Search

Boron-based two-dimensional (2D) materials are an excellent platform for nanoelectronics applications. Rhombohedral boron monosulfide (r-BS) is attracting particular attention because of its unique layered crystal structure suitable for exploring various functional properties originating in the 2D nature. However, studies to elucidate its fundamental electronic states have been largely limited because only tiny powdered crystals were available, hindering a precise investigation by spectroscopy such as angle-resolved photoemission spectroscopy (ARPES). Here we report the direct mapping of the band structure with a tiny (∼20 × 20 μm2) r-BS powder crystal by utilizing microfocused ARPES. We found that r-BS is a p-type semiconductor with a band gap of >0.5 eV characterized by the anisotropic in-plane effective mass. The present results demonstrate the high applicability of micro-ARPES to tiny powder crystals and widen an opportunity to access the yet-unexplored electronic states of various novel materials.

Non-coding RNAs have an integral regulatory role in numerous functions related to lung cancer development. Here, we report identification of a novel lncRNA, termed TP53-inhibitinglncRNA(TILR), which was found to function as a constitutive negative regulator of p53 expression, including activation of downstream genes such as p21and MDM2, and induction of apoptosis. A proteomic search for TILR-associated proteins revealed an association with PCBP2, while the mid-portion of TILRwas found to be required for both PCBP2 and p53mRNA binding. In addition, depletion of PCBP2 resulted in phenocopied effects of TILRsilencing. TILRwas also shown to suppress p53 expression in a post-transcriptional manner, as well as via a positive feedback loop involving p53 and Fanconi anemia pathway genes. Taken together, the present findings clearly demonstrate that TILRconstitutively inhibits p53 expression in cooperation with PCBP2, thus maintaining p53 transcriptional activity at a level sufficiently low for avoidance of spurious apoptosis induction.

Compressed sensing (CS) model of complex-valued data can represent the signal recovery process of many types of radar systems, especially when the measurement matrix is row-orthogonal. Based on debiased least absolute shrinkage and selection operator (LASSO), the detection problem under the Gaussian random design model, i.e. the elements of the measurement matrix are drawn from a Gaussian distribution, is studied by literature. However, these approaches are unsuitable for the row-orthogonal measurement matrices, which are of more practical relevance. In view of statistical mechanics approaches, we provide derivations of more accurate test statistics and thresholds (or p-values) under the row-orthogonal design model and theoretically analyze the detection performance of the present detector. Such a detector can analytically provide the threshold according to a given false alarm rate, which is not possible with the conventional CS detector, and the detection performance is proved to be better than that of the traditional LASSO detector. Compared with other debiased LASSO based detectors, simulation results indicate that the proposed approach can achieve a more accurate probability of false alarm when the measurement matrix is row-orthogonal, leading to better detection performance under the Neyman-Pearson principle.

Nanomaterials based on monoatomic bismuth (Bi) are attracting particular attention because they are candidates of two-dimensional (2D) topological insulators and Rashba metals useful for spintronic applications. We report convenient selective fabrication of two different types of ultrathin Bi films, bismuthene and α-Bi on hydrogen-terminated SiC(0001), by combining the molecular-beam-epitaxy (MBE) method and the low-temperature and low-pressure hydrogen chemical etching of SiC. We have succeeded in selectively fabricating these two different Bi phases by simply tuning the substrate temperature during the MBE process. We observed that while bismuthene and α-Bi showed a similar low-energy electron diffraction pattern of the (√3 × √3)R30° periodicity, angle-resolved photoemission spectroscopy revealed a sizable difference in the band structure; bismuthene shows a massive Dirac cone, a signature of 2D topological insulators, whereas α-Bi exhibits an insulating behavior with a large band gap of more than 1.8 eV. We discuss the underlying mechanism of selective fabrication in terms of hydrogen desorption from the hydrogen-terminated SiC substrate.

Background Among patients with non-small-cell lung cancer (NSCLC), those with poor prognosis cannot be distinguished from those with good prognosis. Methods Matrix-assisted laser desorption-ionization mass spectrometry was used to analyze protein profiles of 174 specimens from NSCLC tumors and 27 specimens from normal lung tissue and to derive a prognosis-associated proteomic signature. Frozen resected tissue specimens were randomly divided into a training set (116 NSCLC and 20 normal lung specimens) and an independent, blinded validation set (58 NSCLC and seven normal lung specimens). Mass spectrometry signals from training set specimens that were differentially associated with specimens from patients with a high risk of recurrence (i.e., who died within 5 years of surgical treatment because of relapse) compared with those from patients with a low risk of recurrence (i.e., alive with no symptoms of relapse after a median follow-up of 89 months) were selected by use of the Fisher's exact test, the Kruskal-Wallis test, and the significance analysis of microarray test. These signals were used to build an individualized, weighted voting-based prognostic signature. The signature was then validated in the independent dataset. Survival was assessed by multivariable Cox regression analysis. Proteins corresponding to individual signals were identified by ion-trap mass spectrometry coupled with high-performance liquid chromatography. All statistical tests were two-sided. Results From 2630 mass spectrometry signals from specimens in the training cohort, we derived a signature of 25 signals that was associated with both relapse-free survival and overall survival. Among stage I NSCLC patients in the validation set, the signature was statistically significantly associated with both overall survival (hazard ratio [HR] of death for patients in the high-risk group compared with those in the low-risk group = 61.1, 95% confidence interval [CI] = 8.9 to 419.2, P Conclusions We defined a mass spectrometry signature that was associated with survival among NSCLC patients and appeared to distinguish those with poor prognosis from those with good prognosis.

