ZAK is required for doxorubicin,a novel ribotoxic stressor,to induce SAPK activation and apoptosis in HaCaT cells

Doxorubicin is an anthracycline drug that is one of the most effective and widely used anticancer agents for the treatment of both hematologic and solid tumors. The stress-activated protein kinases (SAPKs) are frequently activated by a number of cancer chemotherapeutics. When phosphorylated, the SAPKs initiate a cascade that leads to the production of proinflammatory cytokines. Some inhibitors of protein synthesis, known as ribotoxic stressors, coordinately activate SAPKs and lead to apoptotic cell death. We demonstrate that doxorubicin effectively inhibits protein synthesis, activates SAPKs, and causes apoptosis. Ribotoxic stressors share a common mechanism in that they require ZAK, an upstream MAP3K, to activate the pro-apoptotic and proinflammatory signaling pathways that lie downstream of SAPKs. By employing siRNA mediated knockdown of ZAK or administration of sorafenib and nilotinib, kinase inhibitors that have a high affinity for ZAK, we provide evidence that ZAK is required for doxorubicin-induced proinflammatory and apoptotic responses in HaCaT cells, a pseudo-normal keratinocyte cell line, but not in HeLa cells, a cancerous cell line. ZAK has two different isoforms, ZAK-α (91 kDa) and ZAK-β (51 kDa). HaCaT or HeLa cells treated with doxorubicin and immunoblotted for ZAK displayed a progressive decrease in the ZAK-α band and the appearance of ZAK-β bands of larger size. Abrogation of these changes after exposure of cells to sorafenib and nilotinib suggests that these alterations occur following stimulation of ZAK. We suggest that ZAK inhibitors such as sorafenib or nilotinib may be effective when combined with doxorubicin to treat cancer patients.Key words: doxorubicin, ZAK, ribotoxic stressor, SAPKs, apoptosis     

The change in capacity and service delivery at public and private hospitals in Turkey: A closer look at regional differences

Background  

Substantial regional health inequalities have been shown to exist in Turkey for major health indicators. Turkish data on hospitals deserves a closer examination with a special emphasis on the regional differences in the context of the rapid privatization of the secondary or tertiary level health services.     

Melanoma/skin cancer screening in a Mediterranean country: results of the Euromelanoma Screening Day Campaign in Greece

Background Since the year 2000 a melanoma/skin cancer screening campaign has been organized annually in Greece in the context of the Euromelanoma Screening Day Campaign. Objectives We aimed to analyse the characteristics of the screened population, to recognize relevant risk factors and to identify the cases of histologically confirmed malignant melanoma (MM) in individuals with suspicious skin lesions. Methods An analysis of the completed screening forms from the years 2000–2004 was performed with respect to relevant demographic, epidemiological and clinical data. Results A total of 9723 individuals were screened, most of whom where below the age of 50 years (71%), female (59%), and of skin phototype II and III (76%). Sunburn during childhood was reported in 47% of participants, while 5% of the screened population had a personal or family history of melanoma. On clinical examination, 14.4% had actinic keratoses, 31.2% had dysplastic nevi, while 6.4% carried a presumptive diagnosis of non‐melanoma skin cancer. In the 2003–2004 screening campaign, 19 out of the 171 clinically suspicious lesions were histologically proven to be MM, the majority of which (58%) were ‘thin’ melanomas (Breslow's thickness of ≤ 1 mm) of the superficial spreading type. Conclusions Our study suggested that, a melanoma/skin cancer screening programme in a Mediterranean country, supported by an intense publicity campaign, attracted many individuals at risk for skin cancer and detected mostly thin melanomas of the superficial spreading type.     

Incidence and Predictors of Permanent Pacemaker Requirement after Transcatheter Aortic Valve Implantation with a Self‐Expanding Bioprosthesis

Background: Previous reports have suggested the occurrence of cardiac conduction disorders and permanent pacemaker (PPM) requirement after transcatheter aortic valve implantation (TAVI). Based on a single‐center experience, we aim to assess the incidence of postprocedural conduction disorders, need for PPM, and its determinants after TAVI with a self‐expanding bioprosthesis. Methods: From August 2007 to October 2009, 32 consecutive patients underwent TAVI with the Medtronic CoreValve (MCV) System (Medtronic Inc., Minneapolis, MN, USA). Three patients paced at baseline and two cases of procedure‐related mortality were excluded. We analyzed the 12‐lead electrocardiogram at baseline, immediately after procedure and at discharge. Requirements for PPM were documented and potential clinical, electrophysiological, echocardiographic, and procedural predictors of PPM requirement were studied. Results: After TAVI, eight patients (29.6%) required PPM implantation due to high‐grade atrioventricular (AV) block. The prevalence of left bundle branch block increased from 13.8% to 57.7% directly after implantation (P = 0.001). Need for PPM was correlated to the depth of prosthesis implantation (r = 0.590; P = 0.001). At a cutoff point of 10.1 mm, the likelihood of pacemaker could be predicted with 87.5% sensitivity and 74% specificity and a receiver operator characteristic curve area of 0.86 ± 0.07 (P = 0.003). Of the seven patients with preexisting right bundle branch block (RBBB), four (57.1%) required PPM implantation after TAVI. Conclusions: High‐grade AV block requiring PPM implantation is a common complication following TAVI and could be predicted by a deeper implantation of the prosthesis. Patients with preexisting RBBB also seem to be at risk for the development of high‐grade AV block and subsequent pacemaker implantation. (PACE 2010; 1364–1372)     

Erosive mucosal lichen planus and secondary epiphora responding to systemic cyclosporin A treatment

Erosive mucosal lichen planus (LP) is a well-established variant of LP characterized by the formation of ulcerative lesions predominantly involving the oral and genital mucosae. Less commonly, this condition may involve oesophageal and/or ocular mucosal surfaces, and case reports within the ophthalmology literature have recently confirmed the potential for this condition to affect the nasolacrimal ducts. We report the case of a woman with severe cicatrizing mucosal LP and ocular symptoms secondary to presumed nasolacrimal duct involvement. We also report the potential for this newly appreciated manifestation of LP to respond to systemic cyclosporin A.     

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