WO2001085994A2 - Procede et moyens destines a identifier le virus du papillome humain (hpv) - Google Patents
Procede et moyens destines a identifier le virus du papillome humain (hpv) Download PDFInfo
- Publication number
- WO2001085994A2 WO2001085994A2 PCT/IB2001/000771 IB0100771W WO0185994A2 WO 2001085994 A2 WO2001085994 A2 WO 2001085994A2 IB 0100771 W IB0100771 W IB 0100771W WO 0185994 A2 WO0185994 A2 WO 0185994A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- identifying
- identifying means
- sequences
- primer
- genome
- Prior art date
Links
- 241000700605 Viruses Species 0.000 title claims abstract description 84
- 238000000034 method Methods 0.000 title claims abstract description 30
- 108020004414 DNA Proteins 0.000 claims abstract description 32
- 230000000295 complement effect Effects 0.000 claims abstract description 24
- 239000000463 material Substances 0.000 claims abstract description 17
- 238000009007 Diagnostic Kit Methods 0.000 claims abstract description 10
- 230000001413 cellular effect Effects 0.000 claims abstract description 8
- 239000003550 marker Substances 0.000 claims abstract description 8
- 239000002480 mineral oil Substances 0.000 claims abstract description 6
- 235000010446 mineral oil Nutrition 0.000 claims abstract description 6
- 108020005202 Viral DNA Proteins 0.000 claims abstract description 5
- 231100000590 oncogenic Toxicity 0.000 claims description 12
- 230000002246 oncogenic effect Effects 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 239000000872 buffer Substances 0.000 claims description 7
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 claims description 5
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 claims description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 5
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 208000022361 Human papillomavirus infectious disease Diseases 0.000 description 29
- 208000015181 infectious disease Diseases 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 6
- 230000003321 amplification Effects 0.000 description 6
- 238000003199 nucleic acid amplification method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 210000003679 cervix uteri Anatomy 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 239000012188 paraffin wax Substances 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000001574 biopsy Methods 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 210000004400 mucous membrane Anatomy 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 208000003322 Coinfection Diseases 0.000 description 2
- 230000004544 DNA amplification Effects 0.000 description 2
- 206010040844 Skin exfoliation Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000035618 desquamation Effects 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 210000001215 vagina Anatomy 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 241000701806 Human papillomavirus Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000009608 Papillomavirus Infections Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000002573 colposcopy Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- FXPVUWKFNGVHIZ-UHFFFAOYSA-L disodium;dodecyl sulfate Chemical compound [Na+].[Na+].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O FXPVUWKFNGVHIZ-UHFFFAOYSA-L 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 210000005002 female reproductive tract Anatomy 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 238000009595 pap smear Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
- C12Q1/701—Specific hybridization probes
- C12Q1/708—Specific hybridization probes for papilloma
Definitions
- the invention relates to a method and means for identifying the presence of HPV virus in specimens of cells collected from the anogenital region of a patient.
- the HPV virus or Human Papilloma Virus, plays an etiologic role in development of uterine cervix, cancer in women, which is the second most frequent type of tumour for women. It is further involved in tumoural lesions of low female genital tract and of penis, as well as of anal and perianal region.
- the HPV virus is sexually transmitted and it is a small virus without envelope, provided with a protein capsid having an icosahedral geometry with a diameter of about 45 nm, which contains inside a double chain DNA single circular molecule having a length of about 8000 bases.
- the various genotypes of HPV virus may be divided into three groups, from the oncogenic hazard point of view: a first group having a low oncogenic hazard, for example the genotypes 6, 11, 42, 43 and 44, for which the probability of causing a tumour is nearly null, even if it should not be completely excluded; a middle hazard group, for example the genotypes 31, 33, 35, 45, 51, 52, 56, for which there is a greater probability of causing a tumour and a high hazard group, for example the genotypes 16 and 18, for which the probability of causing a tumour is high.
