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Chemokines are a family of cytokines that mediate leukocyte trafficking and are involved in tumor cell migration, growth, and progression. Although there is emerging evidence that multiple chemokines are expressed in tumor tissues and that each chemokine induces receptor-mediated signaling, their collaboration to regulate tumor invasion and lymph node metastasis has not been fully elucidated. In this study, we examined the effect of CXCL12 on the CCR7-dependent signaling in MDA-MB-231 human breast cancer cells to determine the role of CXCL12 and CCR7 ligand chemokines in breast cancer metastasis to lymph nodes. CXCL12 enhanced the CCR7-dependent in vitro chemotaxis and cell invasion into collagen gels at suboptimal concentrations of CCL21. CXCL12 promoted CCR7 homodimer formation, ligand binding, CCR7 accumulation into membrane ruffles, and cell response at lower concentrations of CCL19. Immunohistochemistry of MDA-MB-231-derived xenograft tumors revealed that CXCL12 is primarily located in the pericellular matrix surrounding tumor cells, whereas the CCR7 ligand, CCL21, mainly associates with LYVE-1

Supplementary Figures S1-S3 from Activation of KIF4A as a Prognostic Biomarker and Therapeutic Target for Lung Cancer

Purpose and Experimental Design: To identify molecules that might be useful as diagnostic/prognostic biomarkers and as targets for the development of new molecular therapies, we screened genes that were highly transactivated in a large proportion of 101 lung cancers by means of a cDNA microarray representing 27,648 genes. We found a gene encoding KIF4A, a kinesin family member 4A, as one of such candidates. Tumor tissue microarray was applied to examine the expression of KIF4A protein and its clinicopathologic significance in archival non–small cell lung cancer (NSCLC) samples from 357 patients. A role of KIF4A in cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of KIF4A on mammalian cells was examined using Matrigel assays.Results: Immunohistochemical staining detected positive KIF4A staining in 127 (36%) of 357 NSCLCs and 19 (66%) of 29 small-cell lung cancers examined. Positive immunostaining of KIF4A protein was associated with male gender (P = 0.0287), nonadenocarcinoma histology (P = 0.0097), and shorter survival for patients with NSCLC (P = 0.0005), and multivariate analysis confirmed its independent prognostic value (P = 0.0012). Treatment of lung cancer cells with small interfering RNAs for KIF4A suppressed growth of the cancer cells. Furthermore, we found that induction of exogenous expression of KIF4A conferred cellular invasive activity on mammalian cells.Conclusions: These data strongly implied that targeting the KIF4A molecule might hold a promise for the development of anticancer drugs and cancer vaccines as well as a prognostic biomarker in clinic.

Purpose and Experimental Design: To identify novel biomarkers and therapeutic targets for lung cancers, we screened for genes that were highly transactivated in lung cancers using a cDNA microarray representing 27,648 genes. DLX5 gene, a member of the human distal-less homeobox transcriptional factor family that is expressed during early embryonic development, was found to be overexpressed in the great majority of lung cancers. Tissue microarray consisting of archival non–small cell lung cancer samples from 369 patients was applied to examine the clinicopathologic significance of DLX5 protein. A role of DLX5 in cancer cell growth and/or survival was investigated through small interfering RNA experiments.Results: Northern blot and immunohistochemical analyses detected expression of DLX5 only in placenta among 23 normal tissues examined. Immunohistochemical analysis showed that positive immunostaining of DLX5 was correlated with tumor size (pT classification; P = 0.0053) and poorer prognosis of non–small cell lung cancer patients (P = 0.0045). It was also shown to be an independent prognostic factor (P = 0.0415). Treatment of lung cancer cells with small interfering RNAs for DLX5 effectively knocked down its expression and suppressed cell growth.Conclusions: These data implied that DLX5 is useful as a target for the development of anticancer drugs and cancer vaccines as well as for a prognostic biomarker in clinic.

