| 1. |
- Andersson, Emma K, 1978-, et al.
(författare)
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Small molecule screening using a whole cell viral replication reporter gene assay identifies 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid as a novel anti-adenoviral compound
- 2010
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American society for microbiology. - 0066-4804 .- 1098-6596. ; 54:9, s. 3871-3877
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Tidskriftsartikel (refereegranskat)abstract
- Adenovirus infections are widespread in society and are occasionally associated with severe, but rarely with life-threatening, disease in otherwise healthy individuals. In contrast, adenovirus infections present a real threat to immunocompromised individuals and can result in disseminated and fatal disease. The number of patients undergoing immunosuppressive therapy for solid organ or hematopoietic stem cell transplantation is steadily increasing, as is the number of AIDS patients, and this makes the problem of adenovirus infections even more urgent to solve. There is no formally approved treatment of adenovirus infections today, and existing antiviral agents evaluated for their anti-adenoviral effect give inconsistent results. We have developed a whole cell-based assay for high-throughput screening of potential anti-adenoviral compounds. The assay is unique in that it is based on a replication competent adenovirus type 11p GFP-expressing vector (RCAd11pGFP). This allows measurement of fluorescence changes as a direct result of RCAd11pGFP genome expression. Using this assay, we have screened 9,800 commercially available small organic compounds. Initially, we observed approximately 400 compounds that inhibited adenovirus expression in vitro by >/= 80% but only 24 were later confirmed as dose-dependent inhibitors of adenovirus. One compound in particular, 2-[[2-(benzoylamino)benzoyl]amino]-benzoic acid, turned out to be a potent inhibitor of adenovirus replication.
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| 2. |
- Holm, Anna, et al.
(författare)
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Absence de papillomavirus humain à risque élevé dans le papillome inversé naso-sinusien p16 positif : [Absence of high-risk human papillomavirus in p16 positive inverted sinonasal papilloma]
- 2020
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Ingår i: Annales Francaises d'Oto-Rhino-Laryngologie et de Pathologie Cervico-Faciale. - : Elsevier. - 1879-7261. ; 137:3, s. 186-191
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Tidskriftsartikel (refereegranskat)abstract
- Le papillome inversé naso-sinusien (PINS) est une tumeur relativement rare dont l’étiologie est mal connue. Elle se caractérise par une agressivité locale et un fort potentiel de récidive en dépit d’une histologie bénigne.Objectif: L’objectif de cette étude était d’identifier la présence du papillomavirus humain (HPV) et de son marqueur de substitution, la protéine p16, dans des prélèvements tissulaires de PINS issus d’une cohorte régionale.Matériels et méthodes: À partir de notre cohorte régionale de 88 patients atteints de PINS traités entre 1984 et 2014, 54 sujets ont été sélectionnés et inclus dans cette étude. La technologie PCR a été réalisée sur 53 prélèvements et la coloration immunohistochimique pour recherche de p16 a été réalisée sur 54 prélèvements. L’ADN a été extrait après confirmation histopathologique du PINS. Un génotypage pour 13 types de HPV à risque élevé, 5 types de HPV à risque oncogène et 6 types de HPV à faible risque a été réalisé à l’aide du test de dépistage HPV PapilloCheck®.Résultats: L’analyse HPV a été réalisable sur 38 des 53 prélèvements. Sur ces 38 prélèvements, seuls 2 étaient positifs pour HPV 11. L’analyse immunohistochimique a montré que p16 était présent dans l’épithélium de tous les prélèvements, et dans les régions papillomateuses de 37 prélèvements.Conclusion: Étant donné que seuls 2 sur 38 PINS étaient positifs pour HPV (type 11) et que, dans le même temps, p16 était positif dans l’épithélium de tous les prélèvements et dans 37 des 38 régions papillomateuses, nous avons conclu que p16 ne peut pas être utilisé comme marqueur de substitution pour l’infection HPV à risque élevé dans le PINS. Nous préparons actuellement une étude multicentrique prospective afin d’augmenter la puissance de l’étude et de pouvoir mieux évaluer les implications cliniques de HPV et de p16 dans le PINS.
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| 3. |
- Holm, Anna, et al.
