LT7135B - USE OF 16S RRRNA GENE SEQUENCES OF THE STAPHYLOCOCCACEAE BACTERIAL FAMILY AND STAPHYLOCOCCUS HOMINIS BACTERIAL SPECIES FOR THE DIAGNOSTIC METHOD OF COLORECTAL CANCER FROM PATIENT BLOOD PLASMA - Google Patents
USE OF 16S RRRNA GENE SEQUENCES OF THE STAPHYLOCOCCACEAE BACTERIAL FAMILY AND STAPHYLOCOCCUS HOMINIS BACTERIAL SPECIES FOR THE DIAGNOSTIC METHOD OF COLORECTAL CANCER FROM PATIENT BLOOD PLASMA Download PDFInfo
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- 206010009944 Colon cancer Diseases 0.000 title claims abstract description 24
- 230000001580 bacterial effect Effects 0.000 title claims abstract description 22
- 241000295644 Staphylococcaceae Species 0.000 title claims abstract description 12
- 241000192087 Staphylococcus hominis Species 0.000 title claims abstract description 12
- 108090000623 proteins and genes Proteins 0.000 title claims description 7
- 210000002381 plasma Anatomy 0.000 title abstract description 10
- 208000001333 Colorectal Neoplasms Diseases 0.000 title description 8
- 241000894007 species Species 0.000 title description 8
- 238000002405 diagnostic procedure Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 17
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 8
- 108020004465 16S ribosomal RNA Proteins 0.000 claims description 6
- 238000007481 next generation sequencing Methods 0.000 claims description 2
- 230000035945 sensitivity Effects 0.000 abstract description 7
- 238000013399 early diagnosis Methods 0.000 abstract description 2
- 239000012472 biological sample Substances 0.000 abstract 4
- 108020004414 DNA Proteins 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000000090 biomarker Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- 108020000946 Bacterial DNA Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000009534 blood test Methods 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 230000002550 fecal effect Effects 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000009004 PCR Kit Methods 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000007622 bioinformatic analysis Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 108091092240 circulating cell-free DNA Proteins 0.000 description 1
- 238000002052 colonoscopy Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000002563 stool test Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
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Abstract
Išradime aprašytas storosios žarnos vėžio (SŽV) nustatymo būdas. Šis būdas apima biologinio mėginio paėmimą, laisvai cirkuliuojančios DNR išskyrimą iš biologinio mėginio (kraujo plazmos), Staphylococcaceae ir Staphylococcus hominis bakterijų sekų nustatymą laisvai cirkuliuojančioje DNR naudojant naujos kartos sekoskaitą, Staphylococcaceae ir Staphylococcus hominis bakterijų sekų santykinio skaičiaus biologiniame mėginyje paliginimo su referentinėmis reikšmėmis (atitinkamai 9,0 proc. ir 0.3 proc.), jei Staphylococcaceae ir Staphylococcus hominis bakterijų sekų santykinis skaičius paciento biologiniame mėginyje viršija referentinę reikšmę, pacientui nustatomas SŽV. Būdas pasižymi aukštu jautrumu ir specifiškumu, todėl jis yra perspektyvi alternatyva ankstyvajai SŽV diagnostikai.The invention describes a method for detecting colon cancer (CRC). This method includes taking a biological sample, isolating free circulating DNA from the biological sample (blood plasma), determining the sequences of Staphylococcaceae and Staphylococcus hominis bacteria in the free circulating DNA using a next-generation sequencer, comparing the relative number of Staphylococcaceae and Staphylococcus hominis bacterial sequences in the biological sample with reference values (9.0 percent and 0.3 percent, respectively), if the relative number of Staphylococcaceae and Staphylococcus hominis bacterial sequences in the patient's biological sample exceeds the reference value, the patient is diagnosed with CRC. The method is characterized by high sensitivity and specificity, therefore it is a promising alternative for early diagnosis of CRC.
Description
TECHNIKOS SRITISTECHNICAL FIELD
Šis išradimas priklauso medicinos mokslų sričiai, onkologijai.This invention belongs to the field of medical sciences, oncology.
