Probing real-world Central European population midfacial skeleton symmetry for maxillofacial surgery.

OBJECTIVES: Symmetry is essential for computer-aided surgical (CAS) procedures in oral and maxillofacial surgery (OMFS). A critical step for successful CAS is mirroring the unaffected side to create a template for the virtual reconstruction of the injured anatomical structure. The aim was to identify specific anatomical landmarks of the midfacial skeleton, to evaluate the symmetry in a group of the real-world Central European population, and to use these landmarks to assess midfacial symmetry in CT scans. MATERIAL AND METHODS: The retrospective cross-sectional study defined landmarks of the midface's bony contour using viscerocranial CT data. The distances of the skeletal landmarks (e.g., the frontozygomatic suture and temporozygomatic suture) of the left and right sides from the midline were measured and statistically compared. Midfacial symmetry for reference points was defined as a difference within 0 mm and their mean difference plus one standard deviation. RESULTS: We examined a total of 101 CT scans. 75% of our population shows symmetrical proportions of the midface. The means of the differences for the left and right sides ranged from 0.8 to 1.3 mm, averaging 1.1 ± 0.2 mm for all skeletal landmarks. The standard deviations ranged from 0.6 to 1.4 mm, with a computed mean of 0.9 ± 0.3 mm. CONCLUSION: We established a methodology to assess the symmetry of the bony midface. If the determined differences were equal to or lower than 2.5 mm in the mentioned midfacial skeletal landmarks, then the symmetry of the bony midface was considered present, and symmetry-based methods for CAS procedures are applicable. CLINICAL RELEVANCE: Many CAS procedures require facial symmetry. We provide an easy-to-apply method to probe for symmetry of the midface. The method may be used for population-based research, to check for proper reduction of fractures after reposition or to screen for symmetry prior to CAS planning.

The impact of resveratrol on skin wound healing, scarring, and aging.

Resveratrol is a well-known antioxidant that harbours many health beneficial properties. Multiple studies associated the antioxidant, anti-inflammatory, and cell protective effects of resveratrol. These diverse effects of resveratrol are also potentially involved in cutaneous wound healing, scarring, and (photo-)aging of the skin. Hence, this review highlighted the most relevant studies involving resveratrol in wound healing, scarring, and photo-aging of the skin. A systematic review was performed and the database PubMed was searched for suitable publications. Only original articles in English that investigated the effects of resveratrol in wound healing, scarring, and (photo-)aging of the skin were analysed. The literature search yielded a total of 826 studies, but only 41 studies met the inclusion criteria. The included studies showed promising results that resveratrol might be a feasible treatment approach to support wound healing, counteract excessive scarring, and even prevent photo-aging of the skin. Resveratrol represents an interesting and promising novel therapy regime but to confirm resveratrol-associated effects, more evidence based in vitro and in vivo studies are needed.

miRNAs as Regulators of the Early Local Response to Burn Injuries.

In burn injuries, risk factors and limitations to treatment success are difficult to assess clinically. However, local cellular responses are characterized by specific gene-expression patterns. MicroRNAs (miRNAs) are single-stranded, non-coding RNAs that regulate mRNA expression on a posttranscriptional level. Secreted through exosome-like vesicles (ELV), miRNAs are intracellular signalers and epigenetic regulators. To date, their role in the regulation of the early burn response remains unclear. Here, we identified 43 miRNAs as potential regulators of the early burn response through the bioinformatics analysis of an existing dataset. We used an established human ex vivo skin model of a deep partial-thickness burn to characterize ELVs and miRNAs in dermal interstitial fluid (dISF). Moreover, we identified miR-497-5p as stably downregulated in tissue and dISF in the early phase after a burn injury. MiR-218-5p and miR-212-3p were downregulated in dISF, but not in tissue. Target genes of the miRNAs were mainly upregulated in tissue post-burn. The altered levels of miRNAs in dISF of thermally injured skin mark them as new biomarker candidates for burn injuries. To our knowledge, this is the first study to report miRNAs altered in the dISF in the early phase of deep partial-thickness burns.

