CN112245584B - Use of polyphosphate inositol phosphatase 1 as target molecule - Google Patents
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Abstract
The invention discloses an application of MINPP1 as a target molecule in preparing a medicine for resisting HBV-related hepatocellular carcinoma, which inhibits the growth and invasion of HBV-related hepatoma cells by over-expressing or activating MINPP1 gene. The invention proves that the MINPP1 gene can be used as an important target spot for effectively inhibiting the proliferation of HBV-related liver cancer cells.
Description
Technical Field
The invention relates to application of a Polyphosphate Inositol Phosphatase 1(Multiple Inositol Phosphatase 1, MINPP1) gene as a target point for resisting hepatocellular carcinoma related to hepatitis B virus.
Background
The primary liver cancer is caused by canceration of related liver cells in vivo, has the characteristics of high malignancy, easy relapse and metastasis, poorer prognosis and the like, and seriously harms the health of human beings. According to statistics, about 84.1 ten thousand new liver cancer cases and 78.1 ten thousand death cases are found in 2018 worldwide. China is a country with high incidence of liver cancer, and about 46 ten thousand new cases occur every year. According to the pathological tissue type, the primary liver cancer can be divided into hepatocellular carcinoma, intrahepatic cholangiocellular carcinoma and mixed cell carcinoma. Among them, Hepatocellular carcinoma (HCC) is a malignant tumor occurring in liver epithelial cells, and is one of the most common pathological types in primary liver cancer.
The risk factors causing the occurrence and development of liver cancer include viral infection, drinking, obesity, eating moldy food, etc. Among them, Hepatitis and cirrhosis caused by chronic infection of virus and the cases that finally develop into hepatocellular carcinoma account for the main proportion of liver cancer patients in our country, while the problem of hepatocellular carcinoma associated with Hepatitis B Virus (HBV) is particularly serious. According to the existing research, many cell signaling pathways are abnormally regulated in the HBV infection process, and the normal functions of liver cells are influenced, such as a p53 signaling pathway, a MAPK signaling pathway, a PI3K/Akt signaling pathway, a TLR-4/MyD88/NF-kB signaling pathway and the like. However, the pathogenic mechanism of HBV-related hepatocellular carcinoma is not completely disclosed, and the therapeutic approaches include surgical resection, radiotherapy and chemotherapy, and small molecule compound drug therapy. Therefore, there is still a need to find more potential targets to provide new approaches for the treatment of HBV-associated hepatocellular carcinoma.
Inositol Polyphosphate Phosphatase 1 (MINPP 1) is a protein mainly localized in endoplasmic reticulum lumen of cells, and has the main function of hydrolyzing various Inositol phosphates and participating in regulation of biological processes such as vesicle trafficking, cell differentiation and the like. Other functions of MINPP1 have also been reported in recent years: sabine et al in vitro experiments demonstrated that MINPP1 can promote proliferation of a non-small cell lung cancer cell line by dephosphorylating phosphoinositides, i.e., MINPP1 protein can promote proliferation of a non-small cell lung cancer cell line; peak et al disclose that a hypoxia-associated gene comprising MINPP1 can be used for prognostic test in patients with colorectal cancer.
However, the expression of MINPP1 in HBV-associated hepatocellular carcinoma patients and the regulation mechanism of MINPP1 after HBV infects host cells have not been reported yet. In addition, whether MINPP1 can be used as a new target point for resisting HBV-related hepatocellular carcinoma has not been researched yet.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a new target spot which can be effectively applied to the anti-HBV-related hepatocellular carcinoma.
In order to solve the technical problems, the invention provides an application of MINPP1 as a target molecule in preparing a drug for resisting HBV-related hepatocellular carcinoma.
As an improvement of the application of the invention: the growth and invasion of HBV related hepatoma cells are inhibited by over-expressing or activating MINPP1 gene. The mode for over-expressing or activating the MINPP1 gene expression is as follows: the MINPP1 gene is expressed in HBV-related hepatoma cells by an adenovirus vector or a lentivirus vector. Overexpression or activation of MINPP1 in HBV-associated hepatoma cells is mainly achieved by activating the function of MINPP1 in the 2, 3-diphosphoglycerate metabolic bypass, thereby reducing carbohydrate metabolism in cancer cells and thus reducing the growth and invasion of cancer cells.
