Explore the vast range of titles available.

The significance of l‐type amino acid transporter (LAT) 1 expression remains unclear in the metastatic process of human neoplasms, whereas experimental studies have demonstrated that LAT1 is associated with the metastatic process of cancer cells. We compared the immunohistochemical expression of LAT1 and CD98 between the primary site and a concordant pulmonary metastatic site in 93 cancer patients, all of whom had undergone thoracotomy. LAT1, CD98, Ki‐67 labeling index, vascular endothelial growth factor (VEGF), CD31, and CD34 were analyzed by immunohistochemical staining in the resected tumors of 93 cancer patients: 45 colon cancers; nine breast cancers; eight head and neck cancers; 11 genital cancers; 14 soft‐tissue sarcomas; and six other cancers. The expression of these markers was significantly higher in the metastatic sites than in the primary sites. In total, the positive rates of LAT1, CD98, Ki‐67, VEGF, CD31, and CD34 were 40, 24, 56, 41, 45, and 39%, respectively, in the primary sites and 65, 45, 84, 67, 73, and 61%, respectively, in the metastatic sites. LAT1 expression was closely correlated with CD98 expression, angiogenesis, and cell proliferation. The association between LAT1 and CD98 expression was strongest in the primary and metastatic sites. The present study suggests that overexpression of LAT1 and CD98 has an important role to play in the metastatic process of variable human neoplasms. Moreover, LAT1 expression was significantly correlated with cell proliferation and angiogenesis. (Cancer Sci 2008; 99: 2380–2386)

The aim of this study was to produce a simplified questionnaire for evaluation of the symptoms of gastroesophageal reflux disease (GERD). A total of 124 patients with an endoscopic diagnosis of GERD completed a 50-part questionnaire, requiring only \"yes\" or \"no\" answers, that covered various symptoms related to the upper gastrointestinal tract, as well as psychosomatic symptoms. The 12 questions to which patients most often answered \"yes\" were selected, and were assigned scores (never = 0; occasionally = 1; sometimes = 2; often = 3; and always = 4) to produce a frequency scale for symptoms of GERD (FSSG). Sensitivity, specificity, and accuracy of the FSSG questionnaire were evaluated in another group of patients with GERD and non-GERD. The usefulness of this questionnaire was evaluated in 26 other GERD patients who were treated with proton pump inhibitors for 8 weeks. When the cutoff score was set at 8 points, the FSSG showed a sensitivity of 62%, a specificity of 59%, and an accuracy of 60%, whereas a cutoff score of 10 points altered these values to 55%, 69%, and 63%. The score obtained using the questionnaire correlated well with the extent of endoscopic improvement in patients with mild or severe GERD. This new questionnaire is useful for the objective evaluation of symptoms in GERD patients.

We examined whether the chemogenetic activation of endogenous arginine vasopressin (AVP) affects central nesfatin-1/NucB2 neurons, using a transgenic rat line that was previously generated. Saline (1 mL/kg) or clozapine-N-oxide (CNO, 1 mg/mL/kg), an agonist for hM3Dq, was subcutaneously administered in adult male AVP-hM3Dq-mCherry transgenic rats (300–370 g). Food and water intake were significantly suppressed after subcutaneous (s.c.) injection of CNO, with aberrant circadian rhythmicity. The percentages of Fos expression in nesfatin-1/NucB2-immunoreactive neurons were significantly increased in the hypothalamus and brainstem at 120 min after s.c. injection of CNO. Suppressed food intake that was induced by chemogenetic activation of endogenous AVP was ablated after intracerebroventricularly administered nesfatin-1/NucB2-neutralizing antibody in comparison with vehicle, without any alteration of water intake nor circadian rhythmicity. These results suggest that chemogenetic activation of endogenous AVP affects, at least in part, central nesfatin-1/NucB2 neurons and may exert anorexigenic effects in the transgenic rats.

