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1.
  • Areberg, Johan, et al. (författare)
  • Antitumor effect of radioactive cisplatin (191Pt) on nude mice
  • 2001
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - 0360-3016. ; 49:3, s. 827-832
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: To investigate the effect of (191)Pt-cisplatin in vivo in terms of the antitumor effect and general toxicity on tumor-bearing nude mice. METHODS AND MATERIALS: Tumor-bearing (human squamous cell carcinoma, AB) nude mice were divided into four groups and given, i.p., physiological saline (controls), cisplatin, (191)Pt-cisplatin (80 MBq/mg), or (191)Pt-cisplatin (160 MBq/mg), respectively. Mortality and weight were used as parameters for monitoring general toxic effect, while specific growth delay (SGD) and the area under the logarithm of the relative tumor size curve (AUC-log[RTS]) were used to evaluate the antitumor effect of the treatments. RESULTS: Both SGD and AUC-log(RTS) values showed that (191)Pt-cisplatin was significantly (P < 0.05) more effective in retarding tumor growth than nonradioactive cisplatin. No differences in mortality between the different groups could be observed and no significant differences in weight change between the mice treated with cisplatin or (191)Pt-cisplatin could be seen. CONCLUSION: (191)Pt-cisplatin is a more effective drug than nonradioactive cisplatin in retarding tumor growth on nude mice without adding systemic toxic effects. We believe that radioactive cisplatin may prove to be an alternative to conventional cisplatin; however, the possible toxic effects on organs at risk have to be thoroughly investigated.
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2.
  • Henriksson, Eva, et al. (författare)
  • Differences in estimates of cisplatin-induced cell kill in vitro between colorimetric and cell count/colony assays
  • 2006
  • Ingår i: In Vitro Cellular & Developmental Biology - Animal. - 1071-2690. ; 42:10, s. 320-323
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to evaluate some bioassays that are different in principle: cell counting, colony forming assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), sulforhodamine B (SRB), crystal violet, and alamarBlue, with respect to their ability to measure cisplatin-induced cell death of in vitro-cultivated squamous cell carcinoma of the head and neck (SCCHN). Cisplatin was applied in concentrations of 1.0, 5.0, 10.0, 50.0, and 100 mu M. The cells were incubated for 1 h, and the cell survival was measured 5 d after treatment. We found the colorimetric assays and cell counting to be comparable. The colony forming assay indicated a higher degree of cell kill compared with the other techniques. Measurement of cell survival after treatment with cisplatin can be done by use of any of the above tested assays. However, the majority of SCCHN cell lines available do not form colonies easily, or at all. Therefore, comparing the chemosensitivity between such cell lines is limited to alternative assays. In this respect, any of the tested colorimetric assays can be used. However, they seem to underestimate cell kill. Cell counting is also an alternative. This technique, however, is time consuming and operator dependent, as in the ease of manual counting, or relatively expensive when counting is performed electronically, compared with the colorimetric assays.
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3.
  • Högmo, Anders, et al. (författare)
  • Base of tongue squamous cell carcinomas, outcome depending on treatment strategy and p16 status. A population-based study from the Swedish Head and Neck Cancer Register
  • 2022
  • Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 61:4, s. 433-440
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The base of tongue squamous cell carcinoma (BOTSCC) is mainly an HPV-related tumor. Radiotherapy (EBRT) ± concomitant chemotherapy (CT) is the backbone of the curatively intended treatment, with brachytherapy (BT) boost as an option. With four different treatment strategies in Sweden, a retrospective study based on the population-based Swedish Head and Neck Cancer Register (SweHNCR) was initiated.Material and methods: Data on tumors, treatment and outcomes in patients with BOTSCC treated between 2008 and 2014 were validated through medical records and updated as needed. Data on p16 status were updated or completed with immunohistochemical analysis of archived tumor material. Tumors were reclassified according to the UICC 8th edition.Results: Treatment was EBRT, EBRT + CT, EBRT + BT or EBRT + CT + BT in 151, 145, 82 and 167 patients respectively (n = 545). A p16 analysis was available in 414 cases; 338 were p16+ and 76 p16−. 5-year overall survival (OS) was 68% (95% CI: 64–72%), with76% and 37% for p16+ patients and p16− patients, respectively. An increase in OS was found with the addition of CT to EBRT for patients with p16+ tumors, stages II–III, but for patients with tumor stage I, p16+ (UICC 8) none of the treatment strategies was superior to EBRT alone.Conclusion: In the present retrospective population-based study of BOTSCC brachytherapy was found to be of no beneficial value in curatively intended treatment. An increase in survival was found for EBRT + CT compared to EBRT alone in patients with advanced cases, stages II and III (UICC 8), but none of the regimes was significantly superior to EBRT as a single treatment modality for stage I (UICC 8), provided there was p16 positivity in the tumor. In the small group of patients with p16− tumors, a poorer prognosis was found, but the small sample size did not allow any comparisons between different treatment strategies.
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4.
  • Johannsson, Oskar T, et al. (författare)
  • Characterization of a novel breast carcinoma xenograft and cell line derived from a BRCA1 germ-line mutation carrier
  • 2003
  • Ingår i: Laboratory Investigation. - 1530-0307. ; 83:3, s. 96-387
  • Tidskriftsartikel (refereegranskat)abstract
    • A human tumor xenograft (L56Br-X1) was established from a breast cancer axillary lymph node metastasis of a 53-year-old woman with a BRCA1 germ-line nonsense mutation (1806C>T; Q563X), and a cell line (L56Br-C1) was subsequently derived from the xenograft. The xenograft carries only the mutant BRCA1 allele and expresses mutant BRCA1 mRNA but no BRCA1 protein as determined by immunoprecipitation or Western blotting. The primary tumor, lymph node metastasis, and xenograft were hypodiploid by DNA flow cytometry, whereas the cell line displayed an aneuploidy apparently developed via polyploidization. Cytogenetic analysis, spectral karyotyping, and comparative genomic hybridization of the cell line revealed a highly complex karyotype with numerous unbalanced translocations. The xenograft and cell line had retained a somatic TP53 missense mutation (S215I) originating from the primary tumors, as well as a lack of immunohistochemically detectable expression of steroid hormone receptors, epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER-2), and keratin 8. Global gene expression analysis by cDNA microarrays supported a correlation between the expression profiles of the primary tumor, lymph node metastasis, xenograft, and cell line. We conclude that L56Br-X1 and L56Br-C1 are useful model systems for studies of the pathogenesis and new therapeutic modalities of BRCA1-induced human breast cancer.
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6.
  • Kjellström, Johan, et al. (författare)
  • Increased toxicity of a trinuclear Pt-compound in a human squamous carcinoma cell line by polyamine depletion
  • 2012
  • Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 12
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Mononuclear platinum anticancer agents hold a pivotal place in the treatment of many forms of cancers, however, there is a potential to improve response to evade resistance development and toxic side effects. BBR3464 is a promising trinuclear platinum anticancer agent, which is a polyamine mimic. The aim was to investigate the influence of polyamine pool reduction on the cytotoxic effects of the trinuclear platinum complex BBR3464 and cisplatin. Polyamine pool reduction was achieved by treating cells with either the polyamine biosynthesis inhibitor alpha-difluoromethylornithine (DFMO) or the polyamine analogue N-1,N-11-diethylnorspermine (DENSPM). Methods: A human squamous cell carcinoma cell line, LU-HNSCC-4, established from a primary head and neck tumour was used to evaluate cellular effects of each drug alone or combinations thereof. High-performance liquid-chromatography was used to quantify intracellular polyamine contents. Inductively coupled mass spectroscopy was used to quantify intracellular platinum uptake. Cells were exposed to DFMO or DENSPM during 48 h at concentrations ranging from 0 to 5 mM or 0 to 10 mu M, respectively. Thereafter, non-treated and treated cells were exposed to cisplatin or BBR3464 during 1 h at concentrations ranging from 0 to 100 mu M. A 96-well assay was used to determine cytotoxicity after five days after treatment. Results: The cytotoxic effect of BBR3464 on LU-HNSCC-4 cells was increased after cells were pre-treated with DENSPM or DFMO, and the interaction was found to be synergistic. In contrast, the interaction between cisplatin and DFMO or DENSPM was near-additive to antagonistic. The intracellular levels of the polyamines putrescine and spermidine were decreased after treatment with DFMO, and treatment with DENSPM resulted in an increase in putrescine level and concomitant decrease in spermidine and spermine levels. The uptake of BBR3464 was significantly increased after pre-treatment of the cells with DFMO, and varied dependent on the concentration of DENSPM. The uptake of cisplatin was unchanged. Conclusions: Taken together, these results demonstrate that combinations of polyamine synthesis inhibitors with BBR3464 appear to be a promising approach to enhance the anticancer activity against HSCC.