(författare)
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Absence of high-risk human papilloma virus in p16 positive inverted sinonasal papilloma
- 2020
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Ingår i: European Annals of Otorhinolaryngology, Head and Neck Diseases. - : Elsevier Masson SAS. - 1879-7296 .- 1879-730X. ; 137:3, s. 201-206
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Sinonasal inverted papilloma (SIP) is a relatively rare disease, and its etiology is not understood. It is characterized by locally aggressive growth and a strong tendency to recur despite its benign histology.Aims: The aim of this study was to identify the presence of human papilloma virus (HPV) and its surrogate marker p16 in SIP tissue samples from a regional cohort.Material and methods: Subjects were identified from our regional center cohort of 88 SIP patients treated between 1984–2014. From these subjects, 54 were included in this study. Of these, 53 biopsies were analyzed with PCR, and 54 samples were immunohistochemically stained for p16. DNA was extracted from histopathologically verified SIP. Genotype screening for 13 high risk-, 5 oncogenic and 6 low risk HPV types was performed using the PapilloCheck® HPV-screening test.Results: HPV analysis was successful for 38 of 53 samples. Of the 38 successfully analyzed samples, only 2 samples were positive for HPV 11. Notably, p16 was present in the epithelia in all samples, and in the papilloma lesions in 37 samples.Conclusion: Since only 2 out of 38 SIPs were positive for HPV (type 11), and at the same time p16 was positive in epithelia in all samples and in 37 of 38 papilloma lesions of the samples, it is concluded that p16 cannot be used as a surrogate marker for high-risk HPV-infection in SIP. We are currently planning a prospective, multicenter study in order to increase the study power and in order to be able to better evaluate the clinical implications of HPV-and p16 in SIP.
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| 4. |
- Holm, Anna, et al.
(författare)
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Mapping of Human Papilloma Virus, p16, and Epstein-Barr Virusin Non-Malignant Tonsillar Disease
- 2019
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Ingår i: Laryngoscope Investigative Otolaryngology (LIO). - : Wiley-Blackwell. - 2378-8038. ; 4:3, s. 285-291
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Due to their location in the entrance of the aero‐digestive tract, tonsils are steadily exposed to viruses. Human papilloma virus (HPV) and Epstein‐Barr virus (EBV) are two potentially oncogenic viruses that tonsils encounter. The incidence of HPV positive tonsillar cancer is on the rise and it is unknown when infection with HPV occurs.Aim: To investigate if tonsils are infected with HPV and EBV, to study the co‐expression of HPV and its surrogate marker p16, and to evaluate the number of EBV positive cells in benign tonsillar disease.Materials and Methods: Tonsils from 40 patients in a university hospital were removed due to hypertrophy, chronic or recurrent infection. These were analyzed for presence of HPV, its surrogate marker p16, and EBV. HPV was studied using PapilloCheck (a PCR method), while p16 was identified in epithelial and lymphoid tissue with immunohistochemistry and EBV using EBER‐ISH (Epstein‐Barr encoding region–in situ hybridization).Results: HPV was not detected, and p16 was present at low numbers in all epithelial samples as well as in 92.5% of the lymphoid tonsillar samples. At least one EBER‐positive cell was seen in 65% of cases. Larger numbers of EBER‐expressing cells were only seen in two cases.Conclusion: These findings demonstrate that EBV and HPV infect tonsils independently, but further studies are warranted to confirm their infectious relationship.Level of Evidence: Cross‐sectional study
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| 5. |
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| 6. |
- Schindele, Alexandra, et al.
