WO2010115442A1 - Masse à mastiquer pour l'obtention d'acides nucléiques permettant de déterminer des variantes de séquences - Google Patents

Masse à mastiquer pour l'obtention d'acides nucléiques permettant de déterminer des variantes de séquences Download PDF

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Publication number
WO2010115442A1
WO2010115442A1 PCT/EP2009/002669 EP2009002669W WO2010115442A1 WO 2010115442 A1 WO2010115442 A1 WO 2010115442A1 EP 2009002669 W EP2009002669 W EP 2009002669W WO 2010115442 A1 WO2010115442 A1 WO 2010115442A1
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WIPO (PCT)
Prior art keywords
compact
chewing
nucleic acids
nucleic acid
chewing gum
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PCT/EP2009/002669
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German (de)
English (en)
Inventor
Lee S. Griffith
Hanns-Christian Tillmann
Wolfgang Greb
Original Assignee
Awenydd Diagnostic Gmbh
Eucro Gmbh & Co. Kg
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Publication date
Application filed by Awenydd Diagnostic Gmbh, Eucro Gmbh & Co. Kg filed Critical Awenydd Diagnostic Gmbh
Priority to PCT/EP2009/002669 priority Critical patent/WO2010115442A1/fr
Publication of WO2010115442A1 publication Critical patent/WO2010115442A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1003—Extracting or separating nucleic acids from biological samples, e.g. pure separation or isolation methods; Conditions, buffers or apparatuses therefor
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
    • A23G4/064—Chewing gum characterised by the composition containing organic or inorganic compounds containing inorganic compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1003—Extracting or separating nucleic acids from biological samples, e.g. pure separation or isolation methods; Conditions, buffers or apparatuses therefor
    • C12N15/1006—Extracting or separating nucleic acids from biological samples, e.g. pure separation or isolation methods; Conditions, buffers or apparatuses therefor by means of a solid support carrier, e.g. particles, polymers

Definitions

  • the invention relates to gums for use in diagnostic procedures under nucleic acid isolation, the use of chewing gums and corresponding methods and methods. This allows the recognition of gene polymorphisms and the selection of appropriate forms of therapy, drugs and / or dosages for humans, as well as the identification of individuals at risk of certain substances, methods for performing a genetic analysis as well as the use of gizzards for investigations of gene polymorphisms in the context of Screening procedures and for purely informative (eg empirical) purposes.
  • cytochrome P450 monoxygenases in the human body often participate in the metabolism of
  • Antidepressants selective serotonin reuptake inhibitors
  • potent metabolizers may be suitable for therapy with drugs that are activated only by metabolism (such as codeine that is converted to morphine, for pain therapy), or they can break down drugs too quickly, so that they do not have their full effect reachable.
  • Other cytochromes such as CYP 2C9 or CYP 2C19, may have similar sequence variants. The same applies to greater or lesser affinity of drugs, such as inhibitors or activators, for certain receptors, enzymes, regulatory proteins, and the like.
  • direct targets of modulating drugs such as certain enzymes or receptors, may also have sequence variants that sensitize or desensitize certain substances (such as drugs or substances from the environment).
  • genotyping is enabled, i. the determination of certain in one
  • the advantages of this method are obvious: there is no cumbersome sample collection, such as with cotton swabs, and the sample collection can be done in a manner that is comfortable for the individual concerned (without pain, gagging or the like).
  • the small traces of nucleic acids on the surface (for example in cells or cell components of the oral mucosa) of the compact chewing mass are sufficient for analysis and can be easily isolated.
  • the compact samples are easy to store and can be kept for a long time, for example by cooling or freezing, and even stored by the subject without cooling until they can be brought to analysis.
  • the invention therefore in one embodiment relates to a compact chewing mass for use in a method for obtaining nucleic acids from the oral cavity of a human body as part of a diagnostic procedure on a human body.
