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Multiple myeloma (MM) is an incurable hematopoietic neoplasm derived from plasma cells, and existing in the bone marrow. Recent developments in the field of myeloma onco‐biology have enabled the use of proteasome inhibitors (PIs) as key drugs for MM. PIs can increase cell sensitivity to endoplasmic reticulum stress, leading to apoptosis of myeloma cells. PI cannot kill all myeloma cells, however; one reason of this might be activation of autophagy via hypoxic stress in the bone marrow microenvironment. Hypoxia‐inducible gene(s) that regulate autophagy may be novel therapeutic target(s) for PI‐resistant myeloma cells. Here, a hypoxia‐inducible glycolytic enzyme hexokinase‐2 (HK2) was demonstrated to contribute by autophagy activation to the acquisition of an anti‐apoptotic phenotype in myeloma cells. We found that hypoxic stress led to autophagy activation accompanied by HK2 upregulation in myeloma cells. Under hypoxic conditions, HK2 knockdown inhibited glycolysis and impaired autophagy, inducing apoptosis. The cooperative effects of a PI (bortezomib) against immunodeficient mice inoculated with HK2‐knocked down myeloma cells were examined and significant tumor reduction was observed. An HK2 inhibitor, 3‐bromopyruvate (3‐BrPA), also induced apoptosis under hypoxic rather than normoxic conditions. Further examination of the cooperative effects between 3‐BrPA and bortezomib on myeloma cells revealed a significant increase in apoptotic myeloma cells. These results strongly suggested that HK2 regulates the activation of autophagy in hypoxic myeloma cells. Cooperative treatment using PI against a dominant fraction, and HK2 inhibitor against a minor fraction, adapted to the bone marrow microenvironment, may lead to deeper remission for refractory MM., Contribution of the HK2‐autophagy pathway to cell survival of myeloma in an hypoxic microenvironment and complementary effects of conventional and hypoxia‐targeting therapies.

Improperly secured furniture, especially on the upper floors of high‐rise buildings under long‐period ground motion, can prove dangerous to human life. Fallen items of furniture such as chairs and desks could become fatal obstacles that prevent efficient evacuation. In this research, an effective numerical code for analyzing the motion of furniture subjected to seismic excitations was developed. The numerical code is based on the adaptively shifted integration — Gauss technique, which is a finite element scheme that provides higher computational efficiency than the conventional code. The frictional contact between objects was fully considered by employing a sophisticated penalty method. Various excitation tests of furniture were conducted on a shake‐table. In the experiments, steel cabinets were excited by seismic waves and displacement data were recorded by a motion capture system. The numerical results were validated through a comparison with the shake‐table test results.

Multiple myeloma (MM) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow and its microenvironment. A hypoxic niche is located within the microenvironment, which causes myeloma cells to become quiescent, anti-apoptotic, glycolytic, and immature. Cell heterogeneity may be related to distinct gene expression profiles under hypoxic and normoxic conditions. During hypoxia, myeloma cells acquire these phenotypes by downregulating interferon regulatory factor 4 (IRF4), an essential transcription factor in myeloma oncogenesis. To identify essential microRNAs and their targets regulated under hypoxic conditions, we undertook microRNA and cDNA microarray analyses using hypoxia-exposed primary MM samples and myeloma cell lines. Under hypoxia, only miR-210 was highly upregulated and was accompanied by direct downregulation of an 18S rRNA base methyltransferase, DIMT1. This inverse expression correlation was validated by quantitative RT-PCR for primary MM samples. We further determined that DIMT1 has an oncogenic potential as its knockdown reduced tumorigenicity of myeloma cells through regulation of IRF4 expression. Notably, by analyzing gene expression omnibus datasets in the National Center for Biotechnology Information database, we found that DIMT1 expression increased gradually with MM progression. In summary, by screening for targets of hypoxia-inducible microRNA-210, we identified DIMT1 as a novel diagnostic marker and therapeutic target for all molecular subtypes of MM.