Background: Vascular endothelial growth factor C (VEGF-C) stimulates tumor lymphangiogenesis (i.e., formation of lymphatic vessels) and metastasis to regional lymph nodes by interacting with VEGF receptor 3 (VEGFR-3). We sought to determine whether inhibiting VEGFR-3 signaling, and thus tumor lymphangiogenesis, would inhibit tumor metastasis. Methods: We used the highly metastatic human lung cancer cell line NCI-H460-LNM35 (LNM35) and its parental line NCI-H460-N15 (N15) with low metastatic capacity. We inserted genes by transfection and established a stable N15 cell line secreting VEGF-C and a LNM35 cell line secreting the soluble fusion protein VEGF receptor 3-immunoglobulin (VEGFR-3-Ig, which binds VEGF-C and inhibits VEGFR-3 signaling). Control lines were transfected with mock vectors. Tumor cells were implanted subcutaneously into severe combined immunodeficient mice (n = 6 in each group), and tumors and metastases were examined 6 weeks later. In another approach, recombinant adenoviruses expressing VEGFR-3-Ig (AdR3-Ig) or [beta]-galactosidase (AdLacZ) were injected intravenously into LNM35 tumor-bearing mice (n = 14 and 7, respectively). Results: LNM35 cells expressed higher levels of VEGF-C RNA and protein than did N15 cells. Xenograft mock vector-transfected LNM35 tumors showed more intratumoral lymphatic vessels (15.3 vessels per grid; 95% confidence interval [CI] = 13.3 to 17.4) and more metastases in draining lymph nodes (12 of 12) than VEGFR-3-Ig-transfected LNM35 tumors (4.1 vessels per grid; 95% CI = 3.4 to 4.7; P

Background: The presence of autoantibodies to p53 protein has been associated with the presence of p53 (also known as TP53) gene mutations in primary tumors and with poor prognosis. This study was undertaken to determine the clinical significance of p53 autoantibodies in patients with non-small-cell lung cancer (NSCLC). Methods: We studied 18X consecutive patients with NSCLC who underwent pulmonary resection and for whom preoperative serum was available. The presence of p53 autoantibodies, detected by use of two amino-terminal and two carboxy-terminal peptides (20-30 mers) as antigens and an enzyme-linked immunosorbent assay, was related to various clinicopathologic parameters and to overexpression of p53 protein in the primary tumor. For 22 patients who had p53 autoantibodies before surgery, we also examined sera taken during postoperative follow-up. Reported P values are two-sided. Results: Autoantibodies to p53 protein were detected in 38 patients. Patients with squamous cell carcinoma, those with more advanced disease (stage III-IV), and those with tumors that overexpressed p53 had a significantly higher incidence of p53 autoantibodies (P = .05, .0079, and .02, respectively). In all but one of the patients with postoperative serum samples, the antibody titer declined after surgery; however, there was no relationship between clinical course and this change in antibody titer. In addition, there was no relationship between the presence of p53 autoantibodies and overall survival in 171 patients who underwent potentially curative resection (P = .28); however, 13 patients with autoantibodies to amino-terminal peptides had a worse overall survival (P = .02). Conclusions: In NSCLC, the incidence of p53 autoantibodies is associated with histologic type, stage, and p53 overexpression--but not with patient survival. Our data do not support the clinical utility of p53 autoantibodies as diagnostic or prognostic markers in patients with NSCLC. [J Natl Cancer Inst 1998;90:1563-8]

Background. Resistance to chemotherapeutic agents is a major problem in non-small cell lung cancer (NSCLC) chemotherapy, and recent studies have indicated that glutathione S-transferase-[Pi] (GST-.[Pi]) may play an important role in the resistance of cancer cells to alkylating agents that include platinum compound. Methods. GST-[Pi] in serum of 121 patients with NSCLC was measured by a sandwich enzyme-linked immunosorbent assay, and the serum concentrations of carcinoembryonic antigen (CEA), squamous cell carcinoma (SCC) antigen, and neuron-specific enolase (NSE) were also examined. Serum levels of these tumor markers were also evaluated in relation to therapeutic response in 69 patients who received combination chemotherapy with platinum compound. Results. Fifty of 121 patients with NSCLC (41.3%) showed elevated serum GST-[Pi] levels above a cutoff value of 34.8 ng/ml (mean + two standard deviations in 30 healthy control subjects). The positive rate of GST-[Pi] in patients with NSCLC was higher than those of CEA 37.2%), SCC (15.7%), and NSE (14.9%). The mean pretreatment GST-[Pi] level was significantly lower in patients with a partial response to chemotherapy than in those with no response (26.9 [plus or minus] 11.3 ng/ml versus 38.8 + 16.7 ng/ml; P < 0.003). Among patients with elevated levels of pretreatment serum GST-[Pi], only 13.8% (four of 29) responded to the combination chemotherapy, whereas partial response was observed in 40.0% of patients (16 of 40) with serum GST-[Pi] concentration below the cutoff level (P < 0.02). Neither CEA, SCC, nor NSE showed such a relationship. Conclusions. The serum GST-[Pi] level may have limited value as a tumor marker for NSCLC. Interestingly, pretreatment serum Gst-[Pi] levels may be a useful parameter for predicting therapeutic response to combination chemotherapy regimens that include platinum compound. Cancer 1994; 73:1377-82.

