Search

This paper proposes the forward-backward spatial smoothing with overlapped and augmented arrays (FBSSOA) to improve the conventional spatial smoothing for DOA (Direction-Of-Arrival) estimation. The computer simulation using FBSSOA with MUSIC demonstrates the effectiveness of the FBSSOA in improving the estimation accuracy and the angular resolution of MUSIC.

Despite recent advances in therapeutic modalities for autoimmune disease (AID) or allogeneic organ transplant, the resultant increase in the number of long-term survivors with sustained immunologic...

Epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are common in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). The aim of the present study was to develop a simple and versatile tool to determine EGFR and KRAS mutations for pre-clinical research in the laboratory. We developed a melting curve analysis to detect exon 19 deletion, L858R mutation, and T790M mutation of EGFR, and codon 12/13 and codon 61 mutations of KRAS using LightCycler480 with mutation-specific sensor and anchor probes. The analytical method was applicable to determine the approximate rate of heterogeneity of mutation in the genomic DNA of cancer cell lines. In conclusion, our melting curve analysis is a rapid and semi-quantitative method to screen for exon 19 deletion, L858R or T790M mutations of EGFR and codon 12/13/61 mutations of KRAS in cancer cell lines.

We recently reported an internal tandem duplication of the human flt3 receptor gene (FLT3) as a somatic mutation in 17% of acute myelogenous leukemia (AML). The present study revealed the duplication at the juxtamembrane and the first tyrosine kinase domains of FLT3 in seven of 92 (8%) patients with myelodysplastic syndrome (MDS) and AML with trilineage myelodysplasia (AML/TMDS), the diseases which may represent neoplastic changes of pluripotent stem cells. A tandem duplication of exon 11 of FLT3 was harbored by two of 58 (3%) patients with MDS and five of 34 (15%) with overt leukemia, including MDS-derived leukemia, AML/TMDS and therapy-related leukemia. Although the duplicated regions varied within exon 11 in each case, they occurred in-frame, and altered mRNA expressions were demonstrated by reverse-transcription polymerase chain reaction. Two cases of MDS with a FLT3 duplication transformed to overt leukemia within a few months. Longitudinal analyses in two other patients with leukemia revealed that the duplication was a late genetic event during the disease course; one of whom showed two independent duplications of FLT3 at the terminal therapy-resistant phase. Of seven patients with the FLT3 duplication, six had abnormal karyotypes, and four harbored a point mutation of the N-RAS and/or TP53 genes. Patients with FLT3 mutations have poor prognoses. This study uncovered the fact that the accumulation of genetic events, including FLT3 duplication, correlates with leukemic transformation from antecedent myelodysplasia and with subsequent disease progression.

We propose a method for measuring effects of surface roughness on transmission characteristics eliminating the manufacturing error. We verified the structure using electromagnetic simulation and measured three different types of surface roughness.

Objective We retrospectively investigated the efficacy and predictive factors for the treatment outcomes of bortezomib plus dexamethasone (BD) as second-line induction therapy prior to high-dose chemotherapy sup- ported by autologous stem cell transplantation (HDT/ASCT) in multiple myeloma (MM) patients. Methods Sixty-six transplant eligible MM patients treated by the Kyoto Clinical Hematology Study Group between 2006 and 2011 were investigated. Conventional induction chemotherapy, including vincristine, dox- orubicin and dexamethasone (VAD) and high-dose dexamethasone (HDD), was used as first-line induction therapy in all patients, seven (10.6%) of whom attained a very good partial response (VGPR). Of the 59 pa- tients who did not attain VGPR with VAD or HDD, 33 were given BD as second-line induction therapy prior to HDT/ASCT. Results Patients not treated with BD induction showed an overall response rate (ORR, i.e., better than par- tial response) of 85.3% after induction therapy, while the ORR of patients treated with BD induction im- proved from 42.4% after conventional induction therapy to 84.8% after BD. The overall survival (OS) and progression-free survival (PFS) of patients not treated with BD induction were not significantly influenced by the response to induction therapy. Among the patients treated with BD, failure in attaining VGPR prior to ASCT was associated with a significantly shorter PFS and it also tended to show a shorter OS, while the dis- ease stage and achievement of a complete response after HDT/ASCT had no impact on OS or PFS. Conclusion The achievement of at least VGPR with second-line BD induction therapy is a prerequisite for attaining longer OS and PFS after HDT/ASCT.