- a first group having a low oncogenic hazard for example the genotypes 6, 11, 42, 43 and 44, for which the probability of causing a tumour is nearly null, even if it should not be completely excluded
- a middle hazard group for example the genotypes 31, 33, 35, 45, 51, 52, 56, for which there is a greater probability of causing a tumour
- the uterine cervix cancer is a pathology which may be easily treated if early identified, it is very important being able both to identify the presence of HPV virus in the uterine cervix epithelium, and to identify the virus genotype, or at least its group, even if there are no evident epithelium injuries .
- the techniques actually used for identifying the onset of an HPV virus infection in women are PAP test and colposcopy observation of uterine cervix epithelium with collection of biopsy specimens in possible suspicious regions of mucous membrane, ⁇ rethral swabs and seminal fluid collection, or biopsy in the anal region, are used for men.
- the HPV virus may be present even if visible lesions and atypisms in the mucous membrane are absent, even though it belongs to the high hazard genotype. In this case, the above-mentioned techniques for identifying the virus are completely ineffective.
- one of the main problems to be solved for searching viral DNA of HPV virus is that, while at infection beginning the virus is well represented in infected cells, at a rate, for example, of 2000-3000 virus copies every cell, when the infection proceeds the virus tends to integrate in the cellular DNA. Therefore, the original viral genome is substantially absent in the infected cells and only the genes integrated in DNA of cells may be detected, particularly if the infection is in an advanced stage. Determining the existence of an HPV infection is now based on identification of a sequence of nucleotides in the region Ll belonging to the late region L of the virus genome.
- a further object of the invention is to make available a test for identifying the presence of HPV virus in cells infected by said virus, in particular when the virus genome is integrated in DNA of cells.
- the present invention is based on identifying sequences of nucleotides of the HPV virus genome, said sequences allowing the virus to be identified in all significant phases of infection and further allowing low hazard virus typologies to be distinguished from middle and high hazard virus typologies.
- two sequences have been identified in the regions E6 and E7 belonging to the early region E of the virus genome, which keeps even when the virus is partially or totally integrated in a cell genome.
- a method for identifying the presence of viral DNA of HPV virus in cellular material collected from an individual comprising the following steps: - extracting DNA from said cellular material amplifying said DNA by means of polymerase, using identifying means for identifying sequences complementary to sequences of the genome of HPV virus, characterized in that said identifying means comprises identifying means suitable for identifying sequences complementary to sequences of said genome in the regions E of genome .
- identifying means are provided for identifying sequences complementary to sequences of the genome of HPV virus, characterized in that said identifying means comprises identifying means suitable for identifying sequences complementary to sequences of said genome in the regions E of genome .
- a diagnostic kit for amplifying DNA of HPV virus comprising identifying means suitable for identifying sequences complementary to sequences of the genome of said virus in the regions Ll, E6 and E7 of genome, amplifying means for amplifying DNA of said virus, marker means, mineral oil.
- DNA preparation from tissue fixed and embedded in paraffin 1) 1-6 small slices of waxed tissue are introduced in a 1,5 ml test tube of the Eppendorf type;
- DNA preparation from desquamation cells obtained through vaginal swab or material collected from vagina using a spatula obtained through vaginal swab or material collected from vagina using a spatula.
- DNA is amplified through polymerase reaction, using amplifying means for amplifying DNA, said amplifying means comprising identifying means for identifying sequences of nucleotides of region Ll and of regions E6 and E7 of the HPV virus genome.
- the identifying means for identifying said sequences of said regions E6 and E7 comprises a first primer representative of said region E7, with sequence 5' -GAG-CTG-TCG-CTT-AAT-TGC-TC- 3' , a second primer with sequence 5' -TGT-CAA-AAA-CCG-TTG-TGT- CC-3' representative of said region E6 of strains of HPV virus having high-middle hazard, a third primer representative of said region E6 of strains of HPV virus having low hazard with sequence 5' -TGC-TAA-TTC-GGT-GCT-ACC-TG-3' .
- the identifying means for identifying said sequences in said region Ll comprises a fourth primer with sequence 5'-CGT-CCM- ARR-GGA-WAC-TGA-TC-3' and a fifth primer with sequence 5'-GCM- CAG-GGW-CAT-AAY-AAT-GG-3' .
