CXCL12 promotes CCR7 ligand-mediated breast cancer cell invasion and migration toward lymphatic vessels.

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+ intratumoral and peritumoral lymphatic vessels. In the three-dimensional tumor invasion model with lymph networks, CXCL12 stimulation facilitates breast cancer cell migration to CCL21-reconstituted lymphatic networks. These results indicate that CXCL12/CXCR4 signaling promotes breast cancer cell migration and invasion toward CCR7 ligand-expressing intratumoral lymphatic vessels and supports CCR7 signaling associated with lymph node metastasis.

Identification and Synthesis of DDI-6, a Quinolinol Analog Capable of Activating Both Caenorhabditis 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.

Proteinase K is an activator for the male-dependent spermiogenesis pathway in Caenorhabditis elegans: Its application to pharmacological dissection of spermiogenesis.

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.

Geriatric Nutritional Risk Index Predicts Cardiovascular Events in Patients at Risk for Heart Failure.

BACKGROUND: The geriatric nutritional risk index (GNRI) is a simple and objective nutritional assessment tool for elderly patients. Lower GNRI values are associated with a worse prognosis in patients with heart failure (HF). However, few data are available regarding the prognostic effect of the GNRI value for risk stratification in patients at risk for HF.Methods and Results:We retrospectively investigated 1,823 consecutive patients at risk for HF (Stage A/B) enrolled in the IMPACT-ABI Study. GNRI on admission was calculated as follows: 14.89×serum albumin (g/dL)+41.7×body mass index/22. Patients were divided into 2 groups according to the median GNRI value (107.1). The study endpoint was a composite of cardiovascular (CV) events, including CV death and hospitalization for worsening HF. Over a 4.7-year median follow-up, CV events occurred in 130 patients. In the Kaplan-Meier analysis, patients with low GNRI (<107.1, n=904) showed worse prognoses than those with high GNRI (≥107.1, n=919) (20.2% vs. 12.4%, P<0.001). In the multivariable Cox proportional hazards analysis, low GNRI was significantly associated with the incidence of CV events (hazard ratio: 1.48, 95% confidence interval: 1.02-2.14; P=0.040). CONCLUSIONS: The simple and practical assessment of GNRI may be useful for predicting CV events in patients with Stage A/B HF.

Plausible link between circa'bi'dian activity rhythms and circadian clock systems in the large black chafer Holotrichia parallela.

Two-day rhythms, referred to as circa'bi'dian rhythms, have been reported in humans and mosquitos. However, these rhythms only appear under constant conditions, and the functional mechanisms of 2-day rhythms were unknown. Here, we report clear circabidian rhythms of large black chafers (Holotrichia parallela, Coleoptera: Scarabaeidae) in both the laboratory and field. Under 12 h:12 h light:dark (L:D) conditions at 25°C, H. parallela appeared on the ground at the beginning of the dark phase every 2 days. Under constant darkness, H. parallela exhibited free-running with a period of 47.9±0.3 h, suggesting the existence of a clear circabidian rhythm entrained to two 12 h:12 h L:D cycles. Phase responses of the circabidian rhythm to light pulses occurred under constant darkness in a phase-dependent manner. Phase responses suggest that there are two circadian cycles, each consisting of a less-responsive and more-responsive period, in a circabidian oscillation, and the circabidian rhythm is driven by the circadian clock. A mark-recapture study showed that beetles repeatedly appeared on the same tree approximately every 2 days. However, the periodicity was not as rigid as that observed under laboratory conditions in that individuals often switched appearance days. For instance, a large precipitation made the 2-day rhythm shift phase by half a cycle of the rhythm at a time. We propose a novel function of the circadian clock characterized by the release of an output signal every two cycles to produce the 2-day rhythm.

The usefulness of brachial-ankle pulse wave velocity in predicting long-term cardiovascular events in younger patients.