In this research, bump-shaped Vertically Aligned Multi-walled Carbon Nanotubes (VA-CNTs) were bonded to Au substrate as flip-chip interconnect, and the behaviors of the VA-CNT bumps under compression pressure were studied. The resistance of the bonded VA-CNT bumps with load was decreased under compression pressure. In this model, it is considered that the VA-CNTs were deformed permanently by the friction among the VA-CNTs. In order to solve the cause of the permanent deformation of the VA-CNT bumps, the friction among the CNTs during the compression is calculated.

The incidence of Hodgkin lymphoma (HL) is paradoxically increasing in the combination anti-retroviral therapy (cART) era. However, there has been no nationwide survey of human immunodeficiency virus (HIV)-associated HL (HIV-HL) in Japan. We retrospectively examined the clinical characteristics and outcomes of 19 newly diagnosed HIV-HL patients at 11 HIV/AIDS and hematology regional hospitals in Japan between 1991 and 2010. At the time of HL diagnosis, 79 % of patients were receiving cART. All the patients, but one received HL diagnoses in the cART era. The median CD4+ cell count at HIV-HL diagnosis was 169/μl. Mixed-cellularity classical Hodgkin lymphoma was the most common subtype occurring in 68 % of the patients; 89 % of the patients were positive for Epstein–Barr virus. Of these 19 patients, 84 % were in advanced stages, with bone marrow involvement observed in 47 % of the patients; 58 % had extranodal sites. All the treated patients were given cART concurrent with HL therapy. The complete remission rate of the treated patients was 87 %. The median OS of the entire cohort was 17 months. These results suggest that the characteristics of HIV-HL in Japan are more aggressive than those of non-HIV-associated HL in Japan, but standard chemotherapy is effective and feasible.

Recombinant human erythropoietin (rhEPO) has been used in the EU and the United States for the treatment of anemia in cancer patients after myelosuppressive chemotherapy or radiotherapy. However, several conflicting results have been reported concerning the detrimental effect of rhEPO on survival benefit in cancer patients. In experimental studies, contradictory results were also reported in in vitro tumor cell proliferation studies and in vivo tumor growth studies using tumor cells expressing EPO-receptor (EPO-R). Therefore, we tried to clarify the effect of epoetin β, a product of rhEPO, on tumor growth in xenograft models using five EPO-R-positive human cancer cell lines, namely the MCF7 breast, 786-O renal, SCH gastric, A549 lung and SK-OV-3 ovarian cancer cell lines. Epoetin β was administered once a week for 3 weeks at doses of 1,000, 3,000 and 10,000 IU/kg in accordance with the clinical administration schedule and dosages. As a result, no enhancement of tumor growth from the administration of epoetin β was observed in any of the xenograft models throughout the experiment duration. The effect of epoetin β on the antitumor activity of bevacizumab, an anti-angiogenic agent, was additionally examined using A549 and MCF7 xenograft models, since rhEPO reportedly stimulates tumor neovascularization. Epoetin β showed no significant effect on the antitumor activity of bevacizumab in either xenograft model. These findings suggest that epoetin β is not involved in in vivo tumor growth promotion.