  • a preferred variant relates to such a compact chewing gum, wherein the diagnostic method for testing the human body for sequence variations of certain genes or DNA sections, in particular in connection with susceptibility to and / or the ability to be treated (in particular for the selection of suitable forms of therapy) of diseases or risks when exposed to certain substances. Also for other purposes, such as the determination of other physiological or pathophysiological characteristics, such as eye color, gene defects, paternity tests, genealogical examinations or the like, the corresponding diagnostic method is applicable, as well as for investigations of gene polymorphisms in the context of screening methods and for purely informative (eg empirical) purposes.
  • Paragraphs characterized in that it is an easily deformable compact mass on which it is also possible to chew for up to several hours, without the nucleic acids to be examined, which are bound directly or indirectly to it, being destroyed.
  • a further preferred embodiment of the invention relates to a compact chewing mass according to one of the preceding three Paragraphs, characterized in that it contains as base (gum base) natural resins, such as mastic or chicle, waxes and / or natural or synthetic rubbers, such as polyisobutylene.
  • base such as mastic or chicle, waxes and / or natural or synthetic rubbers, such as polyisobutylene.
  • substances as described below for Gum Base may be included.
  • Another preferred variant of the invention according to the above four paragraphs relates to a compact chewing gum for the determination of single nucleotide polymorphisms, in particular those which make it possible to decide whether a therapy (this term includes both in the context of the present disclosure a prophylactic as well as a therapeutic treatment) with a certain active substance or specific active ingredients or other therapeutic methods is promising and whether or which risk exists for the occurrence of adverse drug reactions.
  • Yet another preferred variant relates to a method for carrying out a genetic analysis in which first oral mucosal cells and / or cell fragments are collected with a chewing gum according to the invention (in presence or absence of the subject) the cells and / or cell fragments are separated from the chewing gum be subjected to DNA extraction and an individual gene expression analysis, for example an SNP analysis, is performed.
  • a further preferred embodiment of the invention relates to a kit comprising a chewing gum according to the invention and further reagents required for separating cells and / or cell fragments from chewing gum, nucleic acid (in particular DNA) extraction and / or for gene analysis, in particular described above and below.
  • Yet another preferred embodiment of the invention relates to a drug kit containing a drug
  • an anti-rheumatic drug for example, an anti-rheumatic drug, a graft rejection-preventing agent
  • Antibiotic an antiviral agent, a painkiller, an anti-inflammatory agent, an antihypertensive agent, an endocrine disruptor, a lipid lowering agent, a
  • Cholesterol-lowering agent, a chemotherapeutic agent for the treatment of proliferative diseases or the like) and a compact chewing gland according to the invention for collecting oral mucosal cells and / or cell fragments, in particular for use and for methods as described above and below.
  • the chewing gum can then be used to obtain appropriate samples for gene analysis (e.g., by sending it to a laboratory or donating to a doctor or the like), for example, to optimize dosage for a subject.
  • a compact chewing mass in particular according to one of the preceding paragraphs, is characterized in that it contains at least one abrasive. This allows a particularly good recovery of cells and cell fragments of
  • Oral mucosa possibly due to the abrasive and possibly also adsorptive properties of such abrasives, without these explanations being exhaustive.
  • such an abrasive in a weight fraction of 0.01 to 20%, in particular from 0.1 to 10 wt .-%, for example from 0.1 to 5%, in particular from 0.2 to 3 wt .-%, based on the gum, includes.
  • the abrasive is for example selected from sparingly soluble calcium salts, aluminum oxides, silica, complex silicates, powdered plastics, bioactive glass pastes and titanium dioxide.
  • An important aspect of the invention also relates to the use of a chewing gum, in particular as described above and below, for obtaining nucleic acids, oral mucosal cells and / or oral mucous membrane fragments from the oral cavity of humans.
  • a chewing gum in particular as described above and below, for obtaining nucleic acids, oral mucosal cells and / or oral mucous membrane fragments from the oral cavity of humans.
  • Particularly important in the context of the present invention is the use of further including the determination of sequence variants of certain genes or DNA sections, which are related to the susceptibility to and / or the treatability of diseases and / or risks associated with exposure to certain substances.
