Morphological and mechanical characterisation of three-dimensional gyroid structures fabricated by electron beam melting for the use as a porous biomaterial.

Additive manufactured porous biomaterials based on triply periodic minimal surfaces (TPMS) are a highly discussed topic in the literature. With their unique properties in terms of open porosity, large surface area and surface curvature, they are considered to have bone mimicking properties and remarkable osteogenic potential. In this study, scaffolds of gyroid unit cells of different sizes consisting of a Ti6Al4V alloy were manufactured additively by electron beam melting (EBM). The scaffolds were analysed by micro-computed tomography (micro-CT) to determine their morphological characteristics and, subsequently, subjected to mechanical tests to investigate their quasi-static compressive properties and fatigue resistance. All scaffolds showed an average open porosity of 71-81%, with an average pore size of 0.64-1.41 mm, depending on the investigated design. The design with the smallest unit cell shows the highest quasi-elastic gradient (QEG) as well as the highest compressive offset stress and compression strength. Furthermore, the fatigue resistance of all unit cell size (UCS) variations showed promising results. In detail, the smallest unit cells achieved fatigue strength at 106 cycles at 45% of their compressive offset stress, which is comparatively good for additively manufactured porous biomaterials. In summary, it is demonstrated that the mechanical properties can be significantly modified by varying the unit cell size, thus enabling the scaffolds to be specifically tailored to avoid stress shielding and ensure implant safety. Together with the morphological properties of the gyroid unit cells, the fabricated scaffolds represent a promising approach for use as a bone substitute material.

Alterations in the mechanical, chemical and biocompatibility properties of low-cost polyethylene and polyester meshes after steam sterilization.

INTRODUCTION: In Africa and other Low Resource Settings (LRS), the guideline-based and thus in most cases mesh-based treatment of inguinal hernias is only feasible to a very limited extent. This has led to an increased use of low cost meshes (LCMs, mostly mosquito meshes) for patients in LRS. Most of the LCMs used are made of polyethylene or polyester, which must be sterilized before use. The aim of our investigations was to determine changes in the biocompatibility of fibroblasts as well as mechanical and chemical properties of LCMs after steam sterilization. MATERIAL AND METHODS: Two large-pored LCMs made of polyester and polyethylene in a size of 11 x 6 cm were cut and steam sterilized at 100, 121 and 134 °C. These probes and non-sterile meshes were then subjected to mechanical tensile tests in vertical and horizontal tension, chemical analyses and biocompatibility tests with human fibroblasts. All meshes were examined by stereomicroscopy, scanning electron microscopy (SEM), LDH (cytotoxicity) measurement, viability testing, pH, lactate and glycolysis determination. RESULTS: Even macroscopically, polyethylene LCMs showed massive shrinkage after steam sterilization, especially at 121 and 134 °C. While polyester meshes showed no significant changes after sterilization with regard to deformation and damage as well as tensile force and stiffness, only the unsterile polyethylene mesh and the mesh sterilized at 100 °C could be tested mechanically due to the shrinkage of the other specimen. For these meshes the tensile forces were about four times higher than for polyester LCMs. Chemical analysis showed that the typical melting point of polyester LCMs was between 254 and 269 °C. Contrary to the specifications, the polyethylene LCM did not consist of low-density polyethylene, but rather high-density polyethylene and therefore had a melting point of 137 °C, so that the marked shrinkage described above occurred. Stereomicroscopy confirmed the shrinkage of polyethylene LCMs already after sterilization at 100 °C in contrast to polyester LCMs. Surprisingly, cytotoxicity (LDH measurement) was lowest for both non-sterile LCMs, while polyethylene LCMs sterilized at 100 and 121 °C in particular showed a significant increase in cytotoxicity 48 hours after incubation with fibroblasts. Glucose metabolism showed no significant changes between sterile and non-sterile polyethylene and polyester LCMs. CONCLUSION: The process of steam sterilization significantly alters mechanical and structural properties of synthetic hernia mesh implants. Our findings do not support a use of low-cost meshes because of their unpredictable properties after steam sterilization.

TNF-α modulates genome-wide redistribution of ΔNp63α/TAp73 and NF-κB cREL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer.