Erlotinib is used as a standard treatment for recurrent advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations in NSCLC have been shown to be a predictive factor of erlotinib, although the relationship between K-ras oncogene (KRAS) mutations and erlotinib resistance is controversial. Recently, in vitro sequence-dependent interactions of erlotinib and docetaxel have been studied on as a novel therapeutic approach against NSCLC. The purpose of the present study was to determine the optimum novel regimen of erlotinib and docetaxel against NSCLC cells which have EGFR mutation (HCC827 cells), KRAS mutation (A549 cells) or both wild-type (NCI-H292 cells). First, we analyzed the effects of in vitro combination for cell proliferation-inhibition using a combination index. In all cell lines, docetaxel followed by erlotinib treatment showed nearly additive effects. On the other hand, erlotinib followed by docetaxel treatment showed remarkable antagonistic interactions. Second, we examined the effect of combinations on the in vitro apoptosis induction. Erlotinib followed by docetaxel treatment reduced apoptosis induction compared with docetaxel alone; in contrast, docetaxel followed by erlotinib treatment had no inhibitory effects on docetaxel-induced apoptosis in any of the cell lines. Finally, an in vivo tumor growth inhibition test was performed using xenograft models. Docetaxel followed by erlotinib administration resulted in significant tumor growth inhibition compared with erlotinib or docetaxel monotherapy in all models. In conclusion, we demonstrated that docetaxel followed by erlotinib therapy was a potentially optimum regimen against NSCLC regardless of the mutation status of EGFR and KRAS.

We demonstrate, for the first time, carbon nanotube (CNT) flip chip bumps for LSI modules. The CNT bump is composed of a bundle of multi-walled CNTs. Resilient and flexible CNT bumps make flip chip LSI modules resistant to thermal stress. Furthermore, CNT bumps have a low electrical resistance and robustness over electromigration. In the experiment, the CNT bumps were used to connect a test evaluation group (TEG) chip and a host substrate, and their electrical resistance was evaluated. We found that the electrical contacts of CNT bumps with the chip and the substrate are important. For a good electrical contact, the CNT bumps were coated with gold and fixed to the chip and substrate. The resultant CNT bump with a diameter of 170 mum and a height of 100 mum exhibited a low resistance of 2.3 Omega. We then evaluated the flexibility of CNT bumps by pressing the TEG chip and measuring the displacement. The displacement between the TEG chip and host substrate was 10-20% of the bump height, demonstrating an excellent flexibility.

Background The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show notable effects for non-small cell lung cancers (NSCLC) harboring EGFR activating mutations. However, almost all patients eventually acquire resistance to EGFR-TKIs within several years. The major mechanisms of acquired resistance including 2nd mutation of T790M and amplification of MET have been identified. However, the mechanisms of other resistance remain unclear. In this study, we established novel erlotinib-resistant NSCLC cells and examined their resistant mechanisms. Methods NSCLC HCC827 cells have an EGFR Exon 19 deletion and gene amplification and are highly sensitive to erlotinib. The resistant cells were established by continuously exposing HCC827 cells to 0.1, 1 or 10 µM of erlotinib in 96 well plates for three months. The resistant mechanisms were determined by direct sequence analysis and EGFR FISH analysis. Results The fourteen and three resistant cells were established by 0.1 µM and 1 µM of erlotinib exposure, respectively. No resistant cells appeared in the wells of 10 µM of erlotinib. The IC50 values of these resistant cells were more than 25-fold higher than that of parental cells. No 2nd mutation of T790M was detected in any of the resistant cells and MET gene amplification was detected in only one resistant cells. Instead, we found that 13/17 resistant cells were dominated by EGFR not amplified cells and one of resistant cells B10 consisted of more than 99.9% of EGFR not amplified cells, and that the parental cells consisted of only 2.5% of EGFR not amplified cells and 97.5% of EGFR amplified cells. EGFR not amplified clone 4D8 isolated from parental cells and showed resistance to erlotinib comparable to the resistant cells B10. Furthermore, we found that EGFR not amplified cells were constantly emerged from EGFR amplified clone isolated from parental cells under normal cell culture condition. Conclusion Loss of amplified EGFR gene with mutation causes acquired resistance in HCC827 cells when exposed to relatively low concentration of erlotinib while high concentration of erlotinib deprives HCC827 cells of the chance of emergence of resistant cells. Disclosure All authors have declared no conflicts of interest.

