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WO2018009700A1 - Surveillance de l'exposition au rayonnement et de la radiosensibilité par spectrométrie de masse à ionisation ambiante - Google Patents

Surveillance de l'exposition au rayonnement et de la radiosensibilité par spectrométrie de masse à ionisation ambiante Download PDF

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Publication number
WO2018009700A1
WO2018009700A1 PCT/US2017/040950 US2017040950W WO2018009700A1 WO 2018009700 A1 WO2018009700 A1 WO 2018009700A1 US 2017040950 W US2017040950 W US 2017040950W WO 2018009700 A1 WO2018009700 A1 WO 2018009700A1
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Prior art keywords
radiation
sample
subject
exposure
radiation exposure
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English (en)
Inventor
Giuseppe ASTARITA
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Waters Technologies Corp
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Waters Technologies Corp
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6848—Methods of protein analysis involving mass spectrometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/40—Disorders due to exposure to physical agents, e.g. heat disorders, motion sickness, radiation injuries, altitude sickness, decompression illness
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present disclosure relates generally to methods and apparatus for determining the effects of radiation exposure on a subject.
  • the present disclosure relates to the use of surface desorption ionization mass spectrometry methods and apparatus to determine and quantify molecular markers of radiation exposure that can be used in large-scale epidemiology and human biomonitoring studies.
  • the method and apparatus can determine the maximum levels of radiation exposure of a subject, improve radiotherapy using real-time analysis and reduce the incidence of adverse side effects such as secondary cancer.
  • Ionizing radiation is radiation that carries enough energy to free electrons from atoms or molecules, thereby ionizing them.
  • Non-ionizing radiation is radiation that only excites the motion of the atoms or molecules, or excites an electron from an occupied orbital into an empty, higher-energy orbital.
  • Exposure to ionizing radiation has dramatically increased in modern society, raising serious health concerns.
  • Ionizing radiation is widely used in medicine, research, diagnosis, therapy, manufacturing, and construction. It is also present in air and space travel. Some radiation exposures are known events, such as, for example, exposure used in a therapy treatment. Other exposures are unknown to a subject (e.g., air travel or space travel). And still yet other exposure may be unexpected (e.g., as a consequence of an industrial accident or malfunctioning equipment).
  • Exposure to ionizing radiation can result in radiation damage to tissue and/or organs.
  • Ionizing radiation can alter the structure and function of key cellular components, such as proteins and lipids. It can activate a pro-inflammatory response. It can affect cell signaling. Radiation exposure can also result in cancer and non-cancer-related diseases, including cardiovascular diseases and cognitive decline. The potential damage from an absorbed dose depends on the amount and type of radiation and the sensitivity of different tissues and organs.
  • the present technology provides new tools that can effectively and rapidly screen populations for radiation exposure.
  • some embodiments of the present disclosure relates to the use of surface desorption ionization mass spectrometry methods and apparatus to determine and quantify radiation exposure effects.
  • the method and apparatus can allow real-time monitoring of radiation exposure and radio sensitivity for personalized treatments.
  • the present disclosure relates to methods and apparatus for real-time analysis of subjects and samples for the molecular consequences of irradiation.
  • the present disclosure can identify, quantitate and ameliorate the effects of exposure to ionizing radiation on multiple cellular components.
  • the present disclosure relates to a method of identifying the effects of radiation on a subject.
  • This method includes acquiring a sample from a subject exposed to radiation, testing the sample to generate a molecular profile, comparing the molecular profile to a standard, and identifying at least one effect of the radiation related to the sample.
  • Testing of the sample can include generating sample ions from the sample using a surface desorption ionization source, receiving the ions into a mass spectrometer, and identifying at least one compound in the sample to generate the molecular profile.
  • the present disclosure also relates to a method of quantifying the effects of radiation on a subject further including quantifying the at least one effect of the radiation related to the sample.
  • the present disclosure relates to a method of determining the maximum radiation exposure of a subject.
  • This method includes acquiring a first sample from a subject prior to radiation exposure, testing the first sample to generate a first molecular profile, exposing the subject to a known quantity of radiation, acquiring a second sample from the subject after exposure to radiation, testing the second sample to generate a second molecular profile, comparing the first and second profiles to identify at least one effect of the radiation related to the sample, quantifying the at least one effect of the radiation related to the sample, and determining the maximum radiation exposure of the subject based on the quantity of the at least one effect of the radiation and the known amount of radiation exposure.
  • Testing of the sample can include generating sample ions from the sample using a surface desorption ionization source, receiving the ions into a mass spectrometer, and identifying at least one compound in the sample to generate the molecular profile.
  • the present disclosure also relates to reducing the risk of secondary cancers from radiotherapy including exposing the subject to an amount of radiation that does not exceed the maximum radiation exposure of the subject.
  • the present disclosure also relates to improving radiotherapy including treating the subject with a second therapy that reduces the at least one effect of the radiation, such as providing omega-3 supplementation or a nonsteroidal ant i- inflammatory compound.
  • the methods and apparatus of the present disclosure provide several advantages over the prior art.
  • the present disclosure can be used for real-time, robust, rapid, testing, including in-situ testing, of subjects exposed to radiation.
  • the quick feedback provided by the methods of the present disclosure can assist in identifying and quantifying the effects of radiation exposure by assessing the molecular profile(s) in the sample. The effects can then be monitored, reduced, treated or prevented.
  • Personalized products can also be designed to avoid excess exposure to radiation without requiring extensive and expensive laboratory testing.
  • the present disclosure can also be performed without an internal standard or pre-calibrations.
  • Figure 1 shows an exemplary embodiment of the present disclosure.
  • FIG. 1A shows a subject preparing for radiotherapy.
  • Figure IB shows the level of the subject's radio sensitivity to the radiotherapy determined using a surface desorption ionization mass spectrometry method.
  • Figure 1C shows the subject treated with a personalized dose of radiation.
  • Figure ID shows the subject's response to the radiotherapy can be monitored, and further personalization can be provided.
  • Figure 2 shows another exemplary embodiment of the present disclosure.
  • Figure 2A shows a subject exposed to radiation selected for monitoring.
  • the radiation source can be occupational, medical exposure, environmental, radon, earth gamma radiation, cosmic rays, accidental, etc.