Evidence-based therapy in hypertrophic scars: An update of a systematic review.

Hypertrophic scars are still a major burden for numerous patients, especially after burns. Many treatment options are available; however, no evidence-based treatment protocol is available with recommendations mostly emerging from experience or lower quality studies. This review serves to discuss the currently available literature. A systematic review was performed and the databases PubMed and Web of Science were searched for suitable publications. Only original articles in English that dealt with the treatment of hypertrophic scars in living humans were analyzed. Further, studies with a level of evidence lower than 1 as defined by the American Society of Plastic Surgeons were excluded. After duplicate exclusion, 1638 studies were screened. A qualitative assessment yielded 163 articles eligible for evidence grading. Finally nine studies were included. Four of them used intralesional injections, four topical therapeutics and one assessed the efficacy of CO2 -laser. Intralesional triamcinolone + fluorouracil injections, and topical pressure and/or silicone therapy revealed significant improvements in terms of scar height, pliability, and pigmentation. This systematic review showed that still few high-quality studies exist to evaluate therapeutic means and their mechanisms for hypertrophic scars. Among these, most of them assessed the efficacy of intralesional triamcinolone injections with the same treatment protocol. Intralesional injection appears to be the best option for hypertrophic scar treatment. Future studies should focus on a possible optimization of infiltrative therapies, consistent end-point evaluations, adequate follow-up periods, and possibly intraindividual treatments.

Determination of the mesio-distal tooth width via 3D imaging techniques with and without ionizing radiation: CBCT, MSCT, and µCT versus MRI.

Objective: The purpose of this study was to estimate the feasibility and accuracy of mesio-distal width measurements with magnetic resonance imaging (MRI) in comparison to conventional 3D imaging techniques [multi-slice CT (MSCT), cone-beam CT (CBCT), and µCT]. The measured values of the tooth widths were compared to each other to estimate the amount of radiation necessary to enable orthodontic diagnostics. Material and Methods: Two pig skulls were measured with MSCT, CBCT, µCT, and MRI. Three different judges were asked to determine the mesio-distal tooth width of 14 teeth in 2D tomographic images and in 3D segmented images via a virtual ruler in every imaging dataset. Results: Approximately 19% (27/140) of all test points in 2D tomographic slice images and 12% (17/140) of the test points in 3D segmented images showed a significant difference (P ≤ 0.05). The largest significant difference was 1.6mm (P < 0.001). There were fewer significant differences in the measurement of the tooth germs than in erupted teeth. Conclusions: Measurement of tooth width by MRI seems to be clinically equivalent to the conventional techniques (CBCT and MSCT). Tooth germs are better illustrated than erupted teeth on MRI. Three-dimensional segmented images offer only a slight advantage over 2D tomographic slice images. MRI, which avoids radiation, is particularly appealing in adolescents if these data can be corroborated in further studies.

Combination treatment with oncolytic Vaccinia virus and cyclophosphamide results in synergistic antitumor effects in human lung adenocarcinoma bearing mice.

