Advances in Preventive Therapy for Estrogen-Receptor-Negative Breast Cancer.

Preventing breast cancer is an effective strategy for reducing breast cancer deaths. The purpose of chemoprevention (also termed preventive therapy) is to reduce cancer incidence by use of natural, synthetic, or biological agents. The efficacy of tamoxifen, raloxifene, and exemestane as preventive therapy against estrogen-receptor (ER)-positive breast cancer is well established for women at increased risk for breast cancer. However, because breast cancer is a heterogeneous disease, distinct preventive approaches may be required for effective prevention of each subtype. Current research is, therefore, focused on identifying alternative mechanisms by which biologically active compounds can reduce the risk of all breast cancer subtypes including ER-negative breast cancer. Promising agents are currently being developed for prevention of HER2-positive and triple-negative breast cancer (TNBC) and include inhibitors of the ErbB family receptors, COX-2 inhibitors, metformin, retinoids, statins, poly(ADP-ribose) polymerase inhibitors, and natural compounds. This review focuses on recent progress in research to develop more effective preventive agents, in particular for prevention of ER-negative breast cancer

Joint single-cell DNA accessibility and protein epitope profiling reveals environmental regulation of epigenomic heterogeneity.

Here we introduce Protein-indexed Assay of Transposase Accessible Chromatin with sequencing (Pi-ATAC) that combines single-cell chromatin and proteomic profiling. In conjunction with DNA transposition, the levels of multiple cell surface or intracellular protein epitopes are recorded by index flow cytometry and positions in arrayed microwells, and then subject to molecular barcoding for subsequent pooled analysis. Pi-ATAC simultaneously identifies the epigenomic and proteomic heterogeneity in individual cells. Pi-ATAC reveals a casual link between transcription factor abundance and DNA motif access, and deconvolute cell types and states in the tumor microenvironment in vivo. We identify a dominant role for hypoxia, marked by HIF1α protein, in the tumor microvenvironment for shaping the regulome in a subset of epithelial tumor cells

Single-cell epigenomic variability reveals functional cancer heterogeneity.

BackgroundCell-to-cell heterogeneity is a major driver of cancer evolution, progression, and emergence of drug resistance. Epigenomic variation at the single-cell level can rapidly create cancer heterogeneity but is difficult to detect and assess functionally.ResultsWe develop a strategy to bridge the gap between measurement and function in single-cell epigenomics. Using single-cell chromatin accessibility and RNA-seq data in K562 leukemic cells, we identify the cell surface marker CD24 as co-varying with chromatin accessibility changes linked to GATA transcription factors in single cells. Fluorescence-activated cell sorting of CD24 high versus low cells prospectively isolated GATA1 and GATA2 high versus low cells. GATA high versus low cells express differential gene regulatory networks, differential sensitivity to the drug imatinib mesylate, and differential self-renewal capacity. Lineage tracing experiments show that GATA/CD24hi cells have the capability to rapidly reconstitute the heterogeneity within the entire starting population, suggesting that GATA expression levels drive a phenotypically relevant source of epigenomic plasticity.ConclusionSingle-cell chromatin accessibility can guide prospective characterization of cancer heterogeneity. Epigenomic subpopulations in cancer impact drug sensitivity and the clonal dynamics of cancer evolution

Особенности принятия управленческих решенийв финансовой деятельности

PURPOSE: To test the ability of a new IGF-IR tyrosine kinase inhibitor BMS-536924 to reverse the ability of constitutively active IGF-IR (CD8-IGF-IR) to transform MCF10A cells, and to examine the effect of the inhibitor on a range of human breast cancer cell lines. EXPERIMENTAL DESIGN: CD8-IGF-IR-MCF10A cells were grown in monolayer culture, three-dimensional (3D) culture, and as xenografts, and treated with BMS-536924. Proliferation, cell-cycle, polarity, and apoptosis were measured. Twenty three human breast cancer cell lines were treated in monolayer culture with BMS-536924 and cell viability was measured. MCF7, MDA-MB-231, and MDA-MB-435 were treated with BMS-536924 in monolayer and 3D culture and proliferation, migration, polarity, and apoptosis were measured. RESULTS: Treatment of CD8-IGF-IR-MCF10A cells grown in 3D culture with BMS-536924 caused a blockade of proliferation, restoration of apical-basal polarity, and enhanced apoptosis, resulting in a partial phenotypic reversion to normal acini. In monolayer culture, BMS-536924 induced a dose-dependent inhibition of proliferation, with an accumulation of cells in G(0)/G(1,) and completely blocked CD8-IGF-IR-induced migration, invasion, and anchorage-independent growth. CD8-IGF-IR-MCF10A xenografts treated with BMS-536924 (100mg/kg/day) showed a 76% reduction in xenograft volume. In a series of twenty three human breast cancer cell lines, BMS-536924 inhibited monolayer proliferation of sixteen cell lines. Most strikingly, treatment of MCF7 cells grown in 3D culture with BMS-536924 caused blockade of proliferation, and resulted in the formation of hollow polarized lumen. CONCLUSIONS: These results demonstrate that the new small molecule BMS-536924 is an effective inhibitor of IGF-IR, causing a reversion of an IGF-IR-mediated transformed phenotype