  • Figure 2B shows the level and effect of the radiation exposure determined using a surface desorption ionization mass spectrometry method.
  • Figure 2C shows a personalized treatment, such as a pharmacological or dietary intervention, selected and provided to the subject. Based on the effects of the radiation therapy, certain therapies may not be indicated for the subject (X).
  • Figure 2D shows the subject's response to the personalized treatment monitored, and further personalization can be provided.
  • the present disclosure relates to the use of surface desorption ionization mass spectrometry methods and apparatus to determine and quantify radiation exposure effects.
  • the method and apparatus of the present disclosure can identify, quantify or both identify and quantify molecular targets or similar biosignatures that are indicators of radiation exposure. These molecular targets and biosignatures can be used in treating exposure or improving radiotherapy, such as predictors of radiosensitivity.
  • the method and apparatus of the present disclosure can be used to monitor in real-time the targets (or biomarkers) and biosignatures of radiation exposure using mass spectrometry, in particular ambient ionization mass spectrometry.
  • the present disclosure relates to a method of identifying the effects of radiation on a subject including acquiring a sample from a subject exposed to radiation, testing the sample to generate a molecular profile, comparing the molecular profile to a standard, and identifying at least one effect of the radiation related to the sample.
  • the present disclosure relates to a method of identifying a model or standard associated with radiation effects on a subject including acquiring at least one sample from a subject exposed at least once to radiation, testing the at least one sample to generate at least one molecular profile, analyzing the at least one molecular profile for at least one molecule or class of molecules that are indicative of the radiation exposure, e.g., demonstrate a proportional response to the radiation.
  • a sample can be acquired from a subject using various, known means.
  • the sample can be any biological sample taken from a person or subject (e.g., person, animal, etc.).
  • the sample can be a biofluid, a biopsy, a stool, a skin or a hair sample, including a secretion or extract from the subject.
  • the sample can also be tested, screened or analyzed directly, i.e., wherein samples ions are generated in situ directly from the subject.
  • the surface desorption ionization source used to generate the sample ions can be a gentle or soft ionization technique which does not substantially damage or exhaust an in situ biological sample.
  • the sample can also be tested, screened or analyzed indirectly or ex vivo (e.g., biofluids, stool, biopsies).
  • the method of the present disclosure can be applied to volatile, liquid and solid samples.
  • the sample can be loaded into or onto a sample probe and inserted into a surface desorption ionization source for data acquisition via mass spectrometry.
  • the sample can be analyzed with no substantial preparation, such as filtering, extraction, isolation or combinations thereof.
  • the sample can be analyzed neat, or with no sample preparation.
  • a sample or samples can be swiped on a glass capillary and held, placed or otherwise introduced to an ionization source, e.g., held in a metastable gas beam between a direct analysis in real-time ion source and a mass spectrometer detector.
  • the sample preparation is simple such that the sample can be a biological sample place on a slide or grid.
  • the sample can also be associated with a treatment or supplement to treat radiation exposure in a subject.
  • the sample can be a dosage form in any form, e.g., tablet, capsule, pill, film, liquid, etc.
  • the sample can be prepared neat or by altering the dosage form to access the sample.
  • the sample can be a dietary supplement containing encapsulated dosages of fatty acids.
  • the sample preparation can include removing a portion of the contents from inside the encapsulation.
  • the sample can be acquired from a subject that is exposed to radiation.
  • the sample can also be acquired from a subject that is expected to be exposed to radiation.
  • Ionizing radiation can be categorized by the nature of the particles or electromagnetic waves that create the ionizing effect.
  • Ionizing radiation can include photon-radiation (e.g., gamma rays, X-rays, etc.) and particle radiations (e.g., alpha-, beta-particles, neutrons, heavy ions, etc.).
  • the ionizing radiation can be delivered via radiation therapy or can be encountered by incidental or accidental exposure.
  • the primary type of radiation therapy is external beam radiation therapy or teletherapy.
  • Conventional external beam radiation therapy is usually delivered via two- dimensional beams using kilovoltage therapy x-ray units or medical linear accelerators which generate high energy x-rays.
  • These forms of radiation therapy include magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and ultrasound.
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • ultrasound ultrasound.
  • Brachytherapy can be delivered by placing radiation source(s) inside or next to the area requiring treatment.
  • Systemic radioisotope therapy or unsealed source radiotherapy is another type of radiation therapy.
  • the differences among the types of therapies relate to the position of the radiation source.
  • Brachytherapy uses sealed radioactive sources placed precisely in the area under treatment, and systemic radioisotopes are given by infusion or oral ingestion.
  • the amount of radiation a subject is exposed to can vary.
  • the amount of radiation can be expressed in Sievert (Sv).
  • the Sievert represents the equivalent biological effect of the deposit of a joule of radiation energy in a kilogram of human tissue.
  • the amount of radiation exposed to or applied can vary depending, for example, on the type of activity or exposure that occurs, or the type and stage of cancer being treated.
  • the treatment of solid tumors requires a typical radiation dose ranging from 60 to 80 Sv.
  • a typical does can range from 20 to 40 Sv.
  • the annual exposure for medical persons is 0.75 mSv, for aviators is 3.07 mSv, for nuclear power workers is 1.87 mSv, for industrial workers is 0.81 mSv, for educational researchers is 0.79 mSv and for military personnel is 0.59 mSv.
  • the amount of radiation that a subject can be exposed to or that can be applied to a subject such that the method and apparatus of the present disclosure can identify, quantitate and/or ameliorate the effects can be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or about 100 mSv.
  • the amount can also be about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or about 100 Sv.
  • the method and apparatus of the present disclosure can monitor the effect of low doses of radiation, such as the ones used in routine scans (e.g., security at the airports, dentist office, aviation exposure, work related exposure, etc.) for which molecular biomarkers are not yet available. Such molecular biomarkers can be identified and quantified, including the rate of
  • the radiation exposure or the radiation delivered, such as in radiotherapy can be in fractional amounts or in prescribed doses.
  • the incidental exposure can occur over time or the total radiation amount can be spread out over time via a treatment plan.
  • the number of exposures or doses of a treatment plan can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or about 30 exposures or doses. These values can be used to define a range, such as about 10 or about 20 exposures or doses.