Background. The molecular genetic changes associated with colorectal carcinoma are among the best understood of any common human cancer. The genetic changes during the late stages of colorectal carcinomas may be useful in clinical management for determining the metastatic potential of the carcinoma. Methods. Tumor tissues were evaluated by restriction fragment length polymorphism (RFLP) analysis of chromosomes 5q, 17p, 18q, and 22q (n = 98), by reverse transcription-polymerase chain reaction (RT-PCR) analysis of messenger RNA expression of the DCC gene (deleted in colorectal carcinoma) (n = 27) and by immunohistochemical analysis of p53 protein expression (n = 44). Results. Loss of heterozygosity (LOH) on chromosomes 17p, 18q, and 22q, but not on 5q, was much more frequently detected in advanced carcinomas than in intramucosal carcinomas (P < 0.01). 17p LOH was significantly correlated with vascular invasion (P < 0.001), whereas 18q LOH was correlated with lymphatic invasion and hepatic metastasis (P < 0.01), and 22q LOH was correlated with lymph node metastasis (P < 0.05). LOH on 5q did not show a significant correlation with any factors of tumor invasion or metastasis. DCC expression was not observed in any of five hepatic metastasis or in five of seven advanced carcinomas that were accompanied by hepatic metastasis (10 of 12). However, a similar lack of expression was observed in only 5 of 15 carcinomas without hepatic metastasis (P < 0.05). p53 Expression was found to vary in both primary and metastatic carcinomas by immunohistochemistry. Conclusions. The clinical application of molecular genetics (i.e., RFLP analysis of chromosome 17p, 18q, and 22q and RT-PCR analysis of DCC expression into messenger RNA) can be used to determine the metastatic potential of colorectal carcinomas. Cancer 1994; 73:1324-31.

To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1532-5415.2009.02422.x Byline: Takashi Takahashi (*), Miyuki Morozumi ([dagger]), Naoko Chiba ([dagger]), Ryoko Asami ([double dagger]), Kozue Kishii ([dagger]), Somay Y. Murayama ([dagger]), Kimiko Ubukata ([dagger]) Author Affiliation: (*)Division of Internal MedicineTama-Hokubu Medical CenterTokyo Metropolitan Health and MedicalTreatment CorporationHigashi-murayamaTokyo, Japan ([dagger])Laboratory of Molecular Epidemiology forInfectious AgentsKitasato Institute for Life SciencesKitasato UniversityMinato-kuTokyo, Japan ([double dagger])Divisions of Clinical LaboratoryTama-Hokubu Medical CenterTokyo Metropolitan Health and MedicalTreatment CorporationHigashi-murayamaTokyo, Japan

To purchase or authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1532-5415.2007.01534.x Byline: Koji Nomura (*), Hiroshi Murai (*), Takeshi Nakahashi (*), Satoru Mashiba ([dagger]), Yukihiro Watoh ([dagger]), Takashi Takahashi ([double dagger]), Shigeto Morimoto (*) Author Affiliation: (*)Department of Geriatric Medicine, Kanazawa Medical University Hospital, Kahoku-gun, Ishikawa, Japan ([dagger])Department of Emergency Medicine, Kanazawa Medical University Hospital, Kahoku-gun, Ishikawa, Japan ([double dagger])Division of Infection Control, Kanazawa Medical University Hospital, Kahoku-gun, Ishikawa, Japan

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P< 9.58 × 10−9). East Asian–specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2(associated with coronary artery disease) and p.V326A of POT1(associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.

We describe a case of synchronous primary lung cancer presenting with small cell carcinoma and adenocarcinoma, in which expression of the cell surface antigens and also tumor markers were evaluated [...]

We have performed scanning angle-resolved photoemission spectroscopy with a nanometer-sized beam spot (nano-ARPES) on the cleaved surface of Pb5Bi24Se41, which is a member of the (PbSe)5(Bi2Se3)3mhomologous series (PSBS) with m= 4 consisting of alternate stacking of the topologically trivial insulator PbSe bilayer and four quintuple layers (QLs) of the topological insulator Bi2Se3. This allows us to visualize a mosaic of topological Dirac states at a nanometer scale coming from the variable thickness of the Bi2Se3nanoislands (1–3 QLs) that remain on top of the PbSe layer after cleaving the PSBS crystal, because the local band structure of topological origin changes drastically with the thickness of the Bi2Se3nanoislands. A comparison of the local band structure with that in ultrathin Bi2Se3films on Si(111) gives us further insights into the nature of the observed topological states. This result demonstrates that nano-ARPES is a very useful tool for characterizing topological heterostructures.

