Management of immune-related adverse events in anti-PD-1-treated patients with advanced cutaneous squamous cell carcinoma.

Immune checkpoint inhibitors (ICI) have shown very promising results in the management of patients with inoperable or metastatic cutaneous squamous cell carcinoma (cSCC). However, ICI can cause a range of immune-related adverse events (irAEs) affecting a multitude of organs including skin, gastrointestinal tract, endocrine system, heart, lung, kidneys and the nervous system. In principle, clinical management irAEs does not change significantly with respect to the kind of cancer treated with ICI. However, advanced cSCC typically occurs in a clinically challenging patient population typically presenting with advanced age and/or significant comorbidities such as immunosuppression due to haematological malignancies and their respective treatment. Moreover, many patients with advanced cSCC are organ transplant patients taking immunosuppressants. As a consequence use of ICI per se and management of ICI-induced irAEs generates more complexity and difficulties in patients with cSCC compared to other entities. Here, we provide a brief review on the management of anti-programmed cell death protein 1-induced irAEs in patients with cSCC focusing on the characteristic clinical challenges present in this population.

A population-based study examining the influence of a specialized rapid-access cancer clinic on initial treatment choice in localized prostate cancer.

INTRODUCTION: Treatment decisions in localized prostate cancer are complicated by the available choices. A rapid-access cancer clinic (RAC) has been unique to Calgary, AB, since 2007. This RAC offers multidisciplinary prostate cancer education by a urologist, medical oncologist, and radiation oncologist. It is hypothesized that treatment utilization data from decisions taken at RAC may serve to benchmark the appropriateness of treatment decisions on a population level. METHODS: Records of patients with clinically localized prostate cancer in Alberta between October 1, 2007 and September 30, 2009 were reviewed with ethics approval. Records were linked to the Alberta Cancer Registry database. Clinical, treatment, and health services characteristics pertaining to patients attending RAC were compared to the general population. The primary endpoint was utilization rates of each initial treatment. RESULTS: During this two-year period, 2838 patients were diagnosed with localized prostate cancer; 375 attended RAC. The utilization rates among RAC patients vs. the whole Alberta population were: prostatectomy 60.3% (95% confidence interval [CI] 55.3-65.2) vs. 48.0% (95% CI 47.1-50.7; χ2 p<0.001); active surveillance 16.0% (95% CI 12.3-19.7%) vs. 13.5% (95% CI 12.2-15.8; χ2 p=0.214); radiotherapy 11.7% (95% CI 8.5-15.0) vs. 18.0% (95% CI 16.9-20.5; χ2 p=0.002); and hormone therapy 8.0% (95% CI 5.2-10.8) vs. 17.4% (95% CI 16.1-18.9; χ2 p<0.001). CONCLUSIONS: A specialized clinic for localized prostate cancer may be associated with a higher likelihood of receiving surgery or active surveillance as initial treatment compared to the prostate cancer population in Alberta.

Relevance of the Heisenberg-Kitaev model for the honeycomb lattice iridates A2IrO3.

Combining thermodynamic measurements with theoretical calculations we demonstrate that the iridates A2IrO3 (A=Na, Li) are magnetically ordered Mott insulators where the magnetism of the effective spin-orbital S=1/2 moments can be captured by a Heisenberg-Kitaev (HK) model with interactions beyond nearest-neighbor exchange. Experimentally, we observe an increase of the Curie-Weiss temperature from θ≈-125 K for Na2IrO3 to θ≈-33 K for Li2IrO3, while the ordering temperature remains roughly the same T(N)≈15 K. Using functional renormalization group calculations we show that this evolution of θ and T(N) as well as the low temperature zigzag magnetic order can be captured within this extended HK model. We estimate that Na2IrO3 is deep in a magnetically ordered regime, while Li2IrO3 appears to be close to a spin-liquid regime.

Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) was recently described in patients with multiple sclerosis (MS). A subject is considered CCSVI positive if ≥ 2 venous hemodynamic (VH) criteria are fulfilled. OBJECTIVE: To determine prevalence of CCSVI in a large cohort of patients with MS, clinically isolated syndrome (CIS), other neurologic diseases (OND), and healthy controls (HC), using specific proposed echo-color Doppler (ECD) criteria. METHODS: Transcranial and extracranial ECD were carried out in 499 enrolled subjects (289 MS, 163 HC, 26 OND, 21 CIS). Prevalence rates for CCSVI were calculated in 3 ways: first, using only the subjects for whom diagnosis was certain (i.e., borderline subjects were excluded); secondly, including the borderline subjects in the "no CCSVI" group; and finally, taking into account subjects who presented any of the VH criteria. RESULTS: CCSVI prevalence with borderline cases included in the "no CCSVI" group was 56.1% in MS, 42.3% in OND, 38.1% in CIS, and 22.7% in HC (p < 0.001). The CCSVI prevalence figures were 62.5% for MS, 45.8% for OND, 42.1% for CIS, and 25.5% for HC when borderline cases were excluded (p < 0.001). The prevalence of one or more positive VH criteria was the highest in MS (81.3%), followed by CIS (76.2%), OND (65.4%), and HC (55.2%) (p < 0.001). CCSVI prevalence was higher in patients with progressive than in nonprogressive MS (p = 0.004). CONCLUSIONS: Our findings are consistent with an increased prevalence of CCSVI in MS but with modest sensitivity/specificity. Our findings point against CCSVI having a primary causative role in the development of MS.

[Rapid prototyping in planning reconstructive surgery of the head and neck. Review and evaluation of indications in clinical use]. / Rechnergestützte Modellbauverfahren zur Planung ausgedehnter Rekonstruktionseingriffe im Schädelbereich. Ubersicht und Indikationsevaluation zum klinischen Einsatz.

PURPOSE: The aim was to define the indications for use of rapid prototyping models based on data of patients treated with this technique. PATIENTS AND METHODS: Since 1987 our department has been developing methods of rapid prototyping in surgery planning. During the study, first the statistical and reproducible anatomical precision of rapid prototyping models was determined on pig skull measurements depending on CT parameters and method of rapid prototyping. RESULTS: Measurements on stereolithography models and on selective laser sintered models confirmed an accuracy of +/-0.88 mm or 2.7% (maximum deviation: -3.0 mm to +3.2 mm) independently from CT parameters or method of rapid prototyping, respectively. With the same precision of models multilayer helical CT with a higher rate is the preferable method of data acquisition compared to conventional helical CT. From 1990 to 2002 in atotal of 122 patients, 127 rapid prototyping models were manufactured: in 112 patients stereolithography models, in 2 patients an additional stereolithography model, in 2 patients an additional selective laser sinter model, in 1 patient an additional milled model, and in 10 patients just a selective laser sinter model. CONCLUSION: Reconstructive surgery, distraction osteogenesis including midface distraction, and dental implantology are proven to be the major indications for rapid prototyping as confirmed in a review of the literature. Surgery planning on rapid prototyping models should only be used in individual cases due to radiation dose and high costs. Routine use of this technique only seems to be indicated in skull reconstruction and distraction osteogenesis.

[Mandibular reconstruction with autologous bone and osseoinductive implant in the Göttingen minipig]. / Unterkieferrekonstruktion mit autologem Knochen und einem induktiven Implantat beim Göttinger Minischwein.

BACKGROUND: Direct mandibular reconstruction with an autologous bone transplant was compared with an osteoinductive implant following an extensive continuity resection of the lower jaw in Göttinger mini-pigs. METHOD: In nine full-grown mini-pigs a one-sided continuity defect (5 cm) was created in the lower jaw. In four animals it was filled with a 50 x 25 x 15 mm(3) collagenous carrier enhanced by rhBMP-2 (400 micro g/cm(3) rhBMP-2). In two animals only the carrier was implanted as a control. Three animals received the resected autologous bone as a free transplant. Bone regeneration and consolidation of the defects was analyzed radiographically and histologically. RESULTS: Following implantation of the osteoinductive implant, complete osseous consolidation of the continuity defect in the lower jaw was observed in all animals. The defects were completely filled with a biomechanically stable bone which showed signs of functional adaptation. The replantation of the orthotopic autologous bone did not lead to functional stability quickly enough. In the periphery only an incomplete bony bridge was formed which was interrupted by large pseudarthrosis. No consolidation of the defects was found in the control group (carrier alone). CONCLUSION: Direct reconstruction of an extensive, biomechanically loaded defect with an osteoinductive implant proved to be the superior method. The osseous regeneration observed shows an immediate functional orientation. The necessity for extensive adaptive remodeling is thus minimized.