TECHNIKOS LYGISSTATE OF THE ART
Storosios žarnos vėžys (SŽV) yra vienas dažniausių vėžio susirgimų pasaulyje. Kasmet diagnozuojama daugiau nei pusė milijono naujų šio susirgimo atvejų. SŽV yra trečia pagal dažnumą onkologinė liga Lietuvoje. Siekiant sumažinti pacientų mirtingumą nuo SŽV svarbu diagnozuoti ligą ankstyvoje stadijoje. Prevencinės SŽV patikros programos vakarų šalyse ir Lietuvoje yra paremtos slapto kraujo nustatymo išmatose testais ir, esant teigiamam rezultatui, po to sekančiu endoskopiniu storosios žarnos tyrimu. Pastarasis tyrimas yra invazinis ir susijęs su dideliais sveikatos priežiūros sistemos kaštais. Šiuo metu SŽV ankstyvos patikros programose naudojami imunocheminiai slapto kraujavimo išmatose testai pasižymi žema diagnostine verte - jų tikslumas nėra pakankamas. Todėl būtina ieškoti naujų molekulinių biožymenų, pasižyminčių lengvu pritaikomumu klinikinėje praktikoje ir aukštu jautrumu bei specifiškumu. Vienas iš išradimo analogų yra metodas, skirtas nustatyti SŽV, naudojant išmatų tyrimą, aprašytas patento paraiškoje WO2019151515A1. Šis metodas pagrįstas subjekto genų esančių išmatose tyrimu tačiau jo jautrumas bei specifiškumas nėra aukštas. Kitas išradimo analogas aprašomas patento paraiškoje WO03059150A2 yra metodas, skirtas nustatyti SŽV, naudojant endoskopinį tyrimą. Šis metodas yra invazinis ir susijęs su dideliais sveikatos priežiūros sistemos kaštais.Colorectal cancer (CRC) is one of the most common cancers in the world. More than half a million new cases of this disease are diagnosed annually. CRC is the third most common oncological disease in Lithuania. In order to reduce patient mortality from CRC, it is important to diagnose the disease at an early stage. Preventive CRC screening programs in Western countries and Lithuania are based on fecal occult blood tests and, if the result is positive, a subsequent colonoscopy. The latter examination is invasive and associated with high costs for the healthcare system. Currently, immunochemical fecal occult blood tests used in CRC early screening programs are characterized by low diagnostic value - their accuracy is not sufficient. Therefore, it is necessary to search for new molecular biomarkers that are easy to apply in clinical practice and have high sensitivity and specificity. One of the analogues of the invention is a method for detecting CRC using a stool test, described in patent application WO2019151515A1. This method is based on the study of the subject's genes in the feces, but its sensitivity and specificity are not high. Another analogue of the invention is described in patent application WO03059150A2, which is a method for detecting SJV using endoscopic examination. This method is invasive and associated with high costs for the healthcare system.
Šioje paraiškoje aprašytas metodas yra naujas išradimas, įgalinantis aptikti SŽV ankstyvoje stadijoje, turi aukštą jautrumą ir specifiškumą.The method described in this application is a new invention that enables the detection of SJV at an early stage, has high sensitivity and specificity.
IŠRADIMO ESMĖESSENCE OF THE INVENTION
Patentuojamas metodas yra skirtas aptikti SŽV ankstyvoje stadijoje, taip mažinant žmonių mirtingumą nuo šio naviko bei trumpinant gydymo laiką ir mažinant sveikatos apsaugos 2 sistemos ir pacientų išleidžiamus gydymui kaštus. Metodas paremtas naujos kartos sekoskaitos metu nustatytų bakterijų šeimos Staphylococcaceae ir bakterijų genties Staphylococcus hominis 16S rRNR geno V12The patented method is designed to detect SJV at an early stage, thereby reducing human mortality from this tumor, shortening treatment time and reducing treatment costs for the healthcare system and patients. The method is based on the V12 16S rRNA gene of the bacterial family Staphylococcaceae and the bacterial genus Staphylococcus hominis identified during next-generation sequencing.