  • a chewing gum sample obtained for example from a test person
  • a customary lysis buffer extraction buffer
  • the DNA is isolated by customary methods, then amplified by conventional methods and finally, if desired, sequenced by customary methods, if the amplification does not already provide adequate detection of corresponding DNA segments with sequence variations m.
  • the invention also relates to a method or method for isolating and determining oral mucosal cells or fragments thereof, in particular for obtaining nucleic acids (especially DNA) bound to a compact chewing mass, including the lysis (extraction) of above all attached thereto (and in part also enclosed therein) cells or cell debris and the subsequent amplification of the nucleic acid or, in particular, specific sections thereof, such as genes, with specific primers and transcriptases which allow the selective recognition of sequence variants of particular genes or nucleic acid segments present in the Related to the susceptibility to and / or the treatability of diseases and / or risks associated with exposure to certain substances, by binding to and amplification of appropriate sections or nucleic acids. The amplification makes it possible to determine which sequences are present (possible amplification means detection of the corresponding sequence).
  • the invention relates, in particular, to such a method or such a method, further comprising the partial or complete purification of the nucleic acid after lysis and before the amplification.
  • Yet another aspect of the invention relates to a method for carrying out a genetic analysis, in particular for testing the human body for sequence variations of specific genes or DNA segments, which are associated with susceptibility to and / or the ability to treat diseases and / or or risks in the Exposure to certain substances is used, including the extraction of appropriate nucleic acids (for example from oral mucosal cells and / or fragments thereof) from the oral cavity, in particular from oral mucosa cells and / or fragments thereof, by means of a compact chewing gauze and the subsequent extraction and amplification of the nucleic acid or in particular, specific sections thereof, such as genes, with specific primers and transcriptases which allow, in particular, an individual genome analysis, preferably the selective recognition of sequence variants of particular genes or nucleic acid sections, for the determination of physiological or pathophysiological characteristics, such as eye color, gene defects, paternity tests , genealogical studies, or the like, or in particular the selective recognition of those genes or nucleic acid segments associated with susceptibility to and / or the
  • Sponge structure is therefore not required.
  • the attachment is more likely due to a kind of "stickiness" or
  • a chewing gum according to the invention includes common materials for the preparation of chews, such as chewing gums, which basically consist of an insoluble gum base and more or less soluble components.
  • a base it may contain the usual gum bases for chewing gums, if appropriate also resins, such as acacia, or waxes, such as carnauba wax.
  • Gum base a water-insoluble mass
  • elastomers waxes, fats, oils, fillers, texturizing agents, and may for example consist of conventional ingredients such as petroleum, lanolin, glycerm, polyethylene, Polivinylacetat, petroleum wax, stearic acid, or in particular natural resins, such as Mastic or natural gums or rubbers such as chicle, waxes and / or synthetic rubbers or gums such as ethylene-propylene rubber, polyisobutylene, isobutylene-isoprene copolymers, styrene-butadiene copolymers, polyisoprene, other polyolefins or thermoplastic elastomers (TPE) or the like, wherein one or more of said components may be present.
  • TPE thermoplastic elastomers
  • the gum base accounts for 5 to 95% of the weight of the chewing gum composition, typically, for example, 10 to 50%, often, for example, 15 to 35% of the
  • additives such as flavorings, e.g. those which produce a medicinal taste, e.g. Menthol, thyme, cinnamon oil, linalool, limonene or the like may also be included.
  • the proportions by weight thereof may be, for example, each in the range of 0.001 to 5 wt .-% for the individual additives, in total, e.g. at 0.005 to 10 wt .-%, are, for example, a total of 0.01 to 3 wt .-%.
  • one or more abrasives are included in the chewing gums of the invention.
  • An abrasive (which facilitates the abrasion and adhesion of cells of the oral mucosa and fragments of such cells and free nucleic acids by its abrasive and sometimes also adsorptive action) is selected in particular from sparingly soluble calcium salts, silicon dioxide, complex silicates, aluminum oxides, powdered plastics, bioactive glass pastes, Titanium dioxide, talc and the like, or a mixture of two or more such abrasives.