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7.
  • Lindgren, Gustaf, et al. (författare)
  • Erythropoietin suppresses the activation of pro-apoptotic genes in head and neck squamous cell carcinoma xenografts exposed to surgical trauma.
  • 2014
  • Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14
  • Tidskriftsartikel (refereegranskat)abstract
    • Several studies on the use of erythropoietin (Epo) to treat anaemia in patients undergoing cancer treatment have shown adverse effects on tumour control and survival. Experimental studies indicate that this could be linked to an interaction with wound healing processes and not an effect on tumour cells per se. We have previously shown that erythropoietin in combination with surgical trauma stimulates tumour growth. In the present study, we investigated the effect of surgery and Epo on gene expression.
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8.
  • Wennerberg, Erik, et al. (författare)
  • Human anaplastic thyroid carcinoma cells are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract NK cells
  • 2014
  • Ingår i: Clinical Cancer Research. - 1078-0432. ; 20:22, s. 5733-5744
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive forms of cancer with no curative therapies available. To date, strategies to target ATC by immunotherapy have not been evaluated. We investigated whether ATC would be a suitable target for natural killer (NK) cell-based immunotherapy.EXPERIMENTAL DESIGN: We first established seven new cell lines from ATC tumors, three from papillary thyroid carcinoma tumors and analyzed them together with eight additional ATC cell lines. Cells were analyzed for sensitivity to lysis by NK cells and their ability to chemoattract and regulate the activity of NK cells. In addition, fresh tumor samples and peripheral blood from six patients with ATC were analyzed for NK cell infiltration and phenotype.RESULTS: We observed that ATC cell lines are sensitive to lysis by ex vivo expanded NK cells and that the lysis was abrogated upon blockade of NKG2D. Sensitivity of thyroid cancer cell lines to NK cell-mediated lysis correlated with surface expression of UL16-binding protein 2 on tumor cells. Moreover, ATC cell lines produced high levels of CXCL10 and stimulated migration of expanded NK cells and ATC tumors were enriched for NK cells expressing the cognate chemokine receptor CXCR3. However, compared with NK cells in peripheral blood, ATC tumor-derived NK cells displayed a suppressed phenotype with a downregulated expression of NKG2D. In vitro, suppression of NK cell-mediated lysis and NKG2D expression by ATC cells was restored upon neutralization of prostaglandin-E2.CONCLUSIONS: ATC cell lines are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract CXCR3-positive NK cells. Patients with ATC may benefit from NK cell-based immunotherapy.
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9.
  • Wennerberg, Johan, et al. (författare)
  • Results from a prospective, randomised study on (accelerated) preoperative versus (conventional) postoperative radiotherapy in treatment of patients with resectable squamous cell carcinoma of the oral cavity : The ARTSCAN 2 study
  • 2022
  • Ingår i: Radiotherapy and Oncology. - : Elsevier. - 0167-8140 .- 1879-0887. ; 166, s. 26-32
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purposeAn earlier prospective randomised multicentre study (ARTSCAN) in head and neck cancer patients that compared conventionally fractionated radiotherapy (CF) with accelerated radiotherapy (AF) was inconclusive. In the subgroup of oral cavity squamous cell cancer (OCSCC) a large absolute, but not statistically significant, difference in local control was seen in favour of AF. This difference was more pronounced in resectable tumours. The finding raised the hypothesis that AF could be beneficial for OCSCC patients. In addition, the longstanding controversy on pre- or postoperative radiotherapy was addressed.Materials and methodsPatients with OCSCC, judged to withstand and likely benefit from combined therapy, were recruited. Subjects were randomised to either preoperative AF with 43 fractions given as a concomitant boost with two fractions/day to the tumour bearing volume to a total dose of 68 Gy in 4.5 weeks followed by surgery, or primary surgery with postoperative CF, total dose 60 or 66 Gy in 6–7 weeks. For patients whose tumours had high-risk features, 66 Gy and concomitant cisplatin was prescribed.Results250 patients were randomised. Median follow-up was 5 years for locoregional control (LRC) and 9 years for overall survival (OS). There were no statistically significant differences between the two treatment arms regarding LRC and OS. LRC at five years was 73% (95% CI, 65–82) in preoperative AF and 78% (95% CI, 70–85) in postoperative CF.Toxicity was more pronounced in preoperative AF.ConclusionThis study does not support that AF prior to surgery improves outcome in oral cavity cancer compared with postoperative CF.
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10.
  • Zackrisson, Björn, et al. (författare)
  • Mature results from a Swedish comparison study of conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma - The ARTSCAN trial
  • 2015
  • Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 117:1, s. 99-105
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose: This report contains the mature five-year data from the Swedish ARTSCAN trial including information on the influence of p16 positivity (p16+) for oropharyngeal cancers. Material and methods: Patients with previously untreated squamous cell carcinoma without distant metastases of the oral cavity, oropharynx, larynx (except T1-2, NO glottic cancers) and hypopharynx were included. Patients were randomised between accelerated fractionation (AF) (1.1 Gy + 2 Gy per day, 5 days/week for 4.5 weeks, total dose 68 Gy) and conventional fractionation (CF) (2 Gy per day, 5 days/week for 7 weeks, total dose 68 Gy). Human papillomavirus (HPV)-associated p16-expression was assessed retrospectively in tumour tissues from patients with oropharyngeal carcinoma. Results: There was no significant difference in loco-regional control (LRC) between AF and CF (log-rank test p = 0.75). LRC at 5 years was 65.5% for AF and 64.9% for CF. Overall survival (OS) was similar in both arms (p = 0.99). The estimated cancer specific survival (CSS) at 5 years was 62.2% (AF) and 63.3% (CF) (p = 0.99). 206 specimens were analysed for p16 with 153 specimens (74%) identified as p16+. P16 status did not discriminate for response to AF vs. CF with regard to LRC, OS or CSS. Patients with p16+ tumours had a statistically significant better overall prognosis compared with p16 tumours. Conclusion: This update confirms the results of the 2-year report. We failed to identify a positive effect resulting from AF with regards to LRC, OS and CSS. The addition of information on the HPV-associated p16 overexpression did not explain this lack of effect.
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11.
  • Abu-Humaidan, Anas H.A., et al. (författare)
  • EGFR modulates complement activation in head and neck squamous cell carcinoma
  • 2020
  • Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The epidermal growth factor receptor (EGFR) is pivotal for growth of epithelial cells and is overexpressed in several epithelial cancers like head and neck squamous cell carcinoma (HNSCC). EGFR signalling is also involved in diverse innate immune functions in epithelia. We previously found a role for EGFR in modulating the complement system in skin, this prompted an investigation into EGFR role in complement modulation in HNSCC. Methods: We used patient derived HNSCC cell lines with varying sensitivities to EGFR inhibitors, and generated EGFR inhibition resistant cell lines to study the role of EGFR in modulating complement in HNSCC. Results: We found that HNSCC cell lines activate the complement system when incubated with human serum. This complement activation was increased in cell lines sensitive to EGFR inhibition following the use of the tyrosine kinase inhibitor Iressa. Sensitive cell line made resistant to EGFR-inhibitors displayed complement activation and a decrease in complement regulatory proteins even in the absence of EGFR-inhibitors. Complement activation did not cause lysis of HNSCC cells, and rather led to increased extracellular signal-regulated kinase (ERK) phosphorylation in one cell line. Conclusion: These data indicate that EGFR has a complement modulatory role in HNSCC, and that a prolonged EGFR-inhibition treatment in sensitive cancer cells increases complement activation. This has implications in understanding the response to EGFR inhibitors, in which resistance and inflammatory skin lesions are two major causes for treatment cessation.
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12.