The invention firstly confirms that the expression level of MINPP1 in hepatocellular carcinoma tissues has obvious correlation with whether the hepatocellular carcinoma is HBV-related or not. According to an embodiment of the present invention, the expression level of MINPP1 in HBV-associated hepatocellular carcinoma was significantly down-regulated compared to non-HBV-associated cellular carcinoma.
Further, the inventors found that MINPP1 has a significant correlation with the growth of HBV-associated hepatoma cells. According to the embodiment of the invention, the growth and invasion capacity of HBV related hepatoma cells can be promoted after the expression of MINPP1 gene is inhibited, and the growth and invasion capacity of HBV related hepatoma cells are obviously inhibited after the MINPP1 gene is over-expressed.
Furthermore, the invention finds that the expression of MINPP1 is mainly inhibited after HBV infects liver cancer cells, and the function of the MINPP1 in glycolysis/gluconeogenesis pathway is inhibited. According to the embodiment of the invention, after the expression of the MINPP1 gene is activated, the sugar metabolism can be inhibited, the generation of lactic acid and 2, 3-diphosphoglycerate can be inhibited, and the growth of tumor cells can be inhibited.
It is to be emphasized that: sabine tells that the MINPP1 protein can promote the proliferation of non-small cell lung cancer cell strains, and the invention is quite different from the invention, and proves that the MINPP1 plays a role in inhibiting the cell proliferation in HBV-related liver cancer cell strains.
The invention has the beneficial effects that: the invention proves that 2, 3-diphosphoglycerate metabolic bypass in glycolysis/gluconeogenesis metabolic pathway is inhibited by activating MINPP1 gene expression (leading MINPP1 gene to be over-expressed) in HBV-related hepatocellular carcinoma, thereby inhibiting the growth and invasion of HBV-related hepatoma cells. The invention proves that the MINPP1 gene can be used as an important target spot for effectively inhibiting the proliferation of HBV-related liver cancer cells.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 is a graph showing the determination of the expression level of MINPP1 in HBV-associated hepatocellular carcinoma tissues and non-HBV-associated hepatocellular carcinoma tissues by real-time fluorescent quantitative PCR; wherein, HBV + positive is HBV-related hepatocellular carcinoma, and HBV + negative is non-HBV-related hepatocellular carcinoma.
FIG. 2 shows the sequencing results of the whole transcriptome of HBV-associated hepatocellular carcinoma tissue and non-HBV-associated hepatocellular carcinoma tissue; wherein, "HBV (+) -T1-T7" represents liver cancer tissue samples of 7 patients with HBV-related hepatocellular carcinoma respectively, and "HBV (-) -T1-T7" represents liver cancer tissue samples of 7 patients with non-HBV-related hepatocellular carcinoma respectively.
FIG. 3 is The results of sequencing data for HBV-associated hepatocellular carcinoma and non-HBV-associated hepatocellular carcinoma in The U.S. tumor Genome map (The Cancer Genome Atlas, TCGA) database; wherein, HBV + positive is HBV-related hepatocellular carcinoma, and HBV + negative is non-HBV-related hepatocellular carcinoma.
FIG. 4 is a graph showing the real-time fluorescence quantitative PCR detection of the expression level of MINPP1 in HBV-related hepatoma cell lines and non-HBV-related hepatoma cell lines;
"Huh 7" is a non-HBV related hepatoma cell line, "Hep 3B" is an HBV related hepatoma cell line (A); and detecting the influence of (B) inhibition or (C) overexpression of MINPP1 gene on the cell proliferation capacity in the HBV-related hepatoma cell strain Hep 3B;
wherein, the 'Control' is a Hep3B cell, the 'siMINPP 1' is a Hep3B cell strain transfected with siRNA capable of inhibiting the expression of MINPP1, and the 'MINPP 1' is a Hep3B cell strain transfected with a plasmid capable of over-expressing MINPP 1.
