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In long-term follow-up of more than 500 patients with melanoma containing a BRAF V600E or V600K mutation, a combination of dabrafenib plus trametinib was associated with progression-free survival in 19% of the patients and overall survival in 34% at 5 years. A complete response to dabrafenib plus trametinib was the strongest predictor of long-term survival.

The microRNA-200 family participates in the maintenance of an epithelial phenotype and loss of its expression can result in epithelial to mesenchymal transition (EMT). Furthermore, the loss of expression of miR-200 family members is linked to an aggressive cancer phenotype. Regulation of the miR-200 family expression in normal and cancer cells is not fully understood. Epigenetic mechanisms participate in the control of miR-200c and miR-141 expression in both normal and cancer cells. A CpG island near the predicted mir-200c/mir-141 transcription start site shows a striking correlation between miR-200c and miR-141 expression and DNA methylation in both normal and cancer cells, as determined by MassARRAY technology. The CpG island is unmethylated in human miR-200/miR-141 expressing epithelial cells and in miR-200c/miR-141 positive tumor cells. The CpG island is heavily methylated in human miR-200c/miR-141 negative fibroblasts and miR-200c/miR-141 negative tumor cells. Mouse cells show a similar inverse correlation between DNA methylation and miR-200c expression. Enrichment of permissive histone modifications, H3 acetylation and H3K4 trimethylation, is seen in normal miR-200c/miR-141-positive epithelial cells, as determined by chromatin immunoprecipitation coupled to real-time PCR. In contrast, repressive H3K9 dimethylation marks are present in normal miR-200c/miR-141-negative fibroblasts and miR-200c/miR-141 negative cancer cells and the permissive histone modifications are absent. The epigenetic modifier drug, 5-aza-2'-deoxycytidine, reactivates miR-200c/miR-141 expression showing that epigenetic mechanisms play a functional role in their transcriptional control. We report that DNA methylation plays a role in the normal cell type-specific expression of miR-200c and miR-141 and this role appears evolutionarily conserved, since similar results were obtained in mouse. Aberrant DNA methylation of the miR-200c/141 CpG island is closely linked to their inappropriate silencing in cancer cells. Since the miR-200c cluster plays a significant role in EMT, our results suggest an important role for DNA methylation in the control of phenotypic conversions in normal cells.

Small volumes of felsic melt, commonly known as oceanic plagiogranites, appear as melt pockets or dikes within the gabbroic section and the sheeted dikes root zone of the oceanic crust. Plagiogranites from the Troodos Ophiolite Complex on Cyprus are among the best exposures of felsic rocks that are embedded in a complete section of obducted oceanic lithosphere. Nevertheless, their exact petrogenesis is still a matter of debate, largely due to limited high-quality trace element and radiogenic isotope data. Previously proposed models for Troodos plagiogranites have included both low-pressure dehydration melting and fractional crystallisation at deeper levels of the oceanic crust. To evaluate both models, oceanic plagiogranites from the Troodos Ophiolite Complex were analysed in this study for their major and trace elements, and for the first time also for Hf–Nd–Sr isotope compositions. The trace element measurements also include for the first time high-precision measurements of high-field-strength element (HFSE) abundances that now permit to better unravel the petrogenesis of the Troodos plagiogranites and their possible mantle sources. In general, the Troodos plagiogranites exhibit a narrow range of Nb/Ta and Zr/Hf that overlap the compositions of mid-ocean ridge basalts (MORB). In line with earlier studies, three compositional groups can be identified: two groups formed by either fractional crystallisation or combined fractional crystallisation and wall rock assimilation, and one group derived from partial melting of slightly altered oceanic crust. The majority of the Troodos plagiogranites (Main Group) are the product of extensive fractional crystallisation of ambient arc-tholeiitic mafic melts. A second group of plagiogranites (Spilia Group) is generated by fractional crystallisation of boninitic precursor melts and the assimilation of arc-tholeiitic crustal material. Variable HFSE concentrations and diagnostic Hf–Nd isotope signatures that are unique to both suites allow discriminating between the two parental melts and fractionation processes. A small group of plagiogranites (Zoopigi Group) is interpreted to derive from partial melting in the conductive layer of active magma chamber lenses (AML). Elevated Nb/Ta, Zr/Hf, and light rare-earth element (LREE) enrichments in these rocks are in support of this model. Collectively, our data suggest that low-pressure fractional crystallisation (also in combination with assimilation of wall rocks) might be the predominant process controlling the formation of felsic rocks on Cyprus, whereas dehydration melting appears to be less important. If compared to Archean tonalitic–trondhjemitic–granodioritic suites (TTGs), compositions of plagiogranites from Cyprus mirror shallow-level processes in thin oceanic crust, which is illustrated by their narrow, MORB-like range of HFSE ratios and their distinct enrichment in heavy rare-earth elements (HREE) that distinguishes them from the Archean TTGs.

