Expression of CXCL10 is associated with response to radiotherapy and overall survival in squamous cell carcinoma of the tongue

Five-year survival for patients with oral cancer has been disappointingly stable during the last decades, creating a demand for new biomarkers and treatment targets. Lately, much focus has been set on immunomodulation as a possible treatment or an adjuvant increasing sensitivity to conventional treatments. The objective of this study was to evaluate the prognostic importance of response to radiotherapy in tongue carcinoma patients as well as the expression of the CXC-chemokines in correlation to radiation response in the same group of tumours. Thirty-eight patients with tongue carcinoma that had received radiotherapy followed by surgery were included. The prognostic impact of pathological response to radiotherapy, N-status, T-stage, age and gender was evaluated using Cox's regression models, Kaplan-Meier survival curves and chi-square test. The expression of 23 CXC-chemokine ligands and their receptors were evaluated in all patients using microarray and qPCR and correlated with response to treatment using logistic regression. Pathological response to radiotherapy was independently associated to overall survival with a 2-year survival probability of 81 % for patients showing a complete pathological response, while patients with a non-complete response only had a probability of 42 % to survive for 2 years (p = 0.016). The expression of one CXC-chemokine, CXCL10, was significantly associated with response to radiotherapy and the group of patients with the highest CXCL10 expression responded, especially poorly (p = 0.01). CXCL10 is a potential marker for response to radiotherapy and overall survival in patients with squamous cell carcinoma of the tongue

MicroRNA Alterations and Associated Aberrant DNA Methylation Patterns across Multiple Sample Types in Oral Squamous Cell Carcinoma

Background: MicroRNA (miRNA) expression is broadly altered in cancer, but few studies have investigated miRNA deregulation in oral squamous cell carcinoma (OSCC). Epigenetic mechanisms are involved in the regulation of .30 miRNA genes in a range of tissues, and we aimed to investigate this further in OSCC. Methods: TaqManH qRT-PCR arrays and individual assays were used to profile miRNA expression in a panel of 25 tumors with matched adjacent tissues from patients with OSCC, and 8 control paired oral stroma and epithelium from healthy volunteers. Associated DNA methylation changes of candidate epigenetically deregulated miRNA genes were measured in the same samples using the MassArrayH mass spectrometry platform. MiRNA expression and DNA methylation changes were also investigated in FACS sorted CD44high oral cancer stem cells from primary tumor samples (CSCs), and in oral rinse and saliva from 15 OSCC patients and 7 healthy volunteers. Results: MiRNA expression patterns were consistent in healthy oral epithelium and stroma, but broadly altered in both tumor and adjacent tissue from OSCC patients. MiR-375 is repressed and miR-127 activated in OSCC, and we confirm previous reports of miR-137 hypermethylation in oral cancer. The miR-200 s/miR-205 were epigenetically activated in tumors vs normal tissues, but repressed in the absence of DNA hypermethylation specifically in CD44high oral CSCs. Aberrant miR-375 and miR-200a expression and miR-200c-141 methylation could be detected in and distinguish OSCC patient oral rinse and saliva from healthy volunteers, suggesting a potential clinical application for OSCC specific miRNA signatures in oral fluids. Conclusions: MiRNA expression and DNA methylation changes are a common event in OSCC, and we suggest miR-375, miR- 127, miR-137, the miR-200 family and miR-205 as promising candidates for future investigations. Although overall activated in OSCC, miR-200/miR-205 suppression in oral CSCs indicate that cell specific silencing of these miRNAs may drive tumor expansion and progression

Subjektiv stress och nöjdhet i samband med arbetsmåltiden i relation till psykisk, social och fysisk måltidsmiljö

I dagens samhälle spenderar de flesta många timmar av dygnet på arbetet. Det innebär att människor troligen äter en betydande del av sina måltider på arbetet. Måltidens betydelse har uppmärksammats de senaste åren och har då syftat till lunchen, matens kvalité, tidpunkten och platsen. Måltidens kontext innefattar innehåll, tid, social och fysisk måltidsmiljö. Eftersom människor äter på arbetet är måltiden på arbetsplatsen viktig när det kommer till anställdas hälsa, arbetstrivsel och prestation. Forskning om var arbetsmåltider äts och hur fysiska och sociala måltidsmiljön upplevs är sparsam. Syftet med denna studie var att beskriva självskattad stress, egen kontroll och måltidsupplevelse i samband med måltider på arbetsplatsen vid ett sjukhus och vid ett stålverk. Studien hade en beskrivande design, där kvantitativ data samlades in med enkäter och skal nivån var nominal. Studien gjordes på ett stålverk och ett universitets sjukhus i mellersta Sverige. Det var både män och kvinnor som arbetade dagtid, schemalagt arbete eller treskift som deltog. Sextio enkäter med fjorton respektive nitton frågeområden delades ut till samtliga på stålverket och till en hel avdelning på sjukhuset. Samtliga i personalen på en avdelning på ett universitetssjukhus och alla på ett stålverk blev tillfrågade om de ville delta i studien. Bortfallet på sjukhuset var tjugotre procent och på stålverket var det tjugo procent. Resultaten visade att arbetarna på både stålverket och sjukhuset var relativt missnöjda med hur deras måltidsmiljö var med lokal, utrustning och möjlighet till att äta enskilt eller med sällskap. De upplevde även liten egen kontroll över temperatur, ljus och ljud i sin måltidsmiljö. Eftersom grupperna som undersöktes inte representerar en population är det inte möjligt att uttala sig om hur alla anställda med skiftarbete eller schemalagt arbete på andra eller samma arbetsplatser upplever sin måltidsmiljö. Vissa generaliseringar om måltidsmiljön kan göras till liknande arbetsplatser än som de som deltog i studien. Nyckelord: Måltidsmiljö, skiftarbete, stress, egen kontroll

