WO2017033897A1 - Iii型高脂血症の判定を補助する方法 - Google Patents
Iii型高脂血症の判定を補助する方法 Download PDFInfo
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- WO2017033897A1 WO2017033897A1 PCT/JP2016/074402 JP2016074402W WO2017033897A1 WO 2017033897 A1 WO2017033897 A1 WO 2017033897A1 JP 2016074402 W JP2016074402 W JP 2016074402W WO 2017033897 A1 WO2017033897 A1 WO 2017033897A1
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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
- G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
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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
- G01N2800/04—Endocrine or metabolic disorders
- G01N2800/044—Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity
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- the present invention relates to a method for assisting determination of type III hyperlipidemia, which is one of the phenotypes of the WHO classification of hyperlipidemia.
- Dyslipidemia is classified as dyslipidemia and refers to an increased state of serum lipids such as cholesterol, phospholipids and free fatty acids.
- Dyslipidemia is a disease that develops arteriosclerosis when left untreated, and develops myocardial infarction and cerebral infarction when it progresses further, leading to death in the worst case. ing. According to the results of the 2010 Ministry of Health, Labor and Welfare National Health and Nutrition Survey, the proportion of suspected dyslipidemia among randomly selected Japanese people over the age of 30 was 22.3% for men and 17.7% for women. It has been reported.
- the standard for dyslipidemia is the serum low density lipoprotein (LDL) -cholesterol (LDL-C ⁇ 140 mg) according to the “arteriosclerotic disease prevention guideline 2012 edition” (hereinafter, also simply referred to as “guideline”) of the Japanese Society for Arteriosclerosis. / DL), serum triglyceride (TG ⁇ 150 mg / dL), serum high density lipoprotein (HDL) -cholesterol (HDL-C ⁇ 40 mg / dL).
- CM chylomicron
- CM remnant chylomicron remnant
- VLDL very low density lipoprotein
- VLDL remnants ultra low density lipoprotein remnants
- LDL low density lipoproteins
- HDL high density lipoproteins
- CM remnants and VLDL remnants are lipoproteins that carry cholesterol into the vascular wall.
- HDL is a lipoprotein that extracts cholesterol from arteriosclerotic lesions.
- RLP is pointed out to be involved in the development of postprandial dyslipidemic arteriosclerotic lesions and is one of the risk factors for arteriosclerosis.
- a partial protein (apoprotein) constituting RLP is composed of exogenous CM and CM remnant including apo B-48, and endogenous VLDL and VLDL remnant including apo B-100.
- Apo B-48 is a peptide having the same amino acid sequence as part of the amino acid sequence of Apo B-100.
- Non-patent document 1 reports the amino acid sequence of Apo B-100 and the amino acid sequence of Apo B-48.
- Anti-apo B-48 specific antiserum is reported in Non-Patent Documents 2-4.
- an anti-apo B-48 monoclonal antibody and a method for measuring blood apo B-48 using the same are reported in Patent Documents 1 and 2, and a calibration curve enabling quantitative measurement of apo B-48.
- a standard solution for preparation is reported in Patent Document 3.
- the phenotype of the hyperlipidemia WHO classification is classified into type I, type IIa, type IIb, type III, type IV, and type V (Reference: Japanese Society for Clinical Laboratory Medicine “Guidelines for Clinical Examination by Diagnosis Group 2003”) pp.118-121).
- Type I is high chylomicronemia
- type IIa is hypercholesterolemia
- type IIb is high cholesterol and hypertriglyceridemia
- type IV is hypertriglyceridemia
- type V is high chylomicron Is hypertension, high VLDL-cholesterolemia.
- type IIa, type IIb, and type IV are particularly common.
- Type III hyperlipidemia (familial ⁇ ⁇ type III hyperlipoproteinemia) is a hypertriglycerideemia and high LDL-cholesterolemia, and has a high risk of leading to arteriosclerosis. It is known that early diagnosis and treatment are very useful.
- the method for determining the phenotype of hyperlipidemia is complicated by operation because it is based on electrophoresis, is not high in throughput, and is difficult to make an objective determination because it is a qualitative method. Therefore, it was not a daily method.