The aryl hydrocarbon receptor in tumor immunity

The aryl hydrocarbon receptor (AHR) binds environmental toxins and mediates immune regulation. The tryptophan metabolite kynurenine has now been identified as an endogenous ligand of the human AHR constitutively produced by gliomas and other types of cancer via tryptophan-2,3-dioxygenase (TDO), thereby suppressing antitumor immune responses via the AHR. Thus, this pathway represents an important novel target for cancer immunotherapy

Parametrisierung unbekannter Zahnoberflächen mittels des biogenerischen Zahnmodells

Längenmessungen und deskriptive Charakterisierungen waren bisher die einzigen Anhaltspunkte zur Beschreibung der Kauflächenmorphologie. Für computergestützte Verfahren in der Zahnmedizin ist dies für die Erstellung eines Datensatzes nicht ausreichend. In der Literatur existieren hierzu bisher keine Lösungsansätze. In dieser Arbeit wurde in einem ersten Schritt eine Zahnbibliothek aus unversehrten Kauflächen aufgebaut. Mit Hilfe dieser Zahndatenbank wurde ein mathematisches Modell (Mehl 2002), das einen bestimmten Zahntypus anhand weniger Parameter unter Berücksichtigung funktioneller und biologisch relevanter Strukturen mathematisch beschreiben kann, erstellt. Dieses biogenerische Zahnmodell wurde an verschiedenen, der Zahnbibliothek unbekannten, Zähnen getestet. Die Ergebnisse zeigen, dass in allen Fällen eine vollautomatische Anpassung möglich war. Die Genauigkeiten der Anpassungen lagen bei etwa 87 μm. Des Weiteren wurden verschiedene Einflussgrößen auf das mathematische Modell untersucht. Dabei konnten keine allgemeingültigen Werte gefunden werden, die in jedem Falle die besten Ergebnisse liefern. Die Bandbreite der entsprechenden Werte konnte jedoch eingegrenzt werden. Die visuelle Auswertung und der metrische Vergleich der Anpassungen verdeutlichen die große Flexibilität des biogenerischen Zahnmodells. In einem weiteren Schritt wurden die Bibliothekskauflächen untereinander verglichen. Der Durchschnittswert für die mittlere Abweichung von dem rechten und dem linken ersten Molaren jeweils eines Probanden beträgt 119 µm im Unterkiefer und 126 µm im Oberkiefer. Bei dem Vergleich von ersten Molaren unterschiedlicher Probanden ergibt sich ein Wert von 276 µm im Unterkiefer und 340 µm im Oberkiefer. In einer Dritten Versuchsanordnung wurden sieben Prothesenzähne mittels biogenerischen Zahnmodells auf ihre „Natürlichkeit“ getestet. Vier Zähne konnten als eher natürliche Durchschnittszähne klassifiziert werden. Zwei Zähne wurden als nicht repräsentative Durchschnittszähne eingestuft. Ein Zahn konnte auf Grund seines starken Abrasionsgrades nicht eingeordnet werden. Insgesamt besteht mit Hilfe des biogenerischen Zahnmodells die Möglichkeit, Kauflächen vollautomatisch unter Berücksichtigung biologischer und funktio¬neller Kriterien zu rekonstruieren. Inwieweit dies bei Zähnen gelingt, die einen großem Substanzverlust erfahren haben, beispielsweise durch Inlay-/Onlaypräperation, müssen weiter Studien zeigen. Auch scheint die Frage interessant, ob es möglich ist, von noch erhaltenen Zähnen Rückschlüsse auf bereits zerstörte Zähne zu erhalten

Diagnostic validity of early proximal caries detection using near-infrared imaging technology on 3D range data of posterior teeth

OBJECTIVES This in vitro study analysed potential of early proximal caries detection using 3D range data of teeth consisting of near-infrared reflection images at 850~nm (NIRR). MATERIALS AND METHODS Two hundred fifty healthy and carious permanent human teeth were arranged pairwise, examined with bitewing radiography (BWR) and NIRR and validated with micro-computed tomography. NIRR findings were evaluated from buccal, lingual and occlusal (trilateral) views according to yes/no decisions about presence of caries. Reliability assessments included kappa statistics and revealed high agreement for both methods. Statistical analysis included cross tabulation and calculation of sensitivity, specificity and AUC. RESULTS Underestimation of caries was 24.8% for NIRR and 26.4% for BWR. Overestimation was 10.4% for occlusal NIRR and 0% for BWR. Trilateral NIRR had overall accuracy of 64.8%, overestimation of 15.6% and underestimation of 19.6%. NIRR and BWR showed high specificity and low sensitivity for proximal caries detection. CONCLUSIONS NIRR achieved diagnostic results comparable to BWR. Trilateral NIRR assessments overestimated presence of proximal caries, revealing stronger sensitivity for initial caries detection than BWR. CLINICAL RELEVANCE NIRR provided valid complement to BWR as diagnostic instrument. Investigation from multiple angles did not substantially improve proximal caries detection with NIRR