  • One or more abrasives are advantageous in a total weight fraction of 0.01 to 20%, in particular from 0.1 to 5 wt .-%, based on the total chewing mass includes.
  • Calcium phosphates such as dicalcium orthophosphate in the form of its dihydrate or anhydrous, tricalcium phosphate, calcium pyrophosphate, insoluble alkali metal metaphosphates, calcium phosphate, hydroxyapatite or calcium carbonate (chalk).
  • Silica which is present in silica gels in the form of more or less highly condensed polysilicic acids. Particular preference is given to precipitated colloidal silica gel, amorphous silica gel or pyrogenic colloidal silica gel.
  • the precipitation of soda waterglass with acids, in particular hydrogen chloride in an aqueous solution is suitable, wherein the gel formation preferably takes place at pH 5.3 to 6 and then the resulting silica gel is washed until, for example, a sodium chloride content of, for example, less than 1, 5 g / l is achieved.
  • particles are obtained down to a size of about 10 nm, which, however, can agglomerate.
  • complex silicates there may be mentioned, for example, such as zirconium silicate or aluminosilicates such as zeolite type A (for example, as described in EP 0 002 690 and 0 003 023).
  • Aluminum oxides may in particular be alumina trihydrates, with a preferred particle size distribution between about 1 and about 20, preferably about 10 microns.
  • powdered plastics for example, polymers, such as polyacrylates or polymethacrylates, for example, as their sodium salts or esters, with a preferred particle size distribution between 0.5 and 5 microns may be mentioned.
  • Titanium dioxide may also be added as a whitening agent due to its action.
  • bioactive glass pastes are usable, for example glass based on silicon dioxide, sodium oxide, calcium oxide and diphosphorus pentoxide, eg S53P4 (Abmin Technologies Ltd., Turku, Finland), which consists of 53% SiO 2 , 23% Na 2 O, 20%. CaO and 4% P 2 O 5 exists.
  • S53P4 Abmin Technologies Ltd., Turku, Finland
  • chewing gums according to the invention may also include sweetening agents such as sugars or sugar substitutes such as sugar alcohols (eg sorbitol, xylitol and / or mannitol) or other sweetening agents such as aspartame, sucralose, acesulfamic acid salts, alitan, neolan, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin , Sterol, dihydrochalcones, thaumalin, monellin or the like.
  • sweetening agents such as sugars or sugar substitutes such as sugar alcohols (eg sorbitol, xylitol and / or mannitol) or other sweetening agents such as aspartame, sucralose, acesulfamic acid salts, alitan, neolan, saccharin and its salts, cyclamic acid and its salts, glycyrrhi
  • ком ⁇ онентs such as dyes, pigments, binders (such as cellulose or starch), film formers, such as shellac, salts, such as potassium chloride, buffers (eg based on 2- [N-morpholino] ethanesulfonic acid, bis [ 2-hydroxyethyl] iminotris [hydroxymethyl] methane, N- [acetamido] 2-iminodiacetic acid, N- [carbamoylmethyl] -2-aminoethanesulfonic acid, 3- [N-morpholino] -2-hydroxypropanesulfonic acid, piperazine-N, N ' bis [2-ethanesulfonic acid], citric acid, lactic acid, tartaric acid, fumaric acid or acetic acid, which (in the case of buffer substances present as base) with a Acid, for example HCl, or (in the case of buffer substances present as acid) with a base, eg
  • Nucleic acids such as glycerol
  • plasticizers such as glycerol
  • humectants such as glycerol
  • Antioxidants such as ascorbic acid (vitamin C), propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene
  • BHT Butylhydroquinone
  • dentifrices such as fluorides, eg sodium fluoride, sodium fluoromonophosphate or oleamine fluoride
  • the substantivity (attachment) increasing agents such as mucoadhesive polymers, such as partial or fully synthetic hydrogel, especially cellulose derivatives (eg, methyl, hydroxyethyl, hydroxypropyl , Carboxymethyl or sodium carboxymethylcellulose), high molecular weight variants of the polyacrylic acid (carbomer, carbopol or polycarbophil), hyaluronic acid, mussel adhesion protein or chitosan, furthermore gelatin, pectins, lectins, eg adhesins, or polyoxyethylene-polyoxypropylene copolymers (eg poloxamer) or non-polymeric compounds , in particular sucrose-octa-sulfate, in particular in the form
  • the sweeteners and additives may be included, for example, in total in a weight proportion of 0 to 20 wt .-%, for example, from 0.01 to 8% by weight.