Brachial-ankle pulse wave velocity (baPWV) is known as a significant predictor of cardiovascular events. However, the previous studies have not considered age, which can affect the baPWV value. We evaluated the predictive value of baPWV for cardiovascular events in various age groups. From January 2005 to December 2012, all patients admitted to our department with any cardiovascular disease and underwent ankle-brachial index (ABI) measurement were enrolled in the IMPACT-ABI registry. The primary endpoints included major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, and stroke). Of the 3131 patients enrolled, 2554 were included in the analysis, whereas 577 were excluded due to missing baPWV data, ABI ≤0.9 and/or >1.4, and the previous endovascular therapy and/or surgical treatment for peripheral artery disease. Patients were divided according to age 30-59 years (n = 580), 60-69 years (n = 730), 70-79 years (n = 862), and ≥80 years (n = 330). The cumulative incidence of MACE through 5 year was significantly higher in the high baPWV group (>1644 cm/s) than in the low baPWV group (≤1644 cm/s; 8.7 vs. 4.6%; log-rank: p < 0.001). However, among the age groups, only the 30-59-year group showed a significant difference in MACE incidence between those with high and low baPWV (7.0 vs. 0.9%; log-rank: p = 0.001). In conclusion, the baPWV could serve as a useful marker to predict cardiovascular events, particularly among younger patients.

Prognostic value of ankle brachial index for future incident heart failure in patients without previous heart failure: data from the impressive predictive value of ankle brachial index for clinical long term outcome in patients with cardiovascular disease examined by ABI study.

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 <0.001). In multivariate Cox proportional hazard analysis, low ABI and borderline ABI were independent predictors of incident HF [hazard ratio (HR) 3.00; 95 % confidence interval (CI) 1.70-5.28; P < 0.001 and HR 2.68; 95 % CI 1.35-5.34; P = 0.005, respectively]. In conclusion, low and borderline ABI were strong predictors for future incident HF in patients without previous HF.

Factors Predicting Recovery of Oral Intake in Stroke Survivors with Dysphagia in a Convalescent Rehabilitation Ward.

BACKGROUND: Percutaneous endoscopic gastrostomy may be performed in dysphagic stroke patients. However, some patients regain complete oral intake without gastrostomy. This study aimed to investigate the predictive factors of intake, thereby determining gastrostomy indications. METHOD: Stroke survivors admitted to our convalescent rehabilitation ward who underwent gastrostomy or nasogastric tube placement from 2009 to 2015 were divided into 2 groups based on intake status at discharge. Demographic data and Functional Independence Measure (FIM), Dysphagia Severity Scale (DSS), National Institutes of Health Stroke Scale, and Glasgow Coma Scale (GCS) scores on admission were compared between groups. We evaluated the factors predicting intake using a stepwise logistic regression analysis. RESULTS: Thirty-four patients recovered intake, whereas 38 achieved incomplete intake. Mean age was lower, mean body mass index (BMI) was higher, and mean time from stroke onset to admission was shorter in the complete intake group. The complete intake group had less impairment in terms of GCS, FIM, and DSS scores. In the stepwise logistic regression analysis, BMI, FIM-cognitive score, and DSS score were significant independent factors predicting intake. The formula of BMI × .26 + FIM cognitive score × .19 + DSS score × 1.60 predicted recovery of complete intake with a sensitivity of 88.2% and a specificity of 84.2%. CONCLUSIONS: Stroke survivors with dysphagia with a high BMI and FIM-cognitive and DSS scores tended to recover oral intake.

Prognostic Impact of Diastolic Wall Strain in Patients at Risk for Heart Failure.

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.

Spermiogenesis in Caenorhabditis elegans: An Excellent Model to Explore the Molecular Basis for Sperm Activation.