  • the amount of radiation per dose can be evenly distributed among the doses or exposures, front loaded or back loaded.
  • a 40 Sv amount of radiation can be delivered on a fractionation schedule of about 2 Sv per day, 5 days a week, for 4 weeks.
  • the sample of the present technology can be tested to generate a molecular profile.
  • the sample can be tested using a surface desorption ionization mass spectrometry apparatus.
  • Sample ions from the sample can be generated using any desorption ionization (DI) source or technique capable of effectively sampling compounds of interest, or classes of compounds of interest, from a sample for introduction into a mass spectrometer.
  • DI desorption ionization
  • the desorption ionization source or technique can also be any capable of real-time, rapid in- situ testing of solid or liquid samples.
  • the desorption ionization source is a surface desorption ionization source or technique.
  • the ionization process can begin by irradiating, or otherwise exposing, a defined area or spot on a sample, e.g., solid sample, using a focused energy source.
  • the energy source can be an excitatory beam such as a laser, ions, charged, solvent droplets or heated gas containing metastable ions.
  • the sample's surface releases a vapor of ionized molecules that can be directed into a mass spectrometer.
  • acoustic or thermal desorption can initiate the ionization process.
  • the analysis of biological samples using a surface desorption ionization mass spectrometry system is provided.
  • the biological samples are particularly suited for surface desorption ionization because they contain many components, such as oxylipins, that can be in high abundance ionize well in negative mode under DI conditions.
  • the surface desorption ionization source can operate by a technique selected from the group consisting of electrospray ionization, nano-electrospray ionization, matrix- assisted laser desorption ionization, atmospheric pressure chemical ionization, desorption electrospray ionization, atmospheric pressure dielectric barrier discharge ionization, atmospheric pressure low temperature plasma desorption ionization, laser-assisted electrospray ionization, and electrospray-assisted laser desorption ionization.
  • the surface desorption ionization source can operate by a technique selected from the group consisting of atmospheric solid analysis probe (i.e., ASAP), direct analysis in real time, rapid evaporative ionization mass spectrometry (REIMS), desorption electrospray ionization (DESI), matrix assisted laser desorption ionization
  • ASAP atmospheric solid analysis probe
  • REIMS rapid evaporative ionization mass spectrometry
  • DESI desorption electrospray ionization
  • MALDI massive laser desorption spectrometry
  • NIMS nano structure and initiated mass spectrometry
  • the desorption ionization source can small and have a small footprint.
  • the desorption ionization source can also be suitable or compatible with ambient mass
  • the desorption ionization source or technique is direct analysis in real time, ASAP, REIMS or DESI. These ionization sources can be small and compatible with ambient mass spectrometry.
  • Direct Analysis in Real Time is an atmospheric pressure ion source that can instantaneously ionizes gases, liquids or solids in open air under ambient conditions. It is an ambient ionization technique that does not require sample preparation, so solid or liquid materials can be analyzed by mass spectrometry in their native state. Ionization can take place directly on the sample surface. Liquids can be analyzed by, for example, dipping an object (such as a glass rod) into the liquid sample and then presenting it to the direct analysis in real time ion source. Vapors can be introduced directly into the direct analysis in real time gas stream.
  • Atmospheric Solids Analysis Probe is an atmospheric pressure ion source that can directly analyze samples using an atmospheric pressure ionization (API) source.
  • the ASAP probe can analyze solid, liquid, tissue, or material samples.
  • vaporization of a sample can occur when it is exposed to a hot desolvation gas, e.g., nitrogen, from an probe, e.g., an electrospray ionization or atmospheric pressure chemical ionization probe.
  • a hot desolvation gas e.g., nitrogen
  • an electrospray ionization or atmospheric pressure chemical ionization probe e.g., an electrospray ionization or atmospheric pressure chemical ionization probe.
  • Both direct analysis in real time and ASAP are similar ionization techniques.
  • ASAP can involve increasing temperature to effect ionization, whereas direct analysis in real time can involve increasing heated, blown gas to effect ionization.
  • Rapid Evaporative Ionization Mass Spectrometry is an ionization technique that can be used as a source for direct analysis of samples by mass spectrometry.
  • REIMS is an atmospheric pressure ion source that can ionize gases, liquids or solids in open air under ambient conditions.
  • the REIMS ionization source can be a probe, e.g., electronic scalpel or tweezers to burn and evaporate ions, that can be used to remotely test the samples. See U.S. Patent Publication No. 2012/0156712, the disclosure of which is incorporated herein in its entirety.
  • Desorption electrospray ionization is an ambient ionization technique that can be used in mass spectrometry for chemical analysis. It is an atmospheric pressure ion source that ionizes gases, liquids and solids in open air under ambient conditions.
  • DESI is a combination of electrospray (ESI) and desorption (DI) ionization methods. Ionization can take place by directing an electrically charged mist to a sample surface. The electrospray mist can be attracted to the surface by applying a voltage on the sample or sample holder. After ionization, the ions can travel through air into the atmospheric pressure interface which can be connected to a mass spectrometer.
  • Thermal desorption ionization can be used as the ionization mechanism.
  • the sample, and biological components, can be exposed to different temperatures to induce ionization. See U.S. Patent Publication No. 2013/0299688, the disclosure of which is incorporated herein in its entirety.
  • the energy or temperature of the ionization source may not be sufficiently high to efficiently ionize a representative sample.
  • the sample may contain compounds having different properties, such as different volatilities. At a certain energy level or temperature, some compounds may be ionized more readily than others, which can create a bias in the ratio at that energy level or temperature.
  • the present disclosure includes a step of determining a sufficient energy level (e.g., temperature in thermal desorption) to ionize a representative sample of all compounds or classes of compounds. For example, the energy level can be tested at increasing values until the intensities or ratio of intensities for the compounds of interest stabilize at a constant value indicative of a representative sampling of compounds.
  • the method can also be robust such that the sampling does not exhaust the compounds or classes of compounds, e.g., oxylipins, in the sample.
  • the ionization process can involve a short, e.g., less than about 10 seconds, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.2 or about 0.1 seconds, exposure of the ionization source to the sample. These values can be used to define a range, such as about 2 to about 0.2 seconds.