- DNA amplification is carried out separately for the late region L of the virus and for the early region E, as described below: the following components are introduced into a thin-walled test tube, for each amplification reaction: for the late region L:
- said first mixture comprising:
- said second mixture comprising:
- said third mixture comprising:
- the amplification reaction of DNA may be subsequently carried out according to the following table:
- Samples of DNA obtained from the amplifying reaction are then sown on an agarose gel in a concentration of 2-4%, together with marker means suitable for highlighting the viral sequences identified by primers.
- the samples are eventually examined with ultraviolet light in order to highlight possible positive results of the amplification of sequences of regions Ll, E6/E7 of the genome of HPV virus .
- the positive results are represented by a band of 450 pb for the region Ll, contained therefore between the first and the second restriction fragment of the molecular weight marker, and by a second band of 233-268 pb for the regions E6, E7, contained between the third and the fifth restriction fragment of the molecular weight marker.
- the primers for the sequences of the region E of the strains of low hazard virus may cause unspecific amplification, i.e. an amplification which does not correspond to an effective presence of virus, but which is represented by a band at about 400 pb, clearly distinguished from the band of 233-268 pb of the specific amplification in presence of virus. In this case, it is advisable to denature the sample for 3 minutes at 94 °C and to repeat the test at a temperature of 0 °C.
- both the band corresponding to strains of virus with high-middle hazard and the band corresponding to strains of virus with low hazard may be present. This means that a co-infection is present, said co-infection being caused by two different types of HPV virus.
- the present invention by searching for the regions E6 and E7 of virus genome, the presence of infection from HPV virus may be detected even in specimens in which the region Ll of the genome is not present, thus reducing significantly the possibility of errors in identifying the virus presence; furthermore, by searching for the above-mentioned regions E6 and E7 an indication may be obtained about the possible integration of the virus into DNA of the infected cells and, therefore, on the progression level of infection.
- the present invention allows even the group of the viral strain responsible for the infection to be identified, i.e. the invention allows to establish whether a strain of low oncogenic hazard or middle-high oncogenic hazard is involved.
- the components for the amplifying reaction of DNA may be provided in a reaction kit containing:
- the final volumes of first, second and third mixture may also be halved, i.e. reduced to 742,5 ⁇ l, without modifying the final concentrations of single components.
- the mineral oil has the function of preventing the buffer of PCR from evaporating if a thermo-cycler without thermo-heated cover is used.
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Wood Science & Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Virology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Analytical Chemistry (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2001252465A AU2001252465A1 (en) | 2000-05-05 | 2001-05-02 | Method and means for identifying hpv virus |
EP01925788A EP1409747A2 (fr) | 2000-05-05 | 2001-05-02 | Procede et moyens destines a identifier le virus du papillome humain (hpv) |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT2000MO000091A IT1316070B1 (it) | 2000-05-05 | 2000-05-05 | Metodo e mezzi per l'identificazione di virus hpv |
ITMO2000A000091 | 2000-05-05 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001085994A2 true WO2001085994A2 (fr) | 2001-11-15 |
WO2001085994A3 WO2001085994A3 (fr) | 2002-05-02 |
Family
ID=11450457