FIG. 5 is a graph which shows that the scratch test analyzes the effect of HBV-related hepatoma cell line Hep3B on the proliferation and migration rate when the MINPP1 is inhibited or over-expressed;
a is a microscopic shooting picture of the cell growth state at 0h, 24h and 48h after scratching in the scratching experiment, and B is used for counting and calculating the migration rate of the three groups of cells in the graph 5A through ImageJ software;
wherein, the 'Control' is a Hep3B cell, the 'siMINPP 1' is a Hep3B cell strain transfected with siRNA capable of inhibiting the expression of MINPP1, and the 'MINPP 1' is a Hep3B cell strain transfected with a plasmid capable of over-expressing MINPP 1.
FIG. 6 shows the effect of MINPP1 on HBV-associated hepatoma cell proliferation as verified by nude mouse tumorigenicity experiments;
a is the change condition of tumor volume along with time after the tumor cells are inoculated to the nude mice subcutaneously;
the left picture of B is the picture of the experimental group (left, middle) and the control group mice (right) when the tumors are formed for 30 days, and the right picture is the picture of the tumor bodies stripped from the experimental group (below the dotted line) and the control group mice (above the dotted line) when the tumors are formed for 30 days;
wherein, the 'Control' is a mouse inoculated with Hep3B cells, and the 'MINPP 1' is a mouse inoculated with Hep3B cells capable of over-expressing MINPP 1.
FIG. 7 is a graph of the relationship of MINPP1 to the metabolic pathways associated with liver cancer as analyzed by transcriptome sequencing data;
a is to analyze the enrichment of differential genes in the "Glycolysis/Gluconeogenesis", "Sphingolipid signalling pathway", "Sphingolipid metabolism", "protein metabolism" and "Axon metabolism" pathways;
and B is correlation analysis of the difference gene and the metabolic pathway.
FIG. 8 is a graph showing the effect of HBV-associated hepatoma cell line Hep3B on the bypass of 2, 3-diphosphoglycerate metabolism when MINPP1 is inhibited or overexpressed;
in FIG. 8, A is a graph showing the measurement of glucose content in cell supernatants when MINPP1 was inhibited or overexpressed in Hep3B cells; b is measuring the content of lactic acid in cell supernatant when the MINPP1 is inhibited or over-expressed in Hep3B cells; c is to measure the content of 2, 3-diphosphoglycerate in cell supernatant when the MINPP1 is inhibited or overexpressed in Hep3B cells.
"Control" is Hep3B cells, "simrinpp 1" is inhibition of MINPP1 gene in Hep3B cells, "MINPP 1" is overexpression of MINPP1 gene in Hep3B cells.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
In one embodiment of the present invention, clinical samples were provided by the first hospital affiliated with the Zhejiang university medical college, and included 24 patients with HBV-associated hepatocellular carcinoma and 24 patients with non-HBV-associated hepatocellular carcinoma. Patients were confirmed by CT, histopathology and serology methods in combination with the relevant medical history, and the pathological tissues were obtained before treatment and approved by the ethical committee of Zhejiang university.
Description of the drawings: as used herein, the term "non-HBV-associated hepatocellular carcinoma" means that the liver cancer of a patient is caused by a non-HBV infection, and the term "non-HBV-associated hepatocellular carcinoma cell line" means that the liver cancer cell line does not contain any HBV-associated genetic information.