  • the sample ions can be received or introduced to a mass spectrometer by any means or technique capable of effectively introducing ions into a mass spectrometer that can allow for real-time, rapid in-situ testing of solid or liquid samples.
  • the ions can be introduced under ambient conditions.
  • the mass spectrometer can be any mass spectrometer capable of receiving the sample ions, of producing accurate mass measurements, and of identifying sample compounds of interest.
  • the mass spectrometer can be a quadrupole mass spectrometer, portable ion trap mass spectrometer, time of flight mass spectrometer, orbitrap, Fourier transform ion cyclotron resonance mass spectrometry, orbi trap or ion mobility spectrometer.
  • the mass spectrometer can be a single quadrupole detector, e.g., a DART®- QDa® (commercially available from IonSense Corporation, Saugus, MA in collaboration with Waters Technologies Corporation, Milford, MA) or a REIMS-single quadrupole mass spectrometer.
  • a DART®- QDa® commercially available from IonSense Corporation, Saugus, MA in collaboration with Waters Technologies Corporation, Milford, MA
  • REIMS-single quadrupole mass spectrometer e.g., a single quadrupole detector, e.g., a DART®- QDa® (commercially available from IonSense Corporation, Saugus, MA in collaboration with Waters Technologies Corporation, Milford, MA) or a REIMS-single quadrupole mass spectrometer.
  • the compounds of interest can be analyzed by selection reaction monitoring in a quadrupole instrument.
  • Selection reaction monitor involves preselection of a list of ions of interest or extracted from full scan accurate mass spectra, in which no ion is preselected but the quadrupole is scanned along all the mass range selected (e.g., 50-2000 m/z).
  • the mass spectrometer can be operated in positive or negative mode. In one embodiment, the mass spectrometer is operated in negative mode under desorption ionization conditions. Oxylipins can ionize particularly well in negative mode.
  • the coupling of a mass spectrometer, e.g., a single quadrupole device, with desorption ionization can also allow for the direct analysis of oxylipins as a function of peak intensity or as a ratio between peaks or groups of peaks.
  • the ratio of oxylipins can be used to normalize for variation in instrument settings and sampling. For example, a variation in intensity of one oxylipin is compensated by an equivalent variation in another oxylipin. Their ratio can be used to normalize for difference between samples.
  • the molecular profile that is generated can provide phenotyping information, e.g., metabolic phenotyping, molecular phenotyping or fingerprinting.
  • the molecular composition of the sample or biofluid can be characterized.
  • the molecular profile can identify one or more biomarkers in the sample that are indicative of the radiation and the molecular response to the radiation, e.g., radiation effects.
  • the molecular profile can also identify one or more mechanisms that are affected by the radiation and can be used as predictors of other effects, conditions, both acute and long term.
  • the molecular profile can identify, quantitate, or both identify and quantitate induced blood factors that contribute to the inflammatory response to radiation exposure.
  • the molecular profile can identify, quantify or both, at least one compound in the sample that is indicative of the radiation exposure.
  • the identified compound(s) can be any compound that can be indicative of radiation exposure, or a condition related to radiation exposure.
  • the number of compound(s) identified and/or monitored can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 50, 100 or greater. These values can define a range, such as between about 5 and 20 compound(s).
  • the compounds that can be identified and/or quantified can include, but are not limited to, small molecules, peptides, lipids, oligonucleotides, glycans, drugs, pesticides and other environmental agents.
  • the molecular profile can identify, quantify or both, at least one class of compounds in the sample that is indicative of the radiation exposure.
  • the class of compounds can include, but are not limited to, oxylipins and other small molecules, peptides, lipids, oligonucleotides, glycans, drugs, pesticides and other environmental agents.
  • the method and apparatus of the present disclosure can generate the molecular profile in a relatively short time after the exposure.
  • the molecular profile can be generated within 30 minutes, 1 hour, 2 hours, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 20, 24, 36, 48 or 72 hours, or more, after the exposure. These time can define a range, such as about 1 to 4 hours.
  • the time after exposure for each molecular profile can be recorded and tracked for measuring the onset and magnitude of changes to the molecular profile with time.
  • the changes observed for molecules, classes of molecules or pathways over time can be used to identify one or more standards or models that can be used as a quick response indicator of radiation exposure.
  • the identify of one or more markers that are indicative of radiation include those that have a direct, or indirect, proportional response to the radiation exposure, e.g., some correlation exists between the exposure and the change in molecule(s), class(es) of molecules or pathway.
  • subjects can be screened at different times after having been exposed to different types and amounts of radiation, as provided herein.
  • the resulting molecular profiles at each time point can be analyzed to identify markers for the radiation exposure.
  • the identification of one or more markers that change over a relatively short time after the exposure can be used to screen subjects exposed to such radiation.
  • the magnitude of the change in molecule(s), class(es) of molecules or pathways can be indicative of an adverse effect or sensitivity, such as a higher risk of cancer or secondary cancer.
  • the magnitude of the change either higher or lower, can be 5%, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100%. These values can be used to define a range, such as about 20 to about 50%.
  • the identity of at least one compound in the sample and/or the amount or relative amount (e.g., ratio) of the at least one compound, or classes of compounds, can be calculated from the mass spectrometry results, such as the intensity of the peaks.
  • the calculations can be made with or without the use of an internal standard.
  • the relative amount can be a simple ratio of the intensities of the mass signals.
  • the use of internal standard(s) can provide semi-quantification after correcting for any isotopic contribution to the signal.
  • internal standards can be used to normalize the concentration of the components in the samples to obtain a more quantitative measurement.
  • the data obtained on the compound(s), e.g., identity and intensity spectrum, can be used to classify the effects of the radiation exposure on one or more groups.
  • the identified and affected compound(s) or groups can be compared to one or more known profiles, e.g., a known standard. These profiles can be population based profiles that the subject's immediate profile can be compared against.
  • the population can be the entire subject population (e.g., all humans) or sub-populations based on age, gender, ethnicity, geographical region, other, or combinations thereof.
  • the profile can also be a personalized profile based on one or more past analyses of the same subject.
  • the effect identified from the molecular profile and classification of the identified compound(s) in the sample can be any radiation exposure related condition, cancer or deficiency that can be determined by identifying or monitoring compounds or components using the methods of the present disclosure.