MicroRNA (miRNA) are non‐coding regulatory RNA usually consisting of 20−24 nucleotides. Over the past decade, increases and decreases in miRNA expression have been shown to associate with various types of disease, including cancer. The first two known miRNA aberrations resulted from altered expression of DLEU2 and C13orf25 in hematological malignancies. DLEU2, which encodes miR‐15a and miR‐16‐1, was discovered from 13q14 deletion in chronic lymphocytic leukemia, while C13orf25, which encodes six mature miRNA (miR‐17, miR‐18, miR‐19a, miR‐19b, miR‐20a and miR‐92a), was identified from 13q31 amplification in aggressive B‐cell lymphomas. These miRNA were downregulated or upregulated in accordance with genomic deletion or amplification, which suggests that they contribute to tumorigenesis through altered regulation of target oncogenes or tumor suppressors. Consistent with that idea, miR‐15a/16‐1 is known to regulate Bcl2 in chronic lymphocytic leukemia, and miR‐17‐92 regulates the tumor suppressors p21, Pten and Bim in aggressive B‐cell lymphomas. Dysregulation of other miRNA, including miR‐21, miR‐29, miR‐150 and miR‐155, have also been shown to play crucial roles in the pathogenesis of aggressive transformed, high‐grade and refractory lymphomas. Addition of miRNA dysregulation to the original genetic events likely enhances tumorigenicity of malignant lymphoma through activation of one or more signaling pathways.

This paper presents the results of a probabilistic evaluation of the seismic performance of 3D steel moment-frame structures. Two types of framing system are considered: one-way frames typical of construction in the United States and two-way frames typical of construction in Japan. For each framing system, four types of beam–column connections are considered: pre-Northridge welded-flange bolted-web, post-Northridge welded-flange welded-web, reduced-beam-section, and bolted-flange-plate connections. A suite of earthquake ground motions is used to compute the annual probability of exceedence (APE) for a series of drift demand levels and for member plastic-rotation capacity. Results are compared for the different framing systems and connection details. It is found that the two-way frames, which have a larger initial stiffness and strength than the one-way frames for the same beam and column volumes, have a smaller APE for small drift demands for which members exhibit no or minimal yielding, but have a larger APE for large drift demands for which members exhibit large plastic rotations. However, the one-way frames, which typically comprise a few seismic frames with large-sized members that have relatively small rotation capacities, may have a larger APE for member failure. The probabilistic approach presented in this study may be used to determine the most appropriate frame configuration to meet an owner's performance objectives. Copyright © 2008 John Wiley & Sons, Ltd.

The c13orf25/miR-17 cluster, which is responsible for 13q31-q32 amplification in malignant lymphoma, contains the microRNA-17-18-19-20-92 polycistron. A previous study demonstrated that this polycistron could modulate tumor formation following transplantation of microRNA 17-19b into Eu-myc mice. Another study reported that Myc can upregulate the miR-17 cluster by binding directly upstream of the miR-17 locus. These findings suggest that Myc and the miR-17 cluster synergistically contribute to cancer development. In the study presented here, we observed recurrent 13q31-32 amplification in MYC-rearranged lymphomas (11 of 47 cases). Quantitative real-time polymerase chain reaction analysis of c13orf25 for MYC-rearranged lymphomas demonstrated that cases with 13q31-32 amplification showed significantly higher expression of c13orf25 than cases without such amplification, although cases without 13q31-32 amplification still showed slight upregulation of c13orf25. To investigate the relationship between Myc and the miR-17 polycistron in tumorigenesis, we engineered rat fibroblasts (Rat-1) that constitutively express the miR-17 polycistron (miR), Myc, or both miR and Myc. The highest level of miR expression was detected in Rat-1 transfected with both miR and Myc, whereas Myc transfectant cells alone also showed slight upregulation of miR. Furthermore, we demonstrated that nude mice injected with Rat-1 transfected with both miR and Myc presented more accelerated tumor growth than those injected with Myc transfectant cells. These results suggest that miR is stably upregulated in the presence of constitutive expression of Myc, and that the deregulation of miR and Myc synergistically contribute to aggressive cancer development, probably by repressing tumor suppressor genes.