The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transcriptional target of the lineage-survival oncogene NKX2–1/TTF-1 in lung adenocarcinomas. In addition to its kinase-dependent role, ROR1 functions as a scaffold protein to facilitate interaction between caveolin-1 (CAV1) and CAVIN1, and consequently maintains caveolae formation, which in turn sustains pro-survival signaling toward AKT from multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET (proto-oncogene, receptor tyrosine kinase), and IGF-IR (insulin-like growth factor receptor 1). Therefore, ROR1 is an attractive target for overcoming EGFR-TKI resistance due to various mechanisms such as EGFR T790M double mutation and bypass signaling from other RTKs. Here, we report that ROR1 possesses a novel scaffold function indispensable for efficient caveolae-dependent endocytosis. CAVIN3 was found to bind with ROR1 at a site distinct from sites for CAV1 and CAVIN1, a novel function required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis, but not caveolae formation itself. Furthermore, evidence of a mechanistic link between ROR1-CAVIN3 interaction and consequential caveolae trafficking, which was found to utilize a binding site distinct from those for ROR1 interactions with CAV1 and CAVIN1, with RTK-mediated pro-survival signaling towards AKT in early endosomes in lung adenocarcinoma cells was also obtained. The present findings warrant future study to enable development of novel therapeutic strategies for inhibiting the multifaceted scaffold functions of ROR1 in order to reduce the intolerable death toll from this devastating cancer.

We performed a spin- and angle-resolved photoemission spectroscopy of bismuth ultrathin film on Si(111) with various film thickness d. We found that the spin polarization of spin-split Rashba surface states near the Brillouin-zone boundary, which is high (0.7) at d= 40 BL (bilayers), is gradually reduced on decreasing dand almost vanishes at d= 8 BL. This finding provides a novel method to generate spin-polarized electrons with tunable spin-polarization.

One of the key challenges in condensed-matter physics is to establish a topological superconductor that hosts exotic Majorana fermions. Although various heterostructures consisting of conventional BCS (Bardeen–Cooper–Schrieffer) superconductors as well as doped topological insulators were intensively investigated, no conclusive evidence for Majorana fermions has been provided. This is mainly because of their very low superconducting transition temperatures (Tc) and small superconducting-gap magnitude. Here, we report a possible realization of topological superconductivity at very high temperatures in a hybrid of Bi(110) ultrathin film and copper oxide superconductor Bi2Sr2CaCu2O8+δ(Bi2212). Using angle-resolved photoemission spectroscopy and scanning tunneling microscopy, we found that three-bilayer-thick Bi(110) on Bi2212 exhibits a proximity-effect-induced s-wave energy gap as large as 7.5 meV which persists up to Tcof Bi2212 (85 K). The small Fermi energy and strong spin–orbit coupling of Bi(110), together with the large pairing gap and high Tc, make this system a prime candidate for exploring stable Majorana fermions at very high temperatures.

The development of new anchoring groups is important to facilitate effective co‐sensitization in dye‐sensitized solar cells (DSSCs). Herein, stable organic D–π–A dyes that contain new heterocyclic hydantoin‐based anchoring groups have been designed, synthesized, and used in DSSCs. These dye sensitizers were evaluated in terms of their absorption spectra, electrochemical properties, and performance in DSSC devices. Although only one‐third of the amount of hydantoin‐containing dyes adsorbed onto TiO2relative to their cyanoacrylic‐acid‐containing analogues, they exhibited effective photoexcited electron‐transfer properties. External quantum efficiencies of over 80 % was observed, which were comparable to those of the cyanoacrylic‐acid‐containing dyes. In addition, the new hydantoin‐containing dyes exhibited significant robustness, which could allow improved stability of their corresponding photovoltaic devices under harsh conditions, such as high temperature and humidity. Too young to dye: D–π–A dyes with new anchoring groups have been designed, synthesized, and used in dye‐sensitized solar cells (DSSCs). The dyes were evaluated in terms of their absorption spectra, electrochemical properties, and device performance. Hydantoin‐containing dyes displayed effective photoexcited electron‐transfer properties.

The recent article by Tsunekawa et al. (1) demonstrates that adiponectin plays an important role in improving insulin resistance. Inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), are associated [...]

We report the isolation of Helicobacter cinaedi(previously called “Campylobacter-like organism”) from the blood of an immunosuppressed Japanese patient receiving immunosuppressive therapy after renal transplantation. The identification of H. cinaediwas based on the findings of microscopic examinations, biochemical properties, and 16S rRNAgene nucleotide sequences. H. cinaedibacteremia should be considered as one of the critical infectious diseases in immunocompromised patients, and the sequencing of 16S rRNAmay be a useful method to confirm the identification of this organism.

We report the direct evidence for superconductivity in Ca-intercalated bilayer graphene C6CaC6, which is regarded as the thinnest limit of Ca-intercalated graphite. We performed the electrical transport measurements with the in situ4-point-probe method in ultrahigh vacuum under zero- or nonzero-magnetic field for pristine bilayer graphene, Li-intercalated bilayer graphene (C6LiC6) and C6CaC6fabricated on SiC substrate. We observed that the zero-resistance state occurs in C6CaC6with the onset temperature (Tconset) of 4 K, while the Tconsetis gradually decreased upon applying the magnetic field. This directly proves the superconductivity origin of the zero resistance in C6CaC6. On the other hand, both pristine bilayer graphene and C6LiC6exhibit nonsuperconducting behavior, suggesting the importance of intercalated atoms and its species to drive the superconductivity.

