| 1. |
- Farnebo, Simon, et al.
(författare)
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Optimized Repopulation of Tendon Hydrogel: Synergistic Effects of Growth Factor Combinations and Adipose-Derived Stem Cells
- 2017
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Ingår i: Hand (New York, N.Y.). - : Sage Publications. - 1558-9447 .- 1558-9455. ; 12:1, s. 68-77
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tendon-derived extracellular matrix (ECM) hydrogel has been shown to augment tendon healing in vivo. We hypothesized that reseeding of the gel with adipose-derived stem cells (ASCs) could further assist repopulation of the gel and that combinations of growth factors (GFs) would improve the survival of these cells after reseeding. Methods: A tendon-specific ECM solution was supplemented with varying concentrations of basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), and platelet-derived growth factor-BB (PDGF-BB). Gels were then seeded with ASCs transfected with a green fluorescent protein/luciferin construct. Cell proliferation was determined using the MTT assay and histology, and GF and ASC augmented gels were injected into the back of Sprague Dawley rats. Bioluminescence of seeded gels was continuously followed after reseeding, and cell counts were performed after the gels were explanted at 14 days. Results: Synergistic effects of the GFs were seen, and an optimal combination was determined to be 10 ng/mL bFGF, 100 ng/mL IGF-1, and 100 ng/mL PDGF-BB (2.8-fold increase; P amp;lt; .05). In vivo bioluminescence showed an improved initial survival of cells in gels supplemented with the optimal concentration of GF compared with the control group (10.6-fold increase at 8 days; P amp;lt; .05). Cell counts of explants showed a dramatic endogenous repopulation of gels supplemented by GF + ASCs compared with both gels with GF but no ASCs (7.6-fold increase) and gels with ASCs but no GF (1.6-fold increase). Conclusion: Synergistic effects of GFs can be used to improve cellular proliferation of ASCs seeded to a tendon ECM gel. Reseeding with ASCs stimulates endogenous repopulation of the gel in vivo and may be used to further augment tendon healing.
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| 2. |
- Garvin, Stina, et al.
(författare)
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Nuclear expression of WRAP53 beta is associated with a positive response to radiotherapy and improved overall survival in patients with head and neck squamous cell carcinoma
- 2015
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Ingår i: Oral Oncology. - : Elsevier. - 1368-8375 .- 1879-0593. ; 51:1, s. 24-30
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Today there are no reliable predictive markers for radiotherapy response in head and neck squamous cell carcinoma (HNSCC), leading to both under-and over-treatment of patients, personal suffering, and negative socioeconomic effects. Inherited mutation in WRAP53 beta (WD40 encoding RNA Antisense to p53), a protein involved in intracellular trafficking, dramatically increases the risk of developing HNSCC. The purpose of this study was to investigate whether WRAP53 beta can predict response to radiotherapy in patients with HNSCC. Materials and methods: Tumor biopsies from patients with HNSCC classified as responders or non-responders to radiotherapy were examined for the expression of the WRAP53 beta protein and single nucleotide polymorphisms in the corresponding gene employing immunohistochemistry and allelic discrimination, respectively. In addition, the effect of RNAi-mediated downregulation of WRAP53 beta on the intrinsic radiosensitivity of two HNSCC cell lines was assed using crystal violet and clonogenic assays. Results: Nuclear expression of WRAP53 beta was significantly associated with better response to radiotherapy and improved patient survival. Downregulation of WRAP53 beta with siRNA in vitro enhanced cellular resistance to radiation. Conclusions: Our findings suggest that nuclear expression of WRAP53 beta promotes tumor cell death in response to radiotherapy and is a promising predictor of radiotherapy response in patients with HNSCC.
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| 3. |
- Tiefenböck Hansson, Katharina, et al.