Approximately 70% of gastric mucosa-associated lymphoid tissue (MALT) lymphomas can be successfully treated with H. pylori eradication. The translocation t(11;18)(q21;q21) characteristic of MALT lymphoma is recognized as a marker for H. pylori independency, but this marker is found in only a half of the MALT lymphomas resistant to H. pylori eradication. Detailed analyses of the genomic features of eradication resistant as well as responsive groups are important for understanding their molecular basis. We performed array-based comparative genomic hybridization (array-CGH) for 29 gastric MALT lymphomas treated with H. pylori eradication. These comprised ten cases of t(11;18) positive MALT, nine cases of t(11;18) negative MALT with H. pylori dependency, and ten cases of t(11;18) negative MALT with H. pylori independency. Array-CGH analysis demonstrated that no significant genetic alterations were found in t(11;18) positive MALT lymphomas, but numerous genomic alterations were detected in t(11;18) negative MALT lymphomas. Many of these alterations were similar to those found in diffuse large B-cell lymphoma with trisomy 3 being the most recurrent alteration. Within the t(11;18) negative MALT lymphoma without large cell components group, genomic imbalances occurred more frequently in the H. pylori independent than in the H. pylori dependent group (P = 0.02). Genomic imbalances are associated with H. pylori independency in t(11;18) negative gastric MALT lymphomas. They may thus play an important role in the development of H. pylori independency.

Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of non-Hodgkin's lymphomas and is known to comprise heterogeneous groups. We previously reported that CD5+ DLBCL is a clinically distinct subgroup of these tumors that is associated with poor prognosis. In our current study, we have used gene expression profiling technology in an attempt to identify new markers and to further characterize the biological features of CD5+ DLBCL. Candidate genes, which showed the greatest difference in expression between 22 CD5+ and 26 CD5− DLBCL cases, were selected from our screening and subjected to clustering analysis. This resulted in identification of a specific mRNA profile (a CD5 signature) for CD5+ DLBCL. The CD5 signature included downregulated extracellular matrix genes such as POSTN, SPARC, COL1A1, COL3A1, CTSK, MMP9 and LAMB3, and comprised upregulated genes including TRPM4. We tested this CD5 signature for its potential use as a relevant marker for CD5+ DLBCL and found that it did indeed recognize this subgroup. The tumors identified by the CD5 signature contained most of the CD5+ DLBCL cases and some CD5− DLBCL cases. Moreover, the subgroup of cases with this CD5 signature showed a poorer prognosis. The subsequent application of the CD5 signature to the analysis of an independent series of DLBCL microarray data resulted in identification of a subgroup of DLBCL cases with a similar clinical outcome, further suggesting that the CD5 signature can be used as a clinically relevant marker of this disease. (Cancer Sci 2006; 97: 868–874)

Acute promyelocytic leukemia (APL) is typically associated with the t(15;17) that generates the PML–RARA fusion protein. Animal models have shown that although the fusion protein is necessary, it is insufficient for the development of APL, implying that additional mechanisms are responsible for full-blown leukemia. The mutation of specific genes has been implicated in leukemogenesis; however, alterations in gene copy number have not been well investigated. Here, we applied the genomewide array-comparative genomic hybridization technique to 30 APL clinical samples and 2 APL cell lines. It was found that (1) approximately half the clinical samples (14 of 30 APL cases) had no detectable chromosomal imbalances; and (2) the remaining 16 cases, including the cell lines, exhibited recurrent chromosomal imbalances, such as loss of 1p36, 2p11, 16p, and 17p, and gain of 8p, 8q, and 13q. These results suggest that chromosomal imbalances are largely absent in APL, although some nonrandom chromosomal imbalances could be linked to the development of APL in a limited number of cases. © 2006 Wiley-Liss, Inc.