- Non-Patent Document 5 it is useful to use the ratio of Apo B-48 value divided by TG value using the quantitative value of Apo B-48 in blood for the determination of type III hyperlipidemia.
- TG value the ratio of Apo B-48 value divided by TG value
- apo B-48 value / TG ratio was significantly higher in type III than in other phenotypes, clinical diagnosis of type III hyperlipidemia is not There was room for improvement.
- type III hyperlipidemic WHO phenotype III
- the present inventors have measured blood apo B-48 levels as a determination of type III hyperlipidemia, and combined with not only blood TG levels but also LDL-C levels to achieve type III It was found that hyperlipidemia can be determined with high judgment efficiency.
- the present invention includes a step of measuring an Apo B-48 value, a TG value, and an LDL-C value in a blood sample separated from a living body, a ratio obtained by dividing the Apo B-48 value by a TG value, and an Apo B- Calculating the ratio of 48 values divided by LDL-C value, and both the ratio of Apo B-48 value divided by TG value and the ratio of Apo B-48 value divided by LDL-C value are both Provided is a method for assisting the determination of type III hyperlipidemia, wherein a value higher than each cut-off value indicates that there is a high possibility of being type III hyperlipidemia.
- type III hyperlipidemia can be distinguished from other phenotypes by a simpler method than before and with high diagnostic efficiency.
- the ROC curve of Apo B-48 prepared in Comparative Example 1 below (when I, III, and V types are positive) is shown.
- the ROC curve of Apo B-48 prepared in Comparative Example 2 below (when type III is positive) is shown.
- the ROC curve of Apo B-48 / TG prepared in Comparative Example 3 below is shown.
- the ROC curve of Apo B-48 / LDL-C prepared in Comparative Example 4 below is shown.
- the apo B-48 value, TG value, and LDL-C value in a blood sample separated from a living body are measured.
- the Apo B-48 value, TG value, and LDL-C value are values in units of ⁇ g / mL, mg / dL, and mg / dL, respectively. It is not limited to.
- serum or plasma, particularly serum can be preferably used as the blood sample.
- the TG value and LDL-C value are also measured in normal health examinations, and these values can be used. However, in order to improve the accuracy of judgment by eliminating changes over time such as the influence of meals.
- the “living body” that is a supply source of the blood sample to be used for the examination is usually a mammal, preferably a human.
- subjects requiring hyperlipidemia type discrimination are usually dyslipidemic patients.
- patients with dyslipidemia are serum low density lipoprotein (LDL) -cholesterol (LDL-C) ⁇ 140 mg / dL, serum triglyceride (TG) ⁇ 150 mg / dL, or serum high density lipoprotein (HDL) -cholesterol. Patients with (HDL-C) ⁇ 40 mg / dL.
- the measurement of blood apo B-48 value is not particularly limited as long as it is a method capable of quantitatively measuring apo B-48, but an immunoassay method using an antibody specific for apo B-48 is used.
- an immunoassay method using an antibody specific for apo B-48 is used.
- the methods disclosed in Patent Documents 1 to 3 can be used.
- an antibody specific for Apo B-48 it is particularly preferable to use an anti-apo B-48 monoclonal antibody that does not substantially react with Apo B-100.
- the measurement of Apo B-48 can be performed using the chemiluminescent enzyme immunoassay method (CLEIA) based on the following two-step sandwich method, but is not limited to this method.
- CLIA chemiluminescent enzyme immunoassay method
- a serum or plasma sample is treated with a treatment liquid containing a surfactant as a main component to expose apo B-48 in chylomicron and chylomicron remnant.
- this treated sample is added to and reacted with a suspension of anti-apo B-48 monoclonal antibody-binding particle (solid phase; first antibody), and after washing the particles, alkaline phosphatase-labeled apo B monoclonal antibody (first antibody) 2 antibodies) and the reaction is carried out to form a three-component sandwich complex of the first antibody-apo B-48-second antibody in the sample.
- ⁇ TG measurement method> Any known method can be used to measure the blood TG level, but usually, a measurement method using an enzyme method from serum, which is widely used in medical institutions, can be preferably used.
- a method for measuring the TC value and a method for measuring the HDL-C value any known method can be used.