Introduction: Usefulness of autologous stem cell transplantation (ASCT) for diffuse large B-cell lymphoma (DLBCL) has been established. However, relapse after ASCT even at complete remission (CR) remains to be crucial. We evaluated outcome of such patients concerning the intervals from ASCT to relapse. Patients and methods: Among 77 patients who received ASCT at CR between 1997 and 2013, 26 relapsed. Their age ranged from 39 to 74 with a median of 58. They included 23 at first CR and 3 second CR. We retrospectively analyzed clinical records to investigate survival outcome. Results: Induction chemotherapy was CHOP-like regimen with or without rituximab (R). 3 patients with second CR had received MECP as re-induction therapy. Stem cells were mobilized by high-dose etoposide and MCVC was used as a conditioning regimen. Most patients had nodal relapse, but 4 patients (15.4%) at central nervous system and one (3.8%) at testis. Patients had received 1 to 4 regimens of salvage therapy, i. e., MECP, CHASE, or DHAP. CR was achieved in 3 patients (11.5%) and PR in 2 (7.7%), resulting in overall response rate of 19.2%. With observation periods of 4 to 198 months (median 22), 1-year overall survival (OS) was 50%. Although OS was significantly poor in patients who relapsed within a year after ASCT, survival from relapse was not different. Discussion: These results suggest that relapse rate after ASCT should be reduced since highly refractory disease might emerge after myeloablative therapy. Deeper remission is required and prophylaxis of sanctuary region appears to be more widely considerable in first-line therapy.

Aim: Bevacizumab (Bev) is a humanized anti-human VEGF monoclonal antibody (Ab), and maintaining VEGF inhibition with Bev plus chemotherapy beyond progression (BBP) has had clinical benefits in patients with metastatic colorectal cancer. However the mechanism of BBP is still unknown and, although some chemotherapeutic agents have been shown to modulate the host immune response against malignancies, the role of chemotherapy in BBP is also unknown. In this study, we examined the mechanism of BBP. Methods: Murine Lewis lung carcinoma (LLC) was s.c. inoculated into C57BL/6 or CCR2-/- knockout (KO) mice. Mice were randomly allocated to control and treatment groups after tumor formation. Anti-VEGF Ab (5 mg/kg, weekly) and anti-G-CSF Ab (10 µg/day, daily) were i.p. administered, and capecitabine (Cape) (718 mg/kg, daily) was p.o. administered for 18 days. Cytokine levels were analyzed by ELISA and cytometric bead array. Myeloid-derived suppressor cells (MDSC) were identified as CD11b +/Gr1 high by flow cytometry. Microvessel density (MVD) was determined by CD31-immunostaining. Results: The LLC model showed resistance to anti-VEGF Ab as previously reported [1]. In this model, anti-VEGF Ab increased the intratumor infiltration by MDSC expressing PD-L1. In addition, a significant increase in G-CSF and CCL2 was observed in the tumors. Although anti-G-CSF Ab did not affect tumor growth, anti-G-CSF combined with anti-VEGF significantly reduced tumor growth compared with anti-VEGF alone. The number of intratumor MDSC was significantly decreased in the combination group compared with the anti-VEGF group. However, no difference in the number of intratumor MDSC induced by anti-VEGF was observed in CCR2 KO mice compared with wild type mice. Adding Cape to anti-VEGF abolished both MDSC and the intratumor G-CSF level, and significantly reduced tumor growth compared with either monotherapy. MVD in the combination group was significantly reduced compared with the anti-VEGF group. Conclusions: Add-on Cape abolished MDSC by decreasing intratumor G-CSF, suggesting that the mechanism of BBP may be that chemotherapy recovers the anti-angiogenic effect of Bev. [1] Nature Biotechnology 25, 911-20 (2007). Disclosure: T. Iwai: COI Disclosure: Research funding from Chugai Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.

