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1.  Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing 
Blood Cancer Journal  2012;2(7):e79-.
The IRE1α-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1α phosphorylation, it prevented IRE1α-induced XBP1 mRNA cleavage in vitro. Thus, toyocamycin is an inhibitor of IRE1α-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy.
doi:10.1038/bcj.2012.26
PMCID: PMC3408640  PMID: 22852048
multiple myeloma; ER stress; IRE1α; XBP1; toyocamycin; adenosine analog
2.  Potent antitumor effects of bevacizumab in a microenvironment-dependent human lymphoma mouse model 
Blood Cancer Journal  2012;2(4):e67-.
We established a mouse model of microenvironment-dependent human lymphoma, and assessed the therapeutic potential of bevacizumab, an antitumor agent acting on the microenvironment. NOD/Shi-scid, IL-2Rγnull (NOG) mice were used as recipients of primary tumor cells from a patient with diffuse large B-cell lymphoma (DLBCL), which engraft and proliferate in a microenvironment-dependent manner. The lymphoma cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Injection of bevacizumab together with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) significantly increased necrosis and decreased vascularization in the tumor, compared with CHOP alone. Levels of human soluble interleukin-2 receptor (sIL2R) in the serum of bevacizumab+CHOP-treated mice (reflecting the DLBCL tumor burden) were significantly lower than in CHOP recipients. Mice receiving bevacizumab monotherapy also showed significant benefit in terms of tumor necrosis and vascularization, as well as decreased serum sIL2R concentrations. The present DLBCL model reflects the human DLBCL in vivo environment more appropriately than current mouse models using established tumor cell lines. This is the first report to evaluate the efficacy of bevacizumab in such a tumor microenvironment-dependent model. Bevacizumab may be a potential treatment strategy for DLBCL patients.
doi:10.1038/bcj.2012.12
PMCID: PMC3346682  PMID: 22829969
bevacizumab; NOD/Shi-scid; IL-2Rγnull (NOG) mouse; lymphoma; tumor microenvironment
3.  Circulating concentrations of cardiac proteins indicate the severity of congestive heart failure 
Heart  2003;89(11):1303-1307.
Objective: To test the hypothesis that myocardium specific proteins may be useful markers for evaluating the severity of congestive heart failure.
Methods: Serum concentrations of myosin light chain I (MLC-I), heart fatty acid binding protein (H-FABP), creatine kinase isoenzyme MB (CK-MB), and troponin T (TnT) and plasma concentrations of brain natriuretic peptide (BNP) were determined in 48 patients with acute deterioration of congestive heart failure, both before and after effective treatment.
Results: Before treatment, MLC-I (mean (SEM) 3.2 (2.2) μg/l), H-FABP (9.0 (3.5) μg/l), TnT (30 (21) ng/l), and BNP (761 (303) ng/l) were higher than the normal reference range, and concentrations of CK-MB (5.4 (2.9) μg/l) were near normal. Treatment of congestive heart failure with conventional medication significantly decreased the concentrations of MLC-I (1.2 (0.3) μg/l, p < 0.0001), H-FABP (6.0 (2.0) μg/l, p < 0.0001), CK-MB (2.9 (1.5) μg/l, p < 0.0001), TnT (9 (1) ng/l, p < 0.001), and BNP (156 (118) ng/l, p < 0.0001). The decreases in H-FABP and CK-MB concentrations after treatment correlated with the decrease in BNP concentrations (p < 0.05). The absolute concentrations of MLC-I, H-FABP, CK-MB, and TnT correlated positively with those of BNP (p < 0.01).
Conclusions: These findings suggest that MLC-I, H-FABP, CK-MB, and TnT may be used as reliable markers for the evaluation of the severity of congestive heart failure.
PMCID: PMC1767943  PMID: 14594884
brain natriuretic peptide; creatine kinase isoenzyme MB; heart fatty acid binding protein; myosin light chain I; troponin T
4.  Transforming growth factor ß1 gene polymorphism in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2002;61(9):826-828.
Method: A total of 155 patients with RA and 110 healthy subjects were studied. DNA was extracted from peripheral leucocytes and TGFß1 codon 10 T869C polymorphism was determined by polymerase chain reaction restriction fragment polymorphism.
Results: A significantly higher proportion of patients with RA with the T allele (CT type or TT type) was found compared with the CC type (p=0.039).
Conclusion: The T allele, previously reported to be linked with production of TGFß1, may be associated with an increased risk of RA.
doi:10.1136/ard.61.9.826
PMCID: PMC1754235  PMID: 12176809
5.  Non-specific interstitial pneumonia as pulmonary involvement of systemic sclerosis 
Annals of the Rheumatic Diseases  2001;60(3):281-283.
The pathological features of lung disease in nine patients with systemic sclerosis (SSc) were evaluated. The patients comprised one man and eight women, with a median age of 58 years. SSc was diagnosed according to the criteria of the American Rheumatism Association. In all patients, high resolution computed radiographic scanning of the lungs (HRCT) was performed, and apparent honeycomb formation was seen in four patients. Pathologically, four patients were diagnosed with usual interstitial pneumonia (UIP), three with non-specific interstitial pneumonia (NSIP) group II, one NSIP group II-III, and one NSIP group II with diffuse alveolar damage. HRCT showed no apparent honeycomb formations in patients diagnosed with NSIP. This is the first report describing NSIP as a pulmonary complication of SSc.


doi:10.1136/ard.60.3.281
PMCID: PMC1753571  PMID: 11171693
6.  Complex intrachromosomal rearrangement in the process of amplification of the L-myc gene in small-cell lung cancer. 
Molecular and Cellular Biology  1992;12(4):1747-1754.
The L-myc gene was first isolated from a human small-cell lung cancer (SCLC) cell line on the basis of its amplification and sequence similarity to c-myc and N-myc. A new mechanism of L-myc activation which results from the production of rlf-L-myc fusion protein was recently reported. On the basis of our earlier observation of a rearrangement involving amplified L-myc in an SCLC cell line, ACC-LC-49, we decided to investigate this rearrangement in detail along with the structure of L-myc amplification units in five additional SCLC cell lines. We report here the identification of a novel genomic region, termed jal, which is distinct from rlf and is juxtaposed to and amplified with L-myc during the process of DNA amplification of the region encompassing L-myc. Long-range analysis using pulsed-field gel electrophoresis revealed that the amplified L-myc locus is involved in highly complex intrachromosomal rearrangements with jal and/or rlf. Our results also suggest that the simultaneous presence of rearrangements both in rlf intron 1 and in regions immediately upstream of L-myc may be necessary for the expression of rlf-L-myc chimeric transcripts.
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PMCID: PMC369618  PMID: 1312669

Results 1-6 (6)