The Cancer Genome Atlas (TCGA) network study of 12 cancer types (PanCancer 12) revealed frequent mutation of TP53, and amplification and expression of related TP63 isoform ΔNp63 in squamous cancers. Further, aberrant expression of inflammatory genes and TP53/p63/p73 targets were detected in the PanCancer 12 project, reminiscent of gene programs comodulated by cREL/ΔNp63/TAp73 transcription factors we uncovered in head and neck squamous cell carcinomas (HNSCCs). However, how inflammatory gene signatures and cREL/p63/p73 targets are comodulated genome wide is unclear. Here, we examined how the inflammatory factor tumor necrosis factor-α (TNF-α) broadly modulates redistribution of cREL with ΔNp63α/TAp73 complexes and signatures genome wide in the HNSCC model UM-SCC46 using chromatin immunoprecipitation sequencing (ChIP-seq). TNF-α enhanced genome-wide co-occupancy of cREL with ΔNp63α on TP53/p63 sites, while unexpectedly promoting redistribution of TAp73 from TP53 to activator protein-1 (AP-1) sites. cREL, ΔNp63α and TAp73 binding and oligomerization on NF-κB-, TP53- or AP-1-specific sequences were independently validated by ChIP-qPCR (quantitative PCR), oligonucleotide-binding assays and analytical ultracentrifugation. Function of the binding activity was confirmed using TP53-, AP-1- and NF-κB-specific REs or p21, SERPINE1 and IL-6 promoter luciferase reporter activities. Concurrently, TNF-α regulated a broad gene network with cobinding activities for cREL, ΔNp63α and TAp73 observed upon array profiling and reverse transcription-PCR. Overlapping target gene signatures were observed in squamous cancer subsets and in inflamed skin of transgenic mice overexpressing ΔNp63α. Furthermore, multiple target genes identified in this study were linked to TP63 and TP73 activity and increased gene expression in large squamous cancer samples from PanCancer 12 TCGA by CircleMap. PARADIGM inferred pathway analysis revealed the network connection of TP63 and NF-κB complexes through an AP-1 hub, further supporting our findings. Thus, inflammatory cytokine TNF-α mediates genome-wide redistribution of the cREL/p63/p73, and AP-1 interactome, to diminish TAp73 tumor suppressor function and reciprocally activate NF-κB and AP-1 gene programs implicated in malignancy.

Is the transnasal access for esophagogastroduodenoscopy in routine use equal to the transoral route? A prospective, randomized trial.

BACKGROUND AND STUDY AIMS: Routine esophagogastroduodenoscopy (EGD) is increasingly performed without sedation. Transoral (TO) and transnasal (TN) EGD offer different patient comfort and complications. PATIENTS AND METHODS: For a controlled, randomized, clinical trial comparing TN-EGD with TO-EGD without sedation, patients were assigned to TN-EGD using a thin endoscope (group 1, 93 patients), or TO-EGD using a standard endoscope (group 2, 90 patients). Physician-rated procedural time and complications as well as patient-rated side effects and preferences were compared. In group 3, patients (118) who had previously undergone TO-EGD, now underwent TN-EGD. RESULTS: Between group 1 and 2 there was no significant difference for procedural time. Nausea (p = 0.047) and epistaxis (p < 0.001) were significantly more frequent for TN-EGD. Conversion rate from TN- to TO-EGD was low with 4.3 %. For TN-EGD, patients' tolerance was better (p < 0.001), gagging was less (p < 0.001). In case of a future EGD, patients who know both procedures (group 3), strongly vote for TN-EGD (80 %). All groups vote against sedation for future procedures (90 %/90 %/89 %). CONCLUSIONS: Epistaxis can be relevant after TN-EGD, but can mostly be managed conservatively. TN-EGD is superior to TO-EGD regarding subjective and objective gagging as well as procedural tolerance. Patients who experienced both access routes, prefer TN-EGD. TN-EGD without sedation should be aspired for patient comfort and is recommended for routine use.

High-quality Si3N4 circuits as a platform for graphene-based nanophotonic devices.

Hybrid circuits combining traditional nanophotonic components with carbon-based materials are emerging as a promising platform for optoelectronic devices. We demonstrate such circuits by integrating single-layer graphene films with silicon nitride waveguides as a new architecture for broadband optical operation. Using high-quality microring resonators and Mach-Zehnder interferometers with extinction ratios beyond 40 dB we realize flexible circuits for phase-sensitive detection on chip. Hybrid graphene-photonic devices are fabricated via mechanical transfer and lithographic structuring, allowing for prolonged light-matter interactions. Our approach holds promise for studying optical processes in low-dimensional physical systems and for realizing electrically tunable photonic circuits.