[Evaluation of the osteoinductive potential of genetically modified BMP-2 variants]. / Evaluation der osteoinduktiven Potenz von gentechnisch modifizierten BMP-2-Varianten.

BACKGROUND: The alteration of the N-terminal amino acid sequence of BMP-2 allows modification of heparin binding of the new protein. This leads to a change in the local retention time at the site of implantation. Mutants with increased (T3, T4) and with no binding (EHBMP-2) to heparin were assessed for their osteoinductivity in vivo and compared with the wild type BMP-2. METHODS: Cylindrical collagenous carriers (diameter = 5 mm, height = 10) were loaded with different concentrations (0.25-4 micro g) of the proteins. Following intramuscular implantation into the hind legs, the bone formation was measured in radiographic follow-ups. After 28 days the newly formed bone was characterized histologically. RESULTS: Elimination of the heparin binding leads to massive reduction in osteoinductivity. On the other hand, an increase in the heparin binding leads to enhancement in the osteoinductive properties, resulting in faster bone formation with a higher yield. CONCLUSION: It could be shown for the first time that modifications of BMP-2 by gene technology can lead to proteins with enhanced binding to components of the extracellular matrix. The resulting prolonged retention time at the implantation site results in an increased osteoinductivity compared with the wild type.

[Bimaxillary osteotomy with and without condylar positioning--a 1981-2002 long-term study]. / Die bimaxilläre Osteotomie mit und ohne Kondylenpositionierung-eine Langzeitstudie 1981-2002.

PURPOSE: The introduction of the four-splint technique in our hospital in 1997 made possible the reproducible centric condyle positioning in bimaxillary osteotomies, while taking the auto rotation of the mandible into consideration and avoiding steps in the mandibular osteotomy line. PATIENTS AND METHODS: From 1981 to 2002 a total of 622 patients underwent bimaxillary osteotomy surgery. During 1981-1997 a total of 395 patients (63.5%) underwent surgery without or only with centric condyle positioning in sagittal ramus osteotomy of the mandible. During 1997-2002 a total of 227 patients (36.5%) underwent surgery with continuous centric condyle positioning with the four-splint technique. RESULTS: In patients with preoperative functional disorders, surgery with continuous centric condyle positioning resulted in statistically significant (p<0.05) improvement compared to those who underwent surgery without continuous centric condyle positioning. CONCLUSION: The results confirm the indication for continuous centric condyle positioning in bimaxillary osteotomies.

[Typical features of craniofacial growth of the FGFR3-associated coronal synostosis syndrome (so-called Muenke craniosynostosis)]. / Typische Merkmale des kraniofazialen Wachstums beim FGFR3-assoziierten Koronarnahtsynostosesyndrom (so genannte Muenke-Kraniosynostose).

BACKGROUND: The FGFR3-associated coronal synostosis syndrome (Muenke craniosynostosis) is caused by a point mutation (C749G) on the FGFR3 gene resulting in a Pro250Arg substitution. METHODS: To characterize this malformation, the neuro- and viscerocranium were analyzed by axial CT scans of the skull and cephalometric radiographs of up to 13 affected children before and in part after fronto-orbital advancement. RESULTS: Preoperative analysis of the intracranial volume of four patients showed a mean decrease of 3.6%, indicating a compensatory growth pattern of the skull in cases of coronal synostosis. The typical brachycephaly could be verified by the significant shortening of the skull length of 13.2% on average and by the significant reduction of the anterior cranial base length of maximal 5.9% on average. The anterior part of the skull was characterized by a significant mean increase of the intercoronal distance of 8.6%, which indicates a compensatory transversal growth in this malformation. The widened bilateral interorbital and anterior interorbital distances were increased by 7.3 or 9.0%, respectively, confirming a hypertelorism typical for this syndrome. The "frontal bossing" frequently found in brachycephaly was characterized by the preoperatively increased sagittal extension of the forehead (about 112.9% above the norm) and by the increased height of the frontal prominence (about 47.8% above the norm). Following surgery, both variables defining the morphology of the forehead were reduced and appeared to be constant throughout the follow-up. Hypoplasia of the midface described by Muenke et al. (1997) was confirmed in the present study only by the significant reduction of the sagittal length of the maxillary base, which was decreased by 6.8%. CONCLUSION: In accordance with the current literature, the skull configuration described for Muenke craniosynostosis shows similarities with the Saethre-Chotzen syndrome.