Example 1: determination of MINPP1 expression in HBV-and non-HBV-associated hepatocellular carcinomas
Tumor tissues of 24 cases of HBV-related hepatocellular carcinoma patients and tumor tissues of 24 cases of non-HBV-related hepatocellular carcinoma patients which are excised through surgical operation are respectively collected, and the specimens are placed in a refrigerator at the temperature of minus 80 ℃ for standby after collection. When extracting RNA from the tissue, the sample is taken out from a low-temperature refrigerator and thawed, 1mL of Trizol reagent is added per 100mg, an electric homogenizer is used for homogenization, and the mixture is kept standing for 5min after the homogenization. Adding 200 μ L of chloroform into the sample, shaking vigorously, standing for 5min, and centrifuging at 12000rpm for 15min in a centrifuge with precooling to 4 deg.C. And (3) after centrifugation, allowing the sample to separate, transferring the upper aqueous phase into a new centrifuge tube, adding isopropanol with the same volume, gently mixing uniformly, and standing at room temperature for 20-30 min. The sample in the centrifuge tube was centrifuged again for 10min and the supernatant solution was discarded. 1mL of 75% ethanol (DEPC water) was added to the sample and mixed gently, and then centrifuged at 10000rpm for 5min at 4 ℃. Centrifuging, discarding the supernatant, placing the centrifuge tube in an ultra-clean workbench for 5-10min to naturally dry the sample, adding appropriate amount of DEPC water, dissolving completely, and standing at 80 deg.C for use. After sample preparation, Reverse transcription PCR (RT-PCR) is used to Reverse-transcribe RNA extracted from the tissue into cDNA. To the reaction tube were added 2. mu.L of PCR buffer, 2. mu.L of cDNA, and 8. mu.L of DEPC water. The reaction conditions are as follows: 15min at 37 ℃; at 85 ℃ for 3 min; storing at 4 ℃. After obtaining the cDNA, the expression level of MINPP1 gene was measured by Quantitative real-time PCR (qPCR). mu.L of each of 10. mu.M forward and reverse primers, 0.5. mu.L, 1. mu.L of cDNA, 5. mu.L of LPCR buffer, and 3. mu.L of DEPC water were added to the reaction tube. The reaction conditions are as follows: at 95 ℃ for 30 s; 40 PCR cycles (95 ℃, 30 s; 60 ℃, 30 s); 95 ℃ for 15 s; 60 ℃ for 60 s; 95 ℃ for 15 s. The sequences of the primers used for qPCR were: 5'-GTCGCTCAGCCCCTATTTCG-3', and 5'-TGCGGATCTGTTTGACCGTG-3'.
The qPCR result is shown in FIG. 1, and it can be seen that MINPP1 has lower expression level in HBV-associated hepatocellular carcinoma tissue compared with non-HBV-associated hepatocellular carcinoma, indicating that the expression of the gene in this tissue is inhibited.
Further, 7 random RNA samples from the tissues (HBV-associated hepatocellular carcinoma and non-HBV-associated hepatocellular carcinoma) were sampled and sent to Nuo He Yuan science and technology Co., Ltd for whole transcriptome sequencing and analysis of the differential genes in the sequencing data, the results are shown in FIG. 2. Among genes associated with HBV infection and liver cancer, 9 genes including MINPP1 (ROBO2, ENPP4, PGM2, MINPP1, PIK3R1, SGPL1, LDHC, SMPD1, POLR1E) were lower in expression level in HBV-associated hepatocellular carcinoma tissue compared to non-HBV-associated hepatocellular carcinoma tissue, and the other 10 genes (WNT5A, FSTL4, MLPH, KLHL34, CAPZA3, TBC1D31, KISS1R, HTR4, TP53TG3D, SKIDA1) were higher in expression level in HBV-associated stem cell carcinoma tissue compared to non-HBV-associated stem cell carcinoma tissue. Of these, MINPP1 was most significantly inhibited in HBV-associated hepatocellular carcinoma tissues.
Furthermore, The present invention retrieves The published sequencing data of HBV-related hepatocellular carcinoma and non-HBV-related hepatocellular carcinoma samples from The Cancer Genome Atlas (TCGA) database, and compares The expression levels of The differential gene MINPP1 in different tissues, and as a result, as shown in fig. 3, it can be seen that The expression level of MINPP1 gene in hepatocellular carcinoma tissue caused by HBV is significantly lower than that of non-HBV-related hepatocellular carcinoma.
The above results show that the expression level of MINPP1 gene is closely related to whether it is HBV-induced hepatocellular carcinoma, and the expression level of the gene in HBV hepatocellular carcinoma tissues is significantly negatively regulated.
Example 2: the MINPP1 gene can inhibit the growth and invasion of HBV-related hepatoma cells
In this example, a strain of HBV-related hepatoma cell line Hep3B and a strain of non-HBV-related hepatoma cell line Huh7 were selected and spread on cell culture dishes containing DMEM medium (containing 10% fetal calf serum and 1% penicillin/streptomycin), and placed in a carbon dioxide incubator (37 ℃, 5% CO)2) Culturing until the number of cells is about 1 × 106cells were collected at cell/mL. The RNA of the cells was extracted by the same method as in example 1, and relative expression of MINPP1 was determined in the two cells by RT-PCR and qPCR experiments, and as a result, as shown in a of fig. 4, it can be seen that the expression level of the MINPP1 gene in Hep3B cells was significantly lower than that in Huh7 cells under the same culture conditions.