The purpose of this study was to evaluate the prognostic value of L‐type amino acid transporter 1 (LAT 1) and 4F2 heavy chain (CD98) in patients with stage I squamous cell carcinoma of the lung. A total of 84 consecutive patients with completely resected pathologic stage I squamous cell carcinoma of the lung were retrospectively reviewed. All patients underwent resection of the tumor and the immunohistochemical analysis was done to determine the expression of LAT 1, CD98, Ki‐67 labeling index, vascular endothelial growth factor, and microvessel density. These pathological parameters were correlated with the prognosis of patients after complete resection of the tumor. A positive rate of LAT 1 expression (87%; 73/84) was significantly higher than that of CD98 expression (65%; 55/84) (P = 0.0018). Cooperative expression of LAT 1 and CD98 was recognized in 62% (52/84). LAT 1 expression was significantly correlated with CD98, Ki‐67 labeling index, vascular endothelial growth factor, and microvessel density. The 5‐year survival rates of the LAT 1‐positive and LAT1‐negative patients were 59% and 88%, respectively (P = 0.2186). Tumor cell proliferation and angiogenesis were not also (a) prognostic factor. However, the 5‐year survival rate of patients with both LAT 1 and CD98‐positivity (57%) was significantly worse than that of other patients (88%; P = 0.0136). Multivariate analysis confirmed that positive cooperative expression of LAT 1 and CD98 was an independent factor for predicting a poor prognosis. A cooperative expression of LAT 1 and CD98 is a significant pathological factor for predicting the poor prognosis in patients with resectable stage I squamous cell carcinoma of the lung. (Cancer Sci 2009; 100: 249–254)

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. However, there is currently no established treatment for NAFLD in obese human subjects. We previously isolated Helz2, the expression of which was upregulated in human and mouse NAFLD, and its deletion activated the hepatic expression of functional leptin receptor long form (Leprb) and suppressed NAFLD development and body weight (BW) gain in obese mice. A high-throughput assay of small-molecule drugs revealed that guanabenz acetate (Ga), originally used to treat hypertension, possesses a high affinity constant against HELZ2, and its administration activates LEPRB expression in HepG2 cells in vitro. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid β-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice. This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. Regarding drug repositioning, Ga has the potential to effectively treat NAFLD and hyperglycemia in obese patients.

Enough is enough Appetite is regulated — at least in part — in the hypothalamus, the brain region that links the nervous and endocrine systems. A screen for appetite-regulating molecules has now identified a fragment of the protein nucleobindin 2, dubbed nesfatin-1, as a satiety molecule produced in the hypothalamus. When nesfatin-1 is injected into the brain, rats eat less and lose weight. When nesfatin-1 is blocked, animals eat more. Nesfatin-1 is therefore a possible target for antiobesity drugs. A secreted protein, nesfatin-1, is expressed in the hypothalamus and induces the feeling of being full. In rats, its injection into the brain decreases food intake, but blocking its action stimulates appetite. The brain hypothalamus contains certain secreted molecules that are important in regulating feeding behaviour 1 , 2 , 3 . Here we show that nesfatin, corresponding to NEFA/nucleobindin2 (NUCB2), a secreted protein of unknown function, is expressed in the appetite-control hypothalamic nuclei in rats. Intracerebroventricular (i.c.v.) injection of NUCB2 reduces feeding. Rat cerebrospinal fluid contains nesfatin-1, an amino-terminal fragment derived from NUCB2, and its expression is decreased in the hypothalamic paraventricular nucleus under starved conditions. I.c.v. injection of nesfatin-1 decreases food intake in a dose-dependent manner, whereas injection of an antibody neutralizing nesfatin-1 stimulates appetite. In contrast, i.c.v. injection of other possible fragments processed from NUCB2 does not promote satiety, and conversion of NUCB2 to nesfatin-1 is necessary to induce feeding suppression. Chronic i.c.v. injection of nesfatin-1 reduces body weight, whereas rats gain body weight after chronic i.c.v. injection of antisense morpholino oligonucleotide against the gene encoding NUCB2. Nesfatin-1-induced anorexia occurs in Zucker rats with a leptin receptor mutation, and an anti-nesfatin-1 antibody does not block leptin-induced anorexia. In contrast, central injection of α-melanocyte-stimulating hormone elevates NUCB2 gene expression in the paraventricular nucleus, and satiety by nesfatin-1 is abolished by an antagonist of the melanocortin-3/4 receptor. We identify nesfatin-1 as a satiety molecule that is associated with melanocortin signalling in the hypothalamus.

Nesfatin-1 is a hypothalamic anorexigenic peptide processed from nucleobindin 2 (NUCB2). Central and peripheral administration of NUCB2/nesfatin-1 enhances glucose metabolism and insulin release. NUCB2/nesfatin-1 is also localized in pancreatic islets, while its function remains unknown. To explore the role of pancreatic β-cell-produced NUCB2/nesfatin-1, we developed pancreatic β-cell-specific NUCB2 knockout (βNUCB2 KO) mice and NUCB2 gene knockdown (shNUCB2) MIN6 β-cell line. In βNUCB2 KO mice, casual blood glucose was elevated from 12 weeks of age. In a glucose tolerance test at 12 weeks, insulin secretion at 15 min was reduced and blood glucose at 2 h increased in βNUCB2 KO mice fasted 8 h. In islets isolated from βNUCB2 KO mice, high glucose-stimulated insulin secretion (GSIS) was impaired. In shNUCB2 MIN6 cells, GSIS was reduced and UCP-2 mRNA expression was elevated. These results show impaired GSIS possibly associated with UCP-2 overexpression in NUCB2-silenced β-cells, suggesting that β-cell-produced NUCB2/nesfatin-1 maintains GSIS and thereby glycemia.

