GB2549712A - Biomarker - Google Patents
Biomarker Download PDFInfo
- Publication number
- GB2549712A GB2549712A GB1607106.0A GB201607106A GB2549712A GB 2549712 A GB2549712 A GB 2549712A GB 201607106 A GB201607106 A GB 201607106A GB 2549712 A GB2549712 A GB 2549712A
- Authority
- GB
- United Kingdom
- Prior art keywords
- subgingival
- lps
- periodontal disease
- activity
- periodontal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- 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
-
- 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
- C12Q1/001—Enzyme electrodes
- C12Q1/004—Enzyme electrodes mediator-assisted
-
- 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
- C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
- C12Q1/04—Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor
-
- 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
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56911—Bacteria
-
- 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
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56911—Bacteria
- G01N33/56955—Bacteria involved in periodontal diseases
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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
- G01N33/579—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving limulus lysate
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
- G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- G01N2400/50—Lipopolysaccharides; LPS
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/18—Dental and oral disorders
Abstract
A method is provided for screening, risk assessment, prevention and early diagnosis ofperiodontal disease and/or peri-implantitis, patient-centred point-of-care periodontal therapy and monitoring treatment outcomes in a subject. The method comprises:collecting subgingival plaque samples from one or more sites around one or more teeth; extracting lipopolysaccharides (LPS, also known as lipoglycans or endotoxin) from the or each sample; and assaying sub-gingival LPS activity after extraction, using recombinant Factor C (EndoZyme or LAL assay).
Description
BIOMARKER
Periodontal diseases can affect one or more of the periodontal tissues/structures (e.g. alveolar bone, periodontal ligament, cementum and gingiva). While there are many different periodontal diseases that can affect these tooth-supporting tissues/structures, by far the most common ones are plaque-induced inflammatory conditions, such as gingivitis and periodontitis. Often the term periodontal disease or gum disease is used as a synonym for periodontitis, specifically chronic periodontitis. Periodontal disease ranges from the mildest stage, known as gingivitis, to severe stage, known, as periodontitis. While in some sites or individuals, gingivitis never progresses to periodontitis, data indicate that periodontitis is always preceded by gingivitis.
Periodontitis, meaning inflammation around the tooth, is a common oral infection which affects the periodontium i.e. the tissues that surround and support the teeth. Periodontitis involves irreversible, progressive loss of the alveolar bone around the teeth and, if left untreated, can lead to the loosening and subsequent loss of teeth.
Periodontitis is caused by microorganisms that adhere to and grow on the tooth's surfaces close and below the gum line, along with an over-aggressive immune response against these microorganisms and their products.
Current, conventional diagnostic procedures for periodontitis are based on visual and radiographic assessment and reflect only historical disease activity, not current disease state. Clinical diagnosis is made by measuring probing pocket depth (PPD), bleeding on probing and attachment loss (AL), and radiographically by detecting loss of alveolar bone. Diseased patients would typically exert PPD>3mm, bleeding on probing and apical migration of junctional epithelium (attachment loss), measured by careful periodontal examination and periodontal probes, while their radiographs would show alveolar bone resorption (Parameters of Care, Journal of Periodontology, Volume 71, Number 5, May 2000 (Supplement)).
These diagnostic criteria do not assess current disease activity nor identify susceptible individuals who might be at risk of periodontitis in the future. They leave no opportunity to predict future tissue destruction or to formulate the appropriate treatment plan specific to each individual patient.
As with other dental procedures, periodontal treatments must be cost-effective; that is, the treatments should be given to those individuals who need them the most and who can benefit from them. This puts a firm demand on the dentist who must have the skills and equipment to single out patients with highest needs.
According to Armitage (Armitage GC, Periodontal diseases: diagnosis. Ann Periodontol. 1996 Nov; I (1):37-215 ), periodontal diagnostic procedures should serve five separate but related purposes:
Screening,
Diagnosis of specific periodontal diseases.
Identification of sites and subjects at an increased risk of experiencing the progression of periodontal destruction.
Treatment planning.
Monitoring of therapy.
The present invention seeks to provide a simple, potentially “chairside” (“nearpatient”) test which can be performed on a patient and then used for screening, risk assessment, prevention, early diagnosis, selection of patient-centred point-of-care management options and for monitoring treatment outcomes.
According to an aspect of the present invention there is provided a method for aiding the diagnosis and/or monitoring of periodontal disease in a subject, the method comprising: collecting one or more subgingival plaques from one or more sites around one or more teeth; and assaying subgingival LPS activity relating to the or each site.
By taking subgingival plaque samples from particular teeth it is possible to assess the risk and give valuable prognosis for each individual tooth and particular sites around the teeth.