[Surgical lengthening of the lower face in patients with class II deformities and skeletal deep bite--"short face syndrome" controlled clinical study on the "Würzburger Konzept"]. / Chirurgische Untergesichts--verlängerung bei der Therapie von Patienten mit Klasse-II-dysgnathien und skelettal tiefem Biss--"Short-face-Syndrom". Kontrollierte klinische Studie zum "Würzburger Konzept"

Among Angle Class II patients scheduled for orthognathic surgery, those with short face syndrome with skeletal deep bite only make up a small portion. Nevertheless, it represents a complex challenge for the orthodontist as well as for the surgeon with respect to the individual treatment goals. The harmony of facial relations is impaired in these patients: The skeletal lower face and consequently the soft tissue profile show a deficit in height compared to the midface. Lengthening of the lower face with its respective effect on facial aesthetics can only be corrected by causal therapy, i.e., a combined approach with surgical enlargement of the gonion angle. In this study, a therapy concept specifically suited for the correction of Class II deformities with short face syndrome is presented. Consequences for the skeletal and dental situation with their benefit for extraoral appearance were tested in a clinical trial ( n=15, patients with class II deformities and short face syndrome). To evaluate skeletal and dental changes, cephalograms were taken prior to initiation of orthodontic treatment, 3 days after surgery but before initiation of postsurgery orthodontics, and 1 year after the end of treatment.

Two transcriptional regulators GlnR and GlnRII are involved in regulation of nitrogen metabolism in Streptomyces coelicolor A3(2).

Streptomyces coelicolor has an unusually large arsenal of glutamine synthetase (GS) enzymes: a prokaryotic GSI-beta-subtype enzyme (encoded by glnA), three annotated glnA-like genes of the GSI-alpha-subtype and a eukaryote-like glutamine synthetase II (encoded by glnII). Under all tested conditions, GSI was found to represent the dominant glutamine synthetase activity. A significant heat-labile GSII activity, which is very low to undetectable in liquid-grown cultures, was only detected in morphologically differentiating S. coelicolor cultures. Analysis of glnA and glnII transcription by S1 nuclease mapping and egfp fusions revealed that, on nitrogen-limiting solid medium, glnII but not glnA expression is upregulated. An OmpR-like regulator protein, GlnR, has previously been implicated in transcriptional control of glnA expression. Gel retardation analysis revealed that GlnR is a DNA-binding protein, which interacts with the glnA promoter. It is not autoregulatory and does not bind to the upstream regions of the glnA-like genes of the alpha-subfamily, nor to the glnII promoter in vitro. A second GlnR target was identified upstream of the amtB gene, encoding a putative ammonium transporter. amtB forms an operon with glnK (encoding a PII protein) and glnD (encoding a putative PII nucleotidylyltransferase) shown by S1 nuclease protection analysis and reverse transcription-polymerase chain reaction (RT-PCR). An amtB and glnA promoter alignment revealed a putative GlnR operator structure. Downstream of glnII, a gene encoding for another OmpR-like regulator, GlnRII, was identified, with strong similarity to GlnR. Gel shifts with GlnRII showed that the promoters recognized by GlnR are also targets of GlnRII. However, GlnRII also interacted with the glnII upstream region. Only inactivation of glnR resulted in a glutamine auxotrophic phenotype, whereas the glnRII mutant can grow on minimal medium without glutamine.

Treatment of a Class II deformity with skeletal open bite and lateroocclusion.

A fundamentally important treatment outcome in orthognathic surgery is improved dentofacial esthetics in both the sagittal and vertical dimensions. In patients with a skeletal open bite, increased lower face height and a strained lip closure, the vertical dimension relationships can be improved by surgical impaction of the maxilla. The consequence of maxillary impaction is an autorotation of the mandible and the elevation of the tip of the nose as the anterior nasal spine is repositioned. Naturally, the skeletal and soft tissue responses are dependent on the extent of surgical repositioning. We present here a clinical case that demonstrates these changes.

Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38.

