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Epigenetic signaling pathways are implicated in tumorigenesis and therefore histone deacetylases (HDACs) represent novel therapeutic targets for cancers, including multiple myeloma (MM). Although non-selective HDAC inhibitors show anti-MM activities, unfavorable side effects limit their clinical efficacy. Isoform- and/or class-selective HDAC inhibition offers the possibility to maintain clinical activity while avoiding adverse events attendant to broad non-selective HDAC inhibition. We have previously reported that HDAC3 inhibition, either by genetic knockdown or selective inhibitor BG45, abrogates MM cell proliferation. Here we show that knockdown of HDAC3, but not HDAC1or HDAC2, as well as BG45, downregulate expression of DNA methyltransferase 1 (DNMT1) mediating MM cell proliferation. DNMT1expression is regulated by c-Myc, and HDAC3 inhibition triggers degradation of c-Myc protein. Moreover, HDAC3 inhibition results in hyperacetylation of DNMT1, thereby reducing the stability of DNMT1 protein. Combined inhibition of HDAC3 and DNMT1 with BG45 and DNMT1 inhibitor 5-azacytidine (AZA), respectively, triggers synergistic downregulation of DNMT1, growth inhibition and apoptosis in both MM cell lines and patient MM cells. Efficacy of this combination treatment is confirmed in a murine xenograft MM model. Our results therefore provide the rationale for combination treatment using HDAC3 inhibitor with DNMT1 inhibitor to improve patient outcome in MM.

Recent studies have delineated cancer-type-specific roles of histone 3 lysine 27 (H3K27) demethylase KDM6B/JMJD3 depending on its H3K27 demethylase activity. Here we show that KDM6B is expressed in multiple myeloma (MM) cells; and that shRNA-mediated knockdown and CRISPR-mediated knockout of KDM6Babrogate MM cell growth and survival. Tumor necrosis factor-α or bone marrow stromal cell culture supernatants induce KDM6B, which is blocked by IKKβ inhibitor MLN120B, suggesting that KDM6Bis regulated by NF-κB signaling in MM cells. RNA-seq and subsequent ChIP-qPCR analyses reveal that KDM6B is recruited to the loci of genes encoding components of MAPK signaling pathway including ELK1and FOS, and upregulates expression of these genes without affecting H3K27 methylation level. Overexpression of catalytically inactive KDM6Bactivates expression of MAPK pathway-related genes, confirming its function independent of demethylase activity. We further demonstrate that downstream targets of KDM6B, ELK1and FOS,confer MM cell growth. Our study therefore delineates KDM6B function that links NF-κB and MAPK signaling pathway mediating MM cell growth and survival, and validates KDM6B as a novel therapeutic target in MM.

The significance of limited resections, including wedge resection and segmentectomy, remains controversial because of their curability rates. In the current study, the objective was to determine a strategy for the treatment of patients with roentgenographically occult bronchogenic squamous cell carcinoma (ROSCC) based on the pathologic findings from 184 patients with ROSCC who underwent resection. In Miyagi Prefecture, 1422 patients with lung carcinoma were diagnosed during a mass screening program between 1982 and 1995. Among them, 236 patients had ROSCC, and 184 patients with ROSCC underwent pulmonary resection followed by systemic lymph node dissection. Pathologically, only 0.9% of the ROSCCs that were within the range of endoscopic visibility were revealed to have lymph node involvement, whereas 13% of patients with extracartilage invasion had lymph node involvement. Early ROSCC, which means ROSCC that is limited within the cartilaginous layer and is without lymph node involvement, comprised 90% of ROSCCs that measured <10 mm in longitudinal extension, comprised 77% of ROSCCs that measured 10–29 mm in longitudinal extension, and comprised 33% of ROSCCs that measured >30 mm in longitudinal extension. Eighty-nine percent of the tumors with lymph node involvement had extracartilaginous invasion. The 3-year survival rate of patients after undergoing photodynamic therapy was 100% when their tumor was regarded as early ROSCC (i.e., within 10 mm in longitudinal extension and within the range of endoscopic visibility). To date, 18 patients with ROSCC underwent segmentectomy, and all of these patients are alive without tumor recurrence. The incidence rate of multiple lung carcinomas, including synchronous and metachronous tumors, in patients with ROSCC was 22%. The authors concluded the following: 1) Patients with lesions that are within the range of endoscopic visibility and that measure <10 mm in longitudinal extension are candidates for photodynamic therapy. 2) Patients with lesions that are beyond the range of endoscopic visibility or that measure >10 mm in longitudinal extension are candidates for segmentectomy as long as intraoperative examination shows a tumor free bronchial stump and negative lymph nodes 11–13. 3) Patients with lesions that show bronchial obstruction or extrabronchial invasion should undergo standard resection. Cancer 2000;89:2445–8. © 2000 American Cancer Society.