V2 regiono sekų santykinio skaičiaus padidėjimu (atitinkamai daugiau nei 9 proc. ir daugiau nei 0.3 proc.) kitų bakterijų atžvelgiu panaudojus pacientų kraujo plazmą. Esminiai techniniai reikalavimai siekiant įgyvendinti metodą: paciento kraujo plazma, komercinis DNR gryninimo rinkinys, komercinis PGR atlikimo rinkinys, specifiniai 27F ir 338R pradmenys skirti 16S rRNR geno V1-V2 pagausinimui, komercinis Illumina sekoskaitos rinkinys, kompiuteris su dada2, phyloseq, vegan, R įrankiais.The increase in the relative number of V2 region sequences (more than 9% and more than 0.3%, respectively) of other bacteria was observed using patient blood plasma. Essential technical requirements for implementing the method: patient blood plasma, commercial DNA purification kit, commercial PCR kit, specific 27F and 338R primers for amplification of 16S rRNA gene V1-V2, commercial Illumina sequencing kit, computer with dada2, phyloseq, vegan, R tools.
DETALUS IŠRADIMO APRAŠYMASDETAILED DESCRIPTION OF THE INVENTION
Storosios žarnos vėžiui nustatyti yra naudojamas paciento kraujo plazmos mėginys, iš kurio išgryninama laisvai cirkuliuojanti DNR. PGR būdu, naudojant 27F ir 338R pradmenis, pagausinamas 16S rRNA geno V1-V2 regionas.To detect colon cancer, a patient's plasma sample is used, from which free circulating DNA is purified. PCR is used to amplify the V1-V2 region of the 16S rRNA gene using primers 27F and 338R.
NAUJOS KARTOS SEKOSKAITA ATLIEKAMA MISEQ ILLUMINA APARATUNEXT GENERATION SEQUENCEING IS PERFORMED WITH THE MISEQ ILLUMINA DEVICE
Pasitelkiant bioinformatinius įrankius (dada2, phyloseq, vegan, R) prijungiama naujausia bakterijų duomenų bazė (Silva 132). Visom nustatytoms bakterijų sekoms priskiriami taksonominiai lygiai (tipas, klasė, eilė, šeima, gentis, rūšis). Vėliau sekos apjungiamos į atitinkamas grupes pagal nustatytus taksonominius lygius.Using bioinformatic tools (dada2, phyloseq, vegan, R), the latest bacterial database (Silva 132) is connected. All identified bacterial sequences are assigned taxonomic levels (phylum, class, order, family, genus, species). The sequences are then combined into appropriate groups according to the identified taxonomic levels.
Iš visų nustatytų šeimų išskiriama Staphylococcaceae, o iš visų nustatytų rūšių išskiriama Staphylococcus hominis. Apskaičiuojamas jų santykinis gausumas (procentais) kitų bakterijų atžvelgiu. Staphylococcaceae santykinis gausumas skaičiuojamas Šeimos lygmeniu, o Staphylococcus hominis - Rūšies lygmeniu.From all identified families, Staphylococcaceae is isolated, and from all identified species, Staphylococcus hominis is isolated. Their relative abundance (in percent) is calculated in relation to other bacteria. The relative abundance of Staphylococcaceae is calculated at the Family level, and Staphylococcus hominis at the Species level.
Storosios žarnos vėžys yra identifikuojamas, jeigu tirtame mėginyje Staphylococcaceae bakterijų šeima, atsižvelgiant į kitas bakterijų šeimas taip pat nustatytas tame mėginyje, viršija 9,0 proc. o Staphylococcus hominis bakterijų rūšis, atsižvelgiant į kitas bakterijų rūšis taip pat nustatytas tame mėginyje, viršija 0,3 proc.Colon cancer is identified if the Staphylococcaceae bacterial family, taking into account other bacterial families also found in that sample, exceeds 9.0 percent in the tested sample and the Staphylococcus hominis bacterial species, taking into account other bacterial species also found in that sample, exceeds 0.3 percent.
Šis būdas pasižymi aukštu jautrumu ir specifiškumu (AUC = 73 proc.), todėl jis yra perspektyvus naujas būdas ankstyvai SŽV diagnostikai.This method has high sensitivity and specificity (AUC = 73%), making it a promising new method for early diagnosis of SLE.