Reducing the dimension in materials sometimes leads to unexpected discovery of exotic and/or pronounced physical properties such as quantum Hall effect in graphene and high-temperature superconductivity in iron-chalcogenide atomically thin films. Transition-metal dichalcogenides (TMDs) provide a fertile ground for studying the interplay between dimensionality and electronic properties, since they exhibit a variety of electronic phases like semiconducting, superconducting, and charge-density-wave (CDW) states. Among TMDs, bulk 1T-TiSe2has been a target of intensive studies due to its unusual CDW properties with the periodic lattice distortions characterized by the three-dimensional (3D) commensurate wave vector. Clarifying the ground states of its two-dimensional (2D) counterpart is of great importance not only to pin down the origin of CDW, but also to find unconventional physical properties characteristic of atomic-layer materials. Here, we show the first experimental evidence for the realization of 2D CDW phase without Fermi-surface nesting in monolayer1T-TiSe2. Our angle-resolved photoemission spectroscopy (ARPES) signifies an electron pocket at the Brillouin-zone corner above the CDW-transition temperature (TCDW∼ 200 K), while, below TCDW, an additional electron pocket and replica bands appear at the Brillouin-zone center and corner, respectively, due to the back-folding of bands by the 2 × 2 superstructure potential. Similarity in the spectral signatures to bulk 1T-TiSe2implies a common driving force of CDW, i.e., exciton condensation, whereas the larger energy gap below TCDWin monolayer 1T-TiSe2suggests enhancement of electron–hole coupling upon reducing dimensionality. The present result lays the foundation for the electronic-structure engineering based with atomic-layer TMDs.

We have demonstrated various synthetic routes to heptaoxazole macrocyclic analogues of telomestatin and evaluated their inhibitory activities against telomerase. We synthesized three heptaoxazole macrocycles consisting of different numbers of methyloxazole moieties and another heptaoxazole analogue with a bromooxazole moiety instead of one of the two methyloxazole moieties found in the structure of telomestatin. The bromooxazole analogue underwent Suzuki–Miyaura coupling leading to six analogues having aromatic substituents on the oxazole moiety. The substituents on the oxazole moiety in the heptaoxazole macrocycles, which include a methyl group, a bromine atom, and aromatic substituents, did not affect the inhibitory activity of the overall molecule. In addition, three amine-linked analogues were synthesized by modification of the S-tert-butyl group in the bromooxazole analogue with amine-linked α-bromoacetamides. Notably, one of the amine-linked heptaoxazole analogues exhibited almost the same inhibitory activity as telomestatin.

Genomic instability plays an important role in cancer susceptibility, though the mechanics of its development remain unclear. An often-stated hypothesis is that error-prone phenotypes in DNA replication or aberrations in translesion DNA synthesis lead to genomic instability and cancer. Mutations in core DNA replication proteins have been identified in human cancer, although DNA replication is essential for cell proliferation and most mutations eliminating this function are deleterious. With recent developments in this field we review and discuss the possible involvement of DNA replication proteins in carcinogenesis.

Strain SpD081030SC-03, representing a novel species of Streptomyces, was isolated from a marine sponge. Two 3,5,6-trisubstituted 2(1H)-pyrazinones, JBIR-56 (1) and JBIR-57 (2), were isolated from a culture of SpD081030SC-03. The planar structures of 1and 2were assigned on the basis of extensive NMR and MS analyses. In addition, analyses of the methylated derivative of 1confirmed a 3,5,6-trisubstituted 2(1H)-pyrazinone moiety. The absolute configurations of the amino acid residues were determined by application of Marfey’s method. Because 1did not appear to comprise the normal connection of amino acid units, we confirmed its structure by the total synthesis of 1. Biosynthetically, 1consists of a unique skeleton connected to the peptide chain at C-5 of the pyrazinone ring.

Amiodarone (AM) is a potent antidysrhythmic agent that can cause potentially life-threatening pulmonary fibrosis, and N-desethylamiodarone (DEA), an AM metabolite, may contribute to AM toxicity. Apoptotic cell death in nontransformed human peripheral lung epithelial 1A (HPL1A) cells was assessed by annexin V-fluorescein isothiocyanate (ann-V) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and necrotic cell death was assessed by propidium iodide (PI) staining. The percentage of cells that were PI-positive increased more than six times with 20 μM AM and approximately doubled with 3.5 μM DEA, relative to control. The percentage of cells that were ann-V-positive decreased by more than 80% after 24-h exposure to 10 μM AM but more than doubled after 24-h incubation with 3.5 μM DEA. Incubation for 24 h with 5.0 μM DEA increased the percentage of cells that were TUNEL-positive more than six times. Incubation with AM (2.5 μM) or DEA (1–2 μM) for 24 h did not significantly alter angiotensinogen mRNA levels. Furthermore, angiotensin II (100 pM–1 μM) alone or in combination with AM or DEA did not alter cytotoxicity, and pretreatment with the angiotensin-converting enzyme inhibitor and antioxidant captopril (3–6 μM) did not protect against AM or DEA cytotoxicity. In conclusion, AM activates primarily necrotic pathways, whereas DEA activates both necrotic and apoptotic pathways, and the renin-angiotensin system does not seem to be involved in AM or DEA cytotoxicity in HPL1A cells.

Two approaches for the solid‐phase total synthesis of apratoxin A and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer‐support, macrolactamization of 10, followed by thiazoline formation, provided apratoxin A. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid‐phase peptide synthesis by using amino acids 13–15and 18. The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34was as potent as apratoxin A, and O‐methyl tyrosine can be replaced by 7‐azidoheptyl tyrosine without loss of activity. The 1,3‐dipolar cycloaddition of 38with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring.