p63 and potential p63 targets in squamous cell carcinoma of the head and neck

Squamous cell carcinoma of the head and neck (SCCHN), the 6th most common cancer worldwide, has a low 5-year survival. Disease as well as treatment often causes patients severe functional and aesthetic problems. In order to improve treatment and diagnosis at earlier stages of tumour development it is important to learn more about the molecular mechanisms behind the disease. p63, an important regulator of epithelial formation, has been suggested to play a role in the development of SCCHN. Six different isoforms of p63 have been found and shown to have various functions. The aim of the studies in this thesis was to learn more about the role of p63 and proteins connected to p63 in SCCHN. Expression of p63, Cox-2, EGFR, beta-catenin, PP2A and p53 isoforms was mapped in tumours and normal tumour adjacent tissue from patients with SCCHN using western blot or RT-PCR. Results showed no significant difference between tumours and normal tumour adjacent tissue concerning expression of EGFR and beta-catenin. Cox-2 and PP2A showed significantly higher expression in tumours while p63 was more expressed in normal tumour adjacent tissue. However, expression of all these proteins in normal tumour adjacent tissue differed from tissue from disease-free non-smoking individuals. Smoking in itself did not affect expression of these proteins. The p53 isoforms p53, p53beta, p53gamma, ∆133p53, ∆133p53beta and ∆133p53gamma were expressed at RNA level in samples both from tumours and normal tumour adjacent tissue, though most of them at fairly low levels. The functional properties of the different p63 isoforms have not been fully mapped. By establishing stable cell lines over-expressing the different p63 isoforms we investigated their specific effect on tumour cells from SCCHN. Only the ∆Np63 isoforms could be stably over-expressed, whereas no clones over-expressing TAp63 could be established. Using microarray technique, cell lines stably expressing the ∆Np63 isoforms were studied and CD44, Keratins 4, 6, 14, 19 and Cox-2 were found to be regulated by p63. In conclusion, the present project adds new data to the field of p63 and SCCHN. For example, we have shown that clinically normal tumour adjacent tissue is altered compared to normal oral mucosa in non tumour patients, and that smoking does not change expression of p63, Cox-2, EGFR, beta-catenin or PP2A in oral mucosa. Novel p53 isoforms are expressed in SCCHN, and even though levels are very low they should not be overlooked. Furthermore, CD44, keratins 4, 6, 14, 19 and Cox-2 were identified as p63 targets in SCCHN

Programmable address lookup unit

The goal of this thesis was to design a programmable Address Lookup unit for use in the forwarding engine in a network device such as a switch or a router. A solution with a special designed processor core with a optimized Instruction Set, an I/O processor for accesses to external memory and a sample of a network software was designed and mapped to a multiprocessor architecture. The multiprocessor architecture implements the same features as in the current non programmable hardware Address Lookup unit, and adds the possibility to upgrade the implementation to meet new features due to the new property of programmability. Three multiprocessor architectures, the Parallel multithreaded multiprocessor architecture, the Macro pipeline RISC multiprocessor architecture and the Superpipeline VLIW multiprocessor architecture, was selected out as the most suitable implementation architectures. An estimated implementation area for the multiprocessor architectures when meeting the current Address Lookup units performance requirements were calculated. The multiprocessor architectures were compared against each other on the issues of performance and area scalability, where the Superpipeline VLIW multiprocessor architecture was found to be the best implementation platform for the programmable Address Lookup unit. The Superpipeline multiprocessor architecture implementation was built on two basic units, a VLIW processor and an I/O processor. These two basic units was designed, implemented, verified and synthesized. The result of this synthesis was compared with the calculated values made during the target architecture evaluation. For the VLIW processor the estimated implementation area was calculated to 0.141405 mm2 and the final synthesis to 0.156647 mm2, a difference of 11%. The difference was analyzed to depend on the control logic added to the final version of the VLIW processor. For the I/O processor the estimated implementation area was 0.80800 mm2 and the final synthesis 0.106653 2, a difference of 32%. The difference was analyzed to depend on multiplexers added to the final version of the I/O processor. Finally a small Superpipeline, holding eight VLIW processors and two I/O processors, was implemented and synthesized. The implementation area for this synthesis was 0.822874 mm2 compared to 1.466482 mm2 when built and synthesized on separate units. This difference of 78%, was analyzed to depend on the synthesis tools ability to effectively optimize the design.Validerat; 20101217 (root

Altered mRNA Expression of Genes Involved in Endocannabinoid Signalling in Squamous Cell Carcinoma of the Oral Tongue

Little is known about the endocannabinoid (eCB) system in squamous cell carcinoma of the oral tongue (SCCOT). Here we have investigated, at the mRNA level, expression of genes coding for the components of the eCB system in tumour and non-malignant samples from SCCOT patients. Expression of NAPEPLD and PLA2G4E, coding for eCB anabolic enzymes, was higher in the tumour tissue than in non-malignant tissue. Among genes coding for eCB catabolic enzymes, expression of MGLL was lower in tumour tissue while PTGS2 was increased. It is concluded that the eCB system may be dysfunctional in SCCOT