- a cholesterol dehydrogenase (UV) method from serum a direct method widely used in medical institutions. Can be preferably used.
- TG ⁇ 400 mg / dL since an accurate value cannot be calculated, the direct method based on the enzyme reaction may be used without using the F formula.
- the ratio obtained by dividing the Apo B-48 value by the TG value and the ratio obtained by dividing the Apo B-48 value by the LDL-C value are calculated from the measured three values. If any of these ratios is higher than each cut-off value, it can be determined that there is a high possibility of being type III hyperlipidemia.
- each cut-off value can be determined preferably by ROC (Receiver Operating Characteristic) analysis, more preferably by ROC (Receiver Operating Characteristic) analysis using various dyslipidemic patients as a population.
- the ROC analysis is an analysis based on an ROC curve in which the cut-off value is changed, the prevalence rate of prevalence at each cut-off value is plotted on the vertical axis, and the prevalence of 1-no disease is plotted on the horizontal axis. Method of adopting the cut-off value corresponding to the point closest to the point (upper left corner of the graph) where the prevalence rate and the non-practice rate are both 1 as the cut-off value with the highest diagnostic efficiency It is.
- the “prevalence rate” is also called “positive probability rate”, “positive rate” or “sensitivity” and is a value indicating the ratio of the number of cases determined to be positive among true positive cases.
- the “no disease correct diagnosis rate” is also referred to as “negative certainty rate” or “specificity”, and is a value indicating the ratio of the number of cases determined to be no disease among true negative cases.
- each cut-off value is not limited to these values and is usually in the range of these values ⁇ 20%, preferably Is selected from a range of these values ⁇ 10%.
- type III hyperlipidemia can be determined with high diagnostic efficiency by a simple operation of measuring apo B-48 value, TG value, and LDL-C value in a blood sample. it can.
- the method using the ratio obtained by dividing the Apo B-48 value described in Non-Patent Document 5 by the TG value had a diagnostic efficiency of 72%, but the method of the present invention had 89%. It was.
- the “diagnosis efficiency” is also called “correct diagnosis rate” and indicates the ratio of the number of correctly determined cases among all test cases.
- Apo B-48 value, TG value, and LDL-C value were measured for sera of 123 human dyslipidemia patients judged to be dyslipidemia according to the guideline criteria (described above).
- the phenotypic classification of hyperlipidemic WHO was 4 cases of type I, 29 cases of type IIa, 33 cases of type IIb, 11 cases of type III, 23 cases of type IV, and 23 cases of type V.
- the Apo B-48 value was measured using an “Apo Protein B-48 Measurement Kit” (Fujirebio Inc.) and a fully automatic immunoassay device “Lumipulse Forte” (Fujirebio Inc.).
- the TG value was calculated using a normal enzyme method
- the LDL-C value was calculated using a normal F method.
- Comparative Example 1 Create a ROC curve (receiver operating characteristic curve) ( Figure 1) for Apo B-48 values with Type I, Type III, and Type V as positive, Type IIa, IIb, and Type IV as negative.
- a cut-off value of 48 values (10.0 ⁇ g / mL) was determined. Based on the cut-off value, a sample showing a measured value equal to or higher than the cut-off value was assigned as positive, and a sample showing a measured value less than the cut-off value was assigned as negative.
- the positive certainty rate (prevalence of correct diagnosis) of the sorted samples, the negative certainty rate (non-disease correct diagnosis rate) of the sorted samples, and the combined diagnostic efficiency were calculated.
- Comparative Example 2 A type III, positive, type I, type IIa, type IIb, type IV, and type V negative, and creating an ROC curve (receiver operating characteristic curve) (Figure 2) for Apo B-48 values.
- a cutoff value of 48 (15.0 ⁇ g / mL) was determined. Based on the cut-off value, a sample showing a measured value equal to or higher than the cut-off value was assigned as positive, and a sample showing a measured value less than the cut-off value was assigned as negative.
- the positive certainty rate (prevalence of correct diagnosis) of the sorted samples, the negative certainty rate (non-disease correct diagnosis rate) of the sorted samples, and the combined diagnostic efficiency were calculated.