BACKGROUND: The capacity of the recombinant Vaccinia virus GLV-1h68 as a single agent to efficiently treat different human or canine cancers has been shown in several preclinical studies. Currently, its human safety and efficacy are investigated in phase I/II clinical trials. In this study we set out to evaluate the oncolytic activity of GLV-1h68 in the human lung adenocarcinoma cell line PC14PE6-RFP in cell cultures and analyzed the antitumor potency of a combined treatment strategy consisting of GLV-1h68 and cyclophosphamide (CPA) in a mouse model of PC14PE6-RFP lung adenocarcinoma. METHODS: PC14PE6-RFP cells were treated in cell culture with GLV-1h68. Viral replication and cell survival were determined by plaque assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, respectively. Subcutaneously implanted PC14PE6-RFP xenografts were treated by systemic injection of GLV-1h68, CPA or a combination of both. Tumor growth and viral biodistribution were monitored and immune-related antigen profiling of tumor lysates was performed. RESULTS: GLV-1h68 efficiently infected, replicated in and lysed human PC14PE6-RFP cells in cell cultures. PC14PE6-RFP tumors were efficiently colonized by GLV-1h68 leading to much delayed tumor growth in PC14PE6-RFP tumor-bearing nude mice. Combination treatment with GLV-1h68 and CPA significantly improved the antitumor efficacy of GLV-1h68 and led to an increased viral distribution within the tumors. Pro-inflammatory cytokines and chemokines were distinctly elevated in tumors of GLV-1h68-treated mice. Factors expressed by endothelial cells or present in the blood were decreased after combination treatment. A complete loss in the hemorrhagic phenotype of the PC14PE6-RFP tumors and a decrease in the number of blood vessels after combination treatment could be observed. CONCLUSIONS: CPA and GLV-1h68 have synergistic antitumor effects on PC14PE6-RFP xenografts. We strongly suppose that in the PC14PE6-RFP model the enhanced tumor growth inhibition achieved by combining GLV-1h68 with CPA is due to an effect on the vasculature rather than an immunosuppressive action of CPA. These results provide evidence to support further preclinical studies of combining GLV-1h68 and CPA in other highly angiogenic tumor models. Moreover, data presented here demonstrate that CPA can be combined successfully with GLV-1h68 based oncolytic virus therapy and therefore might be promising as combination therapy in human clinical trials.

Comparative study of image quality and radiation dose of cone beam and low-dose multislice computed tomography--an in-vitro investigation.

OBJECTIVES: The aim of this study was to evaluate the image quality and dose exposition of different cone-beam computed tomography (CBCT) and low-dose multislice spiral CT (MSCT) scanners. MATERIALS AND METHODS: A human cadaver head was examined with three MSCT and five CBCT scanners. The radiation dose was measured using an Alderson RANDO phantom. Standard protocols were used to obtain the CBCT data. For the MSCT devices, the tube voltage and tube current were modified to obtain acceptable image quality while keeping the radiation dose as low as possible. The image quality of MSCT and CBCT devices was determined by examining the enamel-dentin and dentin-pulp interface and the periodontal ligament space of 22 teeth. RESULTS: Inter- and intra-observer agreement was found for the different groups of raters. CBCT systems were rated superior to MSCT devices in terms of image quality for all dental structures. The differences in image quality among the studied CBCT and MSCT scanner groups did not turn out to be significant but were significant between CBCT and MSCT devices. The organ dose varied considerably between the different CBCT and MSCT devices. The differences concerning the organ dose were notably pronounced in the area of the eye lens. CONCLUSIONS: The tested devices exhibited significant differences with respect to the organ dose. The variance was particularly pronounced in the CBCT devices. With a dose exposition equal or lower than the CBCT, the image quality in the MSCT devices was judged to be significantly worse.

Unlocking longevity: the role of telomeres and its targeting interventions.

Average life expectancy has been steadily increasing in developed countries worldwide. These demographic changes are associated with an ever-growing social and economic strain to healthcare systems as well as society. The aging process typically manifests as a decline in physiological and cognitive functions, accompanied by a rise in chronic diseases. Consequently, strategies that both mitigate age-related diseases and promote healthy aging are urgently needed. Telomere attrition, characterized by the shortening of telomeres with each cell division, paradoxically serves as both a protective mechanism and a contributor to tissue degeneration and age-related ailments. Based on the essential role of telomere biology in aging, research efforts aim to develop approaches designed to counteract telomere attrition, aiming to delay or reduce age-related diseases. In this review, telomere biology and its role in aging and age-related diseases is summarized along with recent approaches to interfere with telomere shortening aiming at well- and healthy-aging as well as longevity. As aging research enters a new era, this review emphasizes telomere-targeting therapeutics, including telomerase activators and tankyrase inhibitors, while also exploring the effects of antioxidative and anti-inflammatory agents, along with indirectly related approaches like statins.

Assessment of Nocturnal Blood Pressure: Importance of Determining the Time in Bed-A Pilot Study.

