Epigenetic Silencing of HOPX Promotes Cancer Progression in Colorectal Cancer

AbstractHomeodomain-only protein X (HOPX)-β promoter methylation was recently shown to be frequent in human cancers and was suggested as tumor suppressor gene in esophageal and gastric cancer. The aim of this study was to investigate the mechanistic roles of HOPX-β promoter methylation and its clinical relevance in colorectal cancer (CRC). HOPX-β promoter methylation was assessed in human CRC cell lines and 294 CRC tissues. HOPX mRNA and protein levels were measured in relation to HOPX-β promoter methylation. The effects of forced HOPX expression on tumorigenesis were studied using in vitro and in vivo assays. The association between HOPX-β promoter methylation and clinical relevance of CRC patients was determined. HOPX-β promoter methylation is cancer-specific and frequently found in CRC cell lines and tissues, resulting in the down-regulation of HOPX mRNA and protein levels. In CRC cell lines, forced expression of HOPX suppressed proliferation, invasion, and anchorage-independent growth. DNA microarray analyses suggested critical downstream genes that are associated with cancer cell proliferation, invasion or angiogenesis. In a mouse xenograft model, HOPX inhibited tumorigenesis and angiogenesis. Finally, HOPX-β promoter methylation was associated with worse prognosis of stage III CRC patients (hazard ratio= 1.40, P = .035) and also with poor differentiation (P = .014). In conclusion, HOPX-β promoter methylation is a frequent and cancer-specific event in CRC progression. This epigenetic alteration may have clinical ramifications in the diagnosis and treatment of CRC patients

Squared frequency-Kt/V: a new index of hemodialysis adequacy—correlation with solute concentrations by computer simulation

Abstract Background In patients undergoing home dialysis, conventionally, Kt/V has been regarded as an index of the removal efficiency per dialysis session. However, more recently, it has been considered that the hemodialysis product (HDP), rather than the Kt/V, is better associated with the clinical symptoms and outcomes in patients undergoing short daily dialysis or nocturnal dialysis. Nevertheless, the HDP lacks a theoretical background, and it does not take into consideration the dialyzer clearance or patient’s body size. The aims of the present study were to clarify the theoretical validity of HDP focusing on its association with solute concentration by computer simulation and to propose a new index of hemodialysis adequacy. Methods We used compartment models and calculated the time course of urea and β2 microglobulin (β2MG) concentrations to determine the peak concentrations and time-averaged concentrations at varying dialysis frequencies (n = 2–7 sessions/week) and durations of dialysis per session (t = 1 to 8 h dialysis sessions). Results It was found that the peak concentrations of urea and β2MG were significantly correlated with the HDP. Based on this, we theoretically extracted the factor related to the peak concentration and defined the squared frequency-Kt/V (sf-Kt/V), as a new index for determining hemodialysis adequacy (sf-Kt/V = n 2 Kt/V; K, clearance; V, solute distribution volume; n, frequency; t, dialysis time); this index was well correlated with the peak concentrations of urea and β2MG, even when the values of K and V were changed. Conclusions Since the sf-Kt/V is an index that reflects peak concentrations of urea and β2MG, which takes into account the dialysis frequency, session duration, dialyzer clearance, and the body weight of the patient, it will be a very useful tool for determining appropriate dialysis schedules and dialysis conditions for individual patients

The Steric Effect in Preparations of Vanadium(II)/(III) Dinitrogen Complexes of Triamidoamine Ligands Bearing Bulky Substituents

The reactions of newly designed lithiated triamidoamines Li3LR (R = iPr, Pen, and Cy2) with VCl3(THF)3 under N2 yielded dinitrogen–divanadium complexes with a μ-N2 between vanadium atoms [{V(LR)}2(μ-N2)] (R = iPr (1) and Pen (2)) for the former two, while not dinitrogen–divanadium complexes but a mononuclear vanadium complex with a vacant site, [V(LCy2)] (R = Cy2 (3)), were obtained for the third ligand. The V–NN2 and N–N distances were 1.7655(18) and 1.219(4) Å for 1 and 1.7935(14) and 1.226(3) Å for 2, respectively. The ν(14N–14N) stretching vibrations of 1 and 2, as measured using resonance Raman spectroscopy, were detected at 1436 and 1412 cm–1, respectively. Complex 3 reacted with potassium metal in the presence of 18-crown-6-ether under N2 to give a hetero-dinuclear vanadium complex with μ-N2 between vanadium and potassium, [VK(LCy2)(μ-N2)(18-crown-6)] (4). The N–N distance and ν(14N–14N) stretching for 4 were 1.152(3) Å and 1818 cm−1, respectively, suggesting that 4 is more activated than complexes 1 and 2. The complexes 1, 2, 3, and 4 reacted with HOTf and K[C10H8] to give NH3 and N2H4. The yields of NH3 and N2H4 (per V atom) were 47 and 11% for 1, 38 and 16% for 2, 77 and 7% for 3, and 80 and 5% for 4, respectively, and 3 and 4, which have a ligand LCy2, showed higher reactivity than 1 and 2

Serum levels of KL-6 reflect disease activity of interstitial pneumonia associated with ANCA-related vasculitis

金沢大学医薬保健研究域医学系Objective. KL-6 is reported to be excreted from the lung alveolar and bronchial epithelial cells and may be a good marker for monitoring disease activity of interstitial pneumonia. This study was designed to ascertain the clinical significance of serum KL-6 levels in interstitial pneumonia associated with anti-neutrophil cytoplasmic antibody (ANCA)-related vasculitis. Methods. Serum KL-6 levels were determined by an enzyme-linked immunosorbent assay. Patients. We examined 20 healthy subjects, 13 patients with perinuclear (myeloperoxidase, MPO) ANCA-related vasculitis and 12 dermatomyositis (DM)/polymyositis (PM) patients as disease controls in this study. Six out of 13 patients with ANCA-related vasculitis had interstitial pneumonia. Results. Serum levels of KL-6 in ANCA-positive patients with interstitial pneumonia were significantly elevated, while they remained as low as those of healthy subjects in ANCA- positive patients without interstitial pneumonia. Similarly, KL-6 levels in sera were higher in 12 dermatomyositis/polymyositis patients with interstitial pneumonia, while they remained low in DM/PM patients without interstitial pneumonia. Moreover, the elevated serum KL-6 level was reduced during the convalescence induced by glucocorticoid therapy and reflected the disease activity of interstitial pneumonia associated with ANCA-related vasculitis. Conclusion. These data suggest that the measurement of serum KL-6 levels may be a good monitoring system for the diagnosis and follow-up of interstitial pneumonia of patients with ANCA-related vasculitis