SŽV sergančiųjų ir kontrolinių asmenų kraujo mėginiai buvo surinkti 20132022 metais Gastroenterologijos ir Chirurgijos skyriuose (Kauno klinikos, Lietuvos sveikatos mokslų universiteto ligoninė) ir saugoti biobanke - 80 °C temperatūroje. Kraujo plazmos bakterijų 16S rRNR analizei buvo panaudoti 56 SŽV ir 66 kontrolinės grupės pacientų mėginiai. Kontrolinę grupę sudarė pacientai, kuriems nenustatyti jokie piktybiniai navikai, SŽV grupės pacientams liga buvo diagnozuota atlikus histologinį tyrimą.Blood samples from patients with SJV and controls were collected in 2013-2022 at the Departments of Gastroenterology and Surgery (Kaunas Clinic, Lithuanian University of Health Sciences Hospital) and stored in a biobank at -80 °C. Blood plasma bacterial 16S rRNA analysis was performed on samples from 56 patients with SJV and 66 controls. The control group consisted of patients without any malignant tumors, while patients with SJV were diagnosed with the disease after histological examination.
BAKTERINĖS DNR GRYNINIMAS IŠ KRAUJO PLAZMOSPURIFICATION OF BACTERIAL DNA FROM BLOOD PLASMA
Siekiant išgryninti bakterinės kilmės DNR frakciją, esančią žmogaus kraujyje, pirmiausiai buvo skiriama visa laisvai kraujyje cirkuliuojanti DNR (lc-DNR). Lc-DNR buvo išgryninta iš periferinio kraujo plazmos (500 μθ naudojant QIAamp MinElute ccfDNA Mini Kit (Qiagen) rinkinį pagal gamintojo pateiktą protokolą. DNR koncentracija išmatuota Bioanalyzer 2100 (Agilent) bei Qubit analizatoriais.In order to purify the bacterial DNA fraction present in human blood, total free circulating DNA (lc-DNA) was first administered. Lc-DNA was purified from peripheral blood plasma (500 μθ) using the QIAamp MinElute ccfDNA Mini Kit (Qiagen) according to the manufacturer's protocol. DNA concentration was measured using the Bioanalyzer 2100 (Agilent) and Qubit analyzers.
16S RRNR GENO SEKOSKAITOS BIBLIOTEKŲ PARUOŠIMAS IR SEKOSKAITAPREPARATION AND SEQUENCE OF 16S RRRNA GENE SEQUENCE LIBRARIES
Siekiant iš visos išskirtos laisvai cirkuliujanti DNR (lc-DNR) atskirti tik bakterinę frakciją, PGR metodu, naudojant 27F-338R pradmenis, buvo pagausintas tik bakterijoms būdingas 16S rRNR genas. PGR reakcijos efektyvumas (produkto susidarymas) buvo įvertinti agarozės gelyje. Tolimesnei analizei tinkantys mėginiai, siekiant suvienodinti koncentraciją, buvo normalizuoti naudojant SequalPrep rinkinį (Thermo Fisher). Po normalizacijos mėginiai buvo apjungti į vieną biblioteką ir pasinaudojant Illumina MiSeq (Illumina) platforma buvo atlikta paruoštos bibliotekos sekoskaita. Lc-DNR mėginių taršai įvertinti kiekvieną kartą gryninant tiriamųjų mėginių seriją, kaip neigiama kontrolė, buvo panaudoti vandens mėginiai, iš kurių buvo gryninama DNR bei atlikta PGR ir sekoskaita.In order to isolate only the bacterial fraction from the total isolated free circulating DNA (lc-DNA), only the bacterial 16S rRNA gene was amplified by PCR using the 27F-338R primers. The efficiency of the PCR reaction (product formation) was assessed on an agarose gel. Samples suitable for further analysis were normalized using the SequalPrep kit (Thermo Fisher) to equalize the concentration. After normalization, the samples were combined into a single library and the prepared library was sequenced using the Illumina MiSeq (Illumina) platform. To assess the contamination of lc-DNA samples during each purification of the series of test samples, water samples from which DNA was purified and PCR and sequencing were performed were used as a negative control.