C. elegans spermiogenesis converts non-motile spermatids into motile, fertilization-competent spermatozoa. Two major events include the building of a pseudopod required for motility and fusion of membranous organelles (MOs)-intracellular secretory vesicles-with the spermatid plasma membrane required for the proper distribution of sperm molecules in mature spermatozoa. The mouse sperm acrosome reaction-a sperm activation event occurring during capacitation-is similar to MO fusion in terms of cytological features and biological significance. Moreover, C. elegans fer-1 and mouse Fer1l5, both encoding members of the ferlin family, are indispensable for MO fusion and acrosome reaction, respectively. Genetics-based studies have identified many C. elegans genes involved in spermiogenesis pathways; however, it is unclear whether mouse orthologs of these genes are involved in the acrosome reaction. One significant advantage of using C. elegans for studying sperm activation is the availability of in vitro spermiogenesis, which enables combining pharmacology and genetics for the assay. If certain drugs can activate both C. elegans and mouse spermatozoa, these drugs would be useful probes to explore the mechanism underlying sperm activation in these two species. By analyzing C. elegans mutants whose spermatids are insensitive to the drugs, genes functionally relevant to the drugs' effects can be identified.

Proton Conduction in Gly-X (X = Ser, Ser-Gly-Ser) and GS50.

In recent years, the use of biomaterials has been required from the viewpoint of biocompatibility of electronic devices. In this study, the proton conductivity of Glycyl-L-serine (Gly-Ser) was investigated to clarify the relationship between hydration and proton conduction in peptides. From the crystal and conductivity data, it was inferred that the proton conductivity in hydrated Gly-Ser crystals is caused by the cleavage and rearrangement of hydrogen bonds between hydration shells formed by hydrogen bonds between amino acids and water molecules. Moreover, a staircase-like change in proton conduction with hydration was observed at n = 0.3 and 0.5. These results indicate that proton transport in Gly-Ser is realized by hydration water. In addition, we also found that hydration of GSGS and GS50 can achieve proton conduction of Gly-Ser tetrameric GSGS and GS50 containing repeating sequences. The proton conductivity at n = 0.3 is due to percolation by the formation of proton-conducting pathways. In addition to these results, we found that proton conductivity at GS50 is realized by the diffusion constant of 3.21 × 10-8 cm2/s at GS50.

Characterization of mouse sperm TMEM190, a small transmembrane protein with the trefoil domain: evidence for co-localization with IZUMO1 and complex formation with other sperm proteins.

TMEM190, a small transmembrane protein containing the trefoil domain, was previously identified by our proteomic analysis of mouse sperm. Two structural features of TMEM190, 'trefoil domain' and 'small transmembrane protein', led us to hypothesize that this protein forms a protein-protein complex required during fertilization, and we characterized TMEM190 by biochemical, cytological, and genetic approaches. We showed in this study that the mouse Tmem190 gene exhibits testis-specific mRNA expression and that the encoded RNA is translated into a 19-kDa protein found in both testicular germ cells and cauda epididymal sperm. Treatment of the cell surface with proteinase K, subcellular fractionation, and immunofluorescence assay all revealed that mouse TMEM190 is an inner-acrosomal membrane protein of cauda epididymal sperm. During the acrosome reaction, TMEM190 partly relocated onto the surface of the equatorial segment, on which sperm-oocyte fusion occurs. Moreover, TMEM190 and IZUMO1, which is an immunoglobulin-like protein required for gamete fusion, co-localized in mouse sperm both before and after the acrosome reaction. However, immunoprecipitates of TMEM190 contained several sperm proteins, but did not include IZUMO1. These findings suggest that a mouse sperm protein complex(es) including TMEM190 plays an indirect role(s) in sperm-oocyte fusion. The role(s), if any, is probably dispensable since Tmem190-null male mice were normally fertile.

Spermatogenesis-defective (spe) mutants of the nematode Caenorhabditis elegans provide clues to solve the puzzle of male germline functions during reproduction.