(författare)
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WRAP53 beta, survivin and p16(INK4a) expression as potential predictors of radiotherapy/chemoradiotherapy response in T2N0-T3N0 glottic laryngeal cancer
- 2017
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Ingår i: Oncology Reports. - : SPANDIDOS PUBL LTD. - 1021-335X .- 1791-2431. ; 38:4, s. 2062-2068
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Tidskriftsartikel (refereegranskat)abstract
- The current treatment recommendation for T2-3N0M0 glottic squamous cell carcinoma (SCC) in the Nordic countries comprises of radiotherapy (RT) and chemoradiotherapy (CRT). Tumor radiosensitivity varies and another option is primary surgical treatment, which underlines the need for predictive markers in this patient population. The aim of the present study was to investigate the relation of the proteins WRAP53 beta, survivin and p16INK4a to RT/CRT response and ultimate outcome of patients with T2-T3N0 glottic SCC. Protein expression was determined using immunohistochemistry on tumors from 149 patients consecutively treated with RT or CRT at Helsinki University Hospital, Karolinska University Hospital, and Linkping University Hospital during 1999-2010. Our results demonstrate a significantly better 5-year relapse-free survival, disease-free survival (DFS), disease-specific survival and overall survival of patients with T3N0 tumors treated with CRT compared with RT alone. Patients with tumors showing a cytoplasmic staining of WRAP53 beta revealed significantly worse DFS compared with those with nuclear staining. For survivin, we observed a trend towards better 5-year DFS in patients with strong nuclear survivin expression compared with those with weak nuclear survivin expression (p=0.091). Eleven (7%) tumors showed p16 positivity, with predilection to younger patients, and this age group of patients with p16-positive SCC had a significantly better DFS compared with patients with p16-negative SCC. Taken together, our results highlight WRAP53 beta as a potential biomarker for predicting RT/CRT response in T2-T3N0 glottic SCC. p16 may identify a small but distinct group of glottic SCC with favorable outcome. Furthermore, for T3N0 patients better outcome was observed following CRT compared to RT alone.
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| 4. |
- Farnebo, Lovisa, et al.
(författare)
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A Nordic survey on the management of head and neck CUP
- 2016
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 136:11, s. 1159-1163
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Farnebo, Lovisa, et al.
(författare)
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DNA repair genes XPC, XPD, XRCC1, and XRCC3 are associated with risk and survival of squamous cell carcinoma of the head and neck
- 2015
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Ingår i: DNA Repair. - : Elsevier. - 1568-7864 .- 1568-7856. ; 31, s. 64-72
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Tidskriftsartikel (refereegranskat)abstract
- Head and neck squamous cell carcinomas (HNSCC) are a heterogenous group of tumors with a high rate of early recurrences, second primary tumors, and mortality. Despite advances in diagnosis and treatment over the past decades, the overall 5-year survival rate remains around 50%. Since the head-and neck-region is continuously exposed to potentially DNA-damaging exogenous and endogenous factors, it is reasonable to expect that the DNA repair genes play a part in the development, progression, and outcome of HNSCC. The aim of this study was to investigate the SNPs XPC A499V, XPD K751Q XRCC1 R399Q and XRCC3 T241M as potential risk factors and indicators of survival among Caucasian patients. One-hundred-sixty-nine patients as well as 344 healthy controls were included and genotyped with PCR-RFLP. We showed that XPC A499V was associated with increased risk of HNSCC, especially laryngeal carcinoma. Among women, XPD K751Q was associated with increased risk of oral SCC. Furthermore, XPD homozygous mutant individuals had the shortest survival time, a survival time that increased however after full dose radiotherapy. Wild-type individuals of XRCC3 T241M demonstrated an earlier age of onset. HPV-positive never smokers had lower frequencies of p53 mutation. Among HNSCC patients, HPV-positivity was significantly associated with XRCC1 R399Q homozygous mutant genotype. Moreover, combinations of putative risk alleles seemed to act synergistically, increasing the risk of HNSCC. In conclusion, our results suggest that SNPs of the DNA repair genes XPC, XPD, XRCC1, and XRCC3 may affect risk and survival of HNSCC. (C) 2015 Elsevier B.V. All rights reserved.
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| 6. |
- Farnebo, Lovisa, et al.
(författare)
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Early death among head and neck cancer patients
- 2016
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Ingår i: Current Opinion in Otolaryngology & Head and Neck Surgery. - : Lippincott Williams & Wilkins. - 1068-9508 .- 1531-6998. ; 24:2, s. 115-120
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Forskningsöversikt (refereegranskat)abstract
- Purpose of reviewManagement of advanced head and neck cancer (HNC) is characterized by high mortality. Furthermore, the treatment involves significant burden to patients and high costs to healthcare systems. Recognizing the risks of early death in patients with a high probability of noncurable disease is important for each individual treatment decision-making. It is thus critical to consider the benefits and side-effects of the planned treatment in relation to the expected survival and to discuss these factors with the patient. However, only few studies have documented early death in HNC patients, that is, during the first posttreatment 6 months. We performed a systematic literature review to find the incidence of this phenomenon and to outline the probable cause.Recent findingsEarly mortality in patients with HNC can be explained either by direct effect of malignant disease, may be related to comorbidities, or secondary to the treatment. These factors act together resulting in expected or unexpected early death.SummaryThe present review provides information on the mechanisms leading to early phase mortality (<6 months) after management of HNC. It also reports the incidence of this phenomenon among Finnish and Swedish patient populations.