Objectives: Nocturnal blood pressure (BP) monitoring is essential for evaluating cardiovascular risk and guiding treatment decisions. However, the standardized narrow-fixed nighttime period between 10 p.m. and 6 a.m. may not accurately reflect individual sleep schedules. This pilot study aimed to investigate the comparability between the standardized nighttime period and actual time in bed (TIB) regarding BP assessment. Further, our goal was to evaluate the clinical relevance of the observed BP differences. Methods: A total of 30 participants underwent 24 h ambulatory blood pressure monitoring (ABPM). Patient-specific TIB was precisely assessed through an accelerometer and a position sensor from the SOMNOtouch NIBP™ (SOMNOmedics GmbH, Randersacker, Germany). We analysed the effect of considering individual TIB as nighttime instead of the conventional narrow-fixed interval on the resulting nocturnal BP levels and dipping patterns. Results: We observed differences in both systolic and diastolic BP between the standardized nighttime period and the TIB. Furthermore, a notable percentage of patients (27%) changed their dipping pattern classification as a function of the nighttime definition adopted. We found strong correlations between the start (r = 0.75, p < 0.01), as well as the duration (r = -0.42, p = 0.02) of TIB and the changes in dipping pattern classification. Conclusions: Definition of nocturnal period based on the individual TIB leads to clinically relevant changes of nocturnal BP and dipping pattern classifications. TIB is easily detected using a body position sensor and accelerometer. This approach may thus improve the accuracy of cardiovascular risk evaluation and enhance treatment strategies.

Treatment of malignant effusion by oncolytic virotherapy in an experimental subcutaneous xenograft model of lung cancer.

BACKGROUND: Malignant pleural effusion (MPE) is associated with advanced stages of lung cancer and is mainly dependent on invasion of the pleura and expression of vascular endothelial growth factor (VEGF) by cancer cells. As MPE indicates an incurable disease with limited palliative treatment options and poor outcome, there is an urgent need for new and efficient treatment options. METHODS: In this study, we used subcutaneously generated PC14PE6 lung adenocarcinoma xenografts in athymic mice that developed subcutaneous malignant effusions (ME) which mimic pleural effusions of the orthotopic model. Using this approach monitoring of therapeutic intervention was facilitated by direct observation of subcutaneous ME formation without the need of sacrificing mice or special imaging equipment as in case of MPE. Further, we tested oncolytic virotherapy using Vaccinia virus as a novel treatment modality against ME in this subcutaneous PC14PE6 xenograft model of advanced lung adenocarcinoma. RESULTS: We demonstrated significant therapeutic efficacy of Vaccinia virus treatment of both advanced lung adenocarcinoma and tumor-associated ME. We attribute the efficacy to the virus-mediated reduction of tumor cell-derived VEGF levels in tumors, decreased invasion of tumor cells into the peritumoral tissue, and to viral infection of the blood vessel-invading tumor cells. Moreover, we showed that the use of oncolytic Vaccinia virus encoding for a single-chain antibody (scAb) against VEGF (GLAF-1) significantly enhanced mono-therapy of oncolytic treatment. CONCLUSIONS: Here, we demonstrate for the first time that oncolytic virotherapy using tumor-specific Vaccinia virus represents a novel and promising treatment modality for therapy of ME associated with advanced lung cancer.

Three-dimensional volume tomographic study of the imaging accuracy of impacted teeth: MSCT and CBCT comparison--an in vitro study.

The aim of this study was to analyze the imaging accuracy of cone beam computed tomography (CBCT) data sets compared with multislice spiral computed tomography (MSCT) data sets in determining the exact mesiodistal width of unerupted porcine tooth germs and to compare the radiologically obtained results of width measurements with the actual mesiodistal dimension of the tooth germs. In MSCT and CBCT data sets, the largest diameter of 24 tooth germs was determined with the aid of the mesial and distal contact points. The reference method used was mesiodistal width measurement using sliding callipers after the tooth germs had been osteotomized. Accuracy and precision were ascertained with difference plots and a one-way model II analysis of variance with random effects. Analysis of accuracy revealed marked differences between the measuring methods in the difference plot: slightly higher mean values were measured by MSCT and markedly lower values by CBCT than by the reference method (calliper); the mean deviation was significantly greater for CBCT. The width of the confidence interval in the comparison of CBCT versus clinical measurements is more than 4 times higher than in the comparison of MSCT versus clinical values. Precision analysis found that repeatability was twice as high with CBCT as with clinical measurement, whereas MSCT and clinical measurement differed only slightly. The mesiodistal width of displaced teeth can be determined by MSCT but also by CBCT. MSCT is superior to CBCT in determining tooth width; the difference was statistically significant (P = 0.05).

