KIAA1114, a full-length protein encoded by the trophinin gene, is a novel surface marker for isolating tumor-initiating cells of multiple hepatocellular carcinoma subtypes

Identification of novel biomarkers for tumor-initiating cells (TICs) is of critical importance for developing diagnostic and therapeutic strategies against cancers. Here we identified the role of KIAA1114, a full-length translational product of the trophinin gene, as a distinctive marker for TICs in human liver cancer by developing a DNA vaccine-induced monoclonal antibody targeting the putative extracellular domain of KIAA1114. Compared with other established markers of liver TICs, KIAA1114 was unique in that its expression was detected in both alpha fetoprotein (AFP)-positive and AFP-negative hepatocellular carcinoma (HCC) cell lines with the expression levels of KIAA1114 being positively correlated to their tumorigenic potentials. Notably, KIAA1114 expression was strongly detected in primary hepatic tumor, but neither in the adjacent non-tumorous tissue from the same patient nor normal liver tissue. KIAA1114(high) cells isolated from HCC cell lines displayed TIC-like features with superior functional and phenotypic traits compared to their KIAA1114(low) counterparts, including tumorigenic abilities in xenotransplantation model, in vitro colony- and spheroid-forming capabilities, expression of stemness-associated genes, and migratory capacity. Our findings not only address the value of a novel antigen, KIAA1114, as a potential diagnostic factor of human liver cancer, but also as an independent biomarker for identifying TIC populations that could be broadly applied to the heterogeneous HCC subtypes.X1110Nsciescopu

Atorvastatin correlates with decreased risk of esophageal cancer: A population-based casecontrol study from Taiwan

Objectives: The aim of this study was to explore the association between the use of statins and esophageal cancer in Taiwan.Methods: We designed a casecontrol study using database from the Taiwan National Health Insurance program. In all, 549 patients (cases) aged 20 years or older diagnosed recently with esophageal cancer, from 2000 to 2009, and 2,196 subjects (controls) without esophageal cancer participated in this study. The association between esophageal cancer and the use of statins and other co-morbidities was measured.Results: After adjustment for covariates, multivariate logistic regression showed that patients with a cumulative duration of ]12 months of using atorvastatin might have a reduced risk of esophageal cancer, compared with those who did not use statins (odds ratio [OR] 0.14, 95% confidence interval [CI] 0.040.56). The other statins could not show a significant association with esophageal cancer. Age (OR 1.01, 95% CI 1.001.01), alcoholism (OR 3.83, 95% CI 3.014.89), and esophageal diseases (OR 4.60, 95% CI 3.466.12) were independent factors significantly associated with esophageal cancer.Conclusions: Use of atorvastatin ]12 months may correlate with an 86% reduction of esophageal cancer risk.Keywords: atorvastatin; esophageal cancer; stati

Atorvastatin correlates with decreased risk of esophageal cancer: A population-based casecontrol study from Taiwan

Objectives: The aim of this study was to explore the association between the use of statins and esophageal cancer in Taiwan.Methods: We designed a casecontrol study using database from the Taiwan National Health Insurance program. In all, 549 patients (cases) aged 20 years or older diagnosed recently with esophageal cancer, from 2000 to 2009, and 2,196 subjects (controls) without esophageal cancer participated in this study. The association between esophageal cancer and the use of statins and other co-morbidities was measured.Results: After adjustment for covariates, multivariate logistic regression showed that patients with a cumulative duration of ]12 months of using atorvastatin might have a reduced risk of esophageal cancer, compared with those who did not use statins (odds ratio [OR] 0.14, 95% confidence interval [CI] 0.040.56). The other statins could not show a significant association with esophageal cancer. Age (OR 1.01, 95% CI 1.001.01), alcoholism (OR 3.83, 95% CI 3.014.89), and esophageal diseases (OR 4.60, 95% CI 3.466.12) were independent factors significantly associated with esophageal cancer.Conclusions: Use of atorvastatin ]12 months may correlate with an 86% reduction of esophageal cancer risk.Keywords: atorvastatin; esophageal cancer; stati

Intravaginal Administration of Fc-Fused IL7 Suppresses the Cervicovaginal Tumor by Recruiting HPV DNA Vaccine-Induced CD8 T Cells