In most species, each sex produces gametes, usually either sperm or oocytes, from its germline during gametogenesis. The sperm and oocyte subsequently fuse together during fertilization to create the next generation. This review focuses on spermatogenesis and the roles of sperm during fertilization in the nematode Caenorhabditis elegans, where suitable mutants are readily obtained. So far, 186 mutants defective in the C. elegans male germline functions have been isolated, and many of these mutations are alleles for one of the approximately 60 spermatogenesis-defective (spe) genes. Many cloned spe genes are expressed specifically in the male germline, where they play roles during spermatogenesis (spermatid production), spermiogenesis (spermatid activation into spermatozoa), and/or fertilization. Moreover, several spe genes are orthologs of mammalian genes, suggesting that the reproductive processes of the C. elegans and the mammalian male germlines might share common pathways at the molecular level.

[Two cases of advanced colorectal cancer which demonstrated the reversibility of oxaliplatin-mediated increase in splenic volume].

Hepatic sinusoidal injury arises occasionally after oxaliplatin-based chemotherapy. As a result, portal hypertension associated with splenomegaly occurs in some cases. We report two cases of advanced colorectal cancer which showed splenomegaly after administration of oxaliplatin-based chemotherapy. In both cases, mFOLFOX6/bevacizumab was administered as a firstline chemotherapy. Splenic volume was determined by loading the CT images onto a commercially available workstation. In case 1, initial splenic volume was 137.82mL. Two months later, it increased to 160.96mL. After six cycles of chemotherapy, we removed oxaliplatin due to peripheral neuropathy. Consequently, the splenic volume decreased to 151.58mL. Subsequent to the reintroduction of oxaliplatin, the splenic volume increased to 177.48mL. Following two cycles of mFOLFOX6/bevacizumab, oxaliplatin was removed again. In a similar way, splenic volume decreased to 158.52mL. In case 2, initial splenic volume was 105.84mL. Ten months later, it increased to 228.54mL. After administration of mFOLFOX6/bevacizumab, we continued chemotherapy with sLV5FU2/bevacizumab and irinotecan. The splenic volume decreased to 197. 06mL. In conclusion, oxaliplatin- based chemotherapy induces an increase in splenic volume, however, it may be reversible after discontinuation of oxaliplatin.

C. elegans spermatozoa lacking spe-45 are incapable of fusing with the oocyte plasma membrane.

C. elegans spe-9 class genes encode sperm proteins with indispensable roles during fertilization. We have previously reported that spe-45 belongs to the spe-9 class, based on the finding that self-sperm of spe-45(tm3715) hermaphrodites were not consumed by fertilization. In this study, we directly observed live fertilization in the spermatheca of fem-1(hc17) females after mating with spe-45(tm3715) males. As expected, it was clearly shown that spe-45 mutant spermatozoa failed to fuse with the oocyte plasma membrane. Thus, our live imaging system for C. elegans fertilization seems to be useful for evaluation of the functions of male and female gametes.

Activation of placenta-specific transcription factor distal-less homeobox 5 predicts clinical outcome in primary lung cancer patients.

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.

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.

Comparison of platelet aggregation response in switching regimen from prasugrel to clopidogrel between CYP2C19 extensive versus non-extensive metabolizers.

Little is known about the response of platelet aggregation in patients with acute coronary syndrome (ACS) when prasugrel is changed to clopidogrel. In this study, we evaluated the pharmacodynamic effects of this medication switch. Twenty-one consecutive ACS patients received prasugrel 20 mg as a loading dose before emergent percutaneous coronary intervention and 3.75 mg as a maintenance dose on days 2-7 (prasugrel phase). From day 8, prasugrel was switched to clopidogrel 75 mg/day (clopidogrel phase). P2Y12 reaction units (PRU) were measured 2-4 h after prasugrel loading, and on days 7, 11, 13, 15, and 42. Eight patients had the CYP2C19 extensive metabolizer (EM) genotype variant, while 13 were non-EM. In the EM group, no changes were observed in PRU level between days 7 and 15 (136.8 ± 51.2 vs. 166.2 ± 41.9, P = 0.07). However, in the non-EM group, a significant increase in PRU levels was observed between days 7 and 15 (165.8 ± 57.2 vs. 223.6 ± 60.9, P = 0.002). However, 2 patients in the non-EM group (15%) showed high on-clopidogrel treatment platelet reactivity (HTPR) 2-4 h after prasugrel loading, and during the clopidogrel phase there were significant differences in the incidence of HTPR between the EM and non-EM groups. Ischemic and bleeding events were not observed during this period. In the acute phase of ACS, changing from prasugrel to clopidogrel therapy decreased the effects of suppressing platelet aggregation. However, this change was not associated with increased ischemic or bleeding events.