  • Albrektsson, Tomas, et al. (författare)
  • Foreign body reactions, marginal bone loss and allergies in relation to titanium implants
  • 2018
  • Ingår i: European Journal of Oral Implantology. - : Quintessence. - 1756-2406 .- 1756-2414. ; 11, s. 37-46
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: To describe general observations of immunological reactions to foreign materials and to realize that CP titanium gives rise to a foreign body reaction with subsequent bone embedment when placed as oral implants. To analyse the possibility of titanium allergy. Materials and methods: The present paper is of a narrative review type. Hand and Medline searches were performed to evaluate marginal bone loss of oral implants and the potential of titanium allergy. Results: Immunological reactions to foreign substances include Type I hypersensitivity reactions such as allergy, Type II hypersensitivity reactions characterised by IgM or IgG antibodies that may react with blood group antigens at transfusion, and Type III hypersensitivity caused by antigen-antibody immune complexes exemplified by acute serum sickness. There is also Type IV hypersensitivity, or delayed hypersensitivity, which is typically found in drug and foreign body reactions. It proved very difficult to find a universally acceptable definition of reasons for marginal bone loss around oral implants, which lead to most varying figures of so-called peri-implantitis being 1% to 2% in some 10-year follow-up papers to between 28% and 56% of all placed implants in other papers. It was recognised that bone resorption to oral as well as orthopaedic implants may be due to immunological reactions. Today, osseointegration is seen as an immune-modulated inflammatory process where the immune system is locally either up- or downregulated. Titanium implant allergy is a rare condition, if it exists. The authors found only two papers presenting strong evidence of allergy to CP titanium, but with the lack of universally accepted and tested patch tests, the precise diagnosis is difficult. Conclusions: CP titanium acts as a foreign body when placed in live tissues. There may be immunological reasons behind marginal bone loss. Titanium allergy may exist in rare cases, but there is a lack of properly designed and analysed patch tests at present.
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13.
  • Albrektsson, Tomas, 1945, et al. (författare)
  • On inflammation-immunological balance theory—A critical apprehension of disease concepts around implants: Mucositis and marginal bone loss may represent normal conditions and not necessarily a state of disease
  • 2019
  • Ingår i: Clinical Implant Dentistry and Related Research. - : Wiley. - 1523-0899 .- 1708-8208. ; 21:1, s. 183-189
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Oral implants have displayed clinical survival results at the 95%-99% level for over 10 years of follow up. Nevertheless, some clinical researchers see implant disease as a most common phenomenon. Oral implants are regarded to display disease in the form of mucositis or peri-implantitis. One purpose of the present article is to investigate whether a state of disease is necessarily occurring when implants display soft tissue inflammation or partially lose their bony attachment. Another purpose of this article is to analyze the mode of defense for implants that are placed in a bacteria rich environment and to analyze when an obtained steady state between tissue and the foreign materials is disturbed. Materials and Methods: The present article is authored as a narrative review contribution. Results: Evidence is presented that further documents the fact that implants are but foreign bodies that elicit a foreign body response when placed in bone tissue. The foreign body response is characterized by a bony demarcation of implants in combination with a chronic inflammation in soft tissues. Oral implants survive in the bacteria-rich environments where they are placed due to a dual defense system in form of chronic inflammation coupled to immunological cellular actions. Clear evidence is presented that questions the automatic diagnostics of an oral implant disease based on the finding of so called mucositis that in many instances represents but a normal tissue response to foreign body implants instead of disease. Furthermore, neither is marginal bone loss around implants necessarily indicative of a disease; the challenge to the implant represented by bone resorption may be successfully counteracted by local defense mechanisms and a new tissue-implant steady state may evolve. Similar reactions including chronic inflammation occur in the interface of orthopedic implants that display similarly good long-term results as do oral implants, if mainly evaluated based on revision surgery in orthopedic cases. The most common mode of failure of orthopedic implants is aseptic loosening which has been found coupled to a reactivation of the inflammatory- immune system. Conclusions: Implants survive in the body due to balanced defense reactions in form of chronic inflammation and activation of the innate immune system. Ten year results of oral and hip /knee implants are hence in the 90+ percentage region. Clinical problems may occur with bone resorption that in most cases is successfully counterbalanced by the defense/healing systems. However, in certain instances implant failure will ensue characterized by bacterial attacks and/or by reactivation of the immune system that now will act to remove the foreign bodies from the tissues.
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14.
  • Anderud, Jonas, et al. (författare)
  • Guided bone augmentation using a ceramic space-maintaining device
  • 2014
  • Ingår i: Oral surgery, oral medicine, oral pathology and oral radiology. - : Elsevier. - 2212-4403 .- 2212-4411. ; 118:5, s. 532-538
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. The purpose of this study was to evaluate 3-dimensionally whether vertical bone augmentation can be achieved using a hollow hydroxyapatite space-maintaining device in a rabbit calvarial model. Furthermore, different inner surface topographies, different permeabilities, and different porosities of the ceramic were tested to determine the optimal conditions for bone regeneration.
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15.
  • Anderud, Jonas, et al. (författare)
  • Guided bone augmentation using ceramic space-maintaining devices : The impact of chemistry
  • 2015
  • Ingår i: Clinical, Cosmetic and Investigational Dentistry. - : Nakladatelstvi Lidove noviny. - 1179-1357. ; 7, s. 45-53
  • Tidskriftsartikel (refereegranskat)abstract
    • The purpose of the study was to evaluate histologically, whether vertical bone augmentation can be achieved using a hollow ceramic space maintaining device in a rabbit calvaria model. Furthermore, the chemistry of microporous hydroxyapatite and zirconia were tested to determine which of these two ceramics are most suitable for guided bone generation. 24 hollow domes in two different ceramic materials were placed subperiosteal on rabbit skull bone. The rabbits were sacrificed after 12 weeks and the histology results were analyzed regarding bone-to-material contact and volume of newly formed bone. The results suggest that the effect of the microporous structure of hydroxyapatite seems to facilitate for the bone cells to adhere to the material and that zirconia enhance a slightly larger volume of newly formed bone. In conclusion, the results of the current study demonstrated that ceramic space maintaining devices permits new bone formation and osteoconduction within the dome.
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16.
  • Anderud, Jonas, et al. (författare)
  • The impact of surface roughness and permeability in hydroxyapatite bone regeneration membranes
  • 2015
  • Ingår i: Clinical Oral Implants Research. - : Blackwell Munksgaard. - 0905-7161 .- 1600-0501. ; 27:8, s. 1047-1054
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: One of the crucial aspects in guided bone regeneration is the space maintenance. This is normally created by a membrane, which should primarily be accepted by the surrounding tissues without causing any adverse reactions. The impact of surface topography, biological acceptance as well as permeability of these membranes has been carefully discussed in the literature. Purpose: The purpose of this study was to evaluate histologically the bone forming properties inside of hollow hydroxyapatite space-maintaining devices with different inner surfaces and different permeabilities in an animal calvaria model in vivo. Materials and methods: A total of 36 hollow domes with three different designs made of hydroxyapatite were surgically attached to the skulls of rabbits. Group 1 had a moderately rough inner surface. Group 2 had a smooth inner surface. Group 3 had the same properties as Group 1 but had macroscopic holes on the top. The domes were left to heal for 12 weeks and were then processed for undecalcified ground sectioning. Histological evaluations were performed using a light microscope and scanning electron microscopy. The bone-implant contact (BIC) percentage along the device was calculated. Results: The median percentage of BIC was higher for Group 1 compared with Group 2 (P = 0.004). Group 1 produced a larger median BIC compared with Group 3 (P < 0.0001). Conclusions: Within the limits of this preclinical study, these findings suggest that a moderately rough inner surface of a ceramic membrane along with a non-permeable device produces more bone than a smooth inner surface.
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17.
  • Annertz, Karin, et al. (författare)
  • Alpha B-crystallin - a validated prognostic factor for poor prognosis in squamous cell carcinoma of the oral cavityl
  • 2014
  • Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 134:5, s. 543-550
  • Tidskriftsartikel (refereegranskat)abstract
    • Conclusion: Alpha B-crystallin was found to be an independent prognostic marker for poor prognosis in oral cavity tumours. For oropharyngeal cancer, alpha B-crystallin had no prognostic value. Objective: The aim of this study was to see if earlier findings of alpha B-crystallin as an independent prognostic marker, and SPARC/osteonectin, PAI-1 and uPA as a prognostic combination for poor outcome in squamous cell carcinoma (SCC) of the head and neck could be confirmed in a new set of tumours. Methods: In a consecutive series of patients, assessed and primarily treated at a tertiary referral centre, histological sections from 55 patients with oral and SCC (OOPHSSC) with complete clinical data and follow-up were obtained. Oral and oropharyngeal tumours were studied separately. Immunohistochemical detection of alpha B-crystallin, SPARC/osteonectin, PAI-1 and uPA expression was performed. Results: Thirty-five patients had an oral tumour and 20 patients an oropharyngeal tumour. Twenty-five oral tumours stained negatively and 10 positively for alpha B-crystallin. For oropharyngeal tumours the figures were 15 negatively and 5 positively. Median disease-specific survival (DSS) for both sites was 33.8 and 11.9 months, for negative and positive alpha B-crystallin staining, respectively (p=0.046). For the oral cavity, median DSS was 27.3 months for negative tumours and 7.5 months for positive tumours (p=0.012). Corresponding figures for oropharyngeal tumours were 33.8 and 34.1 months (p=0.95). Thus, significance in survival was only found in oral cavity tumours. In multivariate analyses there were no significant differences in DSS in the oropharyngeal group when adjusted for tumour size (T status) and presence of neck node metastasis (N status). In the oral cavity group, the significantly better DSS for negative tumours became even stronger when adjusted for T and N status. No statistical difference was found in DSS between positive and negative staining for SPARC/osteonectin, PAI-1 or uPA.