Endotoxin, also known as lipopolysaccharide (LPS), is an integral component of the gram-negative bacterial cell membrane and is responsible for many, if not all, of the toxic effects that occur during gram-negative bacterial sepsis and is one of major bacterial products involved in the development of periodontitis. It causes alveolar bone resorption directly by activating osteoclasts (bone resorbing cells) and indirectly by triggering an inflammatory response within the periodontal tissues. LPS biological activity depends on its chemical structure which could be modified by bacteria involved in the development of periodontitis (Li Y, Powell DA, Shaffer SA, Rasko DA, Pelletier MR, Leszyk JD, Scott AJ, Masoudi A, Goodlett DR, Wang X, Raetz CR, Ernst RK. LPS remodeling is an evolved survival strategy for bacteria. Proc Natl Acad Sci U S A. 2012 May 29,-109(22)). By measuring LPS activity in subgingival areas, it is possible to successfully identify and treat the teeth which are at high risk for periodontal tissue destruction before it occurs (something we are not able to do currently).
The amoebocyte lysate constituted as the Limulus Amoebocyte Lysate (LAL) test has been used for decades as a tool for detecting trace concentrations of LPS in solution. LPS from gram-negative bacteria induces the amoebocytes of horseshoe crabs to aggregate and degranulate. The molecular mechanism of coagulation in horseshoe crab has been established and it involves a protease cascade. This cascade is based on three kinds of serine protease zymogens: Factor C; Factor B, proclotting enzyme; and one clottable protein, coagulogen.
The periodontal disease may be: chronic periodontal disease; aggressive periodontal disease; periodontal disease relating to systemic conditions; necrotising periodontal disease; or gingivitis. A further aspect provides a method for aiding the diagnosis and/or prognostic monitoring of periodontal health in a subject, the method comprising: collecting subgingival plaque from one or more sites around one or more teeth; extracting LPS (lipopolysaccharide- endotoxin) from these samples and assaying subgingival LPS activity. A further aspect provides a method for screening, risk assessment, prevention and early diagnosis of periodontal disease, patient-centred point-of-care periodontal therapy and monitoring treatment outcomes in a subject, the method comprising: collecting subgingival plaque from one or more sites around one or more teeth; extracting LPS from samples and assaying sub-gingival LPS activity.
Peri-implantitis is a destructive inflammatory process affecting the soft and hard tissues surrounding dental implants. The array of periodontal pathogens found around failing implants (those affected by peri-implantitis) are very similar to those found in association with various forms of periodontal disease. A further aspect provides a method for screening, risk assessment, prevention and early diagnosis of peri-implantitis, patient-centred point-of-care therapy and monitoring treatment outcomes in a subject, the method comprising: collecting subgingival plaque from one or more sites around one or more implants; extracting LPS from samples and assaying sub-gingival LPS activity. A further aspect provides a method for aiding the diagnosis and/or monitoring of peri-implantitis in a subject, the method comprising: collecting one or more subgingival plaques from one or more sites around one or more implants; and assaying subgingival LPS activity.
The LPS activity may be assayed using recombinant Factor C.
Factor C is the endotoxin-specific principal receptor in the LAL enzyme cascade. Being the initial activator of the clotting cascade. Factor C functions as a biosensor that responds to LPS. LPS activity of a plurality of sites around a tooth and/or implant may be assayed, for example two or three sites. For example, a sample from at least the front and rear of a tooth/implant may be taken.
The present invention also provides the use of recombinant Factor C for measuring subgingival dental plaque endotoxin activity as a biomarker for periodontal disease progression.
The present invention also provides the use of recombinant Factor C for measuring subgingival dental plaque endotoxin activity as a biomarker for peri-implantitis progression.
The present invention also provides use of recombinant Factor C as a biomarker for periodontal disease activity.
The present invention provides a rapid and reliable test for destructive periodontal activity risk assessment, based on the LAL assay.
Different aspects and embodiments of the invention may be used separately or together.
Further particular and preferred aspects of the present invention are set out in the accompanying independent and dependent claims. Features of the dependent claims may be combined with the features of the independent claims as appropriate, and in combination other than those explicitly set out in the claims.
The present invention will now be more particularly described, by way of example, with reference to the accompanying drawings.
Example embodiments are described below in sufficient detail to enable those of ordinary skill in the art to embody and implement the systems and processes herein described. It is important to understand that embodiments can be provided in many alternate forms and should not be construed as limited to the examples set forth herein.
Accordingly, while embodiments can be modified in various ways and take on various alternative forms, specific embodiments thereof are shown in the drawings and described in detail below as examples. There is no intent to limit to the particular forms disclosed. On the contrary, all modifications, equivalents, and alternatives falling within the scope of the appended claims should be included. Elements of the example embodiments are consistently denoted by the same reference numerals throughout the drawings and detailed description where appropriate.