When a roentgenographically occult bronchogenic squamous cell carcinoma is limited within bronchoscopic visibility and is <10 mm in longitudinal extension, the depth of invasion of the tumor is regarded as within bronchial cartilage, and the patient is a good candidate for photodynamic therapy. Patients with tumors that invade beyond the bronchial cartilage and/or have lymph node involvement should undergo standard surgery.

The corona poling process of electro-optic polymers has been investigated for rodlike aromatic polyimides doped with nonlinear optical chromophores. The dynamics of the chromophores in poling during and after imidization was observed by measuring second harmonic generation (SHG) from the polymer. In the course of poling during imidization, the SHG, observed before imidization, decreases to zero, reappears, and increases as the temperature increases. When poling was after imidization, the SHG intensity increased monotonically with increasing temperature. The disappearance of SHG in the poling during imidization is probably due to the known structural change in the polymer chains during imidization and the subsequent reorientation of the chromophores caused by formation of sheets of polyimides. The characteristics of the samples poled during and after imidization are nearly the same in both the extent of the nonlinear susceptibility and their thermal stability.

Microscopic analysis of the anisotropic properties of Co hyperfine fields in Nd2(Co1-xFe)14B is presented based on the results of 59Co NMR experiment. 4e site reveals a strong uniaxial hyperfine field anisotropy (38.6 kOe) due to the large orbital contribution, which is rapidly decreased by the addition of iron. For x= 0 a large basal plane hyperfine field anisotropy has been found in 4c (13 kOe), 16k2(11 kOe) and 16k1(2.4 kOe) sites.

10B, 11B and 57Fe spin-echo NMR and magnetization experiments have been carried out on naturally abundant and 10B-enriched Nd2Fe14B at 1.3 and 4.2 K at frequencies from 10 to 80 MHz. It was found from a comparison of the NMR spectra in zero field and in an external field of 6.0 kOe that the hyperfine fields at the domain edges and at the domain wall centers are nearly the same. This implies that the Fe hyperfine field anisotropy is small in this system. The presence of spin canting was verified by the result that the 11B NMR frequency shift due to the applied external magnetic field does not exactly follow γ(11B)ΔH. The NMR technique proves to be sensitive in detecting trace bcc Fe precipitates in the Nd-Fe-B permanent magnets.

Radiographically occult bronchogenic squamous cell carcinomas are early lung cancers that localize mainly in the bronchial wall, and are thought to be a good model for investigating genetic alterations through lung cancer progression. In order to elucidate sequential genetic changes in lung cancers, we analysed the incidence of allelic losses on chromosome regions 2q33, 3p21, 5q21, 7q31, 9p21 and 17p13 for 40 cases of radiographically occult bronchogenic squamous-cell carcinomas and 40 cases of advanced lung cancers microdissected. In this study we used eight microsatellite dinucleotide polymorphic markers. Frequent loss of heterozygosity (LOH) was observed on 3p21 (53%), 5q21 (44%) and 17p13 (61%) in roentgenographically occult bronchogenic squamous cell carcinomas. 2q, 7q and 9p were lost less frequently in both roentgenographically occult bronchogenic squamous cell carcinomas and advanced lung cancers. These results suggest that several tumour-suppressor genes are associated with lung cancer progression and that genetic changes on 3p21, 5q21 and 17p13 are early events.