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18.
  • Annertz, Karin, et al. (författare)
  • High-risk HPV and survival in patients with oral and oropharyngeal squamous cell carcinoma : 5-year follow up of a population-based study
  • 2014
  • Ingår i: Acta Oto-Laryngologica. - : Informa Healthcare. - 0001-6489 .- 1651-2251. ; 8:134, s. 843-851
  • Tidskriftsartikel (refereegranskat)abstract
    • CONCLUSION: No statistically significant 5-year survival difference was seen in patients with oral and oropharyngeal squamous cell carcinoma (OOPSCC) between high-risk HPV-positive and -negative groups in this population-based study. OBJECTIVES: To see if the formerly observed higher risk for recurrence or second primary tumour (SPT) in high-risk HPV-positive patients with OOPSCC corresponds to worse survival. METHODS: A total of 128 consecutive, previously untreated patients with OOPSCC, who were part of a population-based case-control study in southern Sweden during 2000-2004, were included. A mouthwash sample was collected and exfoliated cells were collected with cotton-tipped swabs from the tonsillar fossa and the tumour. Specimens were analysed for HPV DNA using nested polymerase chain reaction (PCR). Disease-specific survival (DSS) and DSS difference between HPV-negative and HPV-positive patients were calculated. The relationship between age, stage, high-risk HPV status and DSS was assessed. Oral and oropharyngeal tumours were assessed separately. RESULTS: Mean DSS in months was 80.7/68.6 (high-risk HPV-negative/high-risk HPV-positive) for oral cavity tumours (p = 0.18) and 67.6/78.3 (high-risk HPV-negative/high-risk HPV-positive) for oropharyngeal tumours (p = 0.47). For oral cavity tumours, age, T status, N status and stage all showed significant differences in DSS. For oropharyngeal tumours, no significant difference regarding DSS was found.
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19.
  • Annertz, Karin, et al. (författare)
  • Incidence and survival of squamous cell carcinoma of the tongue in Scandinavia, with special reference to young adults.
  • 2002
  • Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 101:1, s. 95-99
  • Tidskriftsartikel (refereegranskat)abstract
    • In several countries, increased incidence of squamous cell carcinoma (SCC) of the tongue in young adults has been suspected during the last decades. Some reports indicate a lower survival rate for young patients compared to older patients. In other reports, there has not been any considerable difference in survival when comparing young adults to older patients, whereas some authors have shown better survival for young adults. This disease is rare in young adults, and early reports were based on comparable small numbers and selected patients. Our aim was first to perform a population-based study to determine if an increased incidence in SCC of the tongue could be verified in a larger population comprising the Scandinavian countries Denmark, Finland, Sweden and Norway. A second aim was to determine survival rates for young adults compared to older patients. The material was based on the annual cancer incidence and survival reports from the Scandinavian cancer registries. The study period was 1960-1994. During that period, 5,024 SCCs of the tongue were reported. Of these, 276 (5.5%) were young adults (20-39 years). The incidence increased at all ages except for women 65-79 years old. The increase was most pronounced in young adults: 0.06-0.32 for men and 0.03-0.19 for women, counted by 100,000 person-years. Relative survival was significantly better for young adults compared to older patients.
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20.
  • Annertz, Karin, et al. (författare)
  • The increase in incidence of cancer of the tongue in the Nordic countries continues into the twenty-first century
  • 2012
  • Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 132:5, s. 552-557
  • Tidskriftsartikel (refereegranskat)abstract
    • Conclusion: This study shows a persistent trend of an increase in the incidence of carcinoma of the tongue into the twenty-first century for both sexes and all age groups except for young males. Objectives: During the last decades increased incidence of squamous cell carcinoma (SCC) of the tongue in young adults has been reported. We previously showed an increased incidence in SCC of the tongue in Scandinavia in 1960-1994, most pronounced in patients aged 20-39 years. The aim of this study was to investigate whether the trend of increased incidence of tongue cancer continued into the twenty-first century in a population-based study in the Nordic countries. Methods: Data for all reported SCCs of the tongue and base of tongue in patients aged 20-79 years during 1960-2008 were extracted from the NORDCAN registry, based on the National Cancer registries in the Nordic countries. Data from Sweden, Norway, Finland, Denmark, and Iceland were analyzed. The age groups 20-39, 40-64, and 65-79 years were studied separately as well as male and female figures. Results: In all, 12 280 cases were reported, of which 673 were diagnosed in patients aged 20-39 years. The trend of an increase persisted after 1994 in both sexes and all three age groups except in young males.
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21.
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22.
  • Aplander, Karolina, et al. (författare)
  • Asymmetric Lewis Acid Catalysis in Water: alpha-Amino Acids as Effective Ligands in Aqueous Biphasic Catalytic Michael Additions
  • 2009
  • Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; :6, s. 810-821
  • Tidskriftsartikel (refereegranskat)abstract
    • This article explores the potential of native a-amino acids as chiral ligands in aqueous asymmetric Lewis acid catalysis, employing the C-C bond forming Michael addition as a model reaction. Some insights are provided regarding the details of Yb(OTf)(3)/alpha-amino acid-catalyzed Michael additions in water through new kinetic data as well as studies on how both yield and selectivity are influenced by variations in metal/ligand ratio, pH, temperature, and structure of the a-amino acid, Through this investigation it was found that reaction conditions that require only 5 mol-% of the Lewis acid, provides enantiomeric excesses of up to 79 % and is applicable to a wider range of donors and acceptors than previously demonstrated. Importantly, it was also demonstrated that the a-amino acid complexed ytterbium. catalyst might have potential for large-scale applications as it displays not only large ligand accelerations, but also good solubility and stability in water. It can be recycled multiple times without appreciable loss of activity. The result is a promising example of a water-compatible chiral Lewis acid. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
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23.
  • Aplander, Karolina, et al. (författare)
  • Entropy-Controlled and Enantiodivergent Lewis Acid Catalysis in Water
  • 2012
  • Ingår i: Synthesis. - : Georg Thieme Verlag KG. - 0039-7881 .- 1437-210X. ; 44:6, s. 848-856
  • Tidskriftsartikel (refereegranskat)abstract
    • Developing new and useful methods in asymmetric catalysis is of continuous importance. A current challenge is to address the imperatives of green chemistry, such that processes maximize resource-efficiency and minimize the generation of waste. To this end, this article discloses the potential of alpha-amino acids in the development of entropy-controlled and enantiodivergent Lewis acid catalysis. In an ytterbium-catalyzed aqueous Michael addition reaction, natural alpha-amino acids induced not only a large rate acceleration, but also an unusual and remarkable reversed temperature effect on enantioselectivity. As demonstrated with 17 alpha-amino acids, the enantioselectivity of the reaction can be significantly altered, and even reversed, simply by modifying the reaction temperature. After determining differential thermodynamic activation parameters, it was revealed that an unusually large entropy contribution was responsible for the observed effects. By further correlation to the influence of the aqueous medium, we put forward the concept of stereospecific aqueous solvation (SAS), which describes the bearing of aqueous solvation on the equilibrium of diastereomeric transition states, and thus on the R/S ratio of the product.
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24.
  • Bjurberg, Maria, et al. (författare)
  • Early metabolic flare in squamous cell carcinoma after chemotherapy is a marker of treatment sensitivity in vitro
  • 2010
  • Ingår i: Nuclear medicine and molecular imaging. - : Springer. - 1869-3474 .- 1869-3482. ; 44:3, s. 165-169
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose Early metabolic response with a decrease in glucose demand after cytotoxic treatment has been reported to precede tumor volume shrinkage. However, preclinical studies report of a very early rise in metabolism, a flare, following treatment. To elucidate these observations, we performed an experimental study on early metabolic response with sequential analysis of metabolic changes. Methods Three squamous cell carcinoma cell lines and one nontumorigenic cell line were exposed to cisplatin. The uptake of the fluorescent glucose analogue 2-NBDG was examined at days 1-6 using fluorescence microscopy. The relation between 2-NBDG-uptake and cell survival was evaluated. Results The tumor cells exhibited a high uptake of 2-NBDG, whereas the uptake in the nonmalignant cells was low. The more cisplatin sensitive cell lines exhibited a more pronounced metabolic flare than the less sensitive cell line. Conclusion A metabolic flare was a very early sign of treatment response and potentially it could be used as an early marker of treatment sensitivity. 
