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East Newark, NJ, United States

Stern P.L.,Paterson Institute for Cancer Research | van der Burg S.H.,Leiden University | Hampson I.N.,University of Manchester | Broker T.R.,Biochemistry and Molecular Genetics | And 4 more authors.

This chapter reviews the current treatment of chronic and neoplastic human papillomavirus (HPV)-associated conditions and the development of novel therapeutic approaches. Surgical excision of HPVassociated lower genital tract neoplasia is very successful but largely depends on secondary prevention programmes for identification of disease. Only high-risk HPV-driven chronic, pre-neoplastic lesions and some very early cancers cannot be successfully treated by surgical procedures alone. Chemoradiation therapy of cervical cancer contributes to the 66-79% cervical cancer survival at 5 years. Outlook for those patients with persistent or recurrent cervical cancer following treatment is very poor. Topical agents such as imiquimod (immune response modifier), cidofovir (inhibition of viral replication; induction apoptosis) or photodynamic therapy (direct damage of tumour and augmentation of anti-tumour immunity) have all shown some useful efficacy (~50-60%) in treatment of high grade vulvar intraepithelial neoplasia (VIN). Provider administered treatments of genital warts include cryotherapy, trichloracetic acid, or surgical removal which has the highest primary clearance rate. Patient applied therapies include podophyllotoxin and imiquimod. Recurrence after "successful" treatment is 30-40%. Further improvements could derive from a rational combination of current therapy with new drugs targeting molecular pathways mediated by HPV in cancer. Small molecule inhibitors targeting the DNA binding activities of HPV E1/E2 or the antiapoptotic consequences of E6/E7 oncogenes are in preclinical development. Proteasome and histone deacetylase inhibitors, which can enhance apoptosis in HPV positive tumour cells, are being tested in early clinical trials. Chronic high-risk HPV infection/neoplasia is characterised by systemic and/or local immune suppressive regulatory or escape factors. Recently two E6/E7 vaccines have shown some clinical efficacy in high grade VIN patients and this correlated with strong and broad systemic HPV-specific T cell response and modulation of key local immune factors. Treatments that can shift the balance of immune effectors locally in combination with vaccination are now being tested. © 2012 Elsevier Ltd. All rights reserved. Source

Tripon S.,Hepatology and Liver Intensive Care | Francoz C.,Hepatology and Liver Intensive Care | Francoz C.,University Paris Diderot | Albuquerque A.,Hospital Beaujon | And 8 more authors.
Transplant International

Refractory ascites may appear in liver transplant recipients with recurrence of hepatitis C virus infection, even in the absence of advanced fibrosis. The mechanisms are unclear. The aim was to determine whether post-transplant cryoglobulinemia could be a predisposing factor for ascites in this population. Retrospective data of 82 liver transplant recipients with HCV recurrence surviving more than 1 year were collected. Cryoglobulinemia was systematically tested after transplantation. All patients had 1-year protocol biopsy with assessment of sinusoidal distension, perisinusoidal fibrosis, and centrolobular necrosis. Additional biopsies were performed when needed. Fourteen of 82 patients (17%) developed refractory ascites. When ascites appeared, fibrosis was stage F0-F1 in 36% and F2-F3 in 57%. Factors independently associated with post-transplant ascites were pretransplant refractory ascites (P = 0.001), fibrosis ≥stage 2 at 1 year (P = 0.002), perisinusoidal fibrosis at 1 year (P = 0.02), and positive cryoglobulinemia (P = 0.02). Patients with ascites had a significantly worse prognosis compared to those without ascites. Refractory ascites may occur in liver transplant recipients with HCV recurrence in the absence of advanced fibrosis. The finding that both positive cryoglobulinemia and perisinusoidal fibrosis at 1 year were significantly associated with ascites suggests that liver microangiopathy is involved in the mechanisms of HCV-related ascites. © 2014 Steunstichting ESOT. Source