Gene expression profile analyses of non–small cell lung carcinomas (NSCLC) and esophageal squamous cell carcinomas (ESCC) revealed that lymphocyte antigen 6 complex locus K (LY6K) was specifically expressed in testis and transactivated in a majority of NSCLCs and ESCCs. Immunohistochemical staining using 406 NSCLC and 265 ESCC specimens confirmed that LY6K overexpression was associated with poor prognosis for patients with NSCLC (P = 0.0003), as well as ESCC (P = 0.0278), and multivariate analysis confirmed its independent prognostic value for NSCLC (P = 0.0035). We established an ELISA to measure serum LY6K and found that the proportion of the serum LY6K-positive cases was 38 of 112 (33.9%) NSCLC and 26 of 81 (32.1%) ESCC, whereas only 3 of 74 (4.1%) healthy volunteers were falsely diagnosed. In most cases, there was no correlation between serum LY6K and conventional tumor markers of carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA 21-1) values. A combined ELISA for both LY6K and CEA classified 64.7% of lung adenocarcinoma patients as positive, and the use of both LY6K and CYFRA 21-1 increased sensitivity in the detection of lung squamous cell carcinomas and ESCCs up to 70.4% and 52.5%, respectively, whereas the false positive rate was 6.8% to 9.5%. In addition, knocked down of LY6K expression with small interfering RNAs resulted in growth suppression of the lung and esophageal cancer cells. Our data imply that a cancer-testis antigen, LY6K, should be useful as a new type of tumor biomarker and probably as a target for the development of new molecular therapies for cancer treatment. [Cancer Res 2007;67(24):11536–46]

Supplementary Figures 1-4 from Identification of Nectin-4 Oncoprotein as a Diagnostic and Therapeutic Target for Lung Cancer

Supplementary Figure S3 from The Neuromedin U-Growth Hormone Secretagogue Receptor 1b/Neurotensin Receptor 1 Oncogenic Signaling Pathway as a Therapeutic Target for Lung Cancer

Supplementary Figures 1-2 from Cancer-Testis Antigen Lymphocyte Antigen 6 Complex Locus K Is a Serologic Biomarker and a Therapeutic Target for Lung and Esophageal Carcinomas

Supplementary Figure S2A-D from The Neuromedin U-Growth Hormone Secretagogue Receptor 1b/Neurotensin Receptor 1 Oncogenic Signaling Pathway as a Therapeutic Target for Lung Cancer

Supplementary Figure Legends 1-4 from Identification of Nectin-4 Oncoprotein as a Diagnostic and Therapeutic Target for Lung Cancer

Using a genome-wide cDNA microarray to search for genes that were specifically up-regulated in non–small cell lung cancers (NSCLC), we identified an abundant expression of neuromedin U (NMU) in the great majority of lung cancers. Immunohistochemical analysis showed a significant association of NMU expression with poorer prognosis of patients with NSCLC. Treatment of NSCLC cells with short interfering RNA against NMU suppressed its expression and inhibited the growth of the cells; on the other hand, the induction of exogenous expression of NMU conferred growth-promoting activity and enhanced cell mobility in vitro. We found that two G protein–coupled receptors, growth hormone secretagogue receptor 1b and neurotensin receptor 1, were also overexpressed in NSCLC cells, and that a heterodimer complex of these receptors functioned as an NMU receptor. The NMU-receptor interaction subsequently induced the generation of a second messenger, cyclic AMP, to activate its downstream genes including transcription factors and cell cycle regulators. Treatment of NSCLC cells with short interfering RNAs for growth hormone secretagogue receptor or neurotensin receptor 1 suppressed the expression of those genes and the growth of NSCLC cells. These data strongly implied that targeting the NMU signaling pathway would be a promising therapeutic strategy for the treatment of lung cancers. (Cancer Res 2006; 66(19): 9408-19)

Supplementary Tables 1-2 from Identification of Nectin-4 Oncoprotein as a Diagnostic and Therapeutic Target for Lung Cancer

Supplementary Figure S1A-C from The Neuromedin U-Growth Hormone Secretagogue Receptor 1b/Neurotensin Receptor 1 Oncogenic Signaling Pathway as a Therapeutic Target for Lung Cancer

Supplementary Figure Legends 1-2 from Cancer-Testis Antigen Lymphocyte Antigen 6 Complex Locus K Is a Serologic Biomarker and a Therapeutic Target for Lung and Esophageal Carcinomas