Developing tissues contain motile populations of cells that can self-organize into spatially ordered tissues based on differences in their interfacial surface energies. However, it is unclear how self-organization by this mechanism remains robust when interfacial energies become heterogeneous in either time or space. The ducts and acini of the human mammary gland are prototypical heterogeneous and dynamic tissues comprising two concentrically arranged cell types. To investigate the consequences of cellular heterogeneity and plasticity on cell positioning in the mammary gland, we reconstituted its self-organization from aggregates of primary cells in vitro. We find that self-organization is dominated by the interfacial energy of the tissue–ECM boundary, rather than by differential homo- and heterotypic energies of cell–cell interaction. Surprisingly, interactions with the tissue–ECM boundary are binary, in that only one cell type interacts appreciably with the boundary. Using mathematical modeling and cell-type-specific knockdown of key regulators of cell–cell cohesion, we show that this strategy of self-organization is robust to severe perturbations affecting cell–cell contact formation. We also find that this mechanism of self-organization is conserved in the human prostate. Therefore, a binary interfacial interaction with the tissue boundary provides a flexible and generalizable strategy for forming and maintaining the structure of two-component tissues that exhibit abundant heterogeneity and plasticity. Our model also predicts that mutations affecting binary cell–ECM interactions are catastrophic and could contribute to loss of tissue architecture in diseases such as breast cancer. Significance Differences in cell–cell interfacial energies can explain how multiple cell types sort into spatially organized tissues. However, this strategy of self-organization is not robust to heterogeneity or changes to the interfacial energies that drive correct cell positioning. Therefore, heterogeneous epithelial tissues such as the human mammary and prostate glands use a different strategy. First, disorganized aggregates form an adhesive interface at the tissue–ECM boundary that provides geometric constraints to self-organization. Second, only one cell type interacts appreciably with this interface. This strategy can explain how self-organization remains robust in vivo, provides generalizable rules for reconstituting tissues in vitro, and suggests how structure might break down during cancer progression.

The ability to culture normal human mammary epithelial cells (HMEC) greatly facilitates experiments that seek to understand both normal mammary cell biology and the many differences between normal and abnormal human mammary epithelia. To maximize in vivo relevance, the primary cell culture conditions should maintain cells in states that resemble in vivo as much as possible. Towards this goal, we compared the properties of HMEC strains from two different reduction mammoplasty tissues that were grown in parallel using different media and culture conditions. Epithelial organoids were initiated into three different media: two commonly used serum-free-media, MCDB 170-type (e.g. MEGM) and WIT-P, and a low stress media, M87A. Growth, lineage heterogeneity, p16 protein expression, and population doublings to senescence were measured for each culture condition. MCDB 170 caused rapid senescence and loss of heterogeneity within 2 to 3 passages, but some cultures went through the 1 to 2 month process of selection to generate clonal finite post-selection post-stasis cells. WIT-P caused impressive expansion of luminal cells in 2nd passage followed by their near complete disappearance by passage 4 and senescence shortly thereafter. M87A supported as much as twice the number of population doublings compared to either serum-free medium, and luminal and myoepithelial cells were present for as many as 8 passages. Thus, of the three media compared, WIT-P and MCDB 170 imposed rapid senescence and loss of lineage heterogeneity, phenotypes consistent with cells maintained in high-stress conditions, while M87A supported cultures that maintained multiple lineages and robust growth for up to 60 population doublings. In conjunction with previous studies examining the molecular properties of cultures grown in these media, we conclude that M87A medium is most able to support long-term culture of multiple lineages similar to in vivo conditions, thereby facilitating investigations of normal HMEC biology relevant to the mammary gland in situ.

