Biomedical subjects

M Naito

Publications and source records attributed to M Naito.

At least 217 records · Page 12Linked to original sources

PubMed1997

Regression of established tumors expressing P-glycoprotein by combinations of adriamycin, cyclosporin derivatives, and MRK-16 antibodies.

BACKGROUND: Overexpression of P-glycoprotein, a transmembrane protein capable of transporting a broad spectrum of anticancer drugs out of cells, likely contributes to tumor drug resistance. Strategies for overcoming this resistance include the use of specific compounds, such as cyclosporin derivatives, that modulate P-glycoprotein function and antibodies that bind to the protein, thereby altering its activity. PURPOSE: We examined the antitumor activity of combination treatment with the anti-P-glycoprotein monoclonal antibody MRK-16, a cyclosporin derivative (either cyclosporin A [CsA] or PSC 833), and the anticancer drug Adriamycin (ADM) against human colorectal carcinoma cells in vitro and established xenografts of these cells in vivo. METHODS: The human colorectal carcinoma cell line HCT-15 and its ADM-resistant subline HCT-15/ADM2-2 were used in this study. Cellular staining with a tetrazolium dye was used to assess the antitumor (i.e., antiproliferative) effects of treatment in vitro. Caliper measurement of tumor volumes was used to assess the antitumor effects of treatment in vivo. Cell surface binding of MRK-16 was measured by means of an immunofluorescence assay. Differences in the patterns of tumor cell growth in vitro and tumor growth rates in vivo were evaluated by means of repeated measure analysis of variance. Synergy in the combined effects of treatment was evaluated by means of the fractional product method. RESULTS: HCT-15 cells were found to express P-glycoprotein intrinsically; HCT-15/ADM2-2 cells expressed approximately five times more P-glycoprotein than the parental cells. HCT-15/ADM2-2 cells were also found to be about eight times more resistant to ADM in vitro than the parental cells. Incubation of both cell types in vitro with either MRK-16 and ADM or one of the cyclosporin derivatives and ADM inhibited cell growth minimally; however, ternary treatment with MRK-16, one of the cyclosporin derivatives, and ADM dramatically reduced the growth of both cell types. An analysis of treatment effects indicated that synergistic effects were obtained with ternary treatment. When athymic mice bearing established tumors (either HCT-15 or HCT-15/ADM2-2) were treated similarly with various combinations of the tested agents, the most pronounced antitumor effects were observed with ternary treatment. In some mice bearing HCT-15/ADM2-2 xenografts, ternary treatment led to complete tumor regression. Finally, CsA and PSC 833 were both shown to enhance MRK-16 binding to HCT-15 cells and HCT-15/ADM2-2 cells in vitro. CONCLUSION: Combination treatment with a cyclosporin derivative and an anti-P-glycoprotein antibody can be effective in circumventing P-glycoprotein-mediated drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Phosphatidylserine externalization is a downstream event of interleukin-1 beta-converting enzyme family protease activation during apoptosis.

Phosphatidylserine (PS), a class of acidic phospholipids, normally localizes on the internal surface of cellular plasma membranes. The internal PS is externalized when cells undergo apoptosis; however, the mechanism for this is largely unknown. To study the mechanism of PS externalization during development of apoptosis, we examined the correlation between the activation of interleukin-1 beta-converting enzyme (ICE) family protease and PS externalization in human monocytic leukemia U937 cells and in their apoptosis-resistant variants, UK711 and UK110, after treatment with etoposide and anti-Fas antibody. We found that PS externalization accompanied the development of apoptosis and the activation of ICE family proteases in these cell lines. Furthermore, inhibitors of ICE family proteases, Z-Asp and Z-VAD, prevented apoptosis and PS externalization in etoposide-treated U937 cells. These results indicate that PS externalization is a downstream event of ICE family protease activation during apoptosis development. Because ICE family proteases play a crucial role in apoptosis, PS externalization could be a rational and useful marker for the development of apoptosis.

