Successful Desensitization with Imlifidase and Daratumumab in a Highly Immunized, Crossmatch Positive, Blood Group-Incompatible Living-Donor Re-Transplant Recipient with Systemic Lupus Erythematosus and Antiphospholipid Syndrome.

Introduction: The transplantation of highly sensitized patients remains a major obstacle. Immunized patients wait longer for a transplant if not prioritized, and if transplanted, their transplant outcome is worse. Case Presentation: We report a successful AB0- and HLA-incompatible living donor kidney transplantation in a 35-year-old female patient with systemic lupus erythematosus (SLE) and antiphospholipid syndrome. The patient had a positive T- and B-cell complement-dependent cytotoxicity (CDC) crossmatch and previous graft loss due to renal vein thrombosis. We treated the patient with intravenous immunoglobulins, rituximab, horse anti-thymocyte globulin, daratumumab, and imlifidase, besides standard immunosuppression. All IgG antibodies were sensitive to imlifidase treatment. Besides donor-specific HLA antibodies, anti-dsDNA antibodies and antiphospholipid antibodies were cleaved. The patient initially had delayed graft function. Two kidney biopsies (day 7 and day 14) revealed acute tubular necrosis without signs of HLA antibody-mediated rejection. On posttransplant day 30, hemodialysis was stopped, and creatinine levels declined over the next weeks to a baseline creatinine of about 1.7 mg/dL after 12 months. Conclusion: In this case, a novel multimodal treatment strategy including daratumumab and imlifidase enabled successful kidney transplantation for a highly immunized patient with antiphospholipid antibodies.

Surface Chemistry and Specific Surface Area Rule the Efficiency of Gold Nanoparticle Sensitizers in Proton Therapy.

Gold nanoparticles (AuNPs) are currently the most studied radiosensitizers in proton therapy (PT) applicable for the treatment of solid tumors, where they amplify production of reactive oxygen species (ROS). However, it is underexplored how this amplification is correlated with the AuNPs' surface chemistry. To clarify this issue, we fabricated ligand-free AuNPs of different mean diameters by laser ablation in liquids (LAL) and laser fragmentation in liquids (LFL) and irradiated them with clinically relevant proton fields by using water phantoms. ROS generation was monitored by the fluorescent dye 7-OH-coumarin. Our findings reveal an enhancement of ROS production driven by I) increased total particle surface area, II) utilization of ligand-free AuNPs avoiding sodium citrate as a radical quencher ligands, and III) a higher density of structural defects generated by LFL synthesis, indicated by surface charge density. Based on these findings it may be concluded that the surface chemistry is a major and underexplored contributor to ROS generation and sensitizing effects of AuNPs in PT. We further highlight the applicability of AuNPs in vitro in human medulloblastoma cells.

Student experiences of professionalism and role models in an oral and maxillofacial surgery internship: A qualitative study.

INTRODUCTION: Dental students have a clear concept of professionalism and the importance of role models. Our aim was to determine how dental students experience their first oral and maxillofacial surgery internship in terms of their concept of professionalism and their perception of role models. METHODS: From June to August 2020, semi-structured telephone interviews were conducted with 22 dental students in their eighth and ninth semesters at the Medical Faculty of the University of Ulm. The interviews were transcribed and evaluated by qualitative content analysis according to Mayring. RESULTS: The students' concept of dental professionalism was shaped by the elements of a good approach to patients, professional competence, and manual skills. This perception was not changed by the internship. Having a role model was seen as an important learning strategy, and role models were perceived in both positive and negative ways. Role models were perceived as positive if they corresponded to the student's concept of professionalism and as negative if they did not correspond to this concept, especially with regard to social interaction or the approach to patients. Students' reactions to discrepancies between their own moral values and the role models' behaviour were characterised by passivity and withdrawal. With regard to potential future careers, positive internship experiences supported student goals, whereas negative experiences raised doubts about them. CONCLUSION: Supervising dentists may still underestimate the considerable impact of internships, and their awareness of this impact needs to be increased. Students' reactions to conflicts between reality and their own values do not appear to be constructive. One approach to solving this problem may be to include discussions of professional development in curricula.