[What kind of school do children need?]. / Welche Schule brauchen Kinder?

At every age abilities mature and are internalized through corresponding experience. Every child wants to develop and learn, but at his own pace. In this process the child is not only active, but also selective, that is, it seeks experiences that correspond to its stage of development. The task of the school consists of making it possible for the child to gain learning experience that suits its stage of development in the respective areas of competence. Not only does the cognitive competence of children vary, but they also have differing needs as to emotional security and social experience. If it is possible to create an optimal balance in each of the three areas, learning experience, emotional security and socialization, between the needs and the individual development of the child and its environment, then the child can develop in the best possible way.

Comprehensive microRNA expression profiling of the hematopoietic hierarchy.

The hematopoietic system produces a large number of highly specialized cell types that are derived through a hierarchical differentiation process from a common stem cell population. miRNAs are critical players in orchestrating this differentiation. Here, we report the development and application of a high-throughput microfluidic real-time quantitative PCR (RT-qPCR) approach for generating global miRNA profiles for 27 phenotypically distinct cell populations isolated from normal adult mouse hematopoietic tissues. A total of 80,000 RT-qPCR assays were used to map the landscape of miRNA expression across the hematopoietic hierarchy, including rare progenitor and stem cell populations. We show that miRNA profiles allow for the direct inference of cell lineage relations and functional similarity. Our analysis reveals a close relatedness of the miRNA expression patterns in multipotent progenitors and stem cells, followed by a major reprogramming upon restriction of differentiation potential to a single lineage. The analysis of miRNA expression in single hematopoietic cells further demonstrates that miRNA expression is very tightly regulated within highly purified populations, underscoring the potential of single-cell miRNA profiling for assessing compartment heterogeneity.

Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells.

Cancer cells often acquire a constitutively active nuclear factor-kappaB (NF-kappaB) program to promote survival, proliferation and metastatic potential by mechanisms that remain largely unknown. Extending observations from an immunologic setting, we demonstrate that microRNA-146a and microRNA-146b (miR-146a/b) when expressed in the highly metastatic human breast cancer cell line MDA-MB-231 function to negatively regulate NF-kappaB activity. Lentiviral-mediated expression of miR-146a/b significantly downregulated interleukin (IL)-1 receptor-associated kinase and TNF receptor-associated factor 6, two key adaptor/scaffold proteins in the IL-1 and Toll-like receptor signaling pathway, known to positively regulate NF-kappaB activity. Impaired NF-kappaB activity was evident from reduced phosphorylation of the NF-kappaB inhibitor IkappaBalpha, reduced NF-kappaB DNA-binding activity and suppressed expression of the NF-kappaB target genes IL-8, IL-6 and matrix metalloproteinase-9. Functionally, miR-146a/b-expressing MDA-MB-231 cells showed markedly impaired invasion and migration capacity relative to control cells. These findings implicate miR-146a/b as a negative regulator of constitutive NF-kappaB activity in a breast cancer setting and suggest that modulating miR-146a/b levels has therapeutic potential to suppress breast cancer metastases.

Increased target specificity of anti-HER2 genospheres by modification of surface charge and degree of PEGylation.

Genospheres are cationic lipid-nucleic acid nanoparticles prepared by the assembly of the lipids and nucleic acids from an aqueous/organic liquid monophase that independently dissolves the components, where the resultant particles are homogeneously sized (70-110 nm), with efficiently incorporated and protected DNA. In the present study, we demonstrate pH-dependent modulation of the Genosphere surface charge using pH-titratable lipids. By incorporation of the lipids with titratable anionic or imidazole headgroups, Genospheres with neutral or anionic surface charge at neutral pH were produced and compared for cellular uptake and transfection of a reporter gene (luciferase) in culture of breast cancer cells. The extent of particle-cell association was also studied by fluorescent microscopy and quantified by cytofluorometery. The effects of Genosphere surface modification with poly(ethylene glycol) (molecular weight 2000) at low (0.5 mol %) and high (5 mol %) grafting densities, as well as the effects of HER2-receptor-directed targeting by an internalizable anti-HER2 scFv F5, linked via PEG spacer, were also studied. Inclusion in the Genosphere formulation of pH-titratable lipids CHEMS (cholesteryl hemisuccinate), CHIM (1-(3-(cholesteryloxycarbonylamino)propyl)imidazole), or DSGG (1,2-distearoyl-sn-glycero-3-hemiglutarate) rendered the particles surface-charge neutral or slightly anionic at neutral pH, and cationic at mildly acidic pH, as shown by zeta-potential measurements. In HER2-targeted systems, transfection activity and target specificity with HER2-overexpressing SKBR-3 breast cancer cells were dependent on Genosphere surface charge and PEGylation. The highest target specificity correlated with low cationic charge at neutral pH, while incorporation of 5 mol % PEG-lipid had only minor effects on Genosphere-cell association, internalization, and transfection activity. The implications of this work for potential in vivo applications are discussed.