Apoptosis↗

PubMed1997

p160ROCK, a Rho-associated coiled-coil forming protein kinase, works downstream of Rho and induces focal adhesions.

p160ROCK is a serine/threonine protein kinase that binds selectively to GTP-Rho and is activated by this binding. To identify its function, we transfected HeLa cells with wild type and mutants of p160ROCK and examined morphology of the transfected cells. Transfection with wild type and mutants containing the kinase domain and the coiled-coil forming region induced focal adhesions and stress fibers, while no induction was observed with a kinase-defective mutant or a mutant containing only the kinase domain. Furthermore, Rho-induced formation of focal adhesions and stress fibers was inhibited by co-expression of a mutant defective in both kinase and Rho-binding activities. Rho, however, still induced an increase in F-actin content in these cells. These results suggest that p160ROCK works downstream of Rho to induce formation of focal adhesions and that Rho-induced actin polymerization is mediated by other effector(s).

Alanine↗

PubMed1997

Actin cleavage by CPP-32/apopain during the development of apoptosis.

Interleukin-1beta-converting enzyme (ICE)/ced-3 family proteases play key roles in apoptosis. However, cellular substrates for ICE family proteases involved in apoptosis are not well understood. We previously showed that actin is cleaved in vitro by an ICE family protease, distinct from ICE itself, which is activated during VP-16-induced apoptosis. In this report, we demonstrate that the actin-cleaving ICE-family protease in the apoptotic cell extract is the activated CPP-32/apopain. CPP-32 effectively cleaves actin protein to 15 kDa and 31 kDa fragments. Studies with an antibody raised against Gly-Gln-Val-Ile-Thr peptide, the N-terminal sequence of the cleaved 15 kDa actin fragment, showed that actin is also cleaved in vivo during the development of apoptosis. Moreover, Benzyloxycarbonyl-Glu-Val-Asp-CH2OC(O)-2,6,-dichlorobenzene (Z-EVD-CH2-DCB), a selective inhibitor of CPP-32(-like) protease, efficiently inhibited the cleavage of actin and the apoptosis of VP-16-treated U937 cells. Our present results indicate that actin is the substrate of CPP-32/apopain(-like) protease both in vitro and in vivo and suggest the role of actin in the control of cell growth and apoptosis.

Actins↗

PubMed1997

Macrophage differentiation and granulomatous inflammation in osteopetrotic mice (op/op) defective in the production of CSF-1.

Since the osteopetrotic (op/op) mouse was demonstrated to have a mutation within the coding region of the CSF-1 gene itself, it serves as a model for investigating the differentiation mechanism of macrophage populations in the absence of functional CSF-1. The op/op mice were severely monocytopenic and showed marked reduction and abnormal differentiation of tissue macrophages. Osteoclasts as well as marginal metallophilic macrophages and marginal zone macrophages in the spleen were absent. Most of the tissue macrophages were reduced in number and ultrastructurally immature. However, the degree of reduction in numbers of macrophages in the mutant mice was variable among tissues, suggesting that the heterogeneity of macrophages was generated by their different dependency on CSF-1. After daily CSF-1 injection, the numbers of monocytes, tissue macrophages, and osteoclasts were remarkably increased, and the macrophages showed morphological maturation. However, the numbers of macrophages in the ovary, uterus, and synovial membrane were not increased. In the bone marrow, macrophage precursors detected by monoclonal antibody ER-MP58 proliferated and differentiated into preosteoclasts and osteoclasts. In the spleen, marginal metallophilic macrophages and marginal zone macrophages developed slowly. In this manner, CSF-1 plays an important role in the development, proliferation, and differentiation of certain tissue macrophage populations and osteoclasts. In the op/op mice, Kupffer cells proliferated, transformed into epithelioid cells and multinucleated giant cells, and participated in glucan-induced granuloma formation. In CSF-1-treated op/op mice, the process of granuloma formation was similar to that in normal littermates due to increased monocytopoiesis and monocyte influx into the granulomas. These results indicate that CSF-1 is a potent inducer of the development and differentiation of CSF-1-dependent monocyte/macrophages, and that CSF-1-independent macrophages also play an important role in granuloma formation.

Animals↗

PubMed1997

The developmental origin of primordial germ cells and the transmission of the donor-derived gametes in mixed-sex germline chimeras to the offspring in the chicken.