Prior to the frequency doubling of a laser diode through a ring resonator, reflection loss on the surface of a novel organic second-order nonlinear optical crystal, 8-(4′-acetylphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (APDA), was decreased. An optically flat crystal surface with a flatness of λ/10 (λ = 633 nm) and surface roughness of 1.5 nm rms was obtained when an ultraprecision diamond turning lathe was used to machine the crystal surface. After this surface was coated antireflectively with an amorphous fluorinated polymer, Teflon AF-2400, the transmittance at 810 nm was increased to 98%. A laser-diode-pumped ring resonator was built with this crystal, and a blue second-harmonic emission at 405.5 nm was successfully generated.

Objective: The TNM staging system of lung cancer is widely used as a guide for estimating prognosis and selecting treatment modality. In 1997, the International Union Against Cancer and the American Joint Committee on Cancer have adopted a revised stage grouping for lung cancer. However, the validity of the new stage grouping has not been fully established. We investigated the prognoses of patients who had resection of non-small-cell lung cancer to confirm the validity of the revised classification. Methods: A total of 1310 patients with non-small-cell lung cancer underwent complete resection and pathologic staging of the disease in our hospitals from 1980 through 1993. A pulmonary resection was performed with a systematic nodal dissection. The survivals were calculated with the Kaplan-Meier method on the basis of overall deaths, and the survival curves were compared by log rank test. Results: There were significant differences in survival between patients with T1 N0 M0 and T2 N0 M0 disease and between those with T1 N1 M0 and T2 N1 M0 disease. However, there was no significant difference between patients with T2 N0 M0 disease and those with T1 N1 M0 disease. No significant difference in survival was observed among patients with T2 N1 M0, T3 N0 M0, and T3 N1 M0 cancer. Patients with different invaded organs of T3 subdivision (pleura, chest wall, pericardium, or diaphragm) had a different prognosis. There was no significant difference between patients with T3 N2 M0 disease and those with stage IIIB disease. Conclusions: We supported most of the revision, such as dividing stage I, dividing stage II, and putting T3 N0 M0 to stage IIB. Furthermore, we found some candidates for a subsequent revision, such as putting T3 N1 M0 to stage IIB, putting T2 N0 M0 and T1 N1 M0 together, regarding diaphragm invasion as T4, and putting T3 N2 M0 to stage IIIB. (J Thorac Cardiovasc Surg 1998;116:407-11)

In order to determine the topographical distribution of the K-ras codon 12 mutations in carcinoma and preneoplastic lesions of the lung, selective ultraviolet radiation fractionation, as well as microdissection followed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP), was performed. Fourteen of 61 samples amplified (23.0%) had a mutation in the K-ras codon 12. Of 41 adenocarcinoma, 12 samples (29.3%) had a mutation, whereas none of the squamous cell carcinomas had a mutation. One of six large-cell carcinomas, one of three carcinoid tumours and none of three other carcinomas had a mutation. Direct sequencing revealed that K-ras codon 12 of six samples were TGT (Cys), five samples were GTT (Val), two samples were GCT (Ala) and one sample was TTT (Phe). A total of 113 lesions of 13 cases covered by dot were amplified after UV radiation. All of 74 carcinoma lesions had the mutation, and intratumour heterogeneity was not observed. Of 39 non-malignant lesions, one type II cell hyperplasia had the mutation, which suggests that the K-ras mutation occurs in the early stage of carcinogenesis. The lack of intratumour heterogeneity supports the hypothesis.

A new crystal form of an organic nonlinear optical material, 8-(4‘-acetylphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (APDA) was found in the crystal growth by plate sublimation. This new crystal structure belongs to the noncentrosymmetric class, orthorhombic P212121, and the unit-cell dimensions are a = 8.428 (8) Å, b = 28.349 (3) Å, c = 5.634 (2) Å, V = 1346.0 (6) ų, Z = 4, which are different from previously reported, orthorhombic Pna21. The molecule in the P212121 crystal has less twisting and more bending in the structure than in Pna21. The APDA molecules are coupled in an antiparallel system in the P212121 crystal as if to compensate for the repulsion arising from dipole−dipole interactions. This is in contrast to the molecular alignment of the Pna21 crystal in which the molecules are arranged in the same direction. The molecular hyperpolarizabilities (β) and d coefficients of the new crystal form were investigated theoretically by semiempirical CNDO/S-CI.

A 0.98 µm InGaAs/InGaAsP/GaAs strained quantum-well laser with an exponential-shaped-flared stripe has been developed. Its maximum output power is 40 – 60% higher than that of ordinary straight-stripe lasers for the same kink-occurrence output power. Testing at 150 mW showed stable operation with an estimated lifetime of >200000 h.