Sperm activation is an essential process by which the male gametes become capable of fertilization. Because the process in Caenorhabditis elegans is readily reproducible in vitro, this organism serves as an excellent model to investigate it. C. elegans sperm activation in vivo occurs during spermiogenesis. Membranous organelles (MOs) contained within spermatids fuse with the plasma membrane, resulting in extracellular release of their contents and relocation of some proteins indispensable for fertilization from the MO membrane onto the sperm surface. Intriguingly, these cytological alternations are exhibited similarly in mouse spermatozoa during the acrosome reaction, which also represents a form of sperm activation, prompting us to hypothesize that C. elegans and mice share a common mechanism for sperm activation. To explore this, we first screened a chemical library to identify compounds that activate C. elegans spermatozoa. Because a quinolinol analog named DDI-6 seemed to be a candidate sperm activator, we synthesized it to use for further analyses. This involved direct dechlorination and hydrogenolysis of commercially available 5-chloro-8-quinolinol, both of which are key steps to yield 1,2,3,4-tetrahydro-8-quinolinol, and we subsequently introduced the sulfonamide group to the compound. When C. elegans spermatids were stimulated with solvent alone or the newly synthesized DDI-6, approx. 3% and approx. 28% of spermatids became MO-fused spermatozoa, respectively. Moreover, DDI-6 triggered the acrosome reaction in approx. 20% of mouse spermatozoa, while approx. 12% became acrosome-reacted after mock stimulation. Thus, DDI-6 serves as a moderately effective activator for both C. elegans and mouse spermatozoa.

Sperm activation is an essential process by which the male gametes become capable of fertilization. Because the process in Caenorhabditis elegans is readily reproducible in vitro, this organism serves as an excellent model to investigate it. C. elegans sperm activation in vivo occurs during spermiogenesis. Membranous organelles (MOs) contained within spermatids fuse with the plasma membrane, resulting in extracellular release of their contents and relocation of some proteins indispensable for fertilization from the MO membrane onto the sperm surface. Intriguingly, these cytological alternations are exhibited similarly in mouse spermatozoa during the acrosome reaction, which also represents a form of sperm activation, prompting us to hypothesize that C. elegans and mice share a common mechanism for sperm activation. To explore this, we first screened a chemical library to identify compounds that activate C. elegans spermatozoa. Because a quinolinol analog named DDI-6 seemed to be a candidate sperm activator, we synthesized it to use for further analyses. This involved direct dechlorination and hydrogenolysis of commercially available 5-chloro-8-quinolinol, both of which are key steps to yield 1,2,3,4-tetrahydro-8-quinolinol, and we subsequently introduced the sulfonamide group to the compound. When C. elegans spermatids were stimulated with solvent alone or the newly synthesized DDI-6, approx. 3% and approx. 28% of spermatids became MO-fused spermatozoa, respectively. Moreover, DDI-6 triggered the acrosome reaction in approx. 20% of mouse spermatozoa, while approx. 12% became acrosome-reacted after mock stimulation. Thus, DDI-6 serves as a moderately effective activator for both C. elegans and mouse spermatozoa.

Spermiogenesis is the final phase of spermatogenesis in which round spermatids transform into spermatozoa. However, the molecular basis of spermiogenesis is largely unknown in many species. One of the reasons why we use Caenorhabditis elegans to study spermiogenesis is that spermatids from this organism do not require any hormones and accessory cells in vitro to become spermatozoa. C. elegans spermiogenesis consists of two pivotal events, the pseudopod extension from spermatids and the fusion between the plasma membrane and the intracellular membranous organelles (MOs). In vitro activators such as Pronase (Pron) can induce these two cytological reactions in a simple, chemically defined medium. This advantage enables us to explore compounds that up- and downregulate spermiogenesis, which would be powerful tools for basic research and be the seeds of future drugs for infertility and contraception.