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25.
  • Brodin, Bertha A., et al. (författare)
  • Drug sensitivity testing on patient-derived sarcoma cells predicts patient response to treatment and identifies c-Sarc inhibitors as active drugs for translocation sarcomas
  • 2019
  • Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 120:4, s. 435-443
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. RESULTS: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. CONCLUSIONS: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.
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26.
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27.
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28.
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29.
  • Brun, Eva, et al. (författare)
  • Early prediction of treatment outcome in head and neck cancer with 2-18FDG PET
  • 1997
  • Ingår i: Acta Oncologica. - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 36:7, s. 741-747
  • Tidskriftsartikel (refereegranskat)abstract
    • The development of alternative treatment regimens in clinical oncology has increased the need for early prediction of cancer therapy outcome. The aim of this study was, early in the treatment phase, to identify patients with advanced head and neck cancer, responding or not responding to initiated therapy. The tumour metabolic rate of glucose (MRgl) examined by 2-18FDG-PET was determined in 17 patients before and after the first weeks of either radiotherapy (16-35 Gy) or one course of combination chemotherapy. Metabolic values uptake values normalized to plasma activity integrals--were correlated to loco-regional outcome, as evaluated 5-6 weeks after completion of treatment. Initial low tumour MRgl (<20 micromol/min/100 g tissue), in primary lesions or regional metastases, predicted a local complete response. When a high initial tumour MRgl was found, the magnitude of the reduction of MRgl in the second PET examination might be an adjunct in predicting local tumour response.
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30.
  • Brun, Eva, et al. (författare)
  • FDG PET studies during treatment: Prediction of therapy outcome in head and neck squamous cell carcinoma.
  • 2002
  • Ingår i: Head and Neck. - : Wiley. - 1043-3074. ; 24:2, s. 127-135
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Positron emission tomography (PET) provides metabolic information of tissues in vivo. The purpose of this study was to assess the value of PET with 2-[(18) F] fluoro-2-deoxy-D-glucose (FDG) in prediction of therapy outcome (tumor response, survival, and locoregional control) in locally advanced HNSCC. METHODS: Between 1993 and 1999 47 patients underwent PET before (PET(1)) and after (PET(2)) 1 to 3 weeks of radical treatment with evaluation of metabolic rate (MR) and standardized uptake value (SUV) of FDG. All patients received radiotherapy, and 10 also received neoadjuvant chemotherapy. Median follow-up time was 3.3 years. RESULTS: Low and high MR FDG at PET(2), with median value as cutoff, was associated with complete remission in 96% and 62% (p =.007), with 5-year overall survival in 72% and 35% (p =.0042) and with local control in 96% and 55% (p =.002), respectively. CONCLUSIONS: FDG PET in the early phase of treatment of HNSCC is associated with tumor response, survival, and local control. Copyright 2002 John Wiley & Sons, Inc.
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31.
  • Cecchinato, Francesca, et al. (författare)
  • In vitro evaluation of human fetal osteoblast response to magnesium loaded mesoporous TiO2 coating.
  • 2014
  • Ingår i: Journal of Biomedical Materials Research - Part A. - : Wiley. - 1552-4965 .- 1549-3296. ; 102:11, s. 3862-3871
  • Tidskriftsartikel (refereegranskat)abstract
    • This work aimed to evaluate the in vitro response of Transfected Human Foetal Osteoblast (hFOB) cultured on a magnesium-loaded mesoporous TiO2 coating. The application of mesoporous films on titanium implant surfaces has shown very promising potential to enhance osseointegration. This type of coating has the ability to act as a framework to sustain bioactive agents and different drugs. Magnesium is the element that, after calcium, is the most frequently used to dope titanium implant surfaces, since it is crucial for protein formation, growth factor expression, and aids for bone mineral deposition on implant surfaces. Mesoporous TiO2 films with an average pore-size of 6 nm were produced by the evaporation-induced self-assembly method (EISA) and deposited onto titanium discs. Magnesium loading was performed by soaking the mesoporous TiO2 discs in a magnesium chloride solution. Surface characterization was conducted by SEM, XPS, optical interferometry, and AFM. Magnesium release profile was assessed at different time points using a Magnesium Detection kit. Cell morphology and spreading were observed with SEM. The cytoskeletal organization was stained with TRITC-conjugated Phalloidin and cell viability was evaluated through a mitochondrial colorimetric (MTT) assay. Furthermore, gene expression of bone markers and cell mineralization were analyzed by real time RT-PCR and alizarin-red staining, respectively. The surface chemical analysis by XPS revealed the successful adsorption of magnesium to the mesoporous coating. The AFM measurements revealed the presence of a nanostructured surface roughness. Osteoblasts viability and adhesion as well as the gene expression were unaffected by the addition of magnesium possibly due to its rapid burst release, however, were enhanced by the 3D nanostructure of the TiO2 layer.
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32.
  • Cecchinato, Francesca, et al. (författare)
  • Osteogenic potential of human adipose-derived stromal cells on 3-dimensional mesoporous TiO2 coating with magnesium impregnation
  • 2015
  • Ingår i: Materials Science and Engineering C. - : Elsevier BV. - 0928-4931 .- 1873-0191. ; 52, s. 225-234
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to evaluate the osteogenic response of human adipose-derived stromal cells (ADScs) to mesoporous titania (TiO2) coatings produced with evaporation-induced self-assembly method (EISA) and loaded with magnesium. Our emphasis with the magnesium release functionality was to modulate progenitor cell osteogenic differentiation under standard culture conditions. Osteogenic properties of the coatings were assessed for stromal cells by means of scanning electron microscopy (SEM) imaging, colorimetric mitochondrial viability assay (MTT), colorimetric alkaline phosphates activity (ALP) assay and real time RT-polymerase chain reaction (PCR). Using atomic force microscopy (AFM) it was shown that the surface expansion area (S-dr) was strongly enhanced by the presence of magnesium. From MTT results it was shown that ADSc viability was significantly increased on mesoporous surfaces compared to the non-porous one at a longer cell culture time. However, no differences were observed between the magnesium impregnated and non-impregnated surfaces. The alkaline phosphatase activity confirmed that ADSc started to differentiate into the osteogenic phenotype after 2 weeks of culturing. The gene expression profile at 2 weeks of cell growth showed that such coatings were capable to incorporate specific osteogenic markers inside their interconnected nano-pores and, at 3 weeks, ADSc differentiated into osteoblasts. Interestingly, magnesium significantly promoted the osteopontin gene expression, which is an essential gene for the early biomaterial-cell osteogenic interaction. (C) 2015 Elsevier B.V. All rights reserved.
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33.
  • Dictor, Michael, et al. (författare)
  • Abnormal cell cycle regulation in malignancy
  • 1999
  • Ingår i: American Journal of Clinical Pathology. - 0002-9173. ; 112:1 Suppl 1, s. 40-52
  • Forskningsöversikt (refereegranskat)abstract
    • The cell cycle consists of an initial growth phase (G1), DNA replication (S), a gap phase (G2), and mitosis (M), after which the cell may differentiate or enter the resting state (G0). The cycle is driven by a number of positive and negative regulatory phosphorylation and dephosphorylation events, involving protein kinases, protein phosphatases, cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors, that ultimately impinge on the activity of transcription factors. Unreplicated or damaged DNA blocks the progression of the cell cycle at checkpoints, including a late G1 checkpoint regulated by the dephosphorylated retinoblastoma protein and a late G2 checkpoint regulated by the phosphorylation of cyclin-dependent kinase 1 complexed with cyclin B. Many cell cycle regulator genes may be considered proto-oncogenes or tumor suppressor genes, and point mutations, amplifications, deletions, or rearrangements involving their loci, particularly those in the "RB pathway," are associated with various tumors. A number of molecular techniques may be used to detect genomic alterations or posttranscriptional modifications, but immunohistochemistry remains the most common method to determine expression levels of a regulatory protein. Multivariate analysis of the usefulness in prognosis has been applied most often for the general proliferation antigen Ki-67.
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34.