Genospheres: self-assembling nucleic acid-lipid nanoparticles suitable for targeted gene delivery.

We describe the assembly of a cationic lipid-nucleic acid nanoparticle from a liquid monophase containing water and a water miscible organic solvent where both lipid and DNA components are separately soluble prior to their combination. Upon removal of the organic solvent, stable and homogenously sized (70-100 nm) lipid-nucleic acid nanoparticles (Genospheres) were formed. The low accessibility (<15%) of the nanoparticle-encapsulated DNA to a DNA intercalating dye indicated well-protected nucleic acids and high DNA incorporation efficiencies. It was demonstrated that Genospheres could be stably stored under a variety of conditions including a lyophilized state where no appreciable increase in particle size or DNA accessibility was observed following reconstitution. Finally, Genospheres were made target-specific by insertion of an antibody-lipopolymer (anti-HER2 scFv (F5)-PEG-DSPE) conjugate into the particle. The target specificity (>100-fold) in HER2 overexpressing SK-BR-3 breast cancer cells was dependent on the degree of PEGylation, where the incorporation of high amounts of PEG-lipid on the particle surface (up to 5 mol%) had only a minor effect on the transfection activity of the targeted Genospheres. In summary, this work describes a novel, readily scalable method for preparing highly stable immunotargeted nucleic acid delivery vehicles capable of achieving a high degree of specific transfection activity.

Efficacy of intraoral topical anesthetics in children.

OBJECTIVES: The literature reports mixed results regarding the efficacy of intraoral topical anesthetics. Only a few studies have been performed in children. Some non-placebo controlled studies have been carried out to compare the efficacy in reducing children's injection pain between different topical anesthetics METHODS: In a randomized, double blind, placebo controlled study with split-mouth design 104 children were enrolled to evaluate the efficacy of four topical anesthetics (Gingicain Spray, Gingicaine Topical Anesthetic, Legecain-Solution, EMLA Crème) when used prior to buccal injections within the conservative treatment of carious upper primary molars. The heart rate change and a Face Pain Scale were used as primary variables. The Visual Analog Scale, the modified Children's Hospital Pain Scale and the Sound-Eyes-Motor Scale were also evaluated. RESULTS: There was no significant difference between the placebo and any corresponding topical anesthetic with regard to the primary variables (HRC and FPS). A significant difference was found in favour of Gingicain Spray and Gingicaine Topical Anesthetic according to secondary variables (VAS, S(E)MS). CONCLUSION: While the secondary variables point to a benefit of the topical anesthetics Gingicain Spray and Gingicaine Topical Anesthetic compared to placebo, the results of the primary variables showed no differences in effectiveness of topical anesthetics and their corresponding placebos.

Consensus statement. Workshop on therapeutic resistance in breast cancer: impact of growth factor signalling pathways and implications for future treatment.