The serine/threonine kinase Akt/PKB is a potent regulator of cell survival and has oncogenic transformation potential. Previously, it has been shown that Akt can activate the transcription factor NF-kappaB and that this functions to block apoptosis induced by certain stimuli. The mechanism whereby Akt activates NF-kappaB has been controversial, with evidence supporting induction of nuclear translocation of NF-kappaB via activation of IkappaB kinase activity and/or the stimulation of the transcription function of NF-kappaB. Here we demonstrate that Akt targets the transactivation function of NF-kappaB by stimulating the transactivation domain of RelA/p65 in a manner that is dependent on IkappaB kinase beta activity and on the mitogen-activated protein kinase p38 (p38). Activation of RelA/p65 transactivation function requires serines 529 and 536, sites shown previously to be inducibly phosphorylated. Consistent with the requirement of p38 in the activation of NF-kappaB transcriptional function, expression of activated Akt induces p38 activity. Furthermore, the ability of IL-1beta to activate NF-kappaB is known to involve Akt, and we show here that IL-1beta induces p38 activity in manner dependent on Akt and IkappaB kinase activation. Interestingly, activated Akt and the transcriptional co-activators CBP/p300 synergize in the activation of the RelA/p65 transactivation domain, and this synergy is blocked by p38 inhibitors. These studies demonstrate that Akt, functioning through IkappaB kinase and p38, induces the transcription function of NF-kappaB by stimulating the RelA/p65 transactivation subunit of NF-kappaB.

p53 and Ki-67 as predictive markers for radiosensitivity in squamous cell carcinoma of the oral cavity? an immunohistochemical and clinicopathologic study.

PURPOSE: Previously published data relating the expression of p53 and Ki-67 to radiation response in head and neck cancer are conflicting. This may be due to differences in patient selection and treatment modalities. In this study of a homogenous population of patients with oral cavity cancer, Ki-67 and p53 indices were correlated with histopathologically assessed tumor regression after preoperative radiochemotherapy and longterm outcome. METHODS AND MATERIALS: Eighty-eight patients with squamous cell carcinoma of the oral cavity and treated between September 1985 and November 1995 by preoperative radiochemotherapy and definitive surgery were included in this analysis. By immunohistochemistry (IHC) the pre-irradiation expression of p53 and of Ki-67 were analyzed and correlated with the histopathologically proven tumor regression, overall survival and local control. RESULTS: The overall 2- and 5-year survival rates were 76.5% and 63%, the locoregional control rates were 84% and 79%, respectively. After preoperative radiochemotherapy 29 patients (33%) showed complete tumor regression (ypT(0) classification). Survival and local control rates were significantly higher for patients showing ypT(0) classification than ypT(1-4) classification (p < 0.01). This effect was independent of pretreatment tumor classification in multivariate analysis. Pre-irradiation p53 status and Ki-67 index had no influence on tumor regression and clinical outcome in these patients. CONCLUSION: Complete tumor regression after preoperative treatment is related to an improved outcome in combined modality treatment of oral cavity cancer. The presented study could not demonstrate an influence of p53 and Ki-67 status as detected by immunohistochemical staining on survival, local control, or tumor regression after radiochemotherapy.

[Effect of periosteum on induced bone formation by autolyzed, antigen-extracted, allogeneic bone. Determination of the extent of bone formation using quantitative computerized tomography]. / Einfluss des Periosts auf die induzierte Knochenneubildung durch autolysierten, antigenextrahierten, allogenen Knochen. Bestimmung des Ausmasses der Knochenneubildung mittels quantitativer Computertomographie.

Autolyzed, antigen-extracted, allogenic (AAA) bone is an osteoinductive preparation of completely demineralized bone matrix. It has been clinically applied for years. In an experimental study in rabbits, we evaluated the influence of cortical bone and periosteum on the amount of bone formation following augmentation with AAA bone. Two implants of standardized size were placed on the femoral bone of rabbits. A cell-excluding PTFE membrane was wrapped circularly around the femur as well as the anterior implant shielding the implant from the surrounding periosteum. The posterior implant was exposed directly to the periosteum while being shielded from the cortical bone by the membrane. Thus, two compartments were created selectively, preventing contact between the periosteum or cortical bone and the implants. For each compartment the area and volume of the induced new bone were evaluated by computerized radiograph analysis and quantitative CT (pQCT) scans. Implantation of AAA bone led to new bone formation in both compartments. Contact of the periosteum and the implant led to an almost four-fold increase in bone volume. Although bone formation showed interindividual variations, the difference of both compartments was highly significant using the Student's t-test for paired samples (P < 0.0001). The data show that periosteum is the primary source of new bone formation in augmentations with osteoinductive materials as it is rich in inducible progenitor cells and is well vascularized. In osseous augmentations with AAA bone, the periosteum should be preserved in order to achieve a close contact of the osteoinductive implant. Shielding from the periosteum, e.g., by cell-excluding membranes, leads to significantly less bone formation following implantation of AAA bone and should therefore be avoided.