MRONJ of the Mandible-From Decortication to a Complex Jaw Reconstruction Using a CAD/CAM-Guided Bilateral Scapula Flap.

Medication-related osteonecrosis of the jaw (MRONJ) has been an integral part of the maxillofacial patient population for some time. The therapeutic concept ranges from conservative approaches over less extended decortications to major jaw resections, which can result in a considerable loss of quality of life. Based on three case reports, this paper presents the long-term history of patients with MRONJ of the mandible, whose disease ultimately resulted in partial or total mandibular resection and subsequent multisegmental reconstruction using a microvascular anastomosed bone flap. Furthermore, a suitable alternative for complex mandibular reconstruction is demonstrated when using a free fibula flap is not possible. The options are limited, particularly when multisegmental restoration of mandibular continuity is required. One case presents a mandible reconstruction using a CAD/CAM-guided bilateral scapular free flap (CAD/CAM = Computer-Aided Design and Manufacturing), which has not been described for this purpose before. Due to the complexity, computer-assisted surgery and patient-specific implants seem reasonable, which is why a special focus was applied to this topic.

[Principals of Osteosynthesis in the Facial Skeleton]. / Prinzipien der Osteosynthese im Bereich des Gesichtsschädels.

There were no major alterations of the basic principals of osteosynthesis in the facial skeleton over the past years. Nevertheless, by the reason of further developments of the osteosynthesis systems and Instruments as well as by the implementation of computer-assisted surgery including the use of anatomical or customized Implants crucial advancements of the treatment can be seen.

Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.

Maxillofacial injuries in severely injured patients after road traffic accidents-a retrospective evaluation of the TraumaRegister DGU® 1993-2014.

OBJECTIVES: It was the aim of the study to analyse the prevalence of maxillofacial trauma (MFT) in severely injured patients after road traffic accidence (RTA) and to investigate associated factors. MATERIALS AND METHODS: In a retrospective study, data from patients after RTA by the TraumaRegister DGU® from 1993 to 2014 were evaluated for demographical and injury characteristics. The predictor variable was mechanism of injury and the outcome variables were type of injury, severity and hospital resources utilization. RESULTS: During the investigation period, n = 62,196 patients were enclosed with a prevalence of maxillofacial injuries of 20.3% (MFT positive). The injury severity score of MFT-positive patients was higher than in the MTF-negative subgroup (27 ± 12.8 vs. 23.0 ± 12.7). If MFT positive, 39.8% show minor, 37.1% moderate, 21.5% serious and 1.6% severe maxillofacial injuries. Injuries of the midface occurred in 60.3% of MTF-positive patients. A relevant blood loss (> 20% of total blood volume) occurred in 1.9%. MFT-positive patients had a higher coincidence with cervical spine fractures (11.3% vs. 7.8%) and traumatic brain injuries (62.6% vs. 34.8%) than MFT-negative patients. There was a noticeable decrease in the incidence of facial injuries in car/truck drivers during the study period. CONCLUSIONS: Every 5th patient after RTA shows a MFT and the whole trauma team must be aware that this indicates a high prevalence of traumatic brain and cervical spine injuries. CLINICAL RELEVANCE: Even if sole injuries of the face are seldom life threatening, maxillofacial expertise in interdisciplinary trauma centres is strongly recommended.

Streamlining Quantitative Analysis of Long RNA Sequencing Reads.

Transcriptome analyses allow for linking RNA expression profiles to cellular pathways and phenotypes. Despite improvements in sequencing methodology, whole transcriptome analyses are still tedious, especially for methodologies producing long reads. Currently, available data analysis software often lacks cost- and time-efficient workflows. Although kit-based workflows and benchtop platforms for RNA sequencing provide software options, e.g., cloud-based tools to analyze basecalled reads, quantitative, and easy-to-use solutions for transcriptome analysis, especially for non-human data, are missing. We therefore developed a user-friendly tool, termed Alignator, for rapid analysis of long RNA reads requiring only FASTQ files and an Ensembl cDNA database reference. After successful mapping, Alignator generates quantitative information for each transcript and provides a table in which sequenced and aligned RNA are stored for further comparative analyses.