Modelling the Complexity of Human Skin In Vitro.

The skin serves as an important barrier protecting the body from physical, chemical and pathogenic hazards as well as regulating the bi-directional transport of water, ions and nutrients. In order to improve the knowledge on skin structure and function as well as on skin diseases, animal experiments are often employed, but anatomical as well as physiological interspecies differences may result in poor translatability of animal-based data to the clinical situation. In vitro models, such as human reconstructed epidermis or full skin equivalents, are valuable alternatives to animal experiments. Enormous advances have been achieved in establishing skin models of increasing complexity in the past. In this review, human skin structures are described as well as the fast evolving technologies developed to reconstruct the complexity of human skin structures in vitro.

Human In Vitro Skin Models for Wound Healing and Wound Healing Disorders.

Skin wound healing is essential to health and survival. Consequently, high amounts of research effort have been put into investigating the cellular and molecular components involved in the wound healing process. The use of animal experiments has contributed greatly to the knowledge of wound healing, skin diseases, and the exploration of treatment options. However, in addition to ethical concerns, anatomical and physiological inter-species differences often influence the translatability of animal-based studies. Human in vitro skin models, which include essential cellular and structural components for wound healing analyses, would improve the translatability of results and reduce animal experiments during the preclinical evaluation of novel therapy approaches. In this review, we summarize in vitro approaches, which are used to study wound healing as well as wound healing-pathologies such as chronic wounds, keloids, and hypertrophic scars in a human setting.

Individualized erlanger KS-impression trays for infants with cleft lip and palate.

OBJECTIVE: The use of individualized impression trays is required when taking impressions of the maxilla in infants with cleft lip and palate. Custom trays made of plastic such as polymethylmethacrylate, as well as generic, full-arch infant metal trays, have been used up to now. Given the increasing incidence of infectious diseases, the ability to sterilize impression trays for infants with cleft lip and palate is mandatory. Polymethylmethacrylate impression trays are altered in shape and consistency when autoclaved during the sterilization process. Therefore, they have to be fabricated afresh at regular intervals. METHODS: Based on modified mold patterns of the available plastic trays, 44 pieces were sorted into four groups of 11 trays in ascending order of size. On these plaster casts, which served as the male part of the template, a 1-mm layer of sheet wax was applied. An optimized ergonomic wax handle was then fitted to the wax plate. Realization in a chromium-cobalt-molybdenum alloy was performed according to the lost wax principle. CONCLUSIONS: The sterilizable Erlangen KS-Impression tray (Erlanger KS-Abformlöffel®) is now available in 11 sizes for each of four basic forms. They meet current hygiene guidelines. They can be recommended for routine use when taking impressions in infants with any form of cleft lip and palate without complications.

Administration of a VEGFR­2-specific MRI contrast agent to assess orthodontic tooth movement : A pilot study.