The terminology used herein to describe embodiments is not intended to limit the scope. The articles “a,” “an,” and “the” are singular in that they have a single referent, however the use of the singular form in the present document should not preclude the presence of more than one referent. In other words, elements referred to in the singular can number one or more, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises,” “comprising,” “includes,” and/or “including,” when used herein, specify the presence of stated features, items. steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, items, steps, operations, elements, components, and/or groups thereof.
Unless otherwise defined, all terms (including technical and scientific terms) used herein are to be interpreted as is customary in the art. It will be further understood that terms in common usage should also be interpreted as is customary in the relevant art and not in an idealised or overly formal sense unless expressly so defined herein.
In the following description, all orientational terms, such as upper, lower, mesially and distally, are used in relation to the drawings and should not be interpreted as limiting on the invention.
Figure I shows the results of LAL assays performed on a panel of diseased and healthy patients. Diseased patients have high endotoxin activity, and healthy patients have low readings.
Figure 2 shows the results of assays for subgingival LPS activity after conventional periodontal therapy. In other words, only patients which were determined to have periodontitis after a clinical examination were given full periodontal treatment (such as a scale and polish). Patients deemed to be healthy from a clinical examination were given no treatment..
Majority of patient who underwent periodontal therapy exhibited a significant reduction in subgingival LPS activity. Contrary, four patients did not attend their periodontal treatment appointment and visitied 3 to 6 months later without any therapy. Subgingival LPS activity in all of these patients went up (Figure 3.).
Picture I shows a patient with healthy periodontal tissues as diagnosed by a clinical examination. If this patient was tested with the subgingival LAL assay of the present invention and the result was low endotoxin levels it would be possible to say that there was no periodontitis risk. However, if the patient showed a high level they would be more likely to be predisposed to periodontal problems and a course of treatment and/or monitoring could be prescribed.
Picture 2 shows a patient with chronic periodontitis. This patient is diagnosed as clearly diseased by clinical examination. The LAL assay result would be high. A course of therapy would be prescribed.
Picture 3 shows the patient of Picture 2 following a course of periodontal treatment This patient now looks healthy and would be cleared by clinical examination. If the LAL test result was negative then the patient would be declared stable (although once an individual has suffered from periodontitis there is a higher chance it will return, so a monitoring programme may be prescribed). However, it is possible that the LAL test would be unexpectedly positive and this would provoke a more aggressive treatment programme.
In one embodiment of the present invention a method comprises the following steps. Collection of subgingival dental plaque, LPS extraction and EndoZyme© assay: 1. Subgingival dental plaque should be collected from a particular site or sites (mesially, distally, buccally or orally) around the tooth which is being assessed. 2. The tooth is isolated and dried with cotton rolls to remove visible saliva and supragingival dental plaque from the gingival margin and tooth surface. 3. Sterile endodontic paper point is inserted into the chosen site (subgingivally) and left there for 30 seconds. Care should be taken it does not get in contact with saliva or oral mucosa. 4. After 30 seconds, remove the paper point and place it in a sterile container (15ml tube or 1.5ml Eppendorf). 5. Extract LPS from the paper point using either the Tri-reagent or the phenol-water method. Lyophilise the extract and re-dissolve the powder in 500microliters of LPS free water. 6. Perform the EndoZyme© assay with this solution in l/IO dilution.
Table I shows test results (EU/ml) from all healthy and diseased patients in a study, and from about half of the patients who have undergone periodontal treatment
Figure 4 shows the Table I results. A cut-off point for the Recombinant factor C assay has been established in Figures 5 and 6, which would give very good sensitivity and specificity for periodontitis risk assessment
Although illustrative embodiments of the invention have been disclosed in detail herein, with reference to the accompanying drawings, it is understood that the invention is not limited to the precise embodiments shown and that various changes and modifications can be effected therein by one skilled in the art without departing from the scope of the invention.
Claims (10)
1. A method for aiding the diagnosis and/or monitoring of periodontal disease in a subject, the method comprising: collecting one or more subgingival plaques from one or more sites around one or more teeth; and assaying subgingival LPS activity relating to the or each site.
2. A method as claimed in claim I, in which the periodontal disease is: chronic periodontal disease; aggressive periodontal disease; periodontal disease relating to systemic conditions; necrotising periodontal disease; or gingivitis.
3. A method for screening, risk assessment, prevention and early diagnosis of periodontal disease, patient-centred point-of-care periodontal therapy and monitoring treatment outcomes in a subject, the method comprising: collecting subgingival plaque from one or more sites around one or more teeth; extracting LPS from samples and assaying sub-gingival LPS activity.