Background/AimsTo investigate a possible association between the use of hydrochlorothiazide (HCT) and/or angiotensin-converting enzyme inhibitors (ACE inhibitors) and the occurrence of periocular non-melanoma skin cancer.MethodsThe files of 929 patients from the University Medical Center Hamburg-Eppendorf who were surgically treated for suspected periocular malignancy were evaluated retrospectively regarding the occurrence of non-melanoma skin cancer and concomitant medication. To be able to put the data in an overall context, we also analyzed age-matched routine data of the DAK-Gesundheit (DAK-G), a nationwide operating German health insurance company.ResultsOf the 929 patient records examined, who underwent surgical excision for suspected non-melanotic malignancy, non-melanocytic skin cancer could actually be determined by histology in 199 patients. In total, 176 patients (103 women, 72 men) had a basal cell carcinoma and 23 patients (16 women, 7 men) suffered from squamous cell carcinoma. The rate of intake of HCT or ACE inhibitors in our patient collective with non-melanotic skin cancer is significantly higher than in the general age-matched population (ORACE: 2.51, p < 0.001; ORHCT: 7.24, p < 0.001, ORBOTH: 4.61, p < 0.001).ConclusionThe rate of intake of HCT or ACE inhibitors is significantly higher in our patient collective with non-melanotic skin cancer compared to the group from the age-matched general population (DAK insured (p < 0.001)) compared to the routine data of the DAK-G. This leads us to the conclusion that taking the medication is associated with an increased risk for non-melanotic skin cancer. We recommend regular skin cancer screening, moderate ordination of photosensitizing medication, but above all comprehensive clarification of possible risks.

Background: Established prognostic factors are of limited value to predict long-term survival and benefit from metastasectomy in advanced melanoma. This study aimed to identify prognostic factors in patients with distant metastasis. Methods: We analysed overall survival of 855 institutional melanoma patients with distant metastasis by bivariate Kaplan–Meier survival probabilities and multivariate Cox hazard regression analysis. Results: Serum lactate dehydrogenases (LDH), S100B, the interval between initial diagnosis and occurrence of distant metastasis, the site of distant metastases, and the number of involved distant sites were significant independent prognostic factors in both bivariate and multivariate analyses. Visceral metastases other than lung (hazard ratio (HR) 1.8), elevated S100B (HR 1.7) and elevated LDH (HR 1.6) had the highest negative impact on survival. Complete metastasectomy was likewise an independent prognostic factor in multivariate analysis. This treatment was associated with favourable survival for patients with normal LDH and S100B values (5-year survival, 37.2%). Conclusion: The serum markers LDH and S100B were both found to be prognostic factors in melanoma patients with distant metastasis. Furthermore, complete metastasectomy had an independent favourable prognostic impact in particular for the patient subgroup with normal LDH and S100B values.

Background: This retrospective study aimed to identify prognostic factors in patients with brain metastases from cutaneous melanoma. Methods: In all, 265 patients under regular screening according to valid national surveillance guidelines were included in the study. Kaplan–Meier analyses were performed to estimate and to compare overall survival. Cox modeling was used to identify independent determinants of the overall survival, which were used in explorative classification and regression tree analysis to define meaningful prognostic groups. Results: In total, 55.5% of our patients presented with two or less brain metastases, 82.6% had concurrent extracranial metastasis and 64% were asymptomatic and diagnosed during surveillance scans. In all, 36.7% were candidates for local treatment (neurosurgery or stereotactic radiosurgery (SRS)). The median overall survival of the entire collective was 5.0 months (95% confidence interval: 4.3–5.7). Favourable independent prognostic factors were: normal pre-treatment level of serum lactate dehydrogenase ( P <0.001), administered therapy (neurosurgery or SRS vs other, P =0.002), number of brain metastases (single vs multiple, P =0.032) and presence of bone metastasis (false vs true, P =0.044). Three prognostic groups with significantly different overall survival were identified. Candidates for local treatment (group I) had the longer median survival (9 months). Remaining patients could be further classified in two groups on the basis of serum lactate dehydrogenase. Conclusion: Applied treatment and serum lactate dehydrogenase levels were independent predictors of survival of patients with brain metastases from cutaneous melanoma. Patients receiving local therapy have overall survival comparable with general stage IV melanoma patients.

Loss of organization is a principle feature of cancers; therefore it is important to understand how normal adult multilineage tissues, such as bilayered secretory epithelia, establish and maintain their architectures. The self-organization process that drives heterogeneous mixtures of cells to form organized tissues is well studied in embryology and with mammalian cell lines that were abnormal or engineered. Here we used a micropatterning approach that confined cells to a cylindrical geometry combined with an algorithm to quantify changes of cellular distribution over time to measure the ability of different cell types to self-organize relative to each other. Using normal human mammary epithelial cells enriched into pools of the two principal lineages, luminal and myoepithelial cells, we demonstrated that bilayered organization in mammary epithelium was driven mainly by lineage-specific differential E-cadherin expression, but that P-cadherin contributed specifically to organization of the myoepithelial layer. Disruption of the actomyosin network or of adherens junction proteins resulted in either prevention of bilayer formation or loss of preformed bilayers, consistent with continual sampling of the local microenvironment by cadherins. Together these data show that self-organization is an innate and reversible property of communities of normal adult human mammary epithelial cells.