  • Ekblad, Lars, et al. (författare)
  • Anti- or pro-proliferation - Conditional options for TGF-α and cetuximab in head and neck squamous cell carcinoma.
  • 2015
  • Ingår i: Oral Oncology. - : Elsevier BV. - 1879-0593 .- 1368-8375. ; 51:1, s. 46-52
  • Tidskriftsartikel (refereegranskat)abstract
    • Cetuximab is an epidermal growth factor receptor (EGFR)-targeting drug that has shown effects in head and neck squamous cell carcinoma (HNSCC). The effects are, however, small and have mainly been proven in a subset of patients, and the cost-effectiveness has been questioned. For this reason, we need to know more about the basic mechanisms controlling the effect of EGFR signalling on tumour growth.
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35.
  • Ekblad, Lars, et al. (författare)
  • Cell-line-specific stimulation of tumor cell aggressiveness by wound healing factors - a central role for STAT3
  • 2013
  • Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 13, s. 33-
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Local recurrence is a major factor affecting survival after treatment for head and neck squamous cell carcinoma (HNSCC). It is possible that the normal processes involved in wound healing after surgical removal of a primary tumor can boost the regrowth of residual cancer cells, thereby contributing to the recurrent growth. In this work, we collected human wound fluids and used them to investigate the effect of wound healing factors on HNSCC cell lines in vitro. Methods: Wound fluids were collected from thyroidectomized patients diagnosed with benign disease and were included in assays of cell proliferation, migration, cell scattering, and invasion. The involvement of intracellular signaling pathways and membrane receptors were investigated by western blotting and the inclusion of specific inhibitors. Results: One out of four cell lines was greatly stimulated in proliferation, migration, cell scattering, and invasion by the addition of wound fluid as compared with addition of fetal bovine or human serum. These effects were accompanied by a sharp increase in activation of signal transducer and activator of transcription 3 (STAT3). Inhibition of STAT3 activation abolished the wound fluid response, showing that STAT3 plays an important role in the wound healing response. Several of the observed phenotypic changes were epithelial-to-mesenchymal transition (EMT)-like, but the appropriate changes were not seen in any of the EMT markers investigated. The involvement of c-Met or epidermal growth factor receptor family members was excluded, while the interleukin-6 receptor was found to be partly responsible for the activation of STAT3. Conclusions: In conclusion, we found cell-line-specific effects of wound healing factors on HNSCC, setting the stage for therapy development and predictive opportunities.
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36.
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37.
  • Evans Axelsson, Susan, et al. (författare)
  • Targeting free prostate-specific antigen for in vivo imaging of prostate cancer using a monoclonal antibody specific for unique epitopes accessible on free prostate-specific antigen alone
  • 2012
  • Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 27:4, s. 243-251
  • Tidskriftsartikel (refereegranskat)abstract
    • This study investigated the feasibility of targeting the free, unbound forms of prostate-specific antigen (fPSA) for in vivo imaging of prostate adenocarcinomas (PCa), as PSA is produced and secreted at abundance during every clinical stage and grade of PCa, including castration-resistant disease. We injected 125I-labeled monoclonal antibody PSA30 (specific for an epitope uniquely accessible on fPSA alone) intravenously in male nude mice carrying subcutaneous xenografts of LNCaP tumors (n=36). Mice were sacrificed over a time course from 4 hours to 13 days after injecting 125I-labeled PSA30. Tissue uptake of 125I-PSA30 at 48 and 168 hours after intravenous injection was compared with two clinically used positron emission tomography radiopharmaceuticals, 18F-fluoro-deoxy-glucose (18F-FDG) or 18F-choline, in cryosections using Digital AutoRadiography (DAR) and also compared with immunohistochemical staining of PSA and histopathology. On DAR, the areas with high 125I-PSA30 uptake corresponded mainly to morphologically intact and PSA-producing LNCaP cells, but did not associate with the areas of high uptake of either 18F-FDG or 18F-choline. Biodistribution of 125I-PSA30 measured in dissected organs ex vivo during 4 to 312 hours after intravenous injection demonstrated maximum selective tumor uptake 24–48 hours after antibody injection. Our data showed selective uptake in vivo of a monoclonal antibody highly specific for fPSA in LNCaP cells. Hence, in vivo imaging of fPSA may be feasible with putative usefulness in disseminated PCa.
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38.
  • Faust, Helena, et al. (författare)
  • Prevalence of human papillomavirus types, viral load and physical status of HPV16 in head and neck squamous cell carcinoma from the South Swedish Health Care Region
  • 2016
  • Ingår i: Journal of General Virology. - : Microbiology Society. - 0022-1317 .- 1465-2099. ; 97:11, s. 2949-2956
  • Tidskriftsartikel (refereegranskat)abstract
    • Incidence of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is rising in several countries. Intriguingly, large variations of HPV16 viral load and different proportions of the physical viral status among HNSCC have been reported. We analysed fresh biopsies of 275 HNSCC patients from the South Swedish Health Care Region for HPV types with modified general primer PCR and Luminex. Seventy-eight HPV16-positive HNSCC cases were further investigated for viral DNA load and physical status using quantitative PCR for HPV E2 and E7 genes. Presence of intact E2 gene, as a surrogate marker for episomal HPV, was investigated with conventional PCR. Fifteen different HPV types were detected in HNSCC cases and HPV16 was present in 74% of the HPV-positive cases. HPV was detected in 65% (92/141) and 11% (15/134) of oropharyngeal and non-oropharyngeal carcinomas, respectively (P<0.0001). HPV was detected in 73% (75/103) of tonsillar carcinomas. The median load of HPV16 was 13 copies cell-1 (range 0.003–1080). Among HPV16-positive patients with oropharyngeal carcinoma, metastases to regional lymph nodes were observed in 100% (17/17) and 68% (40/58) for those with <1 HPV16 copy cell-1 and >1 HPV16 copy Cell-1, respectively (P=0.007). Among HPV16 cases, purely integrated HPV16 was found in 6%, whereas entirely episomal and mixed virus was detected in 51 and 42% of cases, respectively. Conclusively, HPV16 viral DNA load demonstrated a large diversity among HNSCCs. Although integration of HPV16 is common (48%), the episomal HPV16 is salient (93%) among HPV16 HNSCCs. In addition, low amount of HPV16 was associated with lymph node metastases among oropharyngeal carcinomas.
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39.
  • Forslund, Ola, et al. (författare)
  • A novel human in vitro papillomavirus type 16 positive tonsil cancer cell line with high sensitivity to radiation and cisplatin
  • 2019
  • Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 19:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Human papillomavirus (HPV) is an established risk factor for oropharyngeal squamous cell carcinoma (OSCC). The aim was to establish cell lines from HPV-positive tonsil carcinomas to be used for treatment development. Methods: Fresh samples from 23 HPV-positive tonsil carcinomas were cultivated in vitro. The established cell line was analyzed for viral characteristics, cell karyotype, TP53 status, and growth capabilities in nude mice. In vitro studies of sensitivities to radiation, cisplatin and cetuximab were performed. Results: After 19 months (eight passages), one cell line, LU-HNSCC-26, was established in vitro and also grew as xenografts. The tumor was from a 48 year old non-smoking man with non-keratinizing, p16 positive tonsil OSCC, stage T2N0M0 with HPV16. It contained 19.5 (CV% 3.7) HPV16 copies/cell (passage 8). The complete HPV16 genome sequence was obtained. Episomal HPV16 was present with an E2/E7 ratio of 1.1 (CV% 2.6). In addition, HPV16 mRNA specific for the intact E2 gene was detected. The viral expression manifested 1.0 (CV% 0.1) E7 mRNA copies per HPV16 genome. The karyotype was determined and the cell line demonstrated wild type TP53. The ID50 for radiation was 0.90 Gy and the IC50 for cisplatin was 0.99 μmol/L. The cell line was inhibited to a maximum of 18% by cetuximab. Conclusions: We established an in vitro tonsil carcinoma cell line containing episomal HPV16. This is an important step towards efficient treatment development.
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40.