PURPOSE: It is thought that orthodontic forces initially reduce periodontal blood flow during orthodontic tooth movement (OTM) via tissue compression with cells responding to concomitant oxygen deprivation with expression of vascular endothelial growth factor (VEGF) triggering angiogenesis via binding to its receptor VEGFR­2. To test this hypothesis, we performed a pilot study to establish a protocol for molecular magnetic resonance imaging (MRI) of rat jaws administering a VEGFR-2-specific contrast agent. METHODS: Mesial OTM of a first upper left rat molar was initiated in one male Fischer 344 rat 4 days prior to MRI by insertion of an elastic band between the first and second upper molars with the contralateral side left untreated (internal control). T1-weighted MRI sequences including dynamic contrast-enhanced MRI (DCE-MRI) were recorded before and after administration of a molecular VEGFR­2 MRI marker with a 7 T MRI dedicated for small animal use. RESULTS: After injection of anti-VEGFR2-albumin-gadolinium-DTPA, volume enhancement on T1-weighted images was increased at the OTM side distally of the moved first upper molar (M1) compared to the control side, whereas the T1 relaxation time was reduced on the OTM side. DCE-MRI resulted in an increased area under the curve (AUC), whereas time-to-peak (TTP) and washout rate were reduced during OTM distally of the moved M1 compared to the contralateral side. CONCLUSIONS: OTM resulted in uptake of the VEGFR-2-specific MRI contrast agent in tension areas of the periodontal ligament. The imaging protocol presented here is useful for the assessment of VEGFR­2 expression in tension areas of the periodontal ligament in vivo.

The Impact of Prolonged Inflammation on Wound Healing.

The treatment of chronic wounds still challenges modern medicine because of these wounds' heterogenic pathophysiology. Processes such as inflammation, ischemia and bacterial infection play major roles in the progression of a chronic wound. In recent years, preclinical wound models have been used to understand the underlying processes of chronic wound formation. However, the wound models used to investigate chronic wounds often lack translatability from preclinical models to patients, and often do not take exaggerated inflammation into consideration. Therefore, we aimed to investigate prolonged inflammation in a porcine wound model by using resiquimod, a TLR7 and TLR8 agonist. Pigs received full thickness excisional wounds, where resiquimod was applied daily for 6 days, and untreated wounds served as controls. Dressing change, visual documentation and wound scoring were performed daily. Biopsies were collected for histological as well as gene expression analysis. Resiquimod application on full thickness wounds induced a visible inflammation of wounds, resulting in delayed wound healing compared to non-treated control wounds. Gene expression analysis revealed high levels of IL6, MMP1 and CD68 expression after resiquimod application, and histological analysis showed increased immune cell infiltration. By using resiquimod, we were able to show that prolonged inflammation delayed wound healing, which is often observed in chronic wounds in patients. The model we used shows the importance of inflammation in wound healing and gives an insight into the progression of chronic wounds.

A novel human ex vivo skin model to study early local responses to burn injuries.

Burn injuries initiate numerous processes such as heat shock response, inflammation and tissue regeneration. Reliable burn models are needed to elucidate the exact sequence of local events to be able to better predict when local inflammation triggers systemic inflammatory processes. In contrast to other ex vivo skin culture approaches, we used fresh abdominal skin explants to introduce contact burn injuries. Histological and ultrastructural analyses confirmed a partial-thickness burn pathology. Gene expression patterns and cytokine production profiles of key mediators of the local inflammation, heat shock response, and tissue regeneration were analyzed for 24 h after burn injury. We found significantly increased expression of factors involved in tissue regeneration and inflammation soon after burn injury. To investigate purely inflammation-mediated reactions we injected lipopolysaccharide into the dermis. In comparison to burn injury, lipopolysaccharide injection initiated an inflammatory response while expression patterns of heat shock and tissue regeneration genes were unaffected for the duration of the experiment. This novel ex vivo human skin model is suitable to study the local, early responses to skin injuries such as burns while maintaining an intact overall tissue structure and it gives valuable insights into local mechanisms at the very beginning of the wound healing process after burn injuries.

Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes.