A novel system has been developed to determine the origin and development of primordial germ cells (PGCs) in avian embryos directly. Approximately 700 cells were removed from the center of the area pellucida, the outer of the area pellucida, and the area opaca of the stage X blastoderm (Eyal-Giladi and Kochav, 1976; Dev Biol 49:321-337). When the cells were removed from the center of the area pellucida, the mean number of circulating PGCs per 1 microliter of blood was significantly decreased to 13 (P < 0.05) in the embryo at stage 15 (Hamburger and Hamilton, 1951: J Morphol 88:49-92) as compared to intact embryos of 51. When the removed recipient cells from the center of the area pellucida were replenished with 500 donor cells, no reduction in the PGC number was observed. The removal of cells from the outer of area pellucida or from the area opaca had no effect on the number of PGCs. When another set of the manipulated embryos were cultured ex vivo to hatching and reared to sexual maturity, the absence of germ cells and the degeneration of seminiferous tubules were observed in resulting chickens derived from the blastoderm from which the cells were removed from the center of the area pellucida. Chimeric embryos produced by the male donor cells and the female recipient contained the female-derived cells at 97.2% in the whole embryo and 94.3% in the erythrocytes at 5 days of incubation. At 5-7 days of incubation, masculinization was observed in about one half of the mixed-sex embryos. The proportions of the female-derived cells in the whole embryo and in the erythrocytes were 76.5% and 80.2% at 7 days to 55.7% and 62.5% at 10 days of incubation, respectively. When the chimeras reached their sexual maturity, they were test mated to assess donor contribution to their germline. Five of six male chimeras (83%) and three of five female chimeras (60%) from male donor cells and a female recipient embryo from which 700 cells at the center of area pellucida were removed were germline chimeras. Three of the five male germline chimeras (60%) and one of the three female germline chimeras (33%) transmitted exclusively (100%) donor-derived gametes into the offspring. When embryonic cells were removed from the outer of area pellucida or area opaca, regardless of the sex combination of the donor and the recipient, the transmission of the donor-derived gametes was essentially null. The findings in the present studies demonstrated, both in vivo and in vitro, that the PGCs originate in the central part of the area pellucida and that the developmental fate to germ cell (PGCs) had been destined at stage X blastoderm in chickens.

Animals↗

PubMed1997

Macrophage differentiation and expression of macrophage colony-stimulating factor in murine milky spots and omentum after macrophage elimination.

To elucidate the differentiation mechanisms of macrophages in the murine omentum, we studied the repopulation of these cells and the expression of macrophage colony-stimulating factor (M-CSF) in the milky spots and omental tissues in mice depleted of macrophages following administration of liposome-encapsulated dichloromethylene diphosphonate (clodronate). The macrophages in the omentum were spindle or dendritic in shape, expressed several macrophage-specific antigens and Ia antigen, and phagocytized intraperitoneally injected carbon particles. In the milky spots, macrophages and macrophage precursors were detected, and the number of precursors increased after elimination of macrophages by intraperitoneal injection of liposome-encapsulated clodronate. Macrophage precursors in the milky spots proliferated, moved to the omentum, and transformed into dendritic-shaped macrophages. Expression of M-CSF mRNA extracted from the milky spots was markedly enhanced at 2 and 3 days after macrophage depletion. Localization of M-CSF protein and mRNA was observed in the stromal cells of the milky spots. In osteopetrosis (op/op) mutant mice that are defective in the production of functional M-CSF omental macrophages were absent. These results indicate that M-CSF locally produced in the milky spots plays an important role in providing a microenvironment for development and differentiation of omental macrophages.

Animals↗

PubMed1997

Species-specific B-cell epitope on the C-terminal region of the alpha antigen from Mycobacterium scrofulaceum.

In the amino acid (AA) sequences of alpha antigen from mycobacteria, C-terminal regions were variable among a variety of mycobacterial species though the N-terminal regions were relatively conserved. These regions may possess some species-specific antigenic determinants of the alpha antigen from Mycobacterium scrofulaceum (S-alpha). AAs288-300 of S-alpha fused to beta-galactosidase was reactive with the antisera raised against S-alpha. The same fused peptide did not react with the antisera raised against the alpha antigen from Mycobacterium avium (A-alpha) and Mycobacterium bovis BCG (B-alpha). B-cell epitope mapping then was performed focusing on the C-terminal region of S-alpha using the synthetic peptides. Their reactivities with antisera raised against the alpha antigens of three different mycobacterial species were assessed by ELISA. AAs279-286 were a cross-reactive common immunodominant region among three mycobacterial species. This region may be one of the cross-reactive common epitopes in mycobacterial species. And AAs291-300 were reactive only with the antisera raised against S-alpha. This region may possess a species-specific epitope.