We examined homozygous deletion, point mutation and expression of DPC4 gene, a recently isolated candidate pancreatic tumor suppressor gene, in 53 patients with myelogenous leukemias and 5 cell lines. The patients consisted of 34 cases of chronic myelogenous leukemia including 22 in the chronic phase, 3 in the accelerated phase, and 9 in blastic crisis, and 19 with acute myelogenous leukemia including 9 at the initial presentation and 10 at relapse. Polymerase chain reaction (PCR)-based deletion analysis for DPC4 exon 8 and PCR-single strand conformation polymorphism study for the entire coding region were carried out. Homozygous deletion or subtle mutation was not detected in any of the samples examined. However, 3 patients with various clinical phases showed a decrease of DPC4 expression. These results suggest that DPC4 alteration is not a crucial event in the development or the progression of myelogenous leukemias.

In this study, we examined a large number of patients to clarify the distribution and frequency of a recently described FLT3 tandem duplication among hematopoietic malignancies, including 112 acute myelocytic leukemia (AML), 55 acute lymphoblastic leukemia (ALL), 37 myelodysplastic syndrome (MDS), 20 chronic myelogenous leukemia (CML), 30 non-Hodgkin's lymphoma (NHL), 14 adult T cell leukemia, 15 chronic lymphocytic leukemia (CLL) and 38 multiple myeloma (MM). We also evaluated 71 cell lines derived from 11 AML, 31 ALL, two hairy cell leukemia, three acute unclassified leukemia, 10 CML, 12 NHL including six Burkitt's lymphoma, and two MM. Using genomic PCR of exon 11 coding for the juxtamembrane (JM) domain and first amino acids of the 5'-tyrosine kinase (TK) domain, this length mutation was found only in AML (22/112, 20%) and MDS (1/37). According to the FAB subclassification, they were 5/18 (28%) of M1, 4/29 (14%) of M2, 3/17 (18%) of M3, 6/24 (25%) of M4, 4/20 (20%) of M5 and 1/9 of refractory anemia with excess of blast in transformation. In the various cell lines examined, this abnormality was determined in only one derived from AML and never found in other hematological malignancies. The sequence analysis of the abnormal PCR products revealed that 23 of 24 showed internal tandem duplication with or without insertion of nucleotides. In one AML, insertion and deletion without duplication was determined. All 24 lengthened sequences were in-frame. Duplication takes place in the sequence coding for the JM domain and leaves the TK domain intact. In conclusion, we emphasize that the length mutation of FLT3 at JM/TK-I domains were restricted to AML and MDS. Since all these mutations resulted in in-frame, this abnormality might function for the proliferation of leukemic cells.

Multiple myeloma has seldom been reported to complicate tumor lysis syndrome since it is an indolent disease. We report a case with multiple myeloma who rapidly developed tumor lysis syndrome after conventional induction therapy. A 63-year-old Japanese woman presented with dyspnea on effort was diagnosed as IgA-lambda type myeloma. According to the International Staging System, her stage was defined as III because of elevated serum beta-2 microglobulin at 72mg/L. Remission induction consisted of continuous intravenous administration of vincristine of 0.4mg/day and adriamycin of 15mg/day through days 1 to 4 and infusion of dexamethasone of 40mg/day on days 1-4 was given. On day 7, she felt general fatigue and loss of appetite and her serum uric acid, creatinine, and potassium elevated to 898.1μmol/L, 9.8mg/dL, and 6.7mmol/L, respectively. Inversely, serum calcium decreased to 2.0mmol/L. Under the diagnosis of tumor lysis syndrome, she was treated with hydration and diuretics, resulted in immediate regression of her symptoms and recovery of laboratory data. Besides conventional chemotherapy, newly introduced agents have also been reported to cause tumor lysis in myeloma. While previous description has identified renal dysfunction to play a crucial role in the development of tumor lysis syndrome, myeloma often complicates impaired renal function. Since International Staging System is widely applied for myeloma patients, beta-2 microglobulin that represents renal function is thought to be examined in most of them. Taken together, elevated beta-2 microglobulin appears to easily predict a risk for tumor lysis syndrome. Thus, we postulate that prevention for excessive tumor lysis should be considered for myeloma patients with elevated beta-2 microglobulin.