Caenorhabditis elegans spermiogenesis involves spermatid activation into spermatozoa. Activation occurs through either SPE-8 class-dependent or class-independent pathways. Pronase (Pron) activates the SPE-8 class-dependent pathway, whereas no in vitro tools are available to stimulate the SPE-8 class-independent pathway. Thus, whether there is a functional relationship between these two pathways is currently unclear. In this study, we found that proteinase K (ProK) can activate the SPE-8 class-independent pathway. In vitro spermiogenesis assays using Pron and ProK suggested that SPE-8 class proteins act in the hermaphrodite- and male-dependent spermiogenesis pathways and that some spermatid proteins presumably working downstream of spermiogenesis pathways, including MAP kinases, are preferentially involved in the SPE-8 class-dependent pathway. We screened a library of chemicals, and a compound that we named DDI-1 inhibited both Pron- and ProK-induced spermiogenesis. To our surprise, several DDI-1 analogues that are structurally similar to DDI-1 blocked Pron, but not ProK, induced spermiogenesis. Although the mechanism by which DDI-1 blocks spermiogenesis is yet unknown, we have begun to address this issue by selecting two DDI-1-resistant mutants. Collectively, our data support a model in which C. elegans male and hermaphrodite spermiogenesis each has its own distinct, parallel pathway.

This study was conducted to understand the effect of well-known water-washing process on Ni-rich LiNi0.885Co0.100Al0.015O2 (NCA) cathode material, which reduces the amount of residual lithium compounds in NCA to improve lithium-ion batteries (LIBs) characteristics. X-ray absorption fine structure (XAFS) analysis revealed that the oxidation state of the surface nickel in washed NCA particles was reduced. The fact was consistent with the increase in charge transfer resistance (Rct) measured by the electrochemical impedance spectroscopy (EIS) method. From X-ray photoelectron spectroscopy (XPS) and Auger electron spectroscopy (AES) analyses, it was found that the residual lithium compounds were washed away not only from the surface of NCA particles but also from grain boundaries or voids in between primary particles of NCA, by water-washing process. Differential scanning calorimetry (DSC) measurements suggested that an increase in specific surface area of NCA particles by water-washing was attributed a rapid heat release from the charged cathode material during heating to. On the other hand, cross-sectional scanning electron microscope (SEM) images showed that the crack formation inside washed NCA particles were suppressed after charge/discharge cycling. As a result, the capacity retention of washed NCA electrode at 60 °C cycling was improved.

Most organisms consist of two cell lineages - somatic cells and germ cells. The former are required for the current generation, and the latter create offspring. Male and female germ cells are usually produced during spermatogenesis and oogenesis, which take place in the testis and the ovary, respectively. Spermatogenesis involves the differentiation of spermatogonial stem cells into spermatocytes via mitotic cell division and the production of haploid spermatids from the tetraploid primary spermatocytes via meiotic cell division. Spermatids subsequently give rise to spermatozoa in the final phase of spermatogenesis, called spermiogenesis. These fundamental steps, where mitotic proliferation precedes meiosis during spermatogenesis, are observed in a wide variety of organisms. However, developing a comprehensive understanding of the cell biology and genetics of spermatogenesis is difficult for most species because it occurs within a complex testicular environment characterized by the intimate association of developing sperm with accessory cells. In this Primer, we summarize the processes of spermatogenesis occurring in two pivotal model animals - mouse and Caenorhabditis elegans - and compare them to consider which important features might be evolutionarily conserved.

Since distal femoral varus osteotomy (DFO) -specific plates had not been available in Japan before 2015, we performed DFO using a plate for tibia. The purpose of this study was to elucidate the efficacy and problems associated with the non-specific plate in DFO. We used NCB-PT plates (Zimmer Inc.) in the upside-down position and the minimum 5-year outcomes were evaluated. The mean preoperative weight bearing line ratio and Japanese Orthopaedic Association score improved from 97.6%±35.8% and 68.0±11.5, respectively, to 44.0%±16.1% and 82.0±7.6, respectively, 1 year postoperatively and to 42.8%±15.7% and 86.0±8.2, respectively, 5 years postoperatively. The flexion range decreased from 149.0°±6.5° to 138.0°±5.7° 1 year postoperatively and to 135.0°±20.9° 5 years postoperatively. Although DFO using the NCB-PT plate provided mid-term benefits, it resulted in a loss of knee flexion, possibly due to excessive coverage of the medial femoral epicondyle.