Preclinical Evaluation of Antitumoral and Cytotoxic Properties of Viscum album Fraxini Extract on Pediatric Tumor Cells.

In Europe, especially in German-speaking countries, administration of mistletoe extracts is the most common and popular complementary and alternative therapy approach reported in oncology. Mistletoe therapy is applied to children with cancer for curative and palliative therapeutic regimes with increasing frequency, but at the same time, there are only a few studies on the effectiveness of this therapy. Therefore, we have investigated the response of various pediatric cell lines (acute myeloid leukemia, Ewing's sarcoma, hepatocellular carcinoma, medulloblastoma, neuroblastoma, and osteosarcoma) to mistletoe extract, abnobaVISCUM Fraxini. Effects on cell proliferation, cell cycle distribution as well as on mitochondrial integrity and caspase-mediated apoptosis were investigated in neuroblastoma cell lines, SH-SY5Y and Kelly. Additionally, in vitro tumor cell migration and invasion were studied. In vivo effects of the mistletoe extract were investigated in a syngeneic neuroblastoma mouse model. We could show that tumor cell lines were from 5- to 640-fold more sensitive to abnobaVISCUM Fraxini treatment than non-tumorigenic fibroblasts, whereby neuroblastoma cell lines were the most sensitive. For two neuroblastoma cell lines, SH-SY5Y and Kelly, induction of caspase-9-mediated apoptosis, a decrease of mitochondrial integrity as well as attenuation of migration and invasion were observed. In vivo experiments revealed a reduction of tumor growth and a prolonged survival of tumor-bearing animals. In summary, we can state that these results provide the first preclinical data for cytotoxic activities of abnobaVISCUM Fraxini for a broad panel of pediatric tumor cell lines, in particular, neuroblastoma cells. Thus, it might be a potential remedy for the supportive treatment of neuroblastoma.

Cancer evolution, mutations, and clonal selection in relapse neuroblastoma.

The notion of cancer as a complex evolutionary system has been validated by in-depth molecular analyses of tumor progression over the last years. While a complex interplay of cell-autonomous programs and cell-cell interactions determines proliferation and differentiation during normal development, intrinsic and acquired plasticity of cancer cells allow for evasion of growth factor limitations, apoptotic signals, or attacks from the immune system. Treatment-induced molecular selection processes have been described by a number of studies already, but understanding of those events facilitating metastatic spread, organ-specific homing, and resistance to anoikis is still in its early days. In principle, somatic events giving rise to cancer progression should be easier to follow in childhood tumors bearing fewer mutations and genomic aberrations than their counterparts in adulthood. We have previously reported on the genetic events accompanying relapsing neuroblastoma, a solid tumor of early childhood. Our results indicated significantly higher single nucleotide variants in relapse tumors, gave hints for branched tumor evolution upon treatment and clonal selection as deduced from shifts in allelic frequencies between primary and relapsing neuroblastoma. Here, we will review these findings and give an outlook on dealing with intratumoral heterogeneity and sub-clonal diversity in neuroblastoma for future targeted treatments.

The miR-17-92 microRNA cluster regulates multiple components of the TGF-ß pathway in neuroblastoma.

The miR-17-92 microRNA cluster is often activated in cancer cells, but the identity of its targets remains elusive. Using SILAC and quantitative mass spectrometry, we examined the effects of activation of the miR-17-92 cluster on global protein expression in neuroblastoma (NB) cells. Our results reveal cooperation between individual miR-17-92 miRNAs and implicate miR-17-92 in multiple hallmarks of cancer, including proliferation and cell adhesion. Most importantly, we show that miR-17-92 is a potent inhibitor of TGF-ß signaling. By functioning both upstream and downstream of pSMAD2, miR-17-92 activation triggers downregulation of multiple key effectors along the TGF-ß signaling cascade as well as direct inhibition of TGF-ß-responsive genes.