  • the ionizing radiation can have multiple effects on biological material, e.g., target tissue or cells.
  • the irradiating radiation can cause direct ionization of biological tissues.
  • DNA or other cellular components including proteins and lipids on cellular membranes can be directly ionized.
  • Irradiating radiation can also cause indirect effects. Indirect effects can include those mediated through radiolysis of cellular water which result in the formation of reactive oxygen species.
  • Reactive oxygen species include radicals which can cause damage to nucleic acid and other cellular components through oxidation. In some instances, a majority of the damage, e.g., approximately 70 percent, in cells from gamma radiation can be caused by the indirect effects of radiation.
  • the effect of the radiation can include ionization of DNA, proteins or lipids, generation of oxidative radicals, increase of oxygenated metabolites, decrease of non-oxygenated metabolites, activation of biological pathways, and the discovery of a new biomarker.
  • the effects of radiation, or the symptoms of radiation sensitivity, in subjects can include acute adverse effects and/or late adverse effect.
  • Acute effects of radiation sensitivity generally arise during the treatment or at the end of the treatment and are most often transient and will heal.
  • the acute adverse effects are mainly seen in tissues with a rapid cell turnover and are due to cell death, e.g., desquamation and ulceration of the skin.
  • Other acute effects such as erythema and edema, can be caused by inflammation responses and increased vascularization.
  • the acute adverse effects in skin can be classified according to the Radiation Therapy Oncology Group, acute radiation morbidity scoring criteria (RTOG-scale) wherein RTOG 0 is no change over baseline, RTOG 1 is faint or dull erythema, dry desquamation, RTOG 2 is bright erythema, patchy moist desquamation, moderate edema, RTOG 3 is confluent moist desquamation, pitting edema and RTOG 4 is ulceration, hemorrhage, necrosis.
  • Late adverse effects can arise months to years after the completion of the treatment or radiation exposure. Late effects are generally more persistent than acute effects and will not necessarily heal. These effects are mainly seen in tissues with low cellular turnover.
  • telangiectasia In skin, the main late effects are telangiectasia, atrophy, and necrosis where the severity can be scored on a scale from 0-5. Zero is no effect above base line and 5 is death directly associated with irradiation. Another important late effect seen in breast cancer patients is radiation-induced fibrosis.
  • Statistical approaches can be used to analyze the molecular profile and identify specific molecular alterations or fingerprints of molecular patterns indicative of radiation exposure.
  • the statistical approaches can include univariate analysis, multivariate analysis, principal component analysis (PCA), linear discriminant analysis (LDA), maximum margin criteria (MMC), library-based analysis, soft independent modeling of class analogy (SIMCA), factor analysis (FA), recursive partitioning (decision trees), random forests, independent component analysis (ICA), partial least squares discriminant analysis (PLS-DA), orthogonal (partial least squares) projections to latent structures (OPLS), PLS discriminant analysis (OPLS-DA), support vector machines (SVM), (artificial) neural networks, multilayer perceptron, radial basis function (RBF) networks, Bayesian analysis, cluster analysis, a kernelized method, and subspace discriminant analysis.
  • the one or more correlations can be established by multivariate analysis.
  • a list of analysis techniques are given in the following table:
  • SVM Support Vector Machines
  • PCA is mathematically defined as an orthogonal linear transformation that transforms the data to a new coordinate system such that the greatest variance by any projection of the data comes to lie on the first coordinate (called the first principal component), the second greatest variance on the second coordinate, and so on.
  • PCA can be used for dimensionality reduction in a data set by retaining those characteristics of the data set that contribute most to its variance, by keeping lower-order principal components and ignoring higher-order ones. Such low-order components often contain the "most important" aspects of the data.
  • the common compound peaks for any given sample can be segregated into distinguishing clusters using principle component analysis (PCA).
  • analyzing the molecular profile and identifying specific molecular alterations or fingerprints of molecular patterns indicative of radiation exposure can include principal component analysis (PCA).
  • PCA principal component analysis
  • a PCA model can be calculated by finding eigenvectors and eigenvalues.
  • the one or more components of the PCA model can correspond to one or more eigenvectors having the highest eigenvalues.
  • the PCA can be performed using a non-linear iterative partial least squares (NIPALS) algorithm or singular value decomposition.
  • the PCA model space can define a PCA space.
  • the PCA can comprise probabilistic PCA, incremental PCA, non-negative PCA and/or kernel PCA.
  • LDA expresses one dependent variable as a linear combination of other features or measurements.
  • LDA has continuous independent variables and a categorical dependent variable (i.e. the class label).
  • Both PCA and LDA look for linear combinations of variables to best explain the data.
  • LDA explicitly attempts to model the difference between the classes of data. Discriminant analysis is not an interdependence technique: a distinction between independent variables and dependent variables (also called criterion variables) must be made.
  • analyzing the molecular profile and identifying specific molecular alterations or fingerprints of molecular patterns indicative of radiation exposure can include linear discriminant analysis (LDA).
  • Analyzing spectra can include performing linear discriminant analysis (LDA) after performing principal component analysis (PCA).
  • the LDA or PCA-LDA model can define an LDA or PCA-LDA space.
  • the LDA can include incremental LDA.
  • Analyzing spectra can also include performing a maximum margin criteria (MMC) process after performing principal component analysis (PCA).
  • MMC maximum margin criteria
  • the MMC or PCA-MMC model can define an MMC or PCA-MMC space.
  • oxylipins can be identified as a biomarker for a particular radiation exposure in a particular subject or subjects.
  • the oxylipins can be monitored for and used to determine the radio sensitivity of the subject(s).
  • Some of the most significant molecular alterations following radiation exposure involve changes in molecular species, such as metabolites and lipids.
  • Oxylipins-mediated inflammation can signal a subject's response to radiation. Macrophage activation can lead to a persistent inflammatory response.
  • Oxylipins just like inflammatory cytokines, can be rapidly activated after tissue irradiation as part of the immune response to stress factors. These compounds can eventually disrupt cellular homeostasis resulting in detrimental health effects.
  • baseline levels of oxylipins can serve as a companion diagnostic tool for radiation therapy.
  • Oxylipin levels can be used to differentiate cancer patients based on the response to radiotherapy treatment.