We recently demonstrated that the prognosis for de novo CD5-positive (CD5+) diffuse large-B-cell lymphoma (DLBCL) is markedly worse than that for CD5-negative (CD5-) DLBCL. Our findings also suggested that on the basis of its clinical features CD5+ DLBCL may constitute a unique disease category. However, the genetic basis for these two categories has not been established. Therefore, we performed comparative genomic hybridization analysis (CGH) of 26 cases of CD5+ DLBCL and 44 cases of CD5- DLBCL. Several identical changes in CD5+ and CD5- DLBCLs were found, such as gains of 3q, 9p, 12q, 13q, and 18q and losses of 1p, 6q, 17p, and 19p. However, distinct differences between the two categories were also detected. These included gains of 11q21-q24 (P=0.032) and 16p (P=0.005) in CD5+ DLBCL, and loss of 16p (P=0.028) in CD5- DLBCL. A comparison with results reported for mantle cell lymphoma, chronic lymphocytic leukemia, and Richter's syndrome demonstrated that the CGH pattern of CD5+ DLBCL was markedly different. This indicates that CD5+ DLBCL constitutes a disease category distinct from that of CD5- DLBCL and other CD5+ malignancies.

Chromosome band 6q21 is reported to be one of the most frequent target regions in T-cell lymphoma for both translocations and deletions. To explore whether the breakpoint clustering in T-cell malignancy indicates the presence of a common breakpoint region in 6q, we employed fluorescence in situ hybridization analysis using various YAC, BAC, and PAC clones aligned at 6q21–22. We identified two T-cell lymphoma/leukemia cell lines with different differentiation stages that had breakpoints within the same novel gene, TCBA1 (T-cell lymphoma breakpoint associated target 1). In a T-cell lymphoblastic lymphoma cell line, HT-1, the TCBA1 fused to SUSP1 (SUMO-1-specific protease), creating a SUSP1-TCBA1 chimeric gene. However, in an adult T-cell leukemia cell line, ATN-1, no chimeric gene was detected, although aberrant TCBA1 transcripts were produced. We conclude that TCBA1 is a possible target gene for T-cell lineage-specific chromosome aberrations at 6q21. © 2002 Wiley-Liss, Inc.

Three rare autopsy cases of fetal ascites were presented and the etiology of each case was described. Case 1 was a male neonate, delivered by cesarean section at 32 weeks' gestation, and died of respiratory failure. The abdomen was remarkably distended with 1020 ml of ascites. The etiology of Case 1 remained unknown even after macroscopic and microscopic examinations. We considered this as "idiopathic" fetal ascites. Case 2 was a female neonate, delivered at 31 weeks' gestation, with marked abdominal distension and cyanosis. Autopsy revealed 435 ml of ascites, and she was considered to have had "polysplenia syndrome" with cardiovascular malformations. Intrauterine heart failure due to cardiac anomalies was thought to be the cause of this ascites. In case 3 embryotomy was carried out under the diagnosis of fetal ascites by ultrasound examination at 22 weeks' gestation. An urachal cyst connected to the dilated urinary bladder and deficiency of musculature of the abdominal wall composed of loose connective tissue with calcification were observed. The abdominal wall was ruptured and 1,960 ml of ascites was measured. Polycystic kidney with renal dysplasia was also found. Case 3 showed "Prune-Berry syndrome" and fetal ascites may have arisen from these anomalies.