TrkB-Target Galectin-1 Impairs Immune Activation and Radiation Responses in Neuroblastoma: Implications for Tumour Therapy.

Galectin-1 (Gal-1) has been described to promote tumour growth by inducing angiogenesis and to contribute to the tumour immune escape. We had previously identified up-regulation of Gal-1 in preclinical models of aggressive neuroblastoma (NB), the most common extracranial tumour of childhood. While Gal-1 did not confer a survival advantage in the absence of exogenous stressors, Gal-1 contributed to enhanced cell migratory and invasive properties. Here, we review these findings and extend them by analyzing Gal-1 mediated effects on immune cell regulation and radiation resistance. In line with previous results, cell autonomous effects as well as paracrine functions contribute to Gal-1 mediated pro-tumourigenic functions. Interfering with Gal-1 functions in vivo will add to a better understanding of the role of the Gal-1 axis in the complex tumour-host interaction during immune-, chemo- and radiotherapy of neuroblastoma.

Clinical and radiographic evaluation of early loaded narrow-diameter implants: 5-year follow-up of a multicenter prospective clinical study.

OBJECTIVE: This study was initiated to evaluate the 5-year implant survival rate and marginal bone levels around a 3.0-mm implant when replacing a single tooth in the anterior region. MATERIALS AND METHODS: The study was designed as a prospective, single-arm, multicenter clinical study. Patients missing 12, 22, 32, 31, 41 or 42 teeth were included, and implants of 3.0 mm diameter and different lengths were placed by a one-stage surgery protocol. Definitive cemented crowns were placed 6-10 weeks later. Clinical and radiographic measurements were taken at implant installation, at loading and at the 6-, 12-, 24-, 36-, 48- and 60-month follow-up visits. RESULTS: Sixty-nine patients with 97 implants were included in this study. Four implants were lost before loading (4.12% failure rate). Implant marginal bone levels did not differ statistically after the 1-year follow-up visit. After 5 years, no bone loss was observed for 50.60% of the implants and only 8.43% of them lost more than 1 mm. Similarly, probing pocket depths and gingival zenith scores did not change significantly. CONCLUSIONS: The use of the two-piece narrow 3.0-mm titanium dental implant for the restoration of upper lateral or lower incisors is safe and results in stable marginal bone levels and probing pocket depths after 5 years of function.

The influence of the distance between narrow implants and the adjacent teeth on marginal bone levels.

OBJECTIVE: To investigate how the distance between narrow implants and adjacent teeth influences the marginal bone levels (MBL) up to 3 years after placement. MATERIAL AND METHODS: A prospective, single-arm, multicenter clinical study was designed to include patients missing 12, 22, 32, 31, 41 or 42 teeth. Implants of 3.0 mm diameter and different lengths were used in the study. One-stage surgery was performed and healing abutments placed during the 6-10 weeks healing period. Clinical and radiographic evaluation was performed at implant installation, loading, and at the 6, 12, 24 and 36-months follow-up visits. RESULTS: Eighty-three implants were placed in 59 patients. A total of 48 implants were placed in narrow implant-to-tooth spaces (percentile 25, 0.83(0.25) mm), 80 in regular spaces (percentile 25 < x < 75, 1.59(0.26) mm) and 47 in wide spaces (percentile 75, 2.61(0.51) mm). Implant MBL change from restoration delivery to 36 months was of 0.50(0.79), 0.50(0.98) and 0.00(0.55) mm in the narrow, regular and wide distance groups (P = 0.005, Mann-Whitney U-test). Changes in MBL on the adjacent teeth were not significant. CONCLUSION: The distance between narrow-diameter implants and the adjacent teeth does not influence the marginal bone levels neither at the implant or the tooth side. In this study, less marginal bone loss occurred in the narrower spaces.