Further, the effect of MINPP1 on the growth of HBV-associated liver cancer cells was determined by cell proliferation assay reagents. Transfection of siRNA specific for the MINPP1 gene or transfection of a plasmid overexpressing the MINPP1 gene was used to inhibit or activate the expression of the MINPP1 gene in Hep3B cells, and compared to Hep3B cells. The siRNA specific to MINPP1 gene was synthesized by Suzhou Jima Biotech Co., Ltd as one of nucleotide sequences including 5'-CCUGGCAAUUAAAGGUGUUTT-3', 5'-GCAGUUGAACAGAAACAAATT-3' and 5'-CCUCGAACCUGAUAUUUGUTT-3'. The MINPP1 gene overexpression plasmid is constructed by committee of the Industrial bioengineering (Shanghai) Co., Ltd, and the plasmid vector is pcDNA3.1. And respectively adding 10 mu L of CCK8 solution into the cell culture holes at 48h after transfection, placing the culture dish into a carbon dioxide incubator for incubation for 4h, and measuring the absorbance value at 450nm by using an enzyme-labeling instrument. The results are shown in B, C of FIG. 4: it can be seen that the proliferation rate of Hep3B cells was enhanced and significantly higher than the control group (B of fig. 4) after further inhibiting the expression of the MINPP1 gene; while the proliferation rate of Hep3B was significantly reduced after compensating for the expression of the MINPP1 gene in Hep3B cells (C of FIG. 4).
Further, the effect of MINPP1 on the ability of cells to invade was determined by scratch assay. MINPP 1-specific siRNA or a plasmid overexpressing MINPP1 were transfected into Hep3B cells and compared to Hep3B cells. After 24h of transfection, the cell culture dish was scratched with a pipette tip and washed twice with PBS to remove the scraped cells. The growth state of the cells was observed and photographed at 0h, 24h and 48h after scratching, respectively, and the migration area and the mobility of the cells were analyzed and calculated using Image J software. The results are shown in a of fig. 5, and it can be seen from the under-mirror that Hep3B cells transfected with siRNA specific to MINPP1 grew and migrated at a significantly faster rate than the other two groups of cells (24 h after scratching), and at 48h the scratched cells had substantially confluent at both sides. However, the growth and migration rate of Hep3B cells after transfection with plasmid overexpressing MINPP1 was significantly reduced, and the confluency of cells was lowest at 24h and 48h after scratching compared to the control group and the siRNA-inhibited group. It can also be seen by calculating cell mobility that the mobility of Hep3B cells was increased when the expression of the MINPP1 gene was further inhibited by siRNA, and the mobility of Hep3B cells was decreased when the MINPP1 gene was overexpressed (fig. 5B).
The above results indicate that MINPP1 plays a tumor suppressor function in HBV-associated hepatocellular carcinoma, i.e., can suppress the growth and invasion of the associated cancer cells. However, MINPP1 gene was negatively regulated in HBV-associated hepatoma cells, increasing the growth rate of the cells.
Example 3: MINPP1 can inhibit tumor growth in animal models
In this example, the overexpression MINPP1 plasmid was first transfected into Hep3B cells and Hep3B cells were used as controls. Cells were harvested after transfection and cultured with serum-free DMEMResuspending the medium, adjusting to a cell concentration of 2X 107cell/mL, 100. mu.L of the cell suspension was inoculated subcutaneously into nude mice with a syringe, three per group. And (3) observing the tumor formation condition of the nude mice after inoculation and recording the tumor volume, killing the tumor-forming nude mice by using a neck-removing method on the 30 th day after inoculation, and taking pictures and recording after tumor body is stripped. As shown in A of FIG. 6, it can be seen that the tumor volume on the back side of the nude mice inoculated became gradually larger with the lapse of time, the tumor growth rate of the nude mice of the control group became significantly faster at day 13 after the inoculation, and the tumor volume of the nude mice of the control group was about 4 times that of the MINPP1 gene overexpression group by day 30. From the finally stripped tumor body, it can also be seen that the MINPP1 gene overexpression group is significantly smaller than the control group (FIG. 6B).
