Prospects for non-immunological molecular therapeutics in melanoma

In 2006 there were 60,000 new cases of cutaneous melanoma in the European Union and 13,000 deaths (www.europeancancerleagues.org). Currently available systemic treatment options for metastatic melanoma, including both cytotoxic and immunologic therapies, produce low rates of response and have modest survival impact. Therefore, there is an urgent need for effective novel therapies. Molecularly targeted treatments have demonstrated efficacy in certain cancers e.g. in HER2-positive breast cancer and in chronic myeloid leukaemia. Several pathways are currently being investigated as potential molecular targets in melanoma. The best studied is BRAF which is frequently mutated in melanoma. A multi tyrosine kinase inhibitor, sorafenib, which targets BRAF, has shown promising activity in preclinical studies and is currently being tested in combination with chemotherapy in patients with metastatic disease. In addition to BRAF, therapies which target other components of the Raf/Ras/MAPK pathway are being investigated. Other novel targets currently being investigated include the PI3/AKT pathway, tyrosine kinases, angiogenesis, poly (ADP ribose) polymerases, survivin and heat shock protein 90. Progress on preclinical and clinical evaluation of these novel targets in melanoma will be reviewed

SECRETA: A System for Evaluating and Comparing RElational and Transaction Anonymization algorithms

Publishing data about individuals, in a privacy-preserving way, has led to a large body of research. Meanwhile, algorithms for anonymizing datasets, with relational or transaction attributes, that preserve data truthfulness, have attracted significant interest from organizations. However, selecting the most appropriate algorithm is still far from trivial, and tools that assist data publishers in this task are needed. In response, we develop SECRETA, a system for analyzing the effectiveness and efficiency of anonymization algorithms. Our system allows data publishers to evaluate a specific algorithm, compare multiple algorithms, and combine algorithms for anonymizing datasets with both relational and transaction attributes. The analysis of the algorithm(s) is performed, in an interactive and progressive way, and results, including attribute statistics and various data utility indicators, are summarized and presented graphically

BIP! NDR (NoDoiRefs): A Dataset of Citations From Papers Without DOIs in Computer Science Conferences and Workshops

In the field of Computer Science, conference and workshop papers serve as important contributions, carrying substantial weight in research assessment processes, compared to other disciplines. However, a considerable number of these papers are not assigned a Digital Object Identifier (DOI), hence their citations are not reported in widely used citation datasets like OpenCitations and Crossref, raising limitations to citation analysis. While the Microsoft Academic Graph (MAG) previously addressed this issue by providing substantial coverage, its discontinuation has created a void in available data. BIP! NDR aims to alleviate this issue and enhance the research assessment processes within the field of Computer Science. To accomplish this, it leverages a workflow that identifies and retrieves Open Science papers lacking DOIs from the DBLP Corpus, and by performing text analysis, it extracts citation information directly from their full text. The current version of the dataset contains more than