- Comparative Example 3 ROC curve for ratio (Apo B-48 / TG) in which type III is positive, type I, type IIa, IIb, type IV, and type V are negative and apo B-48 value is divided by TG value (Apo B-48 / TG) ) And a cut-off value (0.045) was determined. Based on the cut-off value, a sample showing a measured value equal to or higher than the cut-off value was assigned as positive, and a sample showing a measured value less than the cut-off value was assigned as negative. The positive certainty rate (prevalence of correct diagnosis) of the sorted samples, the negative certainty rate (non-disease correct diagnosis rate) of the sorted samples, and the combined diagnostic efficiency were calculated.
- Comparative Example 4 Ratio of Apo B-48 value calculated from ROC divided by LDL-C value (Apo B-48 / LDL-) with type III positive, type I, IIa type, IIb type IV, type V negative
- An ROC curve (FIG. 4) was created for C) and a cut-off value (0.109) was determined. Based on the cut-off value, a sample showing a measured value equal to or higher than the cut-off value was assigned as positive, and a sample showing a measured value less than the cut-off value was assigned as negative.
- the positive certainty rate (prevalence of correct diagnosis) of the sorted samples, the negative certainty rate (non-disease correct diagnosis rate) of the sorted samples, and the combined diagnostic efficiency were calculated.
- Example 1 Apo B-48 / TG and Apo B-48 / were determined as positive from type III, negative from type I, type IIa, type IIb, type IV, and type V, respectively from the ROC curves (FIGS. 3 and 4). Based on the LDL-C cutoff (0.045 and 0.109, respectively), all specimens showing measured values above the cutoff value are positive, and other specimens are negative, and each specimen is positive or negative. Sorted. The positive certainty rate (prevalence of correct diagnosis) of the sorted samples, the negative certainty rate (non-disease correct diagnosis rate) of the sorted samples, and the combined diagnostic efficiency were calculated.
- Table 1 shows the prevalence of correct diagnosis, the prevalence of no disease, and the diagnosis efficiency of Comparative Examples 1 to 4 and Example 1.
- the diagnostic efficiency of type I, type III, and type V, with the apo B-48 value determined from the ROC curve as a cutoff was 81%.
- the type III diagnosis efficiency was 77% with the apo B-48 value determined from the ROC curve cut off.
- the diagnosis efficiency of type III was 72% with the apo B-48 / TG value calculated from the ROC curve as a cutoff.
- the type III diagnosis efficiency was 79% using the apo B-48 / LDL-C value determined from the ROC curve as a cutoff.
- Example 1 the diagnosis efficiency of type III with the apo B-48 / TG value and the apo B-48 / LDL-C value calculated from the ROC curve cut off was 89%. Higher diagnostic efficiency was demonstrated by using Apo B-48 / TG and Apo B-48 / LDL-C.
- the TG value and LDL-C value of the subject have already been measured when it is determined that the dyslipidemia.
- the method of the present invention measures the apo B-48 value in the same serum sample from which the TG value and LDL-C value were measured, or a serum or plasma sample collected at almost the same time, and the known TG value. It was found that by combining LDL-C values, specifically, using Apo B-48 / TG and Apo B-48 / LDL-C, high type III judgment efficiency was exhibited.