[Effect of different factors on the bone forming properties of recombinant BMPs]. / Einfluss unterschiedlicher Faktoren auf die knochenbildenden Eigenschaften von rekombinanten BMPs.

The extent of BMP-induced new bone formation is mainly determined by the number of mesenchymal target cells in the recipient bed as well as by the biological half-life of the BMP molecules within the tissue. While the number of inducible cells is determined by the age and vascularization of the tissue, the retention time of the BMP molecules can be influenced. One possibility is the coupling of BMPs to suitable carriers, which significantly increases the osteoinductive effect. The reason for this is the physical binding of BMPs to the carrier material, which delays the resorption of the proteins. Other factors are the composition of the carrier materials, their structural stability, and possible dislocations of carrier particles. The local tissue concentration of BMPs can also be increased by an enhanced binding of the proteins to the extracellular matrix. A BMP-2 mutant (BMP-2xa) was produced by the specific modification of the amino acid sequence using recombinant technologies. BMP-2xa induces heterotopic bone formation at significantly lower concentrations than natural BMP-2. Furthermore, BMP-2xa-induced bone tissue possesses a higher bone density.

[Orthognathic surgery: corrective bone operations]. / Orthognathe Chirurgie: skelettverlagernde Operationen.

The article reviews the history of orthognathic surgery from the middle of the last century up to the present. Initially, mandibular osteotomies were only performed in cases of severe malformations. But during the last century a precise and standardized procedure for correction of the mandible was established. Multiple modifications allowed control of small fragments, functionally stable osteosynthesis, and finally a precise positioning of the condyle. In 1955 Obwegeser and Trauner introduced the sagittal split osteotomy by an intraoral approach. It was the final breakthrough for orthognathic surgery as a standard treatment for corrections of the mandible. Surgery of the maxilla dates back to the nineteenth century. B. von Langenbeck from Berlin is said to have performed the first Le Fort I osteotomy in 1859. After minor changes, Wassmund corrected a posttraumatic malocclusion by a Le Fort I osteotomy in 1927. But it was Axhausen who risked the total mobilization of the maxilla in 1934. By additional modifications and further refinements, Obwegeser paved the way for this approach to become a standard procedure in maxillofacial surgery. Tessier mobilized the whole midface by a Le Fort III osteotomy and showed new perspectives in the correction of severe malformations of the facial bones, creating the basis of modern craniofacial surgery. While the last 150 years were distinguished by the creation and standardization of surgical methods, the present focus lies on precise treatment planning and the consideration of functional aspects of the whole stomatognathic system. To date, 3D visualization by CT scans, stereolithographic models, and computer-aided treatment planning and simulation allow surgery of complex cases and accurate predictions of soft tissue changes.

NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1.

Accumulating evidence implicates the transcription factor NF-kappaB as a positive mediator of cell growth, but the molecular mechanism(s) involved in this process remains largely unknown. Here we use both a skeletal muscle differentiation model and normal diploid fibroblasts to gain insight into how NF-kappaB regulates cell growth and differentiation. Results obtained with the C2C12 myoblast cell line demonstrate that NF-kappaB functions as an inhibitor of myogenic differentiation. Myoblasts generated to lack NF-kappaB activity displayed defects in cellular proliferation and cell cycle exit upon differentiation. An analysis of cell cycle markers revealed that NF-kappaB activates cyclin D1 expression, and the results showed that this regulatory pathway is one mechanism by which NF-kappaB inhibits myogenesis. NF-kappaB regulation of cyclin D1 occurs at the transcriptional level and is mediated by direct binding of NF-kappaB to multiple sites in the cyclin D1 promoter. Using diploid fibroblasts, we demonstrate that NF-kappaB is required to induce cyclin D1 expression and pRb hyperphosphorylation and promote G(1)-to-S progression. Consistent with results obtained with the C2C12 differentiation model, we show that NF-kappaB also promotes cell growth in embryonic fibroblasts, correlating with its regulation of cyclin D1. These data therefore identify cyclin D1 as an important transcriptional target of NF-kappaB and reveal a mechanism to explain how NF-kappaB is involved in the early phases of the cell cycle to regulate cell growth and differentiation.