  • Galli, Silvia, et al. (författare)
  • Local release of magnesium from mesoporous TiO2 coatings stimulates the peri-implant expression of osteogenic markers and improves osteoconductivity in vivo
  • 2014
  • Ingår i: Acta Biomaterialia. - : Elsevier. - 1742-7061 .- 1878-7568. ; 10:12, s. 5193-5201
  • Tidskriftsartikel (refereegranskat)abstract
    • Local release of Mg ions from titanium implant surfaces has been shown to enhance implant retention and integration. To clarify the biological events that lead to this positive outcome, threaded implants coated with mesoporous TiO2 thin films were loaded with Mg-ions and placed in the tibia of rabbits for 3 weeks, after surface characterization. Non-loaded mesoporous coated implants were used as controls. Peri-implant gene expression of a set of osteogenic and inflammatory assays was quantified by means of real-time quantitative polymerase chain reaction. The expression of three osteogenic markers (OC, RUNX-2 and IGF-1) was significantly more pronounced in the test specimens, suggesting that the release of Mg ions directly at the implant sites may stimulate an osteogenic environment. Furthermore, bone healing around implants was evaluated on histological slides and by diffraction-enhanced imaging (DEI), using synchrotron radiation. The histological analysis demonstrated new bone formation around all implants, without negative responses, with a significant increase in the number of threads filled with new bone for test surfaces. DEI analysis attested the high mineral content of the newly formed bone. Improved surface osteoconductivity and increased expression of genes involved in the bone regeneration were found for magnesium-incorporation of mesoporous TiO2 coatings.
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41.
  • Galli, Silvia, et al. (författare)
  • Magnesium release from mesoporous carriers on endosseus implants does not influence bone maturation at 6 weeks in rabbit bone
  • 2017
  • Ingår i: Journal of Biomedical Materials Research - Part B Applied Biomaterials. - : Wiley. - 1552-4981 .- 1552-4973. ; 105:7, s. 2118-2125
  • Tidskriftsartikel (refereegranskat)abstract
    • ObjectivesThe release of magnesium ions (Mg2+) from titanium surfaces has been shown to boost the initial biological response of peri-implant bone and to increase the biomechanical strength of osseointegration. The objective of the present paper was to investigate if the initial improvement in osseointegration would influence the bone remodeling also during the maturation stage of bone healing. Methods: Titanium implants were coated with mesoporous titania layers and either loaded with Mg2+ (test group) or left untreated (control group). The implants were inserted in the tibiae of 10 New Zealand White rabbits. Osseointegration was assessed after 6 weeks by means of biomechanical testing (RTQ), non-decalcified histology and histomorphometry (BIC%, BA%, NBA%). The expression of genes involved in the bone formation and remodeling was quantified using qPCR. Results: Mg2+ releasing mesoporous titania coatings showed, on average, higher removal torques and histomorphometrical outcomes (RTQ: 17.2 Ncm vs. 15 Ncm; BIC: 38.8% vs. 32.1%; BA%: 71.6% vs. 64%; NBA% 62.5% vs. 54% for the tests vs the controls); however, the differences were not statistically significant. Three osteogenic markers, osteocalcin (OC), collagen 1 alpha 1 (COL1A1), and alkalin phosphatase (ALPL), were respectively 2-fold, 1.53-fold, and 1.13-fold up-regulated in the control group compared to the test. The expression of COL1A1 was particularly high in both groups, while the biomarkers for remodeling and inflammation showed a low expression in both groups. Significance: The results suggested that the initial enhancement in osseointegration induced by magnesium release from mesoporous titania coatings has no detrimental effects during bone maturation.
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42.
  • Galli, Silvia, et al. (författare)
  • Magnesium release from mesoporous carriers on endosseus implants does not influence bone maturation at 6 weeks in rabbit bone.
  • 2017
  • Ingår i: Journal of Biomedical Materials Research. Part B - Applied biomaterials. - : Wiley. - 1552-4973 .- 1552-4981. ; 105:7, s. 2118-2125
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: The release of magnesium ions (Mg2+ ) from titanium surfaces has been shown to boost the initial biological response of peri-implant bone and to increase the biomechanical strength of osseointegration. The objective of the present paper was to investigate if the initial improvement in osseointegration would influence the bone remodeling also during the maturation stage of bone healing.METHODS: Titanium implants were coated with mesoporous titania layers and either loaded with Mg2+ (test group) or left untreated (control group). The implants were inserted in the tibiae of 10 New Zealand White rabbits. Osseointegration was assessed after 6 weeks by means of biomechanical testing (RTQ), non-decalcified histology and histomorphometry (BIC%, BA%, NBA%). The expression of genes involved in the bone formation and remodeling was quantified using qPCR.RESULTS: Mg2+ releasing mesoporous titania coatings showed, on average, higher removal torques and histomorphometrical outcomes (RTQ: 17.2 Ncm vs. 15 Ncm; BIC: 38.8% vs. 32.1%; BA%: 71.6% vs. 64%; NBA% 62.5% vs. 54% for the tests vs the controls); however, the differences were not statistically significant. Three osteogenic markers, osteocalcin (OC), collagen 1 alpha 1 (COL1A1), and alkalin phosphatase (ALPL), were respectively 2-fold, 1.53-fold, and 1.13-fold up-regulated in the control group compared to the test. The expression of COL1A1 was particularly high in both groups, while the biomarkers for remodeling and inflammation showed a low expression in both groups.SIGNIFICANCE: The results suggested that the initial enhancement in osseointegration induced by magnesium release from mesoporous titania coatings has no detrimental effects during bone maturation. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2118-2125, 2017.
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43.
  • Galli, Silvia, et al. (författare)
  • Osteoconductive potential of mesoporous titania implant surfaces loaded with magnesium : an experimental study in the rabbit
  • 2015
  • Ingår i: Clinical Implant Dentistry and Related Research. - : John Wiley & Sons. - 1523-0899 .- 1708-8208. ; 17:6, s. 1048-1059
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Mesoporous coatings enable incorporation of functional substances and sustainedly release them at the implant site. One bioactive substance that can be incorporated in mesoporous is magnesium, which is strongly involved in bone metabolism and in osteoblast interaction. Purpose: The aim of this experimental study was to evaluate the effect of incorporation of magnesium into mesoporous coatings of oral implants on early stages of osseointegration. Material and Methods: Titanium implants were coated with thin films of mesoporous TiO2 having pore diameters of 6 nm and were loaded with magnesium. The implant surfaces were extensively characterized by means of interferometry, atomic force microscopy, scanning electron microscopy, and energy-dispersive spectroscopy and then placed in the tibiae of 10 rabbits. After 3 weeks of healing, osseointegration was evaluated by means of removal torque testing and histology and histomorphometry. Results: Histological and biomechanical analyses revealed no side effects and successful osseointegration of the implants. The biomechanical evaluation evidenced a significant effect of magnesium doping on strengthening the implant-bone interface. Conclusions: A local release of magnesium from the implant surfaces enhances implant retention at the early stage of healing (3 weeks after implantation), which is highly desirable for early loading of the implant.
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44.
  • Galli, Silvia, et al. (författare)
  • The effect of magnesium on early osseointegration in osteoporotic bone : a histological and gene expression investigation
  • 2017
  • Ingår i: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 28:7, s. 2195-2205
  • Tidskriftsartikel (refereegranskat)abstract
    • Magnesium has a key role in osteoporosis and could enhance implant osseointegration in osteoporotic patients. Titanium implants impregnated with Mg ions were installed in the tibia of ovariectomized rats. The release of Mg induced a significant increase of bone formation and the expression of anabolic markers in the peri-implant bone. The success of endosseous implants is highly predictable in patients possessing normal bone status, but it may be impaired in patients with osteoporosis. Thus, the application of strategies that adjuvate implant healing in compromized sites is of great interest. Magnesium has a key role in osteoporosis prevention and it is an interesting candidate for this purpose. In this study, the cellular and molecular effects of magnesium release from implants were investigated at the early healing stages of implant integration. Osteoporosis was induced in 24 female rats by means of ovariectomy and low-calcium diet. Titanium mini-screws were coated with mesoporous titania films and were loaded with magnesium (test group) or left as native (control group). The implants were inserted in the tibia and femur of the rats. One, 2 and 7 days after implantation, the implants were retrieved and histologically examined. In addition, expression of genes was evaluated in the peri-implant bone tissue at day 7 by means of quantitative polymerase chain reactions with pathway-oriented arrays. The histological evaluation revealed that new bone formation started already during the first week of healing for both groups. However, around the test implants, new bone was significantly more abundant and spread along a larger surface of the implants. In addition, the release of magnesium induced a significantly higher expression of BMP6. These results provide evidence that the release of magnesium promoted rapid bone formation and the activation of osteogenic signals in the vicinity of implants placed in osteoporotic bone.
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45.