Predictive Value of Underweight Status for Patients With Peripheral Artery Disease With Claudication.

We evaluated whether underweight status is associated with poor prognosis in patients with peripheral artery disease (PAD) with claudication, excluding critical limb ischemia. We identified 441 claudicants hospitalized for cardiovascular disease between 2005 and 2012. Patients were divided into 4 groups according to body mass index (BMI): an underweight group (BMI < 18.5 kg/m2; n = 48), a normal group (BMI = 18.5-25.0 kg/m2; n = 286), an overweight group (BMI = 25.0-30.0 kg/m2; n = 92), and an obese group (BMI ≥ 30.0 kg/m2; n = 15). The mean follow-up period was 3.5 ± 1.9 years. The underweight group had significantly lower levels of hemoglobin, albumin, estimated glomerular filtration rate, triglycerides, and hemoglobin A1c; higher levels of C-reactive protein and B-type natriuretic peptide; and a higher prevalence of hemodialysis. The incidence of all-cause death and cardiovascular death was significantly higher in the underweight group (underweight vs normal, 77.1% vs 33.0%; P < .001 and 43.3% vs 14.4%; P < .001, respectively). In a multivariate Cox analysis, underweight status was an independent predictor of all-cause death (hazard ratio, 2.53; 95% confidence interval, 1.58-4.18; P < .001). Therefore, promoting weight gain, as well as managing cardiovascular disease, may be important for underweight patients with PAD.

Fibroblast growth factor receptor 1 oncogene partner as a novel prognostic biomarker and therapeutic target for lung cancer.

To screen candidate molecules that might be useful as diagnostic biomarkers or for development of novel molecular-targeting therapies, we previously carried out gene-expression profile analysis of 101 lung carcinomas and detected an elevated expression of FGFR1OP (fibroblast growth factor receptor 1 oncogene partner) in the majority of lung cancers. Immunohistochemical staining using tumor tissue microarrays consisting of 372 archived non-small cell lung cancer (NSCLC) specimens revealed positive staining of FGFR1OP in 334 (89.8%) of 372 NSCLCs. We also found that the high level of FGFR1OP expression was significantly associated with shorter tumor-specific survival times (P < 0.0001 by log-rank test). Moreover, multivariate analysis determined that FGFR1OP was an independent prognostic factor for surgically treated NSCLC patients (P < 0.0001). Treatment of lung cancer cells, in which endogenous FGFR1OP was overexpressed, using FGFR1OP siRNA, suppressed its expression and resulted in inhibition of the cell growth. Furthermore, induction of FGFR1OP increased the cellular motility and growth-promoting activity of mammalian cells. To investigate its function, we searched for FGFR1OP-interacting proteins in lung cancer cells and identified ABL1 (Abelson murine leukemia viral oncogene homolog 1) and WRNIP1 (Werner helicase interacting protein 1), which was known to be involved in cell cycle progression. FGFR1OP significantly reduced ABL1-dependent phosphorylation of WRNIP1 and resulted in the promotion of cell cycle progression. Because our data imply that FGFR1OP is likely to play a significant role in lung cancer growth and progression, FGFR1OP should be useful as a prognostic biomarker and probably as a therapeutic target for lung cancer.