Anti-hormones (notably tamoxifen), chemotherapy and modern radiotherapeutic approaches are invaluable in the management of breast cancer, and collectively have contributed substantially to the improved survival in this disease. Moreover, there is promise that these successes will continue with the emergence of other endocrine agents (for example, aromatase inhibitors and pure anti-oestrogens). However, de novo and acquired resistance comprises a significant problem with all treatment approaches examined to date. This Workshop aimed to evaluate the contribution made by growth factor signalling pathways in the various resistant states, primarily focusing on resistance to anti-hormonal strategies and spanning experimental models and, where possible, clinical breast cancer data. The successes and limitations of therapeutic targeting of these pathways with various signal transduction inhibitors (STIs) were evaluated in model systems and from emerging clinical trials (including epidermal growth factor receptor inhibitors such as gefitinib). It was concluded that growth factor signalling is an important contributor in the development of endocrine resistance in breast cancer and that use of STIs provides a promising therapeutic strategy for this disease. However, the cancer cell is clearly able to harness alternative growth factor signalling pathways for growth and cell survival in the presence of STI monotherapy and, as a consequence, the efficacy of STIs is likely to be limited by the acquisition of resistance. A number of strategies were proposed from studies in model systems that appeared to enhance anti-tumour actions of existing STI monotherapy, notably including combination therapies targeting multiple pathways. With the increased availability of diverse STIs and improved drug delivery, there is much hope that the more complex therapeutic strategies proposed may ultimately be achievable in clinical practice.

The NFkappaB pathway and endocrine-resistant breast cancer.

Endocrine therapy with an estrogen receptor (ER)-targeted antiestrogen, such as tamoxifen, or estrogen ablation by aromatase inhibitors is clinically indicated for the management of all forms of ER-positive breast cancer. However, 30-50% of ER-positive breast cancer cases fail to benefit clinically from endocrine therapy alone, and recent molecular evidence suggests that 'crosstalk' pathways originating from activated receptor tyrosine kinases and/or other proliferative and survival signals may be contributing to this endocrine resistance. Molecular identification and validation of candidate ER crosstalking pathways will likely lead to clinically important prognostic markers and targets for the application of novel therapeutics in combination with standard endocrine agents. This review focuses on a critical survival and proliferation pathway involving activation of nuclear factor-kappaB (NFkappaB), a family of ubiquitously expressed transcription factors that for nearly two decades have been known to be critical regulators of mammalian immune and inflammatory responses, and more recently have been associated with chemotherapy resistance. With the demonstration that activation of NFkappaB is absolutely required for normal mammary gland development, NFkappaB involvment in human breast cancers was initially explored and linked to the development of hormone-independent (ER-negative) breast cancer. Newer clinical evidence now implicates NFkappaB activation, particularly DNA-binding by the p50 subunit of NFkappaB, as a potential prognostic marker capable of identifying a high-risk subset of ER-positive, primary breast cancers destined for early relapse despite adjuvant endocrine therapy with tamoxifen. Furthermore, initial preclinical studies suggest that treatment strategies designed to prevent or interrupt activation of NFkappaB in cell-line models of these more aggressive, ER-positive breast cancers can restore their sensitivity to such standard endocrine agents as tamoxifen.

Impact of dominant stenoses on the serum level of the tumor marker CA19-9 in patients with primary sclerosing cholangitis.

BACKGROUND/AIMS: Patients with primary sclerosing cholangitis (PSC) have an increased risk of developing hepatobiliary tumors. The tumor marker CA19-9 was claimed to indicate the occurrence of bile duct carcinoma. This study aimed to assess whether increased serum levels of CA19-9 in PSC patients with dominant stenoses indicate bile duct carcinoma. METHODS: The study cohort comprised 106 patients treated over a median time of 5.0 years (range 0.5 - 13 years). All patients were treated with ursodeoxycholic acid (UDCA) and whenever they developed dominant stenoses by endoscopic dilatation of these stenoses. In endoscopically treated patients, CA19-9 levels were measured before and 3, 6, 12 and 24 months after endoscopic dilatation. RESULTS: Of the 106 patients, 22 carcinoma-free patients and 3 patients with bile duct carcinoma had elevated CA 19 - 9 levels. In 14 out of 25 patients with elevated CA19-9 levels, dominant stenoses were diagnosed and treated by endoscopic dilatation. In 71.4 % of the endoscopically treated patients, CA19-9 levels decreased following the endoscopic intervention. CONCLUSIONS: In PSC patients, increased serum levels of CA19-9 are rarely due to the development of bile duct carcinoma. In patients with dominant stenoses, the relief of biliary obstruction by endoscopic dilatation may lead to a decrease of the serum levels of CA19-9.

Case report: the Lesch-Nyhan syndrome.