Pharmaceutically inhibiting polo-like kinase 1 exerts a broad anti-tumour activity in retinoblastoma cell lines.

BACKGROUND: Retinoblastoma is the most common malignant cancer of the eye in children. Although metastatic retinoblastoma is rare, cure rates for this advanced disease remain below 50%. High-level polo-like kinase 1 expression in retinoblastomas has previously been shown to be correlated with adverse outcome parameters. Polo-like kinase 1 is a serine/threonine kinase involved in cell cycle regulation at the G2/M transition. Polo-like kinase 1 inhibition has been demonstrated to have anti-tumour effects in preclinical models of several paediatric tumours. Here, we assessed its efficacy against retinoblastoma cell lines. METHODS: Expression of polo-like kinase 1 was determined in a panel of retinoblastoma cell lines by polymerase chain reaction and western blot analysis. We analysed viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT assay), proliferation (5-bromo-2'-deoxyuridine enzyme-linked immunosorbent assay), cell cycle progression (propidium iodid staining) and apoptosis (cell death enzyme-linked immunosorbent assay) in three retinoblastoma cell lines after treatment with two adenosine triphosphate-competitive polo-like kinase 1 inhibitors, BI6727 or GSK461364. Activation of polo-like kinase 1 downstream signalling components including TP53 were assessed. RESULTS: Treatment of retinoblastoma cells with either BI6727 or GSK461364 reduced cell viability and proliferative capacity and induced both cell cycle arrest and apoptosis. Polo-like kinase 1 inhibition also induced the p53 signalling pathway. Analysis of key players in cell cycle control revealed that low nanomolar concentrations of either polo-like kinase 1 inhibitor upregulated cyclin B1 and increased activated cyclin-dependent kinase 1 (phosphorylated at Y15) in retinoblastoma cell lines. CONCLUSIONS: These preclinical data indicate that polo-like kinase 1 inhibitors could be useful as components in rationally designed chemotherapy protocols to treat patients with metastasized retinoblastoma in early phase clinical trials.

Application of the PAMONO-Sensor for Quantification of Microvesicles and Determination of Nano-Particle Size Distribution.

The PAMONO-sensor (plasmon assisted microscopy of nano-objects) demonstrated an ability to detect and quantify individual viruses and virus-like particles. However, another group of biological vesicles-microvesicles (100-1000 nm)-also attracts growing interest as biomarkers of different pathologies and needs development of novel techniques for characterization. This work shows the applicability of a PAMONO-sensor for selective detection of microvesicles in aquatic samples. The sensor permits comparison of relative concentrations of microvesicles between samples. We also study a possibility of repeated use of a sensor chip after elution of the microvesicle capturing layer. Moreover, we improve the detection features of the PAMONO-sensor. The detection process utilizes novel machine learning techniques on the sensor image data to estimate particle size distributions of nano-particles in polydisperse samples. Altogether, our findings expand analytical features and the application field of the PAMONO-sensor. They can also serve for a maturation of diagnostic tools based on the PAMONO-sensor platform.

[Virtual Planning of Prosthetic Treatment of the Orbit]. / Virtuelle Planung bei der epithetischen Orbitaversorgung.

Optimal positioning of bone-anchored implants in the treatment of patients with orbital prosthesis is challenging. The definition of implant axis as well as the positioning of the implants is important to prevent failures in prosthetic rehabilitation in these patients. We performed virtual planning of enossal implants at a base of a standard fan beam CT scan using the software CoDiagnostiX™ (DentalWings, Montréal, Canada). By 3D-printing a surgical guide for drilling and implant insertion was manufactured (Med-610™, Stratasys, Rehovot, Israel). An orbital exenteration was performed in a patient after shrinkage of the eyelids 20 years after enucleation and radiation of the orbit due to rhabdomyosarcoma. 4 Vistafix-3 implants (Cochlear™, Cochlea, Centennial, USA) were primarily inserted after resection with the help of the 3D-surgical guide. Prosthetic rehabilitation could be achieved as preplanned to a predictable result. The individual prosthesis of the orbit showed good functional and esthetic outcome. The virtual 3D-planning of endosseous implants for prosthetic orbital and periorbital reconstruction is easy to use and facilitates optimal placement of implants especially in posttherapeutically altered anatomic situations.