(författare)
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Low Epstein-Barr virus count in sinonasal inverted papilloma
- 2020
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Ingår i: Acta Oto-Laryngologica. - : Taylor & Francis. - 0001-6489 .- 1651-2251. ; 140:5, s. 413-417
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sinonasal inverted papilloma (SIP) is a benign tumour originating from the sinonasal mucosa showing an extensive growth pattern, a high risk of recurrence and a 5–10% risk to malignify. Epstein-Barr virus (EBV) is an oncogenic herpesvirus which infects most individuals via the saliva eliciting a latent infection. Previous studies have been reporting variable data on EBV in SIP, and there is no present appreciation regarding the association between these.Aims/objectives: The aims were to investigate the presence and count of EBV in SIP and map the viral distribution in the epithelium versus the connective tissue.Material and method: Fifty-three SIP patients were identified in the Pathology Department register at the University Hospital of Umeå. The biopsies were analysed with Epstein-Barr Encoded Region (EBER) in situ hybridization. EBER-positive cells were counted in the epithelium and connective tissue.Results: We found EBER-stained cells in 30% of the cases, where 19% of these had an abundance of stained cells, and the rest showed a low count.Conclusions/significance: These findings demonstrate a low EBV count in SIP. EBV is less likely to be a causative agent in the formation of SIP, or its malignant transformation.
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| 7. |
- Schindele, Alexandra, et al.
(författare)
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Mapping human papillomavirus, Epstein–Barr virus, cytomegalovirus, adenovirus, and p16 in laryngeal cancer
- 2022
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Ingår i: Discover Oncology. - : Springer. - 2730-6011. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Apart from tobacco and alcohol, viral infections are proposed as risk factors for laryngeal cancer. The occurrence of oncogenic viruses including human papilloma virus (HPV) and Epstein–Barr virus (EBV), in laryngeal squamous cell carcinoma (LSCC) varies in the world. Carcinogenesis is a multi-step process, and the role of viruses in LSCC progression has not been clarified. We aimed to analyze the presence and co-expression of HPV, EBV, human cytomegalovirus (HCMV) and human adenovirus (HAdV) in LSCC. We also investigated if p16 can act as surrogate marker for HPV in LSCC.Methods: Combined PCR/microarrays (PapilloCheck®) were used for detection and genotyping of HPV DNA, real-time PCR for EBV, HCMV and HAdV DNA detection, and EBER in situ hybridization (EBER-ISH) for EBV detection in tissue from 78 LSCC patients. Additionally, we analyzed p16 expression with immunohistochemistry.Results: Thirty-three percent (26/78) of LSCC tumor samples were EBV positive, 9% (7/78) HCMV positive and 4% (3/78) HAdV positive. Due to DNA fragmentation, 45 samples could not be analyzed with PapilloCheck®; 9% of the remaining (3/33) were high-risk HPV16 positive and also over-expressed p16. A total of 14% (11/78) of the samples over-expressed p16.Conclusion: These findings present a mapping of HPV, EBV, HCMV and HAdV, including the HPV surrogate marker p16, in LSCC in this cohort. Except for EBV, which was detected in a third of the samples, data show viral infection to be uncommon, and that p16 does not appear to be a specific surrogate marker for high-risk HPV infection in LSCC.
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| 8. |
- Schindele, Alexandra, 1967-
(författare)
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Mapping viruses in non-malignant tonsils, nasal polyps, sinonasal inverted papilloma and laryngeal cancer
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The upper respiratory tract is exposed to viruses, which can lead to infection and cancer development. We chose to study common and/or chronic diseases along with common and cancer related viruses in the upper airway. High-risk human papillomavirus (HPV) causes cancer in tonsils and base of tongue, and Epstein-Barr virus (EBV) in the nasopharynx. p16 is used as a site-specific tumor marker for HPV. Human cytomegalovirus (HCMV) and human adenovirus (HAdV) are proposed to be oncomodulatory. It is unclear what significance these viruses have in benign tonsillar disease, chronic rhinosinusitis with nasal polyps (CRSwNP), sinonasal inverted papillomas (SIP) and laryngeal squamous cell carcinoma (LSCC). If virus is identified, it could make possible the use of current vaccines in prevention and treatment, as well as protection of healthcare providers.Material and Methods: We analyzed 40 benign tonsils, 45 paired nasal polyp and healthy nasal mucosa samples, 53 SIP and 78 LSCC samples. We used PCR/microarrays (PapilloCheck®) for HPV detection and genotyping, immunohistochemistry (IHC) for p16 expression and real-time PCR for EBV, HCMV and HAdV detection. Additionally, Epstein-Barr encoding region (EBER) in situ hybridization (ISH) was used for EBV localization and count.Results: HPV and p16 were not co-expressed, and p16 levels were low in benign tonsils, nasal polyps, and paired controls. Also, 9% of LSCC samples were high-risk HPV 16 positive and over-expressed p16.EBV-positive cells were detected in 65% of the tonsils, nasal polyps (36%) versus controls (12%), 30% of SIP cases and 33% of LSCC samples.Conclusions: EBV is commonly identified in benign tonsils, nasal polyps, SIP and LSCC, when using sensitive and robust detection methods. At the same time, viral infection with HPV, HCMV or HAdV appears to be uncommon in these conditions. p16 does not emerge as a reliable marker for HPV infection in LSCC.
