is a biomarker composition for diagnosing side effects of lower abdominal radiation exposure obtained from a radiation therapy model of a prostate cancer patient.

3. In Paragraph 2, The above blood metabolite is a biomarker composition for diagnosing side effects of radiation exposure to the lower abdomen, which diagnoses diarrhea as a side effect of radiation exposure to the lower abdomen.

4. In Paragraph 3, A biomarker composition for diagnosing side effects of lower abdominal radiation exposure, wherein the substance increasing by 1.5 times or more among the above blood metabolites is Cinnamaldehyde, Oleamide, Guanidinosuccinic acid, or 2-Tridecanone.

5. In Paragraph 3, A biomarker composition for diagnosing side effects of lower abdominal radiation exposure, wherein the reducing substance among the above blood metabolites that decreases to 0.5 times or less is Isatin, Acetylcarnitine, 1-(1-Ethyl-1H-pyrrol-2-yl)ethanone, 1-Methylhistamine, Ecgonine, hexanoylglycine, Boschniakine, or 4-Phenylpyridine.

6. A diagnostic kit for detecting a biomarker composition for diagnosing adverse effects upon lower abdominal radiation exposure according to any one of claims 1 to 5, and diagnosing an increase or decrease thereof.

7. A step of collecting a blood sample from a person whose local area has been exposed to radiation; A step of acquiring and analyzing information on compounds in the plasma of a collected blood sample; A diagnostic method for diagnosing adverse effects of lower abdominal radiation exposure, comprising the step of analyzing plasma compound information of a blood sample collected from each patient after radiation irradiation to determine whether four types of increasing substances, namely Cinnamaldehyde, Oleamide, Guanidinosuccinic acid, or 2-Tridecanone, have increased above a predetermined value, or eight types of decreasing substances, namely Isatin, Acetylcarnitine, 1-(1-Ethyl-1H-pyrrol-2-yl)ethenone, 1-Methylhistamine, Ecgonine, hexanoylglycine, Boschniakine, or 4-Phenylpyridine, have decreased below a predetermined value.

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