Amino Acid Sequence↗

PubMed1997

Self-compressive osteotomy of the greater trochanter.

We have designed a dihedral osteotomy of the greater trochanter which is V-shaped with the apex infero-medially. A single screw is used for fixation. The osteotomy was used in 24 hips (23 patients), as part of a transtrochanteric approach for acetabular reconstruction, carried out for dysplasia or in complicated acetabular fractures. There were no cases of nonunion or painful bursitis at an average follow up of 20 months. The method provides a stable reduction and bony union because of the self-compressive effect of the abductor muscles.

Acetabulum↗

PubMed1997

New multidrug-resistance-reversing drugs, MS-209 and SDZ PSC 833.

The emergence of multidrug resistance (MDR) is a major problem in cancer chemotherapy. Many compounds have been developed to reverse MDR, and some of them are undergoing clinical trials. Among them, MS-209, a novel quinoline derivative, is one of the most potent MDR-reversing agents: MS-209 at 3 microM effectively reverses MDR in various cell lines in vitro. MS-209 directly interacts with P-glycoprotein (Pgp) and inhibits Pgp-mediated drug transport. Oral administration of MS-209 combined with anticancer drugs significantly increases the life span of mice bearing MDR tumor cells without causing serious side effects. SDZ PSC 833, a non-immunosuppressive analogue of cyclosporin A (CsA), is another potent MDR-reversing drug. Interestingly, the MDR-reversing activity of SDZ PSC 833 is enhanced in vitro and in vivo by MRK-16, a monoclonal antibody that recognizes an extracellular epitope of Pgp. Since MRK-16 promotes immune responses to MDR tumor cells expressing Pgp, the combined use of MRK-16, SDZ PSC 833, and antitumor drugs could be an effective therapeutic modality to reverse MDR.

Animals↗

PubMed1997

Characteristics of macrophage-derived foam cells isolated from atherosclerotic lesions of rabbits.

It is generally accepted that the foam cells in atherosclerotic lesions are derived mainly from monocytes/macrophages. We investigated whether the macrophage-derived foam cells, isolated from the atherosclerotic lesions of cholesterol-fed rabbits, would exhibit properties similar to those of blood monocytes in vitro and whether the cholesterol concentration of the macrophage-derived foam cells would decrease in the presence of an appropriate cholesterol acceptor in culture. We found that most (> 98%) of the foam cells isolated from atherosclerotic lesions were positive for anti-monocyte-macrophage antibody and nonspecific esterase. While almost all (> 98%) of the foam cells exhibited NaF-resistant, nonspecific esterase activity, the blood monocytes exhibited no such activity. Macrophage-derived foam cells contained larger amounts of cholesterol, most of it esterified, than the blood monocytes. Although blood monocytes exhibited a substantial amount of lysozyme, the freshly isolated, macrophage-derived foam cells showed no detectable lysozyme activity. The production of superoxide by macrophage-derived foam cells stimulated by PMA or opsonized zymosan was lower than that of stimulated monocytes. The cholesterol concentration of macrophage-derived foam cells decreased during five days of culture in the presence of an appropriate acceptor, such as normal and hypercholesterolemic rabbit serum and high density lipoprotein, although the rate of decrease was slow. Results suggest that macrophage-derived foam cells may be involved in both the progression and the regression of early atherosclerotic lesions.

Animals↗

PubMed1997

Characterization and sensitivity to interleukin 2 and interferon alpha of leukemic cells from a patient with large granular lymphocytic leukemia associated with chronic active Epstein-Barr virus infection.

A patient presented with chronic large granular lymphocyte leukemia associated with chronic active Epstein-Barr virus infection (CAEBV). Cell cycle analysis revealed a minimal growth compatible with chronic lymphocytic leukemia After 5 months of treatment, the patient died from acute transformation of the leukemia. Cell harvested during chronic phase were analyzed for sensitivity to interleukin 2 (IL-2) and interferon alpha (IFN alpha) in vitro by means of surface phenotyping and cell cycle assay. IL-2 induced remarkable growth of the cells, whereas IFN alpha did not confer a growth advantage. Since IFN alpha was expected to have no growth induction effect on the leukemia cells, it was administered to the patient to treat the CAEBV.