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Abstract
Description
ここで、血液試料としては、血清又は血漿、特に血清を好ましく用いることができる。なお、TG値及びLDL-C値は、通常の健康診断でも測定されており、それらの値を利用することもできるが、食事の影響等の経時変化を排除して判定の正確性を高めるためには、上記3つの値は、単一の血液試料の値を測定することが好ましい。また、検査に供する血液試料の供給源である「生体」は、通常、哺乳動物であり、好ましくはヒトである。また、高脂血症の型判別を必要とする対象は、通常、脂質異常症患者である。なお、ヒト脂質異常症患者は、血清低比重リポ蛋白(LDL)-コレステロール(LDL-C)≧140mg/dL、血清トリグリセリド(TG)≧150mg/dL、又は血清高比重リポ蛋白(HDL)-コレステロール(HDL-C)<40mg/dLの患者である。
血中アポB-48値の測定は、アポB-48を定量的に測定できる方法であれば特に限定されるものではないが、アポB-48に特異的な抗体を用いた免疫測定方法を好適に用いることができ、例えば、特許文献1~3に示す方法を用いることができる。アポB-48に特異的な抗体としては、特に、アポB-100とは実質的に反応しない、抗アポB-48モノクローナル抗体を使用することが好ましい。
血中TG値の測定は、公知の方法をいずれも使用可能であるが、通常、医療機関で広く用いられる、血清からの酵素法による測定方法を好適に使用できる。
LDL-C値の測定は、公知の方法をいずれも使用可能である。LDL-Cは、総コレステロール値(TC)を用いてFriedelwaldの式(F式;(LDL-C)=(TC)-(HDL-C)-(TG/5))により算出するのが通常である。TC値の測定方法、HDL-C値の測定方法は、公知の方法をいずれも使用可能であるが、通常、医療機関で広く用いられる、血清からのコレステロール脱水素酵素(UV)法、直接法をそれぞれ好適に使用できる。しかし、TG≧400mg/dLの場合は、正確な値が算出できないので、F式を用いず、酵素反応を原理とする直接法を用いる事もある。
ガイドラインの基準(上述)で脂質異常症と判断された123例のヒト脂質異常症患者の血清について、アポB-48値、TG値及びLDL-C値を測定した。高脂血症のWHOの表現型分類は、I型4例、IIa型29例、IIb型33例、III型11例、IV型23例、V型23例であった。アポB-48値は、「アポ蛋白B-48測定キット」(富士レビオ株式会社製)と、全自動免疫測定装置「ルミパルスフォルテ」(富士レビオ株式会社製)とを用いて測定した。TG値は通常の酵素法、LDL-C値は通常のF式法を用いて算出した。
I型、III型、V型を陽性とし、IIa型、IIb型、IV型を陰性として、アポB-48値についてROC曲線(受信者動作特性曲線)(図1)を作成し、アポB-48値のカットオフ値(10.0μg/mL)を割り出した。前記カットオフ値を基準として、カットオフ値以上の測定値を示す検体を陽性、カットオフ値未満の測定値を示す検体を陰性として振り分けた。振り分けられた検体の陽性確かさ率(有病正診率)、振り分けられた検体の陰性確かさ率(無病正診率)および合算した診断効率を算出した。
III型を陽性とし、I型、IIa型、IIb型、IV型、V型を陰性とし、アポB-48値についてROC曲線(受信者動作特性曲線)(図2)を作成し、アポB-48値のカットオフ値(15.0μg/mL)を割り出した。前記カットオフ値を基準として、カットオフ値以上の測定値を示す検体を陽性、カットオフ値未満の測定値を示す検体を陰性として振り分けた。振り分けられた検体の陽性確かさ率(有病正診率)、振り分けられた検体の陰性確かさ率(無病正診率)および合算した診断効率を算出した。
III型を陽性とし、I型、IIa型、IIb型、IV型、V型を陰性とし、アポB-48値をTG値で除した比(アポB-48/TG)についてROC曲線(図3)を作成し、カットオフ値(0.045)を割り出した。前記カットオフ値を基準として、カットオフ値以上の測定値を示す検体を陽性、カットオフ値未満の測定値を示す検体を陰性として振り分けた。振り分けられた検体の陽性確かさ率(有病正診率)、振り分けられた検体の陰性確かさ率(無病正診率)および合算した診断効率を算出した。
III型を陽性とし、I型、IIa型、IIb型、IV型、V型を陰性とし、ROCから算出したアポB-48値をLDL-C値で除した比(アポB-48/LDL-C)についてROC曲線(図4)を作成してカットオフ値(0.109)を割り出した。前記カットオフ値を基準として、カットオフ値以上の測定値を示す検体を陽性、カットオフ値未満の測定値を示す検体を陰性として振り分けた。振り分けられた検体の陽性確かさ率(有病正診率)、振り分けられた検体の陰性確かさ率(無病正診率)および合算した診断効率を算出した。
III型を陽性とし、I型、IIa型、IIb型、IV型、V型を陰性とし、それぞれROC曲線(図3及び図4)から割り出したアポB-48/TG、及びアポB-48/LDL-Cのカットオフ(それぞれ0.045、0.109)を基準として、いずれもカットオフ値以上の測定値を示す検体を陽性、それ以外の検体を陰性として、各検体を陽性または陰性に振り分けた。振り分けられた検体の陽性確かさ率(有病正診率)、振り分けられた検体の陰性確かさ率(無病正診率)および合算した診断効率を算出した。
Claims (3)
- 生体から分離した血液試料中のアポB-48値、トリグリセリド値及びLDL-コレステロール値を測定する工程と、
アポB-48値をトリグリセリド値で除した比、及びアポB-48値をLDL-コレステロール値で除した比を算出する工程とを含み、