Just three steps!The highly efficient synthesis of 15 analogues of resorcylic acid lactones has been achieved through sequential palladium‐catalyzed coupling reactions based on the aromatic scaffolds and ring‐closing metathesis reactions.

We report on the solid‐phase synthesis of a combinatorial methylated (±)‐epigallocatechin gallate (EGCG) library and its biological evaluation. Epigallocatechin gallate (EGCG) and its methylated derivatives, which are members of the catechin family, exhibit various anti‐cancer effects. The solid‐phase synthesis of methylated EGCG involves the preparation of the α‐acyloxyketone by the coupling of a solid‐supported aldehyde with a ketone and an acid. The subsequent release and reductive etherification reaction of the solid‐supported α‐acyloxyketone provide the protected EGCG in good total yields. Sixty‐four methylated EGCGs were successfully prepared. The growth‐inhibitory effects of the methylated EGCG library were also examined. Although methylation of EGCG generally causes reduced growth inhibition, the growth‐inhibitory effect of 7‐OMe EGCGs was comparable to that of EGCG. The 7‐OMe EGCGs are attractive drug candidates because of their enhanced bioavailability.

Abstract: Purpose: To support preoperative planning of bone drilling for Microendoscopic Discectomy, we present a set of interactive bone-drilling methods using a general 2D pointing device. Methods: Unlike the existing methods, our framework has the following features: (1) the user can directly cut away arbitrary 3D regions on the volumetrically rendered image, (2) in order to provide a simple interface to end-users, our algorithms make 3D drilling possible through only a general-purpose wheel mouse, (3) to reduce both over-drilling and unnatural drilling of an unintended region, we introduce a smart depth control to ensure the continuity of the cutting operation and (4) a GPU-based rendering scheme for high-quality shading of clipped boundaries. Results: We applied our techniques to some CT data of specific patients. Several experiments confirmed that the user was able to directly drill a 3D complex region on a volumetrically rendered lumber spine through simple mouse operation. Also, our rendering scheme clearly visualizes time-varying drilled surfaces at interactive rates. By comparing simulation results to actual postoperative CT images, we confirmed the user interactively simulates similar cutting to that carried out in real surgery. Conclusion: We concluded our techniques perform mouse-based, direct drilling of complex 3D regions with high-quality rendering of drilled boundaries and contribute to preoperative planning of Microendoscopic Discectomy.

Construction of the ABC ring system of taxanes via one-pot three-component coupling and intramolecular alkylation is accomplished. The 1,4-addition of a protected cyanohydrin ether to 2-methyl-2-cyclohexenone and subsequent addition of the resulting enolate to formaldehyde proceeded stereoselectively to provide the AC ring in 90% yield. The stereoselective reduction of the 2-keto group was achieved by using hydroxy-directed hydride reduction with LiAlH4. The intramolecular alkylation of the protected cyanohydrin ether furnished the ABC ring system of taxanes in 43% yield.

In this report, we describe the stereoselective synthesis of a combinatorial library comprised of 16 deoxyhexasaccharides that are related to a landomycin A sugar moiety, based on an orthogonal deprotection strategy. The use of an olivosyl donor containing a benzyl ether at the C3 position and benzoyl ester at the C4 position, and the olivosyl donor, a naphthylmethyl ether, and a p‐nitrobenzylethyl or benzyl sulfonyl ester enabled the synthesis of a set of four diolivosyl units containing a hydroxyl group at the C3 or C4 position by a simple glycosylation and deprotection procedure. Using a phenylthio 2,3,6‐trideoxyglycoside, α‐selective glycosidation proceeded without anomerization of the 2,6‐dideoxy‐β‐glycosides. In addition, alkylhydroquinone and levulinoyl groups were found to be an effective set of orthogonal protecting groups for the anomeric position and a hydroxyl group. The coupling of all combinations of trisaccharide units in a β‐selective manner was accomplished by activation of the glycosyl imidate with I2and Et3SiH. No cleavage of the acid‐labile 2,3,6‐trideoxyglycoside was observed under the conditions used for the reactions. Finally, all of the protected hexasaccharides were deprotected by hydrolysis of the esters, microwave (MW) assisted cleavage of the 2‐trimethylsilylethoxymethoxy (SEM) ether, and a Birch reduction.

During cancer progression, the angiogenesis that occurs is involved in tumor growth and hematogenous-distant metastasis, whereas lymphangiogenesis is involved in regional lymph node metastasis. Angiogenesis is counterregulated by various endogenous inhibitors; however, little is known about endogenous inhibitors of lymphangiogenesis. We recently isolated vasohibin1 as an angiogenesis inhibitor intrinsic to the endothelium and further demonstrated its anticancer activity through angiogenesis inhibition. Here, we examined the effect of vasohibin1 on lymphangiogenesis. Vasohibin1 exhibited broad-spectrum antilymphangiogenic activity in the mouse cornea induced by factors including VEGF-A, VEGF-C, FGF2, and PDGF-BB. We then inoculated highly lymph node–metastatic cancer cells into mice and examined the effect of vasohibin1 on lymph node metastasis. Tail-vein injection of adenovirus containing the human vasohibin1gene inhibited tumor lymphangiogenesis and regional lymph node metastasis. Moreover, local injection of recombinant vasohibin1 inhibited lymph node metastasis. These results suggest vasohibin1 to be the first known intrinsic factor having broad-spectrum antilymphangiogenic activity and indicate that it suppresses lymph node metastasis.