  • Gretarsson, Sigurdur, et al. (författare)
  • Substantial intrinsic variability in chemoradiosensitivity of newly established anaplastic thyroid cancer cell-lines
  • 2020
  • Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 140:4, s. 337-343
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Well characterized human cell lines are needed for preclinical treatment studies of anaplastic thyroid cancer (ATC).Aims/Objectives: The aim was to establish, verify and characterize a panel of ATC cell lines.Material and methods: Cell lines were established from ATC fine-needle aspiration biopsies and characterized genetically and functionally regarding treatment sensitivities.Results: Eight cell lines were established in vitro and the anaplastic thyroid origin was verified. Seven of the cell lines were also grown as xenografts. The cell lines harboured complex karyotypes with modal numbers in hyperdiploid to near-pentaploid range. Five were TP53 mutated and three carried the BRAFV600E mutation. None had rearrangements of RET. For doxorubicin, IC50 ranged from 0.42 to 46 nmol/L and for paclitaxel from 1.6 to 196 nmol/L. Radiation sensitivity varied between 2.6 and 6.3 Gy. Two of the BRAF mutated cell lines displayed high sensitivity to vemurafenib, while the third was similar to the wild-type ones.Conclusions and significance: We describe a series of new ATC cell lines demonstrating large heterogeneity in the response to cytostatic drugs and the BRAF inhibitor vemurafenib. The observations are relevant to future attempts to optimize treatment combinations for ATC.
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46.
  • Hansson, Bengt Göran, et al. (författare)
  • Strong Association between Infection With Human Papillomavirus and Oral and Oropharyngeal Squamous Cell Carcinoma : A Population-based Case-control Study in Southern Sweden
  • 2005
  • Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 125:12, s. 1337-1344
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • CONCLUSIONS: The results of this study demonstrate a strong association between infection with high-risk types of human papillomavirus (HPV) and oral and oropharyngeal squamous cell carcinoma (OOSCC), suggesting that high-risk HPV types play a key role in car-cinogenesis. The estimated proportion of OOSCC cases attributable to HPV infection was 35%. OBJECTIVE: HPV appears to have an aetiological role in OOSCC, despite the fact that the reported prevalences of HPV in both OOSCC patients and healthy individuals have varied widely. We aimed to investigate the presence and spectrum of both high- and low-risk HPVs in all consecutive cases of OOSCC in a Swedish healthcare region over a 3-year period and in population-based, matched healthy controls. MATERIAL AND METHODS: A total of 131 patients with OOSCC were studied. Samples taken from the surface of the tumour and from the tonsillar fossa using cotton-tipped swabs were investigated, together with exfoliated cells collected using a mouthwash. Tonsillar fossa and mouthwash specimens were collected in the same way from 320 matched controls. All samples were tested for HPV DNA by nested polymerase chain reaction using the primer pairs MY09/MY11 and GP5 + /GP6+, and in positive cases the HPV type was determined by DNA sequencing. RESULTS: Infection with high-risk HPV was shown to be a strong risk factor for OOSCC (OR = 63; 95% CI 14-480). Forty-seven (36%) of the cancer patients had > or =1 specimen that was positive for a high-risk HPV type (81% of which were HPV 16), while only 3 (0.94%) of the controls were positive for a high-risk HPV type. Seven (5.3%) of the cancer patients and 13 (4.1%) of the controls were positive for any of the mucosal, mucocutaneous or cutaneous low-risk HPV types.
  •  
47.
  • Henriksson, Eva, et al. (författare)
  • 2-deoxy-2-[F-18]fluoro-D-glucose uptake and correlation to intratumoral heterogeneity
  • 2007
  • Ingår i: Anticancer research. - 1791-7530. ; 27:4B, s. 2155-2159
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to investigate the pattern of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) uptake in relation to the intratumoral histopathological appearance. Materials and Methods: Intratumoral distribution of FDG in nude mice with xenografted tumours originating from an established head and neck squamous cell carcinoma was studied. FDG uptake and the con-elation to histopathological appearance was evaluated in four separate quarters of each tumour. Results: Variations in FDG uptake correlating to the presence of tumour cells was demonstrated. Quarters containing more than 50% tumour cells showed a significantly higher FDG uptake (p=0.028) than quarters with more stromal tissue and necrosis. Conclusion: This Study shows that the heterogenic FDG uptake within a tumour correlates to histopathological findings and that the variable appearance of tracer uptake on the PET scan depends on distribution of different tissue components in the tumour. This intratumoral heterogeneity calls for caution when evaluating a PET scan where median values of larger areas will be misguiding and thus small areas with high uptake should be regarded as the regions of interest.
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48.
  • Henriksson, Eva, et al. (författare)
  • Comparison of cisplatin sensitivity and the 18F fluoro-2-deoxy 2 glucose uptake with proliferation parameters and gene expression in squamous cell carcinoma cell lines of the head and neck
  • 2009
  • Ingår i: Journal of Experimental & Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 28
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The survival of patients with locally advanced head and neck cancer is still poor, with 5-year survival rates of 24-35%. The identification of prognostic and predictive markers at the molecular and cellular level could make it possible to find new therapeutic targets and provide "taylor made" treatments. Established cell lines of human squamous cell carcinoma (HNSCC) are valuable models for identifying such markers. The aim of this study was to establish and characterize a series of cell lines and to compare the cisplatin sensitivity and 18F fluoro-2 deoxy 2 glucose (18F-FDG) uptake of these cell lines with other cellular characteristics, such as proliferation parameters and TP53 and CCND1 status. Methods: Explant cultures of fresh tumour tissue were cultivated, and six new permanent cell lines were established from 18 HNSCC cases. Successfully grown cell lines were analysed regarding clinical parameters, histological grade, karyotype, DNA ploidy, and index and S-phase fraction (Spf). The cell lines were further characterized with regard to their uptake of 18F-FDG, their sensitivity to cisplatin, as measured by a viability test ( crystal violet), and their TP53 and CCND1 status, by fluorescence in situ hybridization (FISH), polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) with DNA sequencing and, for cyclin D1, by immunohistochemistry. Results: Patients with tumours that could be cultured in vitro had shorter disease-free periods and overall survival time than those whose tumours did not grow in vitro, when analysed with the Kaplan-Meier method and the log-rank test. Their tumours also showed more complex karyotypes than tumours from which cell lines could not be established. No correlation was found between TP53 or CCND1 status and 18F-FDG uptake or cisplatin sensitivity. However, there was an inverse correlation between tumour cell doubling time and 18F-FDG uptake. Conclusion: In vitro growth of HNSCC cells seem to be an independent prognostic factor, with cell lines being more readily established from aggressive tumours, a phenomenon more dependent on the molecular genetic characteristics of the tumour cells than on tumour location or TNM status.
  •  
49.
  •  
50.
  • Ivanoff, Carl-Johan, et al. (författare)
  • Histologic evaluation of bone response to oxidized and turned titanium micro-implants in human jawbone
  • 2003
  • Ingår i: International Journal of Oral & Maxillofacial Implants. - 0882-2786 .- 1942-4434. ; 18:3, s. 341-348
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: To evaluate the human bone tissue response to 2 surfaces (oxidized or turned) on commercially available titanium implants. MATERIALS AND METHODS: Screw-type turned (control) and oxidized (test) micro-implants were manufactured in the same manner as commercially available turned and oxidized (TiUnite, Brånemark System) implants. The thickness of the oxide layer of the test implants was on average 10 microm, corresponding to the oxide thickness of the apical part of the TiUnite implant. Twenty patients received 1 test and 1 control micro-implant each during implant surgery. Before placement, the surface topography of the implants was characterized with an optical confocal laser profilometer. After a mean healing period of 6.6 months in the maxilla and 3.5 months in the mandible, the micro-implants and surrounding tissue were removed with a trephine bur. Histologic sections were produced, and the specimens were analyzed histomorphometrically. RESULTS: Surface roughness and enlargement were greater for the oxidized implants than for the turned implants. All micro-implants, except for 2 controls, were found to be clinically stable at the time of retrieval. Histomorphometric evaluation demonstrated significantly higher bone-to-implant contact for the oxidized implants, whether placed in the maxilla or in the mandible. Significantly more bone was found inside the threaded area for the oxidized implants placed in the mandible and maxilla, but there was no difference between implants with regard to position (maxilla or mandible). DISCUSSION: The stronger bone response to the oxidized implants may have contributed to the fact that 2 control implants but no test implants were lost. The reason for these findings may depend on one or multiple differences of the surfaces between test and control implants: (1) the thicker oxide layer itself, (2) increased surface roughness, (3) different surface morphology in terms of porosity, or (4) change in crystal structure. CONCLUSION: The present histologic study in human jawbone demonstrated a significantly higher bone response for anodic oxidized titanium implants than for implants with a turned surface.
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