In order to predict ash deposition in a pulverized coal combustion process, the fragmentation, detachment, and coalescence behavior of ash particles in coal were quantitatively evaluated to distinguish between excluded and included minerals. The experiments for simulated EM heating and simulated coal combustion were carried out in a drop tube furnace. Change in the numbers of EM and IM particles were measured at different residence times by scanning a sampling probe along the flow direction in the reactor tube. The rate constants of EM fragmentation were estimated from the simulated EM heating experiment. The solution to a system of differential equations that includes the effects of fragmentation, detachment, and coalescence as functions for the numbers of EM and IM was obtained as a kinetic model. These functions were fitted to the experimental results for simulated coal combustion experiment to obtain the rate constants for detachment and coalescence. This method was also applied to previous experimental results using three actual coal samples. The rate constants of detachment and coalescence were mainly affected by char structure during coal combustion.

Objective A low ankle-brachial index (ABI) is a known predictor for future cardiovascular events and mortality in patients with chronic kidney disease (CKD). While most prior studies have defined CKD as an estimated glomerular filtration rate (eGFR) 0.9 (90.8%). The primary outcome measured was the cumulative incidence of major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, and stroke). Results Over a mean follow-up of 5.0 years, 101 MACE occurred. The incidence of MACE was significantly higher in patients with low ABI than in those with ABI >0.9 (30.2% vs. 14.4%, log rank p

Diastolic wall strain (DWS) is based on the linear elastic theory, according to which decreased wall thinning during diastole reflects reduced left ventricular compliance and thus increased diastolic stiffness. Increased diastolic stiffness as assessed by DWS is associated with a worse prognosis in patients who have heart failure (HF) with preserved ejection fraction. However, there are no data about the prognostic value of DWS derived by M-mode echocardiography in patients at risk for HF. We retrospectively enrolled 1829 consecutive patients without prior HF who were hospitalized for cardiovascular (CV) diseases in our hospital between 2005 and 2012. Patients were divided into two groups stratified by DWS (median value 0.34). The study endpoint was the composite of major adverse cardiovascular events (MACE), including all-cause death, myocardial infarction, stroke, and hospitalization for HF. Over a 4.2-year median follow-up, adverse events were observed in 322 patients (17.6%). In Kaplan-Meier analysis, patients with low DWS (≤ 0.34, n = 915) showed worse prognoses than those with high DWS (> 0.34, n = 914) (MACE incidence 39.4% versus 31.9%, P = 0.011). In multivariate Cox proportional hazards analysis after the adjustment for age, sex, and echocardiographic parameters, low DWS (≤ 0.34) was significantly associated with the incidence of MACE (hazard ratio: 1.26, 95% confidence interval: 1.01-1.59; P = 0 .045). In patients without prior HF, DWS is an independent predictor of MACE. Simple assessment of DWS might improve risk stratification for CV events in those patients.

The maximum cause to make mechanical toughness of a weld metal reduce in process management is known to be a mixture of nitrogen including in the atmosphere by breaking the shield condition. Mixtur...

The ankle brachial index (ABI) is regarded as a predictor of future cardiovascular events. However, the relationship between ABI and incident heart failure (HF) in patients without previous HF is poorly understood. This study aimed to assess the prognostic value of ABI for incident HF in patients without previous HF. The IMPACT–ABI study was a retrospective, single-center, cohort study that enrolled and measured ABI in 3131 patients hospitalized for cardiovascular disease between January 2005 and December 2012. From this cohort, 307 patients were excluded because of previous HF and high (>1.4) ABI. The remaining 2824 patients were stratified into three groups: low ABI (≤0.9), borderline ABI (0.91–0.99), and normal ABI (1.0–1.4). The primary endpoint was hospitalization for HF. Over a mean 4.8-year follow-up, 105 cases of HF occurred. The cumulative incidence of HF was significantly higher in patients with low and borderline ABIs than in those with normal ABI (19.3 vs. 21.0 vs. 10.4 %, log rank P

インタープリテーションとは「環境保全地域や公園、博物館など、社会教育の場における持続可能な社会づくりのための教育的コミュニケーション」である。近年、ESDや科学技術コミュニケーションなどの領域でもこの活動が取り入れられるようになったことで、新しい役割が付け加わるようになっている。社会問題の解決や、持続可能な社会づくりにむけて、インタープリテーションが果たすべき役割はさらに拡大すると考えられる。, 20周年記念特集号