WRAP53 promotes cancer cell survival and is a potential target for cancer therapy

We previously identified WRAP53 as an antisense transcript that regulates the p53 tumor suppressor. The WRAP53 gene also encodes a protein essential for Cajal body formation and involved in cellular trafficking of the survival of motor neuron complex, the telomerase enzyme and small Cajal body-specific RNAs to Cajal bodies. Here, we show that the WRAP53 protein is overexpressed in a variety of cancer cell lines of different origin and that WRAP53 overexpression promotes cellular transformation. Knockdown of the WRAP53 protein triggers massive apoptosis through the mitochondrial pathway, as demonstrated by Bax/Bak activation, loss of mitochondrial membrane potential and cytochrome c release. The apoptosis induced by WRAP53 knockdown could moreover be blocked by Bcl-2 overexpression. Interestingly, human tumor cells are more sensitive to WRAP53 depletion as compared with normal human cells indicating that cancer cells in particular depends on WRAP53 expression for their survival. In agreement with this, we found that high levels of WRAP53 correlate with poor prognosis of head and neck cancer. Together these observations propose a role of WRAP53 in carcinogenesis and identify WRAP53 as a novel molecular target for a large fraction of malignancies

WRAP53 (WD repeat containing, antisense to TP53)

Review on WRAP53 (WD repeat containing, antisense to TP53), with data on DNA, on the protein encoded, and where the gene is implicated

Monitoring the effect of anti- cancer treatment in uro- oncological malignancies with molecular imaging

In the last decade, new therapies have changed the management of patients with metastatic renal cell carcinoma (mRCC) and metastatic castration resistant prostate cancer (mCRPC). Although new therapies have improved survival, drug response varies widely with some patients not responding to treatment. Unfortunately, traditional assessment of drug response with computed tomography (CT) has limitations, and novel biomarkers of treatment response are warranted in order to reduce unnecessary side-effects and costs. The general aim of this thesis was to identify imaging biomarkers that can help predict the treatment response in mRCC and mCRPC. In the first study, metabolic changes of tumour lesions detected by 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) and CT (PET/CT) after 14 days of treatment predicted the progression-free (PFS) and overall survival (OS) in 32 patients. Metabolic response was assessed in several ways revealing that PET parameters measuring FDG uptake within a volume had stronger association to outcome than parameters based on single voxel analysis. In the second study, the benefit of repeated 11C-acetate PET/CT was evaluated retrospectively to assess response in patients with mCRPC treated with abiraterone acetate. Potential association between 11C-acetate PET/CT, serum levels of prostate specific antigen (PSA), PFS and OS were investigated. 11C-acetate PET/CT predicted PFS and OS which may be of particular clinical interest in patients who do not exhibit a PSA response to treatment. In the third study, the maximal diameter of metastatic lesions originating from mRCC as determined by diffusion-weighted magnetic resonance imaging (DWI) were compared with the corresponding measurements on CT. These measurements appeared to be in close agreement warranting for a larger trial investigating the feasibility of employing DWI in clinical trials that follow the Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) guideline. In conclusion, the novel imaging biomarkers evaluated here have the ability to predict response of mRCC and mCRPC to targeted therapies, but need to be validated in a larger setting before being implemented into the clinic

A Nordic survey of the management of palliative care in patients with head and neck cancer

Background The five Nordic countries with a population of 27M people form a rather homogenous region in terms of health care. The management of Head and Neck Cancer (HNC) is centralized to the 21 university hospitals in these countries. Our aim was to survey the current status of organization of palliative care for patients with HNC in the Nordic countries as the field is rapidly developing. Materials and methods A structured web-based questionnaire was sent to all the Departments of Otorhinolaryngology-Head and Neck Surgery and Oncology managing HNC in the Nordic countries. Results All 21 (100%) Nordic university hospitals responded to the survey. A majority (over 90%) of the patients are discussed at diagnosis in a multidisciplinary tumor board (MDT), but the presence of a palliative care specialist is lacking in 95% of these MDT's. The patients have access to specialized palliative care units (n = 14, 67%), teams (n = 10, 48%), and consultants (n = 4, 19%) in the majority of the hospitals. Conclusion The present results show that specialized palliative care services are available at the Nordic university hospitals. A major finding was that the collaboration between head and neck surgeons, oncologists and palliative care specialists is not well structured and the palliative care pathway of patients with HNC is not systematically organized. We suggest that early integrated palliative care needs to be included as an addition to the already existing HNC care pathways in the Nordic countries.Peer reviewe