4. A method for screening, risk assessment, prevention and early diagnosis of peri-implantitis, patient-centred point-of-care therapy and monitoring treatment outcomes in a subject, the method comprising: collecting subgingival plaque from one or more sites around one or more implants; extracting LPS from samples and assaying sub-gingival LPS activity.
5. A method for aiding the diagnosis and/or monitoring of peri-implantitis in a subject, the method comprising: collecting one or more subgingival plaques from one or more sites around one or more implants; and assaying subgingival LPS activity.
6. A method as claimed in any preceding claim, in which the LPS activity is assayed using recombinant Factor C.
7. A method as claimed in any preceding claim, in which LPS activity of a plurality of sites around a tooth/implant are assayed.
8. Use of recombinant Factor C for measuring subgingival dental plaque endotoxin activity as a biomarker for periodontal disease progression.
9. Use of recombinant Factor C for measuring subgingival dental plaque endotoxin activity as a biomarker for peri-implantitis progression.
10. A method substantially as hereinbefore described with reference to, and as shown in, the accompanying drawings.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1607106.0A GB2549712A (en) | 2016-04-24 | 2016-04-24 | Biomarker |
| PCT/EP2017/059415 WO2017186571A1 (en) | 2016-04-24 | 2017-04-20 | Biomarker for periodontal disease and peri-implantitis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1607106.0A GB2549712A (en) | 2016-04-24 | 2016-04-24 | Biomarker |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2549712A true GB2549712A (en) | 2017-11-01 |
Family
ID=58668851
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB1607106.0A Withdrawn GB2549712A (en) | 2016-04-24 | 2016-04-24 | Biomarker |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2549712A (en) |
| WO (1) | WO2017186571A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117169521A (en) * | 2023-08-25 | 2023-12-05 | 暨南大学附属第一医院（广州华侨医院） | Mass spectrum negative ion mode metabonomics biomarker for peri-implant inflammation and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990000620A1 (en) * | 1988-07-15 | 1990-01-25 | The Trustees Of Columbia University | Method for monitoring periodontal disease by monitoring endotoxins and inflammatory agents |
| EP0362998A2 (en) * | 1988-09-07 | 1990-04-11 | Minnesota Mining And Manufacturing Company | Monoclonal antibodies specific for eikenella corrodens |
| WO1992020715A1 (en) * | 1991-05-16 | 1992-11-26 | Associates Of Cape Cod, Inc. | Endotoxin binding and neutralizing protein and uses thereof |
| WO1995013094A1 (en) * | 1993-11-10 | 1995-05-18 | Bristol-Myers Squibb Company | Treatment of bacterially-induced inflammatory diseases |
| JP2005140618A (en) * | 2003-11-06 | 2005-06-02 | Lion Corp | Method for estimating fluctuation of biochemical parameter, and method for predicting onset risk of lifestyle-related disease |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6719973B1 (en) * | 1998-12-24 | 2004-04-13 | National University Of Singapore | Recombinant proteins and peptides for endotoxin biosensors, endotoxin removal, and anti-microbial and anti-endotoxin therapeutics |
-
2016
- 2016-04-24 GB GB1607106.0A patent/GB2549712A/en not_active Withdrawn
-
2017
- 2017-04-20 WO PCT/EP2017/059415 patent/WO2017186571A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990000620A1 (en) * | 1988-07-15 | 1990-01-25 | The Trustees Of Columbia University | Method for monitoring periodontal disease by monitoring endotoxins and inflammatory agents |
| EP0362998A2 (en) * | 1988-09-07 | 1990-04-11 | Minnesota Mining And Manufacturing Company | Monoclonal antibodies specific for eikenella corrodens |
| WO1992020715A1 (en) * | 1991-05-16 | 1992-11-26 | Associates Of Cape Cod, Inc. | Endotoxin binding and neutralizing protein and uses thereof |
| WO1995013094A1 (en) * | 1993-11-10 | 1995-05-18 | Bristol-Myers Squibb Company | Treatment of bacterially-induced inflammatory diseases |
| JP2005140618A (en) * | 2003-11-06 | 2005-06-02 | Lion Corp | Method for estimating fluctuation of biochemical parameter, and method for predicting onset risk of lifestyle-related disease |
Non-Patent Citations (1)
| Title |
|---|
| Subcell Biochem Vol.53, 2010, Ding and Ho, "Endotoxin detection--from limulus amebocyte lysate to recombinant factor C." pp. 187-208, doi: 10.1007/978-90-481-9078-2_9 * |
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| Publication number | Publication date |
|---|---|
| WO2017186571A1 (en) | 2017-11-02 |
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