  • the chewing gum contains an indicator which allows the display of the (for gene analysis) sufficient collection (material acquisition) of cells, Cell fragments and / or nucleic acids by means of the chewing gum allows.
  • This may, for example, be a suitable dye that turns over on the dissolution of a soluble component in the chewing gum, for example a pH indicator which reacts to a change in the pH or an oxygen-sensitive indicator which is oxidized in the oral cavity and thus changes its color, or an indicator that changes its color by an enzyme present in the mouth (such as amylase) or a dye that is dissolved out during chewing so that the chewing gum loses color, or a dye that activates or decolorizes by the moisture in the oral cavity or more suitable enzyme reaction or protein binding or nucleic acid binding or the like, or more such indicators and methods, or the like.
  • Corresponding indicator materials may be included, for example, in a proportion, based on the total mass of the chewing gum, of from 0.0001 to 10, such as, for example, from 0.
  • the invention thus makes it possible in a simple manner to determine, in particular, variations with respect to sequence sections with one or more nucleic acid bases, in particular individual bases in the DNA (so-called single nucleotide polymorphisms) of a human, and thus the test persons, such as humans, certain collectives with regard to therapy with drugs and / or to attribute sensitivity to substances, ie to select the therapy or the protective measures against potentially damaging substances as well as possible by means of appropriate sequence variations as biomarkers.
  • Such single nucleotide polymorphisms can be found, for example, at http://www.pharmgkb.org/index.jsp or at http://www.ncbi.nlm.nih.gov/projects/SNP/, which are preferred here for such polymorphisms Reference be included. For example, this allows to diagnose suitable patients for particular therapies or to identify patients for whom exposure to certain substances poses a higher risk than others. The determination of other physiological or pathophysiological characteristics, such as eye color, gene defects, the performance of paternity tests or genealogical examinations, or the like, can also be done. Furthermore, investigations of gene polymorphisms are possible in the context of screening methods and for purely informative (eg empirical) purposes.
  • a corresponding complete diagnostic procedure therefore preferably includes in the strictest sense the step of a deductive medical decision phase as a purely intellectual measure, the preceding steps of
  • Samples from different volunteers can therefore be examined appropriately (for example, statistically or with regard to subjects).
  • the processing of the chewing gum in the uses and methods of the invention can be such that a (for example, from a subject in a suitable container, such as a plastic bag, a
  • Tube, vials or the like) of a chewing gum according to the invention while avoiding contamination
  • methods can be used in which by means of interesting primers (for example, for certain interesting for sequence variations sections, as for certain diseases or treatment options relevant
  • SNPs gene amplifications (for example by means of polymerase
  • the lysis (also denoted as extraction, since it ultimately serves the extraction of nucleic acids, especially DNA) is preferably carried out by liquid homogenization (eg with Dounce or Potter Elvjehem homogenizers), ultrasound, freezing methods, mortar and pestle, shaking with particles such as glass beads or the like - corresponding methods, solutions, devices and the like are known and, for example, in the manual of Thermo Fisher Scientific Pierce (Thermo Scientific Pierce® Cell Lysis Technical Handbook, 2008), instructions from Quiagen (Hilden, Germany) or below or described in the examples.
  • the lysis / extraction can be carried out as described in the examples.
  • external lysis and purification using other purification systems such as the MagNa Pure® LC system from Roche Diagnostics GmbH, Mannheim, Germany (hereinafter Roche) is conceivable:
  • MGP magnetic particles
  • a short external lysis without proteinase K can be made as follows: 200 ⁇ l lysis buffer (Roche DNA isolation kit I) is added, and it is incubated for 5 min at RT.