16S RRNA SEKOSKAITOS DUOMENŲ BIOINFORMATINĖ IR STATISTINĖ ANALIZĖBIOINFORMATIC AND STATISTICAL ANALYSIS OF 16S RRNA SEQUENCE DATA
Sekoskaitos duomenys išanalizuoti naudojant dada2 ir phyloseq algoritmus R programoje. Nustatytos sekos buvo kiekybiškai ir kokybiškai įvertintos ir tolimesnei analizei paliktos tik kokybės rekomendacijas atitinkančios sekos. Sekos, rastos kontroliniuose vandens mėginiuose, įtariant užterštumą buvo pašalintos iš tyrimo, naudojant decontam paketą. Nustatytoms sekoms buvo priskirta taksonominė klasifikacija, naudojant naujausią SILVA bakterijų duomenų bazę (138 versija). Mėginiai su nuskaitymo lygiu mažesniu nei 500 buvo 4 pašalinti iš analizės. Duomenų normalizavimas ir β-įvairovės analizė buvo atlikta naudojant DESeq2 paketą. β-įvairovės analizė buvo atlikta tik su bakterijomis, kurios buvo aptinkamos daugiau nei 25 proc. mėginių, bent vienoje iš lyginamųjų grupių. Visuose testuose skirtumai buvo laikomi statistiškai reikšmingais, kai koreguota dauginio palyginimo p vertė (p.adj) buvo < 0,05.Sequencing data were analyzed using dada2 and phyloseq algorithms in R program. The identified sequences were quantitatively and qualitatively evaluated and only sequences meeting quality guidelines were retained for further analysis. Sequences found in control water samples due to suspected contamination were removed from the study using the decontam package. The identified sequences were assigned a taxonomic classification using the latest SILVA bacterial database (version 138). Samples with a read level lower than 500 were 4 removed from the analysis. Data normalization and β-diversity analysis were performed using the DESeq2 package. β-diversity analysis was performed only with bacteria that were detected in more than 25 percent. of the samples, in at least one of the comparison groups. In all tests, differences were considered statistically significant when the adjusted multiple comparison p value (p.adj) was < 0.05.
REZULTATAIRESULTS
Vertinant kraujo plazmoje esančias bakterijas, kaip biožymenį, rinkinys iš dviejų bakterijų taksonominių vienetų - Staphylococcus hominis sekos (ASV 8) ir šeimos Staphylococcaceae kaip biožymens jautrumas siekė 68 proc., o specifiškumas - 83 proc., jautrumo ir specifiškumo sąryšis 73 proc.. Sergančiųjų kraujo plazmos mėginiuose Staphylococcaceae bakterijų šeima atsižvelgiant į kitas bakterijų šeimas viršijo 9 proc. o Staphylococcus hominis bakterijų rūšis atsižvelgiant į kitas bakterijų rūšis viršijo 0.3 proc. tai traktuojama kaip SŽV požymis.When evaluating bacteria in blood plasma as a biomarker, the sensitivity of the set of two bacterial taxonomic units - Staphylococcus hominis sequence (ASV 8) and the family Staphylococcaceae as a biomarker reached 68 percent, and the specificity - 83 percent, the sensitivity and specificity ratio was 73 percent. In blood plasma samples of patients, the Staphylococcaceae bacterial family exceeded 9 percent in relation to other bacterial families. and the Staphylococcus hominis bacterial species exceeded 0.3 percent in relation to other bacterial species. This is treated as a sign of SJV.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003059150A2 (en) | 2002-01-09 | 2003-07-24 | Neoguide Systems, Inc. | Apparatus and method for spectroscopic examination of the colon |
| WO2019151515A1 (en) | 2018-02-05 | 2019-08-08 | 国立大学法人東京工業大学 | Method for detecting early colon cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003059150A2 (en) | 2002-01-09 | 2003-07-24 | Neoguide Systems, Inc. | Apparatus and method for spectroscopic examination of the colon |
| WO2019151515A1 (en) | 2018-02-05 | 2019-08-08 | 国立大学法人東京工業大学 | Method for detecting early colon cancer |
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