Background Assessing HER2 status accurately and reliably is of great importance in optimizing treatment of HER2-positive breast or gastric cancer. In gastric cancer, for which trastuzumab treatment has been recently approved in Japan, immunohistochemistry (IHC) is the standard method for evaluating the HER2 level. In this study, we examined the impact of formalin fixation conditions on HER2 staining using xenografted tumor samples from mouse models. Methods Mice (BALB-nu/nu) were subcutaneously inoculated with two human gastric cancer cell lines, SCH (score 2+) and SNU-16 (score 1+). Xenograft tumor tissues were collected and left at room temperature for 0, 6 or 24 h before being fixed with 10% neutral buffered formalin for 24 h, 5, 7 or 10 days and then embedded in paraffin. To examine the effect of fixing solution on HER2 IHC, we used 10 and 20% neutral-buffered or non-buffered formalin or Ufix (Sakura Finetek Japan). HER2 IHC was carried out according to the Hercep test. We assessed the effect on IHC by examining the atrophy of tumor cells, autolysis of tumor tissues, immunostaining intensity and immunostaining area. Results Continuous staining of HER2 on the cell membrane with moderate intensity was observed in SCH tumors, whereas partly localized staining on the cell membrane with weak immunostaining intensity was seen in SNU-16. Leaving samples for 6 h before fixation at room temperature decreased immunostaining intensity and induced atrophy of peripheral tumor tissues in both SCH and SNU-16 specimens. Leaving the specimens for 24 h before fixation induced autolysis of tumor tissues and reduced the immunostaining intensity. On the other hand, fixation in 10% neutral buffered formalin for more than 5 days diminished the HER2-stained area in SNU-16 samples. Fixing in 20% neutral buffered or in 10 or 20% non-buffered formalin reduced the staining intensity by prolonged fixation. Ufix did not influence the staining area, but atrophied the tumor cells. Conclusion Our results suggest that the timing of fixation, including when it starts and how long it takes, will influence the HER2 staining. Non-buffered or highly concentrated formalin also might affect the IHC result. It is important to optimize the conditions of sample collection and fixation.

e18091 Background: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show notable effects for non-small cell lung cancers (NSCLC) harboring EGFR activating mutations. However, almost all patients eventually acquire resistance to EGFR-TKIs within several years. The major mechanisms of acquired resistance are acquisition of a secondary EGFR mutation T790M and amplification of MET. However, the mechanisms of other resistance remain unclear. In this study, we established novel erlotinib-resistant NSCLC cells and examined their resistant mechanism. Methods: Resistant cells were established by continuously exposing EGFR mutated NSCLC cells HCC827 to 0.1, 1 or 10 μM of erlotinib in 96 well plates for three months. The resistant mechanisms were determined by direct sequence analysis and EGFR FISH analysis. Results: Resistant cells were emerged from 14/96 and 3/96 wells by 0.1 μM and 1 μM of erlotinib exposure, respectively. No resistant cells appeared in the wells of 10 μM of erlotinib. The IC50 values of these resistant cells were more than 100-fold higher than that of parental cells. No secondary mutation of T790M was detected in any of the resistant cells. Instead, we found that 13/17 resistant cells were dominated by EGFR not amplified cells and one of resistant cells B10 consisted of more than 99.9% of them, while the parental cells consisted of 2.5% of EGFR not amplified cells. Then, we isolated EGFR not amplified clone 4D8 from parental cells and found that this clone also had a resistance to erlotinib comparable to the resistant cells B10. Metaphase FISH analysis showed that EGFR amplified cells in parental cells had a chromosome 7 containing multiple copies of EGFR, while EGFR not amplified cells in B10 did not have it. Furthermore, we found that EGFR not amplified cells were constantly emerged from EGFR amplified clone isolated from parental cells under normal cell culture condition. Conclusions: Loss of a chromosome 7 containing multiple copies of EGFR causes acquired resistance in HCC827 cells when exposed to relatively low concentration of erlotinib, while high concentration of erlotinib deprives HCC827 cells of the chance of emergence of resistant cells.