  • PCR Polymerase Chain Reaction
  • the usual methods for sequencing include, for example, the methods according to 2.1 Maxam and Gilbert, the Danger Sox method, pyrosequencing, sequencing by hybridization, automated DNA sequencing methods, corresponding methods based on BIOCHIP methods (bioarrays, see, for example, DNA microarrays : A Molecular Cloning Manual (Paperback), David Bowtell (Editor), Joseph Sambrook (Editor), CoId Spring Harbor Laboratory Press, 1st Edition (2002)), or the like.
  • Example 1 Sample collection / chewing mass:
  • the chewing mass consists of a conventional chewing gum mass (chewable mass) as a matrix, to which are added materials which ensure a better binding of nucleic acids from the cells of the oral mucosa to the matrix during the chewing process.
  • a piece of gum (about 1.2 g) [here recipe a)] is chewed by the subject for 2 min.
  • Example 2 Isolation of the DNA from a chewing gum
  • 700 ⁇ l of the pre-lysate obtained are pipetted into a homogenizer for lysing and homogenized there.
  • AW1 buffer (guanidium-containing buffer, Qiagen) are pipetted into the column, and it is for 1 min. centrifuged at 8000 rpm. Then the column m is placed a new tube and the old discarded (or decanted).
  • AW2 buffer Wash Buffer; Qiagen
  • the column is placed in a 1.5 ml Eppendorf tube (polypropylene tube, Eppendorf, Hamburg, Germany) (the tube is discarded).
  • AE buffer protected buffer for DNA with TRIS and EDTA, Qiagen
  • aqua, dist. 150 ⁇ l AE buffer (protective buffer for DNA with TRIS and EDTA, Qiagen) (or aqua, dist.) are pipetted into the column. Then 1 min. incubated at RT and then 1 min. centrifuged at 8000 rpm.
  • DNA samples thus obtained are analyzed for CYP 2D6, CYP 2C9 and CYP 2C19 genes and their polymorphisms according to Taq real-time polymerase chain reaction (TaqMan Real-Time PCR)
  • test subject It should be checked whether the test subject is accessible for a pain therapy with codeine, because it has been shown that he was not found a sufficient analgesic effect.
  • the patient is not able to receive sufficient pain therapy with codeine, since the patient has a markedly slowed down degradation via CYP 2D6 and the active metabolite morphine is formed too slowly.

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Abstract

La présente invention concerne, d'une part une masse à mastiquer, compacte, destinée à un procédé de diagnostic par extraction d'acide nucléique, d'autre part l'utilisation de telles masses à mastiquer, et enfin des procédés et traitements correspondants. L'invention permet notamment, entre autres possibilités, la détection de polymorphismes génétiques et la sélection de médicaments et/ou de posologies adaptés aux humains, ainsi également que l'identification d'individus pour qui des produits spécifiques peuvent s'avérer dangereux.
PCT/EP2009/002669 2009-04-09 2009-04-09 Masse à mastiquer pour l'obtention d'acides nucléiques permettant de déterminer des variantes de séquences WO2010115442A1 (fr)

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Cited By (2)

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CN105189745A (zh) * 2013-03-14 2015-12-23 Wm.雷格利Jr.公司 可延展聚合物内的核酸的检测和定量方法
US20220098675A1 (en) * 2020-09-30 2022-03-31 Thomas K. Leggett, Llc Method of evaluating pre-cancerous or cancerous lesions for oral cancer

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US20030099740A1 (en) * 2000-04-26 2003-05-29 Roberto Colle Chewing gum containing encapsulated abrasive filler substance
US20040237674A1 (en) * 2003-05-30 2004-12-02 Yuchang Wu Fluid collection and application device and methods of use of same
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EP0056241A1 (fr) * 1981-01-12 1982-07-21 MetPath, Inc. Appareil pour le prélèvement de salive
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