  • Radiosensitive subjects can be identified and those subjects who cannot tolerate additional inflammatory responses induced by radiotherapy can be provided an alternate radiotherapy, a treatment to the current radiotherapy or both.
  • Oxylipins levels can affect and be an indicator of intrinsic cellular
  • Oxylipins can also be indicative of the incidence and type of radiation as well as the radiation-induced tissue complications and diseases.
  • the balance between omega-6 pro-inflammatory (e.g., omega-6 oxygenated metabolites of arachidonic acid) and omega-3 anti- inflammatory lipid mediators (e.g., metabolites of omega-3 polyunsaturated fatty acids) can play a role in the different phases of the response to radiation. The balance may result in the occurrence of a pro-inflammatory phase followed by a pro-resolution phase to restore cellular homeostasis.
  • the ratio of omega-6 to omega-3 lipids for a subject can be known or can be initially screened before exposure. The ratio can then be tested and monitored after one or more exposures.
  • the ratio of omega-6 to omega-3 lipids can be 0.1: 1, 0.2: 1, 0.3: 1, 0.4: 1, 0.5: 1, 0.6: 1, 0.7: 1, 0.8: 1, 0.9: 1, 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, 12: 1, 13:1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1 or about 20: 1.
  • These values can also be used to define a range, such as about 0.5 to about 15.
  • the sensitivity of the method and apparatus of the present disclosure can determine differences in the ratio from one sample or test to another by at least 0.01, or in some embodiments by at least 0.01, e.g. an initial value of 1.7: 1 changed to 1.8: 1 can be determined.
  • oxylipins that can be used as an indicator
  • precursor fatty acids for oxylipins such as omega-6 and omega-3 fatty acids.
  • omega-6 and omega-3 fatty acids can be used as a proxy of inflammation status.
  • an excess of omega-6 fatty acids over omega-3 fatty acids e.g., ratio 10: 1-20: 1 can predispose a subject to adverse effects after exposure to radiation.
  • a more balanced omega-6/omega-3 ratio e.g., 2: 1-5: 1 can protect a subject from the adverse effects of radiation, including systemic inflammation.
  • Other biomarkers or class or biomarkers include sphingolipids such as ceramides and sphingo sine- 1 -phosphate and steroid lipids.
  • the effects of the radiation exposure on the subject or sample can be quantified.
  • the degree of change in the ratio of omega-6 to omega-3 lipids can be different for each subject or subject(s) and can be dependent on the magnitude of the radiation exposure.
  • a change in the ratio of 10% after one or more exposures or treatments of a known radiation amount for one subject can indicate a negative effect.
  • a different threshold change in the ratio can be required to indicate a negative effect.
  • the change in the ratio can be about 2%, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or about 200% after one or more exposures or treatments with a known radiation amount to indicate a negative effect.
  • a known radiation amount to indicate a negative effect.
  • These values can be used to define a range, such as about 10 to about 20%.
  • a maximum amount of radiation can be extrapolated.
  • the present disclosure relates to a method of determining the maximum radiation exposure of a subject. An unbalanced inflammatory response, or negative effect, resulting as a consequence to radiation exposure can contribute to both cancer and non-cancer related diseases.
  • the biological pathways associated with oxylipins can be identified from the molecular profile as one of the different biological pathways that can be change, controlled or adjusted in relation to a particular radiation exposure in a particular subject or subjects.
  • Oxylipins are produced via enzymatic or nonenzymatic oxygenation of both omega-6 and omega-3 PUFAs.
  • the three major enzymatic pathways involved in their generation include cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP).
  • COX cyclooxygenase
  • LOX lipoxygenase
  • CYP cytochrome P450
  • Ionizing radiation can activate the COX and LOX pathways.
  • the methods and apparatus of the present disclosure can be used to control the metabolic pathways associated with radiation exposure. For example, acute exposure to gamma radiation can induce a specific
  • mobilization of bioactive oxylipins which can affect cellular homeostasis, inflammation, platelet aggregation, and vascularization.
  • the control or treatment of the mobilized oxylipins can reduce or eliminated the effects of radiation exposure.
  • the integration of metabolic profiling information can provide a detailed molecular profile or biosignature that can be used as an indicator of radiation exposure and, potentially, as a predictor of radio sensitivity.
  • the metabolic profiling related to the molecular alteration(s) that can be identified can include information on various molecular components including plasmalogens and oxylipins.
  • the output of the methods and apparatus of the present disclosure can be a simplified classification based on the data obtained on the compound(s) or classes of compounds such as their correspondence to a deficiency or secondary cancer.
  • the effect identified can include an indication of a metabolite imbalance, e.g., omega-6 versus omega-3 lipids.
  • the effect identified can include an indication of a biological pathway or mechanism change, e.g., activate of the COX or LOX pathway.
  • a biological pathway or mechanism change e.g., activate of the COX or LOX pathway.
  • the subject Based on the molecular profile, including the biomarkers identified, the subject can be classified or segregated into a subtype for treatment with personalized radiation doses or treatments that are suited to the subtype.
  • the method and apparatus of the present disclosure can be configured to monitor a panel of molecular target(s) and differentiate subjects based on the subject's response to radiotherapy treatment. For patients that show a moderate to severe proinflammatory response via their molecular profile, the radiotherapy can be modified or stopped. For patients that tolerate the radiotherapy without significant changes, the radiotherapy can be modified to be more effective and continued.
  • the methods and apparatus of the present disclosure can also be used to estimate the risk of disease induced by medical, occupational, or accidental exposure to radiation. Rapid and efficient biological dosimetry measurements of the absorbed dose delivered by ionizing radiation can be made.
  • the method and apparatus of the present disclosure can assist in determining or predicting the effects of radiation exposure before the appearance of either acute or late adverse effects. Changes in one or more molecular profiles of the subject at the initial instances of radiation exposure can be identified and quantitated. Based on the nature and extent of the changes observed, the radiation exposure can be protected against, regulated, or treated.
  • the methods and apparatus of the present disclosure can be used as a research tool to discover and design a model to generate the correlation.
  • the identification of subjects, e.g., cancer patients, who might develop severe adverse reactions or secondary cancers in response to radiation exposure or radiotherapy is hindered by the complexity of individual variation in sensitivity or effect to radiation.