Fibroblast growth factor 21 (FGF21), liver-derived hormone, exerts diverse metabolic effects, being considered for clinical application to treat obesity and diabetes. However, its anorexigenic effect is debatable and whether it involves the central mechanism remains unclarified. Moreover, the neuron mediating FGF21’s anorexigenic effect and the systemic energy state supporting it are unclear. We explored the target neuron and fed/fasted state dependence of FGF21’s anorexigenic action. Intracerebroventricular (ICV) injection of FGF21 markedly suppressed food intake in fed mice with elevated blood glucose. FGF21 induced c-Fos expression preferentially in hypothalamic paraventricular nucleus (PVN), and increased mRNA expression selectively for nucleobindin 2/nesfatin-1 (NUCB2/Nesf-1). FGF21 at elevated glucose increased [Ca 2+ ] i in PVN NUCB2/Nesf-1 neurons. FGF21 failed to suppress food intake in PVN-preferential Sim1-Nucb2-KO mice. These findings reveal that FGF21, assisted by elevated glucose, activates PVN NUCB2/Nesf-1 neurons to suppress feeding under fed states, serving as the glycemia-monitoring messenger of liver-hypothalamic network for integrative regulation of energy and glucose metabolism.

Background The expression of L-type amino acid transporter 1 (LAT1) has been described to play essential roles in tumor cell growth and survival. However, it remains unclear about the clinicopathological significance of LAT1 expression in biliary tract cancer. This study was conducted to determine biological significance of LAT1 expression and investigate whether LAT1 could be a prognostic biomarker for biliary tract cancer. Methods A total of 139 consecutive patients with resected pathologic stage I-IV biliary tract adenocarcinoma were retrospectively reviewed. Tumor specimens were stained by immunohistochemistry for LAT1, Ki-67, microvessel density determined by CD34, and p53; and prognosis of patients was correlated. Biological significance of LAT1 expression was investigated by in vitro and in vivo experiments with LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) using cholangiocarcinoma cell line. Results In total patients, high LAT1 expressions were recognized in 64.0%. The expression of LAT1 was closely correlated with lymphatic metastases, cell proliferation and angiogenesis, and was a significant indicator for predicting poor outcome after surgery. LAT1 expression was a significant independent predictor by multivariate analysis. Both in vitro and in vivo preliminary experiments indicated that BCH significantly suppressed growth of the tumor and yielded an additive therapeutic efficacy to gemcitabine and 5-FU. Conclusions High expression of LAT1 is a promising pathological marker to predict the outcome in patients with biliary tract adenocarcinoma. Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.

Background Pulmonary alveolar proteinosis (PAP) is a rare disease occurred by idiopathic (autoimmune) or secondary to particle inhalation. The in-air microparticle induced X-ray emission (in-air micro-PIXE) system performs elemental analysis of materials by irradiation with a proton microbeam, and allows visualization of the spatial distribution and quantitation of various elements with very low background noise. The aim of this study was to assess the secondary PAP due to inhalation of harmful particles by employing in-air micro-PIXE analysis for particles and intracellular iron in parafin-embedded lung tissue specimens obtained from a PAP patient comparing with normal lung tissue from a non-PAP patient. The iron inside alveolar macrophages was stained with Berlin blue, and its distribution was compared with that on micro-PIXE images. Results The elements composing particles and their locations in the PAP specimens could be identified by in-air micro-PIXE analysis, with magnesium (Mg), aluminum (Al), silicon (Si), phosphorus (P), sulfur (S), scandium (Sc), potassium (K), calcium (Ca), titanium (Ti), chromium (Cr), copper (Cu), manganase (Mn), iron (Fe), and zinc (Zn) being detected. Si was the major component of the particles. Serial sections stained by Berlin blue revealed accumulation of sideromacrophages that had phagocytosed the particles. The intracellular iron content of alveolar macrophage from the surfactant-rich area in PAP was higher than normal lung tissue in control lung by both in-air micro-PIXE analysis and Berlin blue staining. Conclusion The present study demonstrated the efficacy of in-air micro-PIXE for analyzing the distribution and composition of lung particles. The intracellular iron content of single cells was determined by simultaneous two-dimensional and elemental analysis of paraffin-embedded lung tissue sections. The results suggest that secondary PAP is associated with exposure to inhaled particles and accumulation of iron in alveolar macrophages.