Overexpression of the scaffold WD40 protein WRAP53β enhances the repair of and cell survival from DNA double-strand breaks

Altered expression of the multifunctional protein WRAP53β (WD40 encoding RNA Antisense to p53), which targets repair factors to DNA double-strand breaks and factors involved in telomere elongation to Cajal bodies, is linked to carcinogenesis. While loss of WRAP53β function has been shown to disrupt processes regulated by this protein, the consequences of its overexpression remain unclear. Here we demonstrate that overexpression of WRAP53β disrupts the formation of and impairs the localization of coilin to Cajal bodies. At the same time, the function of this protein in the repair of DNA double-strand breaks is enhanced. Following irradiation, cells overexpressing WRAP53β exhibit more rapid clearance of phospho-histone H2AX (γH2AX), and more efficient homologous recombination and non-homologous end-joining, in association with fewer DNA breaks. Moreover, in these cells the ubiquitylation of damaged chromatin, which is known to facilitate the recruitment of repair factors and subsequent repair, is elevated. Knockdown of the ubiquitin ligase involved, ring-finger protein 8 (RNF8), which is recruited to DNA breaks by WRAP53β, attenuated this effect, suggesting that overexpression of WRAP53β leads to more rapid repair, as well as improved cell survival, by enhancing RNF8-mediated ubiquitylation at DNA breaks. Our present findings indicate that WRAP53β and RNF8 are rate-limiting factors in the repair of DNA double-strand breaks and raise the possibility that upregulation of WRAP53β may contribute to genomic stability in and survival of cancer cells

A Nordic survey on the management of head and neck CUP

Conclusion: The management of Head and Neck Cancer of Unknown Primary (HNCUP) patients varies both between centres within and also between the Nordic countries. This study contributes to a continuing discussion of how to improve the accuracy of diagnosis and quality of treatment of HNCUP patients.Objectives: The initiative for this study was based on the lack of common guidelines for diagnostic procedures and for treatment of HNCUP patients in the Nordic countries constituting a region having a rather homogeneous population.Method: A structured questionnaire was sent to all university hospitals in the five Nordic countries.Results: Four of the five Nordic countries use either national guidelines or specific protocols when handling HNCUP. The main diagnostic tools are PET-CT, fine needle aspiration, endoscopic evaluation with biopsies, and most often bilateral tonsillectomy. At 21 of 22 university hospitals the treatment decision is made at a multidisciplinary conference. Three of seven Swedish centres use only radiotherapy or chemoradiotherapy to treat N+ HNCUP patients. Robotic surgery for biopsy of the tongue base is beginning to become an alternative to targeted biopsies in Sweden and Finland. Narrow Band Imaging is used only in Finland.Peer reviewe

Laryngo-tracheal resections in the Nordic countries : an option for further centralization?

Purpose We aimed to obtain information on the number of Nordic centers performing tracheal resections, crico-tracheal resections, and laryngo-tracheal reconstructions, as well as the patient volume and the standard regimens associated with these procedures. Methods Consultants at all Departments of Otorhinolaryngology-Head and Neck Surgery (ORL-HNS, n = 22) and Thoracic Surgery (n = 21) in the five Nordic countries were invited (April 2018-January 2019) to participate in an online survey. Results All 43 departments responded to the survey. Twenty departments declared to perform one or more of the three types of tracheal resections. At five hospitals, departments of ORL-HNS and Thoracic Surgery perform these operations in collaboration. Hence, one or more of the tracheal operations in question are carried out at 15 centers. The median annual number of tracheal operations per center is five (range 1-20). Great variations were found regarding contraindications (relative and absolute) for surgery, the use of guardian sterno-mental sutures (all patients, 33%; selected cases, 40% of centers), prophylactic antibiotic therapy (cefuroxime +/- metronidazole, penicillin +/- metronidazole, clindamycin, imipenem, or none), post-operative follow-up time (range: children: 3-120 months; adults: 0-60 months), and the performance of postoperative bronchoscopy. Conclusions Fifteen centers each perform a low number of annual operations with significant variations in the selection of patients and the clinical setup, which raises the question if a higher degree of collaboration and centralization would be warranted. We encourage Nordic transnational collaboration, pursuing alignment on central management issues, and establishment of a common prospective database for future tracheal resection surgery.Peer reviewe

Evaluation of Retinoblastoma and Ki-67 Immunostaining as Diagnostic Markers of Benign and Malignant Parathyroid Disease

RID="" ID="" Correspondence to: F. Farnebo, M.D., Ph.D.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42410/1/268-23-1-68_23n1p68.pd