Purpose: The induction of tissue-localized virus-specific CD8 T-cell response is essential for the development of an effective therapeutic vaccine against genital diseases, such as cervical cancer and genital herpes. Here, we aimed to elucidate the immunologic role of IL7 in the induction of mucosal cellular immunity. Experimental Design: IL7 was engineered through Fc fusion to enhance mucosal delivery across the genital epithelial barrier. The immunomodulatory role of IL7 was evaluated by monitoring the kinetics of various immune cells and measuring the expression of chemokines and cytokines after intravaginal administration of Fc-fused IL7 (IL7-Fc). The antitumor effects of intramuscular human papillomavirus (HPV) DNA vaccine or topical IL7-Fc alone or in a combinational regimen on mice survival were compared using a orthotopic cervical cancer model. Results: Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFN-gamma, TNF alpha, IL6, and IL1 beta), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, gamma delta T cells, and dendritic cells. Importantly, in this murine cervical cancer model, topical administration of IL7-Fc after intramuscular HPV DNA vaccination increases the number of HPV-specific CD8 T cells in the genital mucosa, but not in the spleen, leading to stronger antitumor activity than the HPV DNA vaccine alone. Conclusions: Our findings provide an important insight into the immunomodulatory role of IL7-Fc via topical application and the design of therapeutic vaccine regimen that induces effective genital-mucosal CD8 T-cell responses.1110Ysciescopu

Intranasal Introduction of Fc-Fused Interleukin-7 Provides Long-Lasting Prophylaxis against Lethal Influenza Virus Infection

Influenza A virus (IAV) infection frequently causes hospitalization and mortality due to severe immunopathology. Annual vaccination and antiviral drugs are the current countermeasures against IAV infection, but they have a limited efficacy against new IAV variants. Here, we show that intranasal pretreatment with Fc-fused interleukin-7 (IL-7-mFc) protects mice from lethal IAV infections. The protective activity of IL-7-mFc relies on transcytosis via neonatal Fc receptor (FcRn) in the lung and lasts for several weeks. Introduction of IL-7-mFc alters pulmonary immune environments, leading to recruitment of T cells from circulation and their subsequent residency as tissue-resident memory-like T (T-RM-like) cells. IL-7-mFc-primed pulmonary T-RM-like cells contribute to protection upon IAV infection by dual modes. First, T-RM-like cells, although not antigen specific but polyclonal, attenuate viral replication at the early phase of IAV infection. Second, T-RM-like cells augment expansion of IAV-specific cytotoxic T lymphocytes (CTLs), in particular at the late phase of infection, which directly control viruses. Thus, accelerated viral clearance facilitated by pulmonary T cells, which are either antigen specific or not, alleviates immunopathology in the lung and mortality from IAV infection. Depleting a subset of pulmonary T cells indicates that both CD4 and CD8 T cells contribute to protection from IAV, although IL-7-primed CD4 T cells have a more prominent role. Collectively, we propose intranasal IL-7-mFc pretreatment as an effective means for generating protective immunity against IAV infections, which could be applied to a potential prophylaxis for influenza pandemics in the future. IMPORTANCE The major consequence of a highly pathogenic IAV infection is severe pulmonary inflammation, which can result in organ failure and death at worst. Although vaccines for seasonal IAVs are effective, frequent variation of surface viral proteins hampers development of protective immunity. In this study, we demonstrated that intranasal IL-7-mFc pretreatment protected immunologically naive mice from lethal IAV infections. Intranasal pretreatment with IL-7-mFc induced an infiltration of T cells in the lung, which reside as effector/memory T cells with lung-retentive markers. Those IL-7-primed pulmonary T cells contributed to development of protective immunity upon IAV infection, reducing pulmonary immunopathology while increasing IAV-specific cytotoxic T lymphocytes. Since a single treatment with IL-7-mFc was effective in the protection against multiple strains of IAV for an extended period of time, our findings suggest a possibility that IL-7-mFc treatment, as a potential prophylaxis, can be developed for controlling highly pathogenic IAV infections.open1175sciescopu

Cognitive behaviour therapy versus counselling intervention for anxiety in young people with high-functioning autism spectrum disorders: a pilot randomised controlled trial

The use of cognitive-behavioural therapy (CBT) as a treatment for children and adolescents with autism spectrum disorder (ASD) has been explored in a number of trials. Whilst CBT appears superior to no treatment or treatment as usual, few studies have assessed CBT against a control group receiving an alternative therapy. Our randomised controlled trial compared use of CBT against person-centred counselling for anxiety in 36 young people with ASD, ages 12–18. Outcome measures included parent- teacher- and self-reports of anxiety and social disability. Whilst each therapy produced improvements inparticipants, neither therapy was superior to the other to a significant degree on any measure. This is consistent with findings for adults

Polynomial Growth Harmonic Functions on Finitely Generated Abelian Groups

In the present paper, we develop geometric analytic techniques on Cayley graphs of finitely generated abelian groups to study the polynomial growth harmonic functions. We develop a geometric analytic proof of the classical Heilbronn theorem and the recent Nayar theorem on polynomial growth harmonic functions on lattices \mathds{Z}^n that does not use a representation formula for harmonic functions. We also calculate the precise dimension of the space of polynomial growth harmonic functions on finitely generated abelian groups. While the Cayley graph not only depends on the abelian group, but also on the choice of a generating set, we find that this dimension depends only on the group itself.Comment: 15 pages, to appear in Ann. Global Anal. Geo