BACKGROUND: The Lesch-Nyhan syndrome (LNS) is a rare x-linked excessive disorder of purine metabolism, caused by the congenital absence of hypoxanthine guanine phosphoribosyl transferase (HGPRT). CASE REPORT: In January 2000 a 2 year old boy was referred to a paediatric dental office in Landshut, Germany, because of severe and repeated lip chewing and aggressive tongue biting. A medical history revealed a normal pregnancy with no complications but a diagnosis of muscular hypotonia was made at four months of age. At 18 months a diagnosis of LNS was established through biochemical analysis and molecular examinations. The child displayed self-destructive behaviour, typical in children with LNS. Shortly thereafter the patient was supplied with arm cuffs for self-protection which were not tolerated and the self-mutilation continued. Eventually the extraction of all primary teeth was deemed necessary to prevent additional medical problems for this child. FOLLOW-UP: One year after the dental extractions the patient presented with no bite injuries but was now using his fingers to injure himself.

First case of isolated small bowel transplantation at the university of cologne: rejection-free course under quadruple immunosuppression and endoluminal monitoring with video-capsule.

Intestinal transplantation is the only curative form of treatment for fulminant short bowel syndrome. Results have been hampered by frequent rejection episodes as well as technical and infectious complications. We report the first case of complete small bowel transplantation performed at our institution. A 37-year-old male patient suffered from massive gut infarction due to a superior mesenteric artery embolus from a thrombus in the descending aorta resulting from hereditary protein S and C deficiency. The primary surgery resulted in a duodenocolostomy requiring total parenteral nutrition. The course was further complicated by multiple central line infections and pre-renal kidney failure induced by dehydration. After 17 months, we performed a cadaveric small bowel transplant using systemic venous drainage. The ileum was anastomosed end-to-end to the recipient ascending colon. The proximal jejunum was used to create a jejunostomy, with an end-to-side duodenojejunostomy. Immunosuppression consisted of a single-administration of antithymocyte globulin (ATG), tacrolimus, mycophenolate mofetil (MMF), and methylprednisolone given enterally from day 1. Biopsies of the upper jejunum showed no signs of rejection. The graft was monitored via capsule video endoscopy after 9 weeks and appeared normal. The patient was discharged on day 35, completely on an enteral diet and gaining weight with a good quality of life. Oral valganciclovir was given for the cytomegalovirus prophylaxis infection (donor-positive, recipient-negative constellation), with no clinical or serologic signs of infection. The early course after small bowel transplantation using a quadruple regimen was clinically successful. The use of video-capsules allows for noninvasive visual monitoring of bowel segments that cannot be reached endoscopically.

Fulminant liver failure induced by hepatosplenic alphabeta T-cell lymphoma.

Since survival rates of fulminant liver failure are low, early consideration of liver transplantation in patients developing hepatic encephalopathy due to progressive liver failure is mandatory. Rapid diagnostic work-up is necessary to identify the underlying disease and to rule out contraindications to liver transplantation. We report the case of a 35-year-old patient presenting with fulminant hepatitis and a four-week history of biopsy-proven autoimmune hepatitis. Despite high-dose steroid-treatment liver function progressively worsened and hepatic encephalopathy rapidly developed. Histopathologic evaluation of a liver biopsy specimen revealed necrotizing hepatitis and rare atypical lymphocytes. Surgical biopsy specimens confirmed the suspicion of an aggressive hepatosplenic alphabeta T-cell lymphoma which represents a contraindication to liver transplantation.

Digital photography: exposures, editing images, and presentation.

The digital camera is one of the most important electronic articles on the wish list in the private sector, and professional users are also making increasing use of the possibilities that the digital image provides. In dental medicine, nothing speaks for the analog image anymore, and thus many dentists are searching for an expedient solution. Anyone who is faced with deciding on a digital camera will often be confused by the immense variety of models and concepts, which are also subject to rapid change. Fortunately for dental medicine, however, the current camera generation--both viewfinder and SLR systems--offers quality features which will be able to satisfy even high demands for many years.

Understanding the age dependency of breast cancer biomarkers.

This review and study of nearly 4,000 primary breast cancers evaluates the hypothesis that human aging not only increases breast cancer incidence but also alters breast cancer biology. Clinically validated biomarkers were chosen as surrogate measures of genetic instability and tumor growth, invasiveness and metastatic potential. Our results support the premise that breast cancer clinical behavior and biology are significantly affected by patient age, but call into question key aspects of the current cancer-aging paradigm.