The results show that the MINPP1 is over-expressed in the HBV-related hepatoma cell strain Hep3B, the growth of tumors at the inoculation part of experimental animals can be effectively slowed down, and the MINPP1 gene can be used as a potential target spot for inhibiting HBV-related hepatocellular carcinoma.
Example 4: MINPP1 is mainly involved in the bypass of 2, 3-diphosphoglycerate metabolism in glycolysis/gluconeogenesis pathway and exerts related functions
In this example, after 7 sequencing of the tissue samples of HBV-related or unrelated hepatocellular carcinoma were first bioinformatically analyzed, and the results are shown in FIG. 7, it can be seen that the differential gene most related to HBV-related hepatocellular carcinoma was mainly enriched in the glycolysis/gluconeogenesis pathway (A in FIG. 7), in which MINPP1 gene is one of the main differential genes involved in the pathway (B in FIG. 7).
Furthermore, the influence of inhibition of MINPP1 gene expression or over-expression of MINPP1 gene on glycolysis/gluconeogenesis pathway in HBV-related liver cancer cell line Hep3B was analyzed by measuring the metabolic conditions of glucose, lactic acid and 2, 3-diphosphoglycerate, respectively. The results are shown in FIG. 8: it can be seen that when the expression of the MINPP1 gene in Hep3B cells was inhibited, glucose metabolism was enhanced and the production of lactic acid and 2, 3-diphosphoglycerate was promoted; when the MINPP1 gene was overexpressed, glucose metabolism and the production of lactate and 2, 3-diphosphoglycerate were reduced.
The above results indicate that MINPP1 is mainly involved in the bypass of 2, 3-diphosphoglycerate metabolism in glycolysis/gluconeogenesis metabolic pathway in HBV-related hepatocellular carcinoma, and activation of MINPP1 in HBV-related hepatoma cell line can effectively reduce carbohydrate metabolism in cancer cells and thus reduce energy acquisition of cancer cells.
Finally, it is also noted that the above-mentioned lists merely illustrate a few specific embodiments of the invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.
Sequence listing
<110> Zhejiang university
<120> use of inositol polyphosphate phosphatase 1 as target molecule
<160> 2
<170> SIPOSequenceListing 1.0
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<211> 20
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
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<213> Artificial Sequence (Artificial Sequence)
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Claims (4)
1. Application of a carrier for over-expressing or activating MINPP1 gene in preparing a drug for resisting HBV-related hepatocellular carcinoma.
2. The use of the vector for overexpression or activation of MINPP1 gene according to claim 1 in the preparation of drugs for anti-HBV related hepatocellular carcinoma, wherein: the growth and invasion of HBV related hepatoma cells are inhibited by over-expressing or activating MINPP1 gene.
3. The use of the vector for overexpression or activation of MINPP1 gene according to claim 2, for preparing a drug for anti-HBV related hepatocellular carcinoma, wherein: the mode for over-expressing or activating the MINPP1 gene expression is as follows: the MINPP1 gene is expressed in HBV-related hepatoma cells by an adenovirus vector or a lentivirus vector.
4. The use of the vector for overexpression or activation of MINPP1 gene according to any one of claims 1 to 3 in the preparation of drugs for anti-HBV related hepatocellular carcinoma, wherein the vector comprises: overexpression or activation of MINPP1 in HBV-associated hepatoma cells is mainly achieved by activating the function of MINPP1 in the 2, 3-diphosphoglycerate metabolic bypass, thereby reducing carbohydrate metabolism in cancer cells and thus reducing the growth and invasion of cancer cells.
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| WO2009126970A1 (en) * | 2008-04-11 | 2009-10-15 | The Translational Genomics Research Institute | Method of assessing sensitivity to brostallicin |
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| WO2009126970A1 (en) * | 2008-04-11 | 2009-10-15 | The Translational Genomics Research Institute | Method of assessing sensitivity to brostallicin |
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