Antineoplastic Agents↗

PubMed1997

Circulating matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as serum markers of fibrosis in patients with chronic hepatitis C. Relationship to interferon response.

BACKGROUND/AIMS/METHODS: The imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) is considered to be an important determinant of extracellular matrix deposition and breakdown. We measured serum MMP-1, MMP-2, TIMP-1 and TIMP-2 levels using the respective one-step sandwich enzyme immunoassays in 98 patients with chronic hepatitis C treated with interferon beta to examine their clinical significance for assessment of liver histology and to determine whether they can be useful as predictors of the interferon response. RESULTS: Serum TIMP-1 levels showed a positive correlation with the degree of fibrosis (r(s)=0.30, p= 0.004). Serum MMP-2 levels revealed positive relationships with the degree of periportal necrosis (r(s)= 0.32, p=0.002), the degree of fibrosis (r(s)=0.26, p= 0.01) and total score of histological activity index (r(s)=0.24, p=0.02). Serum MMP-2 levels were significantly higher in patients with no response than in those with sustained and transient response (p<0.01 and p<0.05, respectively), while serum MMP-1 levels did not differ among the three groups. Compared with the levels in sustained responders, the total amounts of serum TIMP-1 were significantly lower in transient responders and non-responders (p<0.01 and p<0.001, respectively). As for serum TIMP-2 levels, a significant decrease was found in transient responders and non-responders (p<0.01). The ratios of serum MMP-2 to TIMP-1 levels were significantly higher in transient responders and non-responders than in sustained responders (p<0.001, respectively) even when HCV RNA levels were low in patients with HCV genome subtype 1b or when the HCV genome subtype was 2a or 2b. Sustained response was never found in type 1b patients with ratios of serum MMP-2 to TIMP-1 levels of over 6.0. In logistic multivariate regression analysis, the ratios of serum MMP-2 to TIMP-1 level (p=0.0001), HCV genome subtype (p=0.005) and serum TIMP-2 level (p=0.03) were the independent predictors for sustained response, while serum MMP-2 level (p=0.0006) was the only predictor for no response. CONCLUSIONS: Serum MMP-2 and TIMP-1 levels might be useful for estimating the degree of liver fibrosis. The ratio of serum MMP-2 to TIMP-1 levels may serve as a new predictor of interferon response in patients with chronic hepatitis C.

Alanine Transaminase↗

PubMed1997

Interaction of cyclosporin derivatives with the ATPase activity of human P-glycoprotein.

1. P-glycoprotein, a 170-180 kDa membrane glycoprotein that mediates multidrug resistance, hydrolyses ATP to efflux a broad spectrum of hydrophobic agents. In this study, we analysed the effects of three MDR reversing agents, verapamil, cyclosporin A and [3'-keto-Bmt1]-[Val2]-cyclosporin (PSC 833), on the adenosine triphosphatase (ATPase) activity of human P-glycoprotein. 2. P-glycoprotein was immunoprecipitated with a monoclonal antibody (MRK-16) and the P-glycoprotein-MRK-16-Protein A-Sepharose complexes obtained were subjected to a coupled enzyme ATPase assay. 3. While verapamil activated the ATPase, the cyclosporin derivatives inhibited both the substrate-stimulated and the basal P-glycoprotein ATPase. No significant difference was observed between PSC 833 and cyclosporin A on the inhibition of basal P-glycoprotein ATPase activity. PSC 833 was more potent than cyclosporin A for the substrate-stimulated activity. 4. Kinetic analysis indicated a competitive inhibition of verapamil-stimulated ATPase by PSC 833. 5. The binding of 8-azido-[alpha-32P]-ATP to P-glycoprotein was not altered by the cyclosporin derivatives, verapamil, vinblastine and doxorubicin, suggesting that the modulation by these agents of P-glycoprotein ATPase cannot be attributed to an effect on ATP binding to P-glycoprotein. 6. The interaction of the cyclosporin derivatives with ATPase of P-glycoprotein might present an alternative and/or additional mechanism of action for the modulation of P-glycoprotein function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Induction of in vitro nuclear apoptosis activity coincides with the production of 50 kDa cytosolic protein.