Small cell lung cancer (SCLC) exhibits insulin-like growth factor-dependent growth. SCLC is the most aggressive among known in vivolung cancers, whereas in vitrogrowth of SCLC is paradoxically slow as compared with that of non-SCLC (NSCLC). In this study, we demonstrate that SCLC cells overexpress insulin-like growth factor binding protein (IGFBP)-2 via NeuroD, a neuroendocrine cell-specific transcription factor. Chromatin immunoprecipitation, electrophoretic mobility shift, and IGFBP-2promoter assays all revealed that NeuroD binds to the E-box in the 5′-untranslated region of IGFBP-2. A NeuroD transgene in both airway epithelial and NSCLC cells up-regulated the transcription of IGFBP-2and retarded cell growth. Recombinant IGFBP-2repressed the growth of both airway epithelial and NSCLC cells in a dose-dependent manner. A NeuroD-specific small interfering RNA repressed IGFBP-2expression in SCLC, and neutralization of IGFBP-2 and an IGFBP-2-specific small interfering RNA increased SCLC cell growth. Pathological samples of SCLC also expressed IGFBP-2 abundantly, as compared with NSCLC, and showed only rare (8%) IGFBP-2promoter methylation, whereas the IGFBP-2promoter was methylated in 71% of adenocarcinomas and 29% of squamous cell carcinomas. These findings suggest that 1) SCLC has an IGFBP-2overexpression mechanism distinct from NSCLC, 2) secreted IGFBP-2 contributes to the slow growth of SCLC in vitro, and 3) the epigenetic alterations in the IGFBP-2promoter contribute to the striking differences in IGFBP-2 expression between SCLC and NSCLC in vivo.

Our preliminary studies revealed that oncogenic KRAS (KRAS/V12) dramatically suppressed the growth of immortalized airway epithelial cells (NHBE-T, with viral antigen-inactivated p53 and RB proteins). This process appeared to be a novel event, different from the so-called premature senescence that is induced by either p53 or RB, suggesting the existence of a novel tumor suppressor that functions downstream of oncogenic KRAS. After a comprehensive search for genes whose expression levels were modulated by KRAS/V12, we focused on DUSP6, a pivotal negative feedback regulator of the RAS-ERK pathway. A dominant-negative DUSP6 mutant, however, failed to rescue KRAS/V12-induced growth suppression, but conferred a stronger anchorage-independent growth activity to the surviving subpopulation of cells generated from KRAS/V12-transduced NHBE-T. DUSP6 expression levels were found to be weaker in most lung cancer cell lines than in NHBE-T, and DUSP6 restoration suppressed cellular growth. In primary lung cancers, DUSP6 expression levels decreased as both growth activity and histological grade of the tumor increased. Loss of heterozygosity of the DUSP6locus was found in 17.7% of cases and was associated with reduced expression levels. These results suggest that DUSP6 is a growth suppressor whose inactivation could promote the progression of lung cancer. We have here identified an important factor involved in carcinogenesis through a comprehensive search for downstream targets of oncogenic KRAS.

Sweets for my sweet! Efficient synthesis of the deoxysugar part of versipelostatin (VST) was achieved by direct and stereoselective glycosidation of the reduced VST aglycon. Comparison of the synthetic and natural VST products using NMR indicate that VST has a β‐d‐digitoxose‐(1,4)‐α‐l‐oleandrose‐(1,4)‐β‐d‐digitoxose trisaccharide. A biological assay indicates that the deoxyoligosaccharide unit of the synthetic glycoside is important for biological activity.

A concise and convergent total synthesis of the highly cytotoxic marine natural product apratoxin A is accomplished by an 18‐step linear sequence. The high sensitivity of the thiazoline, bearing an adjacent β‐hydroxyl group at the C35‐position, results in the assembly process requiring the inclusion of appropriate protecting groups and the careful optimization of all individual transformations. In the synthesis of 3,7‐dihydroxy‐2,5,8,8‐tetramethylnonanoic acid (Dtena), the three reagent‐controlled asymmetric reactions enables us to introduce four chiral carbon centers in a dihydroxylated fatty acid moiety. Formation of the hindered ester and sterically‐unfavorable N‐methylamide bonds were successfully demonstrated. The thiazoline in apratoxin A was constructed by Tf2O and Ph3PO‐mediated dehydrative cyclization, and final macrocyclization was achieved between N‐methylisoleucine and proline residues. Moreover, an oxazoline analogue and a C34 epimer of apratoxin A have also been elaborated in a similar approach. This synthetic route would enable assembly of other analogues differing in stereocenters of Dtena and their amino acids.

An effective hydrophilic scaffold composed of D‐trihydroxyllysine‐based oligopeptides and its application in the synthesis of the various 111In–DTPA conjugates with mono‐ to penta‐bisphosphonate units for use as bone tracers are described. The D‐trihydroxyllysine derivative with three orthogonal protecting groups was conjugated with functional devices at the γ position and allowed oligomerization based on peptide chemistry. The radiopharmaceutical complexes of 111InIIIwith selected chelators, 4and 8, were suitable for bone imaging. These results show that D‐trihydroxyllysine 2was an effective building block for the synthesis of multivalent ligands applicable to medical use.