We describe the development of a phase-locked laser system tailored to an ion-trap-based quantum information processor with (40)Ca(+). Laser outputs from an extended cavity diode laser and a Ti:sapphire laser with output laser wavelengths of approximately 850 and 854 nm, respectively, were phase locked and used to excite a Raman transition between the D(3/2) and D(5/2) metastable states qubit. Development and the performance of the laser system are described. We also compare the characteristics and the benefits of the developed qubit coupling with those in the conventional approaches.

Previous preclinical and clinical findings have suggested a potential role of epidermal growth factor receptor (EGFR) in osteoclast differentiation and the pathogenesis of bone metastasis in cancer. In this study, we investigated the effect of erlotinib, an orally active EGFR tyrosine kinase inhibitor (TKI), on the bone invasion of human non-small-cell lung cancer (NSCLC) cell line NCI-H292. First, we established a novel osteolytic bone invasion model of NCI-H292 cells which was made by inoculating cancer cells into the tibia of scid mice. In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction. Erlotinib treatment suppressed osteoclast activation to the basal level through suppressing receptor activator of NF-κB ligand (RANKL) expression in osteoblast/stromal cell at the bone metastatic sites, which leads to inhibition of osteolytic bone destruction caused by NCI-H292 cells. Erlotinib inhibited the proliferation of NCI-H292 cells in in vitro. Erlotinib suppressed the production of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), IL-8, IL-11 and vascular endothelial growth factor (VEGF) in NCI-H292 cells. Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro. In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells.

Introduction Deletions of chromosome 7 are often detected in myelodysplastic syndrome. The most commonly deleted segments are clustered at band 7q22. A critical gene is therefore suggested to be located in this region. We report a patient with myelodysplastic syndrome whose marrow cells carried an inversion of 7q22 and q36 as a sole karyotypic abnormality. How this extremely rare chromosomal aberration contributes to the pathogenesis of myelodysplastic syndrome should be clarified by accumulating clinical data of such cases. Case presentation A 74-year-old Japanese man presented with pancytopenia incidentally detected by routine medical check-up. His complete blood cell counts revealed that his white blood cells had decreased to 2100/mm3, neutrophils 940/mm3, red blood cells 320×104/mm3, hemoglobin 11.1g/dL, hematocrit 33.1%, and platelets 12.6×104/mm3. Bone marrow examination showed normal cellularity with nucleated cells of 9.4×104/mm3. The proportion of blasts was 4%. A morphological examination showed only basophilic stippling of erythroblasts which was seen as dysplasia. According to World Health Organization classification, the diagnosis was myelodysplastic syndrome-u. Karyotypic analysis showed 46,XY,inv(7)(q22q36) in all of 20 metaphases examined. Additional analysis revealed the karyotype of his lymphocytes was 46,XY. He is asymptomatic and cytopenia has slowly progressed. Conclusions To the best of our knowledge, this karyotype from a clinical sample of de novo malignancies has never been documented although the identical karyotype from secondary myelodysplastic syndrome was reported. Despite the extremely low frequency, inversion of 7q22 appears to play a crucial role for myelodysplastic syndrome in this patient.

A broadband parallel-wire meander line deflection circuit has been devised. It has relatively flat deflection characteristics in the range 4–17.5 GHz. A dispersion equation for this circuit is derived by considering the phase delay at the bend of the wire, which can estimate the experimental results fairly well.