アポB-48値をトリグリセリド値で除した比及びアポB-48値をLDL-コレステロール値で除した比の両方が共に各カットオフ値よりも高いことが、III型高脂血症である可能性が高いことを示す、III型高脂血症の判定を補助する方法。 - 前記血液試料が血清試料である請求項1に記載の方法。
- 前記アポB-48値を、アポB-48に特異的な抗体を用いて測定する、請求項1または2に記載の方法。
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US15/754,817 US20180252735A1 (en) | 2015-08-26 | 2016-08-22 | Method for assisting determination of type iii hyperlipidemia |
EP16839244.7A EP3343222A4 (en) | 2015-08-26 | 2016-08-22 | METHOD OF ASSISTING DETERMINATION OF TYPE III HYPERLIPIDEMIA |
CN201680048952.8A CN107923909A (zh) | 2015-08-26 | 2016-08-22 | Iii型高脂血症判定的辅助方法 |
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JP3833183B2 (ja) * | 1997-10-15 | 2006-10-11 | 富士レビオ株式会社 | ハイブリドーマ、モノクローナル抗体、測定方法及び免疫測定試薬 |
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AU2007230967A1 (en) * | 2006-03-23 | 2007-10-04 | Breyer, Emelita De Guzman | Apolipoprotein fingerprinting technique |
CN103472240B (zh) * | 2013-08-23 | 2016-03-23 | 上海北加生化试剂有限公司 | 人血脂(血清/血浆)质量管理参比试剂盒及制备方法 |
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2016
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- 2016-08-22 US US15/754,817 patent/US20180252735A1/en not_active Abandoned
- 2016-08-22 JP JP2017536425A patent/JP6704591B2/ja active Active
- 2016-08-22 EP EP16839244.7A patent/EP3343222A4/en not_active Withdrawn
- 2016-08-22 CN CN201680048952.8A patent/CN107923909A/zh active Pending
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JP3833183B2 (ja) * | 1997-10-15 | 2006-10-11 | 富士レビオ株式会社 | ハイブリドーマ、モノクローナル抗体、測定方法及び免疫測定試薬 |
Non-Patent Citations (4)
Title |
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DAISAKU MASUDA: "Family type III Hyperlipidemia, Mechanism and Clinical Feature", PHARMA. MED., vol. 33, no. 8, 20 August 2015 (2015-08-20), pages 29 - 33 * |
See also references of EP3343222A4 * |
SHIN'ICHIRO MIURA ET AL.: "Shishitsu Ijo no Shindan no Susumekata", RINSHO TO KENKYU, vol. 88, no. 10, 20 October 2011 (2011-10-20), pages 1224 - 1228, XP009509008 * |
YUASA-KAWASE MIYAKO ET AL.: "Apolipoprotein B-48 to Triglyceride Ratio Is A Novel and Useful Marker for Detection of Type III hyperlipidemia after Antihyperlipidemic Intervention", J. ANTHEROSCLER. THROMB., vol. 19, no. 9, 2012, pages 862 - 871, XP055365593 * |
Also Published As
Publication number | Publication date |
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EP3343222A1 (en) | 2018-07-04 |
US20180252735A1 (en) | 2018-09-06 |
JP6704591B2 (ja) | 2020-06-03 |
EP3343222A4 (en) | 2019-04-24 |
CN107923909A (zh) | 2018-04-17 |
JPWO2017033897A1 (ja) | 2018-08-16 |
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