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| 9. |
- Strand, Mårten, et al.
(författare)
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2-[4,5-Difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, an antiviral compound with activity against acyclovir-resistant isolates of herpes simplex virus type 1 and 2
- 2012
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society Microbiology. - 0066-4804 .- 1098-6596. ; 56:11, s. 5735-5743
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Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex viruses (HSV-1 and HSV-2) are responsible for life-long latent infections in humans, with periods of viral reactivation associated with recurring ulcerations in the orofacial and genital tract. In immunosuppressed patients and neonates, HSV infections are associated with severe morbidity, and in some cases even mortality. Today, acyclovir is the standard therapy for management of HSV infections. However, the need for novel antiviral agents is apparent since HSV isolates resistant to acyclovir therapy are frequently isolated in immunosuppressed patients. In this study, we assessed the anti-HSV activity of the anti-adenoviral compounds 2-[2-(2-benzoylamino)-benzoylamino]benzoic acid, (Benzavir-1) and 2-[4,5-difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, (Benzavir-2) on HSV-1 and HSV-2. Both compounds were active against both viruses. Importantly, Benzavir-2 had similar potency to acyclovir against both HSV types and it was active against clinical acyclovir-resistant HSV isolates.
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| 10. |
- Welén, Karin, 1970, et al.
(författare)
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A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome : No Evidence of Benefit, Supported by Epidemiology and In Vitro Data
- 2022
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Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 81:3, s. 285-293
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Tidskriftsartikel (refereegranskat)abstract
- Background: Men are more severely affected by COVID-19. Testosterone may influence SARS-CoV-2 infection and the immune response.Objective: To clinically, epidemiologically, and experimentally evaluate the effect of antiandrogens on SARS-CoV-2 infection.Designs, settings, and participants: A randomized phase 2 clinical trial (COVIDENZA) enrolled 42 hospitalized COVID-19 patients before safety evaluation. We also conducted a population-based retrospective study of 7894 SARS-CoV-2–positive prostate cancer patients and an experimental study using an air-liquid interface three-dimensional culture model of primary lung cells.Intervention: In COVIDENZA, patients were randomized 2:1 to 5 d of enzalutamide or standard of care.Outcome measurements: The primary outcomes in COVIDENZA were the time to mechanical ventilation or discharge from hospital. The population-based study investigated risk of hospitalization, intensive care, and death from COVID-19 after androgen inhibition.Results and limitations: Enzalutamide-treated patients required longer hospitalization (hazard ratio [HR] for discharge from hospital 0.43, 95% confidence interval [CI] 0.20–0.93) and the trial was terminated early. In the epidemiological study, no preventive effects were observed. The frail population of patients treated with androgen deprivation therapy (ADT) in combination with abiraterone acetate or enzalutamide had a higher risk of dying from COVID-19 (HR 2.51, 95% CI 1.52–4.16). In vitro data showed no effect of enzalutamide on virus replication. The epidemiological study has limitations that include residual confounders.Conclusions: The results do not support a therapeutic effect of enzalutamide or preventive effects of bicalutamide or ADT in COVID-19. Thus, these antiandrogens should not be used for hospitalized COVID-19 patients or as prevention for COVID-19. Further research on these therapeutics in this setting are not warranted.Patient summary: We studied whether inhibition of testosterone could diminish COVID-19 symptoms. We found no evidence of an effect in a clinical study or in epidemiological or experimental investigations. We conclude that androgen inhibition should not be used for prevention or treatment of COVID-19.
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