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| 7. |
- Kim, Jeewon, et al.
(författare)
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Targeting aldehyde dehydrogenase activity in head and neck squamous cell carcinoma with a novel small molecule inhibitor
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:32, s. 52345-52356
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Tidskriftsartikel (refereegranskat)abstract
- Chemoresistant cancer cells express high levels of aldehyde dehydrogenases (ALDHs), particularly in head and neck squamous cell carcinoma (HNSCC). The ALDH family of enzymes detoxify both exogenous and endogenous aldehydes. Since many chemotherapeutic agents, such as cisplatin, result in the generation of cytotoxic aldehydes and oxidative stress, we hypothesized that cells expressing high levels of ALDH may be more chemoresistant due to their increased detoxifying capacity and that inhibitors of ALDHs may sensitize them to these drugs. Here, we show that overall ALDH activity is increased with cisplatin treatment of HNSCC and that ALDH3A1 protein expression is particularly enriched in cells treated with cisplatin. Activation of ALDH3A1 by a small molecule activator (Alda-89) increased survival of HNSCC cells treated with cisplatin. Conversely, treatment with a novel small molecule ALDH inhibitor (Aldi-6) resulted in a marked decrease in cell viability, and the combination of Aldi-6 and cisplatin resulted in a more pronounced reduction of cell viability and a greater reduction in tumor burden in vivo than what was observed with cisplatin alone. These data indicate that ALDH3A1 contributes to cisplatin resistance in HNSCC and that the targeting of ALDH, specifically, ALDH3A1, appears to be a promising strategy in this disease.
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| 8. |
- Kiug, Tejs Ehlers, et al.
(författare)
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Laryngo-tracheal resections in the Nordic countries : an option for further centralization?
- 2019
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Ingår i: European Archives of Oto-Rhino-Laryngology. - : Springer. - 0937-4477 .- 1434-4726. ; 276:5, s. 1545-1548
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Tidskriftsartikel (refereegranskat)abstract
- PurposeWe 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.MethodsConsultants 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.ResultsAll 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 post-operative bronchoscopy.ConclusionsFifteen 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.
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| 9. |
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| 10. |
- Melissaridou, Styliani, et al.
(författare)
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The effect of 2D and 3D cell cultures on treatment response, EMT profile and stem cell features in head and neck cancer 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis
- 2019
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Head and Neck Squamous Cell Carcinoma (HNSCC) tumors are often resistant to therapies. Therefore searching for predictive markers and new targets for treatment in clinically relevant in vitro tumor models is essential. Five HNSCC-derived cell lines were used to assess the effect of 3D culturing compared to 2D monolayers in terms of cell proliferation, response to anti-cancer therapy as well as expression of EMT and CSC genes. Methods: The viability and proliferation capacity of HNSCC cells as well as induction of apoptosis in tumor spheroids cells after treatment was assessed by MTT assay, crystal violet- and TUNEL assay respectively. Expression of EMT and CSC markers was analyzed on mRNA (RT-qPCR) and protein (Western blot) level. Results: We showed that HNSCC cells from different tumors formed spheroids that differed in size and density in regard to EMT-associated protein expression and culturing time. In all spheroids, an up regulation of CDH1, NANOG and SOX2 was observed in comparison to 2D but changes in the expression of EGFR and EMT markers varied among the cell lines. Moreover, most HNSCC cells grown in 3D showed decreased sensitivity to cisplatin and cetuximab (anti-EGFR) treatment. Conclusions: Taken together, our study points at notable differences between these two cellular systems in terms of EMT-associated gene expression profile and drug response. As the 3D cell cultures imitate the in vivo behaviour of neoplastic cells within the tumor, our study suggest that 3D culture model is superior to 2D monolayers in the search for new therapeutic targets.
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