  • the risk that radiation therapy can induce secondary cancers in the surrounding healthy tissue exposed during the therapy can be addressed.
  • the method and apparatus of the present disclosure can reduce the risk of induced secondary cancers by about 2%, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100%. These values can be used to define a range, such as 20 to about 60%.
  • the method and apparatus of the present disclosure can be used to prepare personalized treatments or nutritional supplements based on the information obtained from the molecular profile.
  • the personalized treatments or nutritional supplements can be prepared in a shorter time that methodology of the prior art.
  • the method can determine the components etc. and/or prepare a personalized treatment or nutritional supplements within, or less than, about 10 seconds, 20, 30, 40, 50 or 60 seconds, 2 minutes, 3, 4, 5, 10, 20, 30, 40, 50 or 60 minutes, or 1.5 hours, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 24 hours. These values can also be used to define a range, such as between about 10 minutes and about 60 minutes. In one embodiment, the steps of the present disclosure can be performed in less than about 5 minutes.
  • the present disclosure can determine components and associated conditions in a sample and/or prepare personalized treatments or nutritional supplements without sending a sample to a laboratory for analysis.
  • the methodology can be used as a point of care test, e.g., doctor's office, mobile medical unit, etc.
  • the present disclosure can be used to provide results to exposed subjects in real-time, such that future exposure can be managed, limited or extended, or that treatments or supplements can be prepared and administered.
  • the present disclosure can determine components and associated conditions in a sample and/or prepare personalized treatments without extraction, hydrolysis, filtration, derivatization, chromatographic separation (e.g., GC-FID) or combinations thereof. Previous methodologies generally involve one or more of these steps and can take hours to complete, e.g., at least about 2 hours.
  • the method of the present disclosure can reduce the analysis time by about 10%, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 500, or about 1000%. These values can also be used to define a range, such as between about 20% and about 50%.
  • the method of the present disclosure can also include determining a treatment or remedy, such as providing a treatment to address one or more of the effects of radiation exposure.
  • the identification and quantification of the various indicating molecular components can be used to prepare the treatment or nutritional supplement that can, for example, modulate or correct one or more of the compounds or classes of compounds that are affected.
  • the lipid compositions and/or the oxylipin pathways can be controlled with dietary interventions (e.g., omega-3 supplementation) to alleviate or offset the change in omega-6 to omega-3 lipid ratio linked to either radiation therapy or other radiation exposure.
  • the method and apparatus of the present disclosure can serve as a point of care companion diagnostic and prognostic tool for radiation therapy.
  • the ability to control metabolic pathways with pharmacological or dietary interventions, e.g., omega-3 supplementation, can alleviate and can offset the side effects linked to radiation therapy.
  • the treatment of a subject with activated COX and LOX pathways can include administering a non-steroidal anti- inflammatory drug to reduce ionizing radiation-induced expression of pro-inflammatory cytokines (e.g., TNF-a, TGF- ⁇ , IL-6 and IL-1 ⁇ / ⁇ ).
  • pro-inflammatory cytokines e.g., TNF-a, TGF- ⁇ , IL-6 and IL-1 ⁇ / ⁇ .
  • the specific non-steroidal anti- inflammatory drug administered and the amount administered can be determined by the nature and extent of the effect the radiation exposure on the subject.
  • the doses of radiation can be lowered and/or the length of treatment to radiation can be adjusted according to the individual sensitivity to radiation or
  • lipid composition alterations can occur, such as cellular, in the blood, or in the skin. These alterations can be identified as a biomarker for a particular radiation exposure in a particular subject or subjects.
  • the lipid composition can be monitored for and used to determine the radio sensitivity of the subject(s).
  • the methods and apparatus of the present disclosure can be used to analyze lipid profiles in biological samples in real-time, e.g., seconds and minutes. An large group of subjects can be screened for the effects of radiation, such as via an accidental exposure, in a short time.
  • the method and apparatus of the present disclosure can be used to respond to radiological incidents where the need for a quick and reliable way to identify exposed individuals in a relatively short time, e.g., hours or days, following a large scale radiological incident or exposure to radiation as a consequence of air or space travel.
  • Subtle molecular changes caused by the radiation exposure can be detected before the occurrence of cellular and organ damage.
  • the molecular changes can include changes to signaling pathways triggered by ionizing radiation.
  • the method and apparatus of the present disclosure can be used to personalize treatment by titrating the therapeutic doses of radiation based on individual' s sensitivity or response to radiation. It can also allow for screening and monitoring the level of occupational or accidental radiation exposure in a real-time, inexpensive, point of care fashion.
  • the method and apparatus of the present disclosure can reduce the risk of systemic inflammation or secondary cancers from radiotherapy or other exposure including identifying and limiting the exposure of a subject such that the amount of radiation that does not exceed the maximum radiation exposure for the subject. It can also improve the delivery of radiotherapy by treating the subject with a second therapy that reduces at least one effect of the radiation, such as providing omega-3 supplementation or non-steroidal ant i- inflammatory therapy.
  • the present disclosure relates to a method of providing a personalized treatment or nutritional supplement to a subject including receiving molecular profile data from an analysis of a sample provided by the subject, obtaining the components of the treatment or supplement, e.g., an omega-3 supplement, and preparing the customized formulation or product, wherein these steps can be performed in a relatively short period of time, such as less than about 30 minutes.
  • the personalized treatment or nutritional supplement can be provided to a subject by analysis of one or more of the subjects' samples, determining an appropriate treatment or supplement, preparing, formulating and/or supplying the treatment or supplement to the subject.
  • the subject's or sample data received, considered or evaluated can be the identification of one or more individual radiation exposure related components or compounds, the amount of one or more individual radiation exposure related component or compounds, including quantitative and semi-quantitative information, the classification of the radiation exposure related components or compounds identified and/or quantified which can be based on additional calculations of these data (e.g., groups or ratios).
  • the radiation exposure data can also be received by generating sample ions from the subject's sample using a surface desorption ionization source, receiving the ions into a mass spectrometer, and identifying radiation exposure related compounds in the sample as provided herein.
  • the present disclosure can further include a chromatography separation system.
  • the chromatographic separation system can be a liquid, gas or supercritical fluid chromatographic system.