Ishikawa C.,University of Ryukyus | Senba M.,Nagasaki University | Barnes B.J.,Biochemistry and Molecular Genetics | Mori N.,University of Ryukyus
International Journal of Oncology

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL), an aggressive and fatal leukemia of T cells. Interferon regulatory factor (IRF)-5 plays a critical role in the induction of interferon genes in viral infected cells. We examined the specific mechanisms underlying the expression and regulation of IRF-5 in HTLV-1-infected T cells. IRF-5 was constitutively transcribed into three distinct alternatively spliced isoforms (VI, V3 and V4) in HTLV-1-infected T-cell lines but not in uninfected T-cell lines. IRF-5 was also upregulated in HTLV-1-infected T-cell lines at protein level. Nuclear IRF-5 expression was noted in ATL cells present in lymph nodes and skin lesions. IRF-5 mRNA expression was induced following infection of T cells with HTLV-1, and specifically by viral oncoprotein Tax. Tax also activated V3 promoter. Microarray analysis of IRF-5-expressing uninfected T cells demonstrated that IRF-5 induced the expression of tumor necrosis factor family cytokines. The results suggest that IRF-5 is a Tax-regulated gene, and its expression may be associated with the pathogenesis of ATL. Source

Boccardi V.,The Second University of Naples | Razdan N.,Biochemistry and Molecular Genetics | Kaplunov J.,Biochemistry and Molecular Genetics | Mundra J.J.,Rutgers Biomedical and Health science | And 2 more authors.
Aging Cell

Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regulation, and end protection. Although mammalian homologues of CST have been identified recently, their role and function for telomere maintenance in normal somatic human cells are still incompletely understood. Here, we characterize the function of human Stn1 in cultured human fibroblasts and demonstrate its critical role in telomere replication, length regulation, and function. In the absence of high telomerase activity, shRNA-mediated knockdown of hStn1 resulted in aberrant and fragile telomeric structures, stochastic telomere attrition, increased telomere erosion rates, telomere dysfunction, and consequently accelerated entry into cellular senescence. Oxidative stress augmented the defects caused by Stn1 knockdown leading to almost immediate cessation of cell proliferation. In contrast, overexpression of hTERT suppressed some of the defects caused by hStn1 knockdown suggesting that telomerase can partially compensate for hStn1 loss. Our findings reveal a critical role for human Stn1 in telomere length maintenance and function, supporting the model that efficient replication of telomeric repeats is critical for long-term viability of normal somatic mammalian cells. © 2014 The Authors. Source

Koehl B.,Pediatric Unit | Koehl B.,University Paris Diderot | Sommet J.,University Paris Diderot | Sommet J.,Clinic Epidemiology Unit | And 14 more authors.

BACKGROUND Chronic exchange transfusion is effective for primary and secondary prevention of stroke in children with sickle cell anemia (SCA). Erythrocytapheresis is recognized to be the most efficient approach; however, it is not widely implemented and is not suitable for all patients. The aim of our study was to compare automated exchange transfusion (AET) with our manual method of exchange transfusion and, in particular, to evaluate the efficacy, safety, and cost of our manual method. STUDY DESIGN AND METHODS Thirty-nine SCA children with stroke and/or abnormal findings on transcranial Doppler were included in the study. We retrospectively analyzed 1353 exchange sessions, including 333 sessions of AET and 1020 sessions of manual exchange transfusion (MET). RESULTS Both methods were well tolerated. The median decrease in hemoglobin (Hb)S per session was 21.5% with AET and 18.8% with our manual method (p < 0.0001) with no major increase in red blood cell consumption. Iron overload was well controlled, even with the manual method, with a median (interquartile range) ferritin level of 312 (152-994) μg/L after 24 months of transfusions. The main differences in annual cost relate to equipment costs, which were 74 times higher with the automated method. CONCLUSION Our study shows that continuous MET has comparable efficacy to the automated method in terms of stroke prevention, decrease in HbS, and iron overload prevention. It is feasible in all hospital settings and is often combined with AET successively over time. © 2016 AABB. Source

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