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2001/000771 WO2001085994A2 (fr) | 2000-05-05 | 2001-05-02 | Procede et moyens destines a identifier le virus du papillome humain (hpv) |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1409747A2 (fr) |
AU (1) | AU2001252465A1 (fr) |
IT (1) | IT1316070B1 (fr) |
WO (1) | WO2001085994A2 (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1573041A2 (fr) * | 2002-11-01 | 2005-09-14 | Cytyc Corporation | Detection et determination de papillomavirus humains au moyen de sondes pna |
EP1609874A2 (fr) | 2004-05-21 | 2005-12-28 | Bioanalisi Centro Sud S.n.c. di Perseu Sinibaldo e C. | Système pour la recherche et identification d' agents pathogéniques. |
CN105734022A (zh) * | 2016-01-19 | 2016-07-06 | 李娜 | 一种宫颈脱落细胞中hpv抽提方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5283171A (en) * | 1988-09-09 | 1994-02-01 | Hoffmann-La Roche Inc. | Compositions for and detection of human papillomavirus by specific oligonucleotide polymerase primers using the polymerase chain reaction |
EP0662518A2 (fr) * | 1989-12-01 | 1995-07-12 | Amoco Corporation | Sonde d'acide nucléique pour détection des transcriptions du VPH |
US5527898A (en) * | 1988-09-09 | 1996-06-18 | Hoffmann-La Roche Inc. | Detection of human papillomavirus by the polymerase chain reaction |
WO1999029890A2 (fr) * | 1997-12-12 | 1999-06-17 | Digene Corporation | Evaluation de maladies liees au virus du papillome humain |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2785164B2 (ja) * | 1990-08-20 | 1998-08-13 | 寳酒造株式会社 | ヒトパピローマウイルスの検出方法 |
-
2000
- 2000-05-05 IT IT2000MO000091A patent/IT1316070B1/it active
-
2001
- 2001-05-02 AU AU2001252465A patent/AU2001252465A1/en not_active Abandoned
- 2001-05-02 EP EP01925788A patent/EP1409747A2/fr not_active Withdrawn
- 2001-05-02 WO PCT/IB2001/000771 patent/WO2001085994A2/fr not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5283171A (en) * | 1988-09-09 | 1994-02-01 | Hoffmann-La Roche Inc. | Compositions for and detection of human papillomavirus by specific oligonucleotide polymerase primers using the polymerase chain reaction |
US5527898A (en) * | 1988-09-09 | 1996-06-18 | Hoffmann-La Roche Inc. | Detection of human papillomavirus by the polymerase chain reaction |
EP0662518A2 (fr) * | 1989-12-01 | 1995-07-12 | Amoco Corporation | Sonde d'acide nucléique pour détection des transcriptions du VPH |
WO1999029890A2 (fr) * | 1997-12-12 | 1999-06-17 | Digene Corporation | Evaluation de maladies liees au virus du papillome humain |
Non-Patent Citations (2)
Title |
---|
HOEFMANN: "Sequence determination of human papillomavirus type 6a and assembly of virus-like particles in Saccharomyces cerevisiae" VIROLOGY, vol. 209, no. 2, 1995, XP002100680 * |
See also references of EP1409747A2 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1573041A2 (fr) * | 2002-11-01 | 2005-09-14 | Cytyc Corporation | Detection et determination de papillomavirus humains au moyen de sondes pna |
EP1573041A4 (fr) * | 2002-11-01 | 2006-05-31 | Cytyc Corp | Detection et determination de papillomavirus humains au moyen de sondes pna |
EP1609874A2 (fr) | 2004-05-21 | 2005-12-28 | Bioanalisi Centro Sud S.n.c. di Perseu Sinibaldo e C. | Système pour la recherche et identification d' agents pathogéniques. |
EP1609874A3 (fr) * | 2004-05-21 | 2006-05-03 | Bioanalisi Centro Sud S.n.c. di Perseu Sinibaldo e C. | Système pour la recherche et identification d' agents pathogéniques. |
EP1818416A3 (fr) * | 2004-05-21 | 2008-02-27 | BCS BIOTECH S.p.A. | Système de recherche et d'identification d'agents pathogéniques |
CN105734022A (zh) * | 2016-01-19 | 2016-07-06 | 李娜 | 一种宫颈脱落细胞中hpv抽提方法 |
Also Published As
Publication number | Publication date |
---|---|
AU2001252465A1 (en) | 2001-11-20 |
IT1316070B1 (it) | 2003-03-28 |
WO2001085994A3 (fr) | 2002-05-02 |
ITMO20000091A1 (it) | 2001-11-05 |
ITMO20000091A0 (it) | 2000-05-05 |
EP1409747A2 (fr) | 2004-04-21 |
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