BACKGROUND: Tyrosine kinase 2 (Tyk2), a central component of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, has major effects on innate immunity and inflammation. Mice lacking Tyk2 are resistant to endotoxin shock induced by lipopolysaccharide (LPS), and Tyk2 deficient macrophages fail to efficiently induce interferon alpha/beta after LPS treatment. However, how Tyk2 globally regulates transcription of downstream target genes remains unknown. Here we examine the regulatory role of Tyk2 in basal and inflammatory transcription by comparing gene expression profiles of peritoneal macrophages from Tyk2 mutant and wildtype control mice that were either kept untreated or exposed to LPS for six hours. RESULTS: Untreated Tyk2-deficient macrophages exhibited reduced expression of immune response genes relative to wildtype, in particular those that contain interferon response elements (IRF/ISRE), whereas metabolic genes showed higher expression. Upon LPS challenge, IFN-inducible genes (including those with an IRF/ISRE transcription factor binding-site) were strongly upregulated in both Tyk2 mutant and wildtype cells and reached similar expression levels. In contrast, metabolic gene expression was strongly decreased in wildtype cells upon LPS treatment, while in Tyk2 mutant cells the expression of these genes remained relatively unchanged, which exaggerated differences already present at the basal level. We also identified several 5'UR transcription factor binding-sites and 3'UTR regulatory elements that were differentially induced between Tyk2 deficient and wildtype macrophages and that have not previously been implicated in immunity. CONCLUSIONS: Although Tyk2 is essential for the full LPS response, its function is mainly required for baseline expression but not LPS-induced upregulation of IFN-inducible genes. Moreover, Tyk2 function is critical for the downregulation of metabolic genes upon immune challenge, in particular genes involved in lipid metabolism. Together, our findings suggest an important regulatory role for Tyk2 in modulating the relationship between immunity and metabolism.

Octamer-binding factor 6 (Oct-6/Pou3f1) is induced by interferon and contributes to dsRNA-mediated transcriptional responses.

BACKGROUND: Octamer-binding factor 6 (Oct-6, Pou3f1, SCIP, Tst-1) is a transcription factor of the Pit-Oct-Unc (POU) family. POU proteins regulate key developmental processes and have been identified from a diverse range of species. Oct-6 expression is described to be confined to the developing brain, Schwann cells, oligodendrocyte precursors, testes, and skin. Its function is primarily characterised in Schwann cells, where it is required for correctly timed transition to the myelinating state. In the present study, we report that Oct-6 is an interferon (IFN)-inducible protein and show for the first time expression in murine fibroblasts and macrophages. RESULTS: Oct-6 was induced by type I and type II IFN, but not by interleukin-6. Induction of Oct-6 after IFNbeta treatment was mainly dependent on signal transducer and activator of transcription 1 (Stat1) and partially on tyrosine kinase 2 (Tyk2). Chromatin immunopreciptitation experiments revealed binding of Stat1 to the Oct-6 promoter in a region around 500 bp upstream of the transcription start site, a region different from the downstream regulatory element involved in Schwann cell-specific Oct-6 expression. Oct-6 was also induced by dsRNA treatment and during viral infections, in both cases via autocrine/paracrine actions of IFNalpha/beta. Using microarray and RT-qPCR, we furthermore show that Oct-6 is involved in the regulation of transcriptional responses to dsRNA, in particular in the gene regulation of serine/threonine protein kinase 40 (Stk40) and U7 snRNA-associated Sm-like protein Lsm10 (Lsm10). CONCLUSION: Our data show that Oct-6 expression is not as restricted as previously assumed. Induction of Oct-6 by IFNs and viruses in at least two different cell types, and involvement of Oct-6 in gene regulation after dsRNA treatment, suggest novel functions of Oct-6 in innate immune responses.

Regression of human prostate tumors and metastases in nude mice following treatment with the recombinant oncolytic vaccinia virus GLV-1h68.

Virotherapy using oncolytic vaccinia virus strains is one of the most promising new strategies for cancer therapy. In the current study, we analyzed the therapeutic efficacy of the oncolytic vaccinia virus GLV-1h68 against two human prostate cancer cell lines DU-145 and PC-3 in cell culture and in tumor xenograft models. By viral proliferation assays and cell survival tests, we demonstrated that GLV-1h68 was able to infect, replicate in, and lyse these prostate cancer cells in culture. In DU-145 and PC-3 tumor xenograft models, a single intravenous injection with GLV-1h68 resulted in a significant reduction of primary tumor size. In addition, the GLV-1h68-infection led to strong inflammatory and oncolytic effects resulting in drastic reduction of regional lymph nodes with PC-3 metastases. Our data documented that the GLV-1h68 virus has a great potential for treatment of human prostate carcinoma.