The crystal structure of acetoxy(pentamethyleneurethane) dimer, was studied by the X-ray diffraction method. The crystal is triclinic with The diffraction patterns clearly show the existence of a subcell which is also triclinic with two (CH2)2 units in the unitcell. The subcell structure was determined by use of special non space group extinctions. The proposed crystal structure is that each of the two molecular chains in the main unit cell is connected side by side with other chains in the neighbouring cells by two hydrogen bonds to form molecular sheets parallel to the bs cs plane. Die Kristallstruktur des dimeren Acetoxy(pentamethylenurethans) wurde mit Hilfe der Rontgenbeugung ermittelt. Das Gitter ist triklin mit: Die Beugungsdiagramme zeigen klar die Existenz einer Subzelle, die ebenfalls triklin ist und zwei (CH2)2-Gruppen enthalt. Die Struktur der Subzelle wurde mit Hilfe von Berechnungen der Strukturfaktoren ermittelt. Die angenommene Kristallstruktur kann wie folgt beschrieben werden: Jede der beiden Polymerketten in einer Elementarzelle ist uber je zwei Wasserstoffbruckenbindungen mit anderen Ketten in benachbarten Zellen verknupft. Es entstehen so molekulare Schichten, die zur bscs-Flache parallel sind.

To study the dependence of the micro structure of oligomer crystals on the degree of polymerization, the small and wide angle X-ray scattering of the oligomer α-acetoxy-ω-methoxyoligo(oxypentamethyleneiminocarbonyl), CH3CO[O(CH2)5NHCO]nOCH3, having strictly homogeneous molecular weight, and of the corresponding polymer were investigated, together with the IR absorption spectra, the density and the thermal properties. The solution grown crystals of oligomers and of the polymer are composed of the two-phase structure. One is the crystalline phase having the ordered high density, and the other one is the intercrystalline phase of low density occupied by mobile molecular chain ends. The structure of the crystalline phase above trimer is similar to that of the dimer crystal, and the molecular motion in the intercrystalline phase is the local mode motion. This twophase structure could be illustrated by one dimensional density distribution having trapezoidal profile. Die Klein- und Weitwinkel-Rontgenstreuung, die IR-Absorptionsspektra, die Dichte und die thermischen Eigenschaften des oligomeren α-Acetoxy-ω-methoxyoligo(oxypentamethyleniminocarbonyl), CH3CO[O(CH2)3NHCO]nOCH3, mit streng einheitlichem Molekulargewicht und die des entsprechenden Polymeren wurden untersucht, um die Abhangigkeit der Mikrostruktur oligomerer Kristalle vom Polymerisationsgrad zu bestimmen. Die Struktur der in Losung kristallisierten Oligomeren und Polymeren entspricht dem Zwei-Phasen-Modell. Dabei hat die kristalline Phase eine hohe Packungsdichte, die andere, ungeordnete Phase ist von geringerer Packungsdichte und durch bewegliche Molekulkettenenden besetzt. Die Struktur der obengenannten kristallinen Phase oberhalb des Trimeren ist der des dimeren Kristalls ahnlich, und die molekulare Beweglichkeit in der ungeordneten Phase beruht auf einer lokalen Schwingung. Diese Zweiphasenstruktur kann durch eine eindimensionale Dichteverteilung mit einem trapezformigen Profil dargestellt werden.

Photochemical reactions of halogeno-quinones with allylstannane in a benzene or an acetonitrile solution afforded allylated quinones and allyl quinols as major products. Nuclear spin polarization effects observed during irradiation support a contribution of electron transfer process.

Irradiation of aromatic carbonyl compounds and allyl-, 2-methyl-2-propenyl-, or 3-methyl-2-butenyltrimethylstannanes in acetonitrile afforded δ,γ-unsaturated alcohols as major product. A photoinduced electron transfer mechanism is proposed for the allylations.

The title reaction, carried out to study the reactivity of allylic silanes to a photoexcited carbonyl group, leads to the Paterno-Buechi cycloadducts (III) + (IV) and to the products (V) and (VI) resulting from recombination of radicals generated by H-abstraction.