  • the chromatographic separation system can be coupled with the desorption ionization source, in particular an atmospheric pressure ionization sources (e.g., ESI, atmospheric pressure chemical ionization, atmospheric pressure photoionization) to provide an additional separation dimension and enhanced selectivity to identify and monitor additional components and compounds.
  • Figures 1A-1D illustrate an embodiment of a method according to the present technology. In the method of Figures 1A-1D, the effects of radiation on a subject can be determined and the used to generate a personal treatment for a patient. The personal treatment can be monitored and refined to provide additional personal tailoring of the treatment.
  • the method can include: acquiring a sample from a subject exposed to radiation, testing the sample to generate a molecular profile, comparing the molecular profile to a standard, and identifying at least one effect of the radiation related to the sample.
  • the at least one effect of radiation related to the sample can then be utilized to generate a personal treatment or to tailor a treatment to a specific patient.
  • this method can be repeated to monitor the progress and the effects of the personal treatment to further fine tune or tailor the treatment.
  • Figure 1 A shows a subject preparing for radiotherapy.
  • Figure IB shows the level of the subject's radio sensitivity to the radiotherapy determined using a surface desorption ionization mass spectrometry method.
  • Figure 1C shows the subject treated with a personalized dose of radiation.
  • Figure ID shows the subject's response to the radiotherapy can be monitored, and further personalization can be provided.
  • Figure 2 shows another exemplary embodiment of the present technology.
  • the patient/subject is treated (or further treated) with a pharmacological or dietary substance to address the patient's exposure to a radiation event.
  • the pharmacological or dietary substance is supplied to reduce at least one adverse effect of radiation.
  • the patient may be supplied with a treatment or a secondary treatment including omega-3 supplementation and/or non-steroidal anti- inflammatory compounds to alleviate or decrease negative side effects of radiation exposure.
  • Figure 2A shows a subject exposed to radiation selected for monitoring.
  • the radiation source can be occupational, medical exposure, environmental, radon, earth gamma radiation, cosmic rays, accidental, etc.
  • Figure 2B shows the level and effect of the radiation exposure determined using a surface desorption ionization mass spectrometry method.
  • Figure 2C shows a personalized treatment, such as a
  • the maximum radiation exposure for a subject receiving external beam radiation therapy is determined using a portable, small system for real-time analysis of the subject's biological sample.
  • the subject is tested before and after treatments or exposure to fractions of a standard 40 Sv radiation dose. Each treatment delivers a 2 Sv radiation dose.
  • an initial plasma sample is taken from the subject. After each treatment, additional plasma samples are taken. The molecule profile of the plasma samples are analyzed to determine a maximum radiation exposure.
  • the acquisition time is about 5-10 seconds using following conditions: Ionization DART® +ve and -ve; Cone voltage 20.0 V; Source temp. 120.0 °C; direct analysis in real time source temp. 50 to 450 °C.
  • the portable, small design allows the system to located at or near the subject undergoing radiotherapy.
  • the analyzed samples provide detailed assessment of the plasma oxylipins which act as biomarkers of radiation exposure.
  • Each of the samples show a mixture of omega-6 and omega-3 lipids.
  • the initial ratio of omega-6 to omega-3 lipids from the sample prior to treatment is about 3: 1.
  • a low ratio of about 3: 1 can reduce or suppress inflammation associate with radiotherapy.
  • a higher ratio can induce or exaggerate inflammation.
  • a nominal ratio for the subject not to exceed is set at about 10: 1 based known effects of higher ratios.
  • the ratio is monitored after each treatment.
  • Successive samples show a change in the ratio of omega-6 to omega-3 lipids as one of the effects of the radiation on the subject. After 1 treatment, the ratio is about 4: 1. After 2 treatments, the ratio is about 6: 1. These values are plotted to determine a maximum radiation exposure.
  • the maximum radiation exposure is determined by extrapolation of the initial ratios and the cumulative radiation exposure. After 4 treatment, the ratio is about 10: 1. After the 4 th treatment, the subject is treated with an omega-3 supplement. Thereafter, the ratio of omega-6 to omega-3 lipids in successive samples is reduced and radiotherapy is continued.
  • Incidental radiation exposure near an nuclear facility is greater than normal.
  • the population located near the facility is monitored for radiation exposure and tested using a portable surface desorption ionization mass spectrometry apparatus to determine and quantify molecular markers of the radiation exposure.
  • the amount and time of the radiation exposure is measured using standard and known devices.
  • Adverse effects including inflammation, skin redness, cytokines, DNA damage, cancer, secondary cancers, etc. from the radiation are also monitored.
  • a sample of each person's blood is tested for the molecular markers using the instrument described in Example 1.
  • the molecular profile of each sample is determined by identifying and quantifying various small molecules, peptides, lipids, oligonucleotides, glycans, drugs, pesticides and other molecules.
  • An analysis or correlation is performed of the radiation exposure type, amount and time, and each molecular profile to identify markers associated with the radiation exposure.
  • the identified markers include those molecules and classes of molecules that demonstrate a proportional response to the exposed radiation.
  • the analysis includes the use of multivariate statistical approaches to identify specific molecular alterations or fingerprints of molecular patterns indicative of radiation exposure.
  • the molecular features are correlated with outcomes of the radiation exposure to identify which are markers for which outcomes.
  • the identification of such markers allows for objective molecular measurement that can be easily and inexpensively measured in real time such that large populations of individuals can be screened in large-scale epidemiology and human biomonitoring studies.

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Abstract

La présente invention concerne des procédés et un appareil de détermination des effets d'une exposition au rayonnement sur un sujet. En particulier, l'invention concerne l'utilisation de procédés et d'appareils de spectrométrie de masse à ionisation par désorption de surface pour déterminer et quantifier les effets de l'exposition au rayonnement. Le procédé et l'appareil peuvent déterminer l'exposition maximale au rayonnement d'un sujet, surveiller en temps réel l'exposition au rayonnement et la radiosensibilité d'un sujet, permettre la préparation d'un traitement personnalisé contre l'exposition au rayonnement, et réduire l'incidence d'un cancer secondaire.
PCT/US2017/040950 2016-07-06 2017-07-06 Surveillance de l'exposition au rayonnement et de la radiosensibilité par spectrométrie de masse à ionisation ambiante Ceased WO2018009700A1 (fr)

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