Elastic constants of Nd2Fe14B and Y2Fe14B have been measured from 4.2 K up to above the Curie temperature by means of an ultrasonic pulse echo method. The ordinary ΔEeffect has been observed only in the shear modulus of Nd2Fe14B below 150 K. A softening in the longitudinal modulus was observed for both compounds below TC, which is explained as an inverse effect of the volume magnetostriction.

Superconducting bandpass filters of 4.9 GHz with 0.5% relative bandwidth were designed using miniaturised microstrip hairpin resonators and fabricated with GdBa2Cu3Ox thin films prepared on MgO. The passband insertion loss was 0.5dB at 20K and the filter configuration was defined in an area less than 5 × 5 mm2.

A. 0.98 μm InGaAs/InGaAsP strained quantum well distributed feedback laser is demonstrated for the first time. The laser shows stable single longitudinal mode operation over a wide temperature change and output power. The temperature coefficient of the lasing wavelength is as small as 0.05 nm/°C.

A 0.98 µm InGaAs/InGaAsP strained quantum well laser with a laterally tapered waveguide spot-size expander is demonstrated to achieve highly reliable and stable lateral mode operation. This laser, which has a 0.8 µm wide ridge-neck at the facet, showed a linear L-I curve up to 340 mW, with circular and narrow beam divergence of 10° × 15°.

The authors demonstrate the catastrophic-optical-damage-free high-output-power operation of 0.98 µm InGaAs/InGaP/GaAs buried-ridge-structure lasers with non-injection regions near the facets. A maximum output power of 466 mW and fundamental operation at 100 mW were achieved.

Highly reliable operation of 0.98 µm strain-compensated InGaAs/InGaAsP lasers is demonstrated for the first time with an estimated lifetime of 170 kh at 25°C. Moreover, we reveal that the degradation rates at 90°C and 80 mW output power are four times smaller than those of identical lasers with GaAs barriers.

The advantages of 0.98 μm InGaAs/GaAs/InGaP lasers with an InGaAsP SCH layer were investigated by comparing them with identical lasers with a conventional GaAs SCH layer. A higher internal quantum efficiency of 0.817 and low internal loss of 2.11 cm−1 were obtained due to the large conduction band discontinuity. Moreover, high power operation of 80 mW from an uncoated facet was obtained up to 70°C with the laser with the InGaAsP SCH layer.

J Thorac Cardiovasc Surg 1998;116:651-2

Nd2Fe14B and FePt nanoparticles with a diameter below the diffraction limit of laser light were successfully prepared by an ultrashort pulse laser ablation in cyclohexane. The self-passivating amorphous carbon layer resulting from the fragmentation of the surrounding solvent prevents the nanoparticle from aggregation and oxidation. The coercivity of the Nd2Fe14B nanoparticles smaller than the critical single domain size was about 2.2 times as high as that of the initial Nd2Fe14B particles in spite of the decrease in crystallinity. Furthermore, the coercivity of the FePt nanoparticles after heat treatment dramatically increased, which was about 20 times higher than that of the initial FePt sample.

For the study of the relationship between the domain wall motion (DWM) and the coercivity in the samples of Dy-free Nd-Fe-B sintered magnets, the DC susceptibility (* *DC) in the initial magnetization from the thermally demagnetized state and the DWM in the partially demagnetized state after the full magnetization in 5T-pulse field were measured. In the high coercivity (m.Hc) samples of m.Hc=1.35T and 1.62T, the stronger pinning in initial magnetization was detected as the* *DC compared to other samples of the smaller coercivities such as m.Hc=0.80T. The former samples also showed little DWM in the partially demagnetized state even the domain structures were clearly detected by magneto-force microscopy (MFM). In the latter samples, however, the obvious DWM was measured as the differences (DM) between the magnetizations under applied field (Ma) and the remanences (Mr) in demagnetization process (DM = Mr - Ma). The pinning in DWM in initial magnetization process and the DWM in the partially demagnetized state are both originated from the interaction between the domain walls and grain boundary phases. The enhancement in coercivity, therefore, should come from the same interactions in the sintered samples.