No Abstract

The glycosidation of a polymer‐supported glycosyl donor, N‐phenyltrifluoroacetimidate, with various glycosyl acceptors is reported. The application of the polymer‐supported N‐phenyltrifluoroacetimidate is demonstrated in the synthesis of vancomycin derivatives. 2‐O‐[2‐(azidomethyl)benzoyl]glycosyl imidate was attached to a polymer support at the 6‐position by a phenylsulfonate linked with a C13 alkyl spacer. Solid‐phase glycosidation with a vancomycin aglycon, selective deprotection of the 2‐(azidomethyl)benzoyl group, and glycosylation of the resulting 2‐hydroxy group with a vancosamine unit were performed. Nucleophilic cleavage from the polymer support with acetate, chloride, azido, and thioacetate ions provided vancomycin derivatives in pure form after simple purification. The semisynthesis of vancomycin was achieved by deprotection of the acetate derivative.

An efficient solution‐phase synthesis of rac‐15‐deoxy‐Δ12,14‐PGJ2(15dPGJ2) derivatives that contain variable α and ω chains based on a polymer‐assisted strategy and their neurite‐outgrowth‐promoting activity are described. The strategy for the synthesis of PGJ2derivatives involves the use of a vinyl iodide bearing cyclopentenone as a key intermediate, which undergoes Suzuki–Miyaura coupling and subsequent Lewis acid catalyzed aldol condensation for incorporation of the ω and α chains, respectively. For easy access to the PGJ2derivatives, a polymer‐supported catalyst and scavengers were adapted for use in these four diverse steps, in which workup and purification can be performed by simple filtration of the solid‐supported reagents. By using this methodology, we succeeded in the synthesis of 16 PGJ2derivatives with four alkyl boranes and four aldehydes. The neurite‐outgrowth‐promoting activity of the 16 synthetic compounds in PC12 cells revealed that the side‐chains play a major role in modulating their biological activity. The carboxylic acid on the α chain improved the biological activity, although it was not absolutely required. Furthermore, a PGJ2derivative with a phenyl moiety on the ω chain was found to exhibit an activity comparable to that of natural 15dPGJ2.

Methotrexate (MTX) is the anticancer and antirheumatoid drug that is believed to block nucleotide synthesis and cell cycle by inhibiting dihydrofolate reductase activity. We have developed novel affinity matrices, termed SG beads, that are easy to manipulate and are compatible with surface functionalization. Using the matrices, here we present evidence that deoxycytidine kinase (dCK), an enzyme that acts in the salvage pathway of nucleotide biosynthesis, is another target of MTX. MTX modulates dCK activity differentially depending on substrate concentrations. 1-β-d-Arabinofuranosylcytosine (ara-C), a chemotherapy agent often used in combination with MTX, is a nucleoside analog whose incorporation into chromosome requires prior phosphorylation by dCK. We show that, remarkably, MTX enhances incorporation and cytotoxicity of ara-C through regulation of dCK activity in Burkitt’s lymphoma cells. Thus, this study provides new insight into the mechanisms underlying MTX actions and demonstrates the usefulness of the SG beads.

Gain-of-function point mutations in K-rasaffect early events in pulmonary bronchioloalveolar carcinoma. We investigated altered mRNA expression on K-Ras activation in human peripheral lung epithelial cells (HPL1A) using oligonucleotide microarrays. Mutated K-Ras stably expressed in HPL1A accelerated cell growth and induced the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-4 and IGFBP-2, which modulate cell growth via IGF. Other lung epithelial cell lines (NHBE and HPL1D) revealed the same phenomena as HPL1A by mutated K-rastransgene. Lung cancer cell growth was also accelerated by mutated K-rasgene transduction, whereas IGFBP-4/2 induction was weaker compared with mutated K-Ras-expressing lung epithelial cells. To understand the differences in IGFBP-4/2 inducibility via K-Ras-activated signaling between nonneoplastic lung epithelia and lung carcinoma, we addressed the mechanisms of IGFBP-4/2 transcriptional activation. Our results revealed that Egr-1, which is induced on activation of Ras-mitogen-activated protein kinase signaling, is crucial for transactivation of IGFBP-4/2. Furthermore, IGFBP-4and IGFBP-2promoters were often hypermethylated in lung carcinoma, yielding low basal expression/weak induction of IGFBP-4/2. These findings suggest that continuous K-Ras activation accelerates cell growth and evokes a feedback system through IGFBP-4/2 to prevent excessive growth. Moreover, this growth regulation is disrupted in lung cancers because of promoter hypermethylation of IGFBP-4/2genes.

No Abstract

A 36‐step synthesis was carried out in automated synthesizers to provide a synthetic key intermediate of taxol. A key step involved a microwave‐assisted alkylation reaction to construct the ABC ring system from an AC precursor. Subsequent formation of the D ring afforded baccatin III, a well‐known precursor of taxol.

A 24-member combinatorial library based on the structure of aeruginosin 298-A (1a) was synthesized utilizing solid-phase, and their inhibitory activity against trypsin was evaluated. Among the library, we found that d-Hpla-d-Leu-l-Choi-Agma (1h) is 300 times more potent than the parent natural product 1a-i