Small-vessel treatment with contemporary newer-generation drug-eluting coronary stents in all-comers: Insights from 2-year DUTCH PEERS (TWENTE II) randomized trial.

BACKGROUND: Treatment of lesions in small vessels was associated with worse clinical outcome, and various definitions of "small vessels" have been used. Data with novel drug-eluting stents are scarce. METHODS: To compare the outcome of patients with vs without small-vessel treatment, we assessed 2-year follow-up data of the DUTCH PEERS randomized trial (ClinicalTrials.gov: NCT01331707), in which 1,811 all-comers were treated with contemporary zotarolimus-eluting (Resolute Integrity) or everolimus-eluting (Promus Element) stents. Primary end point was target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction, and target lesion revascularization. RESULTS: The rates of TLF (9.5% vs 5.4%; P log rank = .001) and 2 individual components thereof-target vessel myocardial infarction (3.1% vs 1.3%; P log rank = .006) and target lesion revascularization (4.8% vs 2.8%; P log rank = .02)-were higher among 798 (44.1%) patients treated in at least one small vessel (<2.50 mm by quantitative coronary angiography). Multivariate analysis with propensity score adjustment demonstrated that treatment of small-vessel lesions independently predicted TLF at 2-year follow-up (hazard ratio 1.60, 95% CI 1.09-2.34). Patients with the smallest target vessel being <2.25 mm had TLF rates similar to patients with smallest target vessels of 2.25 to <2.50 mm; however, patients treated in vessels no smaller than 2.50 to <3.00 mm and patients treated in vessels ≥3.00 mm had lower TLF rates (9.3%, 9.8%, 5.0%, and 5.8%, respectively; P log rank = .009). CONCLUSION: Patients treated with novel drug-eluting stents in small-vessel lesions had higher adverse event rates than did patients who had no small-vessel treatment. Our data suggest that with current stents, a vessel diameter <2.50 mm is a suitable threshold to identify small target vessels.

miR-542-3p exerts tumor suppressive functions in neuroblastoma by downregulating Survivin.

MicroRNAs (miRNAs) are deregulated in a variety of human cancers, including neuroblastoma, the most common extracranial tumor of childhood. We previously reported a signature of 42 miRNAs to be highly predictive of neuroblastoma outcome. One miRNA in this signature, miR-542, was downregulated in tumors from patients with adverse outcome. Reanalysis of quantitative PCR and next-generation sequencing transcript data revealed that miR-542-5p as well as miR-542-3p expression is inversely correlated with poor prognosis in neuroblastoma patients. We, therefore, analyzed the function of miR-542 in neuroblastoma tumor biology. Ectopic expression of miR-542-3p in neuroblastoma cell lines reduced cell viability and proliferation, induced apoptosis and downregulated Survivin. Survivin expression was also inversely correlated with miR-542-3p expression in primary neuroblastomas. Reporter assays confirmed that miR-542-3p directly targeted Survivin. Downregulating Survivin using siRNA copied the phenotype of miR-542-3p expression in neuroblastoma cell lines, while cDNA-mediated ectopic expression of Survivin partially rescued the phenotype induced by miR-542-3p expression. Treating nude mice bearing neuroblastoma xenografts with miR-542-3p-loaded nanoparticles repressed Survivin expression, decreased cell proliferation and induced apoptosis in the respective xenograft tumors. We conclude that miR-542-3p exerts its tumor suppressive function in neuroblastoma, at least in part, by targeting Survivin. Expression of miR-542-3p could be a promising therapeutic strategy for treating aggressive neuroblastoma.

MiR-34a deficiency accelerates medulloblastoma formation in vivo.

Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option.