Comparison of novel and established caries diagnostic methods: a clinical study on occlusal surfaces

BACKGROUND The purpose of this prospective clinical diagnostic study with validation was to compare the diagnostic accuracy of near-infrared transillumination (NIRT), laser fluorescence measurement (LF), alternating current impedance spectroscopy (ACIS) and their combinations as adjunct methods to visual examination (VE) for occlusal caries detection using a hybrid reference standard. METHODS Ninety-six first and second non-cavitated permanent molars from 76 individuals (mean age 24.2) were investigated using (VE) (ICDAS) and bitewing radiography (BWR), as well as NIRT, LF and ACIS. The findings of BWR and NIRT were evaluated by two examiners while the other examinations were conducted by one calibrated dentist. The hybrid reference standard consisted of non-operative validation based on the results of VE and BWR and operative validation. Statistical analysis included cross-tabulations, calculation of sensitivity, specificity and area under the receiver operating characteristic curve at three diagnostic thresholds: caries in general, enamel caries and dentin caries. RESULTS NIRT, LF and ACIS exhibited high sensitivity for caries in general 1.00 (1.00-1.00), 0.77 (0.65-0.88), 0.75 (0.63-0.87)) and for dentin caries (0.97 (0.91-1.03), 0.76 (0.76-0.90), 0.64 (0.47-0.80). Sensitivity values for enamel caries were weak (0.21, 0.11, 0.37). Specificity values did not fall below 0.65 (NIRT) for all categories and methods, except for NIRT at the caries detection threshold (0.27). A combination of LF and ACIS with VE improved the diagnostic performance at the overall and the enamel caries threshold. The other methods showed fair to excellent discrimination at the overall caries threshold (NIRT 0.64, LF 0.89 and ACIS 0.86) and acceptable discrimination at the dentin caries threshold (NIRT 0.82, LF 0.81 and ACIS 0.79). AUROC for enamel caries exhibited the weakest discrimination. Accuracy was 65.6{\%} for VE, 69.8{\%} for BWR, 50.0{\%} for NIRT, 53.1{\%} for LF and 74.0{\%} for ACIS. Reliability assessment for BWR and NIRT showed at least substantial agreements for all analyses. CONCLUSIONS The methods, NIRT, LF and ACIS, revealed different potential but no impeccable performance for occlusal caries detection. All are suitable instruments to detect hidden carious lesion in dentin. As auxiliaries to VE, LF and ACIS showed an increase in diagnostic performance

Transillumination and HDR Imaging for Proximal Caries Detection

The purpose of this study was to develop an in vitro model for the validation of near-infrared transillumination (NIRT) for proximal caries detection, to enhance NIRT with high-dynamic-range imaging (HDRI), and to compare both methods, using micro-computed tomography (mu CT) as a reference standard. Both proximal surfaces of 53 healthy or decayed permanent human teeth were examined using the Diagnocam (DC) (KaVo) and NIRT with HDRI (NIRT-HDRI). NIRT was combined with HDRI to improve the diagnostic performance by reducing under- and overexposed image areas. For NIRT-HDRI, an exposure series was captured and merged into a single HDR image. A classification was applied according to lesion depth. All surfaces were assessed twice by 2 trained examiners, and additionally with mu CT for validation. The Kappa statistic was used to calculate inter-rater reliability and agreement between DC and NIRT-HDRI. Inter-rater reliability (weighted Kappa, w) showed very good agreement for the DC (0.90) and NIRT-HDRI (0.96). The overall agreement (w) was almost perfect (0.85). In the individual categories (0 to 4), the agreement (simple Kappa) ranged from almost perfect (category 4) to moderate (1 and 2) to substantial (categories 0 and 3). Sensitivity and specificity of sound surfaces, enamel, and dentin caries ranged from 0.57 to 0.99 and were similar for both methods in the different categories. NIRT-HDRI had a higher sensitivity for sound surfaces and enamel caries, as well as a higher specificity for dentin caries. Regarding the obtained images, HDRI allowed for the detection of caries within a greater range of luminance levels, resulting in a more detailed visualization of structures without under- or overexposure. However, HDRI this did not improve the diagnostics significantly. Distinguishing between a processed demineralized enamel and dentin lesions appears to be a problem specific to NIRT and cannot be balanced using HDRI