Human monocytic leukemia U937 cells undergo apoptosis when cells are treated with the anticancer drug etoposide. To study the mechanism of drug-induced apoptosis, we used an in vitro apoptosis system with cytosol from etoposide-treated U937 cells. The cytosol from apoptotic U937 cells showed activity to induce morphologic changes and oligonucleosomal DNA fragmentation in isolated nuclei in vitro; both are typical features of apoptosis. We generated monoclonal antibodies to the proteins in the etoposide-treated U937 cytosol. We found that a 50 kDa protein, recognized by SN-1 monoclonal antibody, appeared in the cytosol of U937 cells, in accordance with its cell-free apoptosis activity. Z-Asp, an inhibitor of interleukin-1beta converting enzyme (ICE) family proteases, inhibited the appearance of the 50 kDa protein and the emergence of the cell-free apoptosis activity in the etoposide-treated U937 cytosol. These results indicate that the 50 kDa protein is produced by the activation of ICE family protease during apoptosis and suggest some roles of the protein in the development of apoptosis.

Journal Article↗

PubMed1997

Differentiation of female chicken primordial germ cells into spermatozoa in male gonads.

In avian species, the developmental fate of different-sex germ cells in the gonads is unclear. The present study attempted to confirm whether genetically female germ cells can differentiate into spermatozoa in male gonads using male germline chimeric chickens produced by the transfer of primordial germ cells (PGC), and employing molecular biological methods. As a result of Southern hybridization, specific sequences of the W chromosome (the female specific sex chromosome in birds) were detected in the genomic DNA extracted from one out of four male germline chimeric chickens. When two-color in situ hybridization was conducted on the spermatozoa of this germline chimera, 0.33% (average) of the nuclei of each semen sample showed the fluorescent signal indicating the presence of the W chromosome. The present study shows that female PGC can differentiate into spermatozoa in male gonads in the chicken. However, the ratio of produced W chromosome-bearing (W-bearing) spermatozoa fell substantially below expectations. It is therefore concluded that most of the W-bearing PGC could not differentiate into spermatozoa because of restricted spermatogenesis.

Animals↗

PubMed1997

Transcriptional analysis of the groESL operon from Porphyromonas gingivalis.

Transcriptional analysis of the groESL operon from Porphyromonas gingivalis, one of the obligative anaerobic oral microorganisms implicated in adult periodontitis, was performed. P. gingivalis 381 cultured at 37 degrees C was shifted to 42 degrees C, 45 degrees C or 48 degrees C for 10 mins. Northern hybridization analysis revealed that a band with 2.1-kb (kilo base pair) was observed, and the transcripts increased greatly by heat shock. Primer extension and S1 mapping detected four different 5'-ending sites of the mRNAs at the upstream region of the groES. Three sites out of the four were heat-inducible. There were inverted repeats and a Escherichia coli sigma 32-recognizing consensus sequence in the promoter region of the groESL, which may be relevant to the regulation of transcription of groESL operon in P. gingivalis. Both a heat shock promoter and inverted repeats may be relevant to the transcriptional regulation of the groESL operon in P. gingivalis.

Bacterial Proteins↗

PubMed1997

A case of multiple myeloma producing granulocyte colony-stimulating factor.

A case of multiple myeloma (IgA-lambda) with marked granulocytosis, which measured up to 9.9 x 10(4)/mm3, is described. Matured neutrophils were predominant and blasts were not found in the peripheral blood. The serum granulocyte colony-stimulating factor (G-CSF) was notably elevated. The disease ran a chronic course and granulocytosis and elevated serum G-CSF continued. The patient developed atelectasis and bronchopneumonia, and died of respiratory failure. At autopsy, bone marrow showed marked myeloid hyperplasia in varying states of differentiation. The enlarged spleen also disclosed numerous myeloid cells of varying differentiation. Small aggregations of atypical plasma cells were present in the marrow and spleen. Immunohistochemically, atypical plasma cells were positive for anti-G-CSF antibody, which indicated G-CSF secretion from the myeloma cells. To our knowledge, this is the first reported case of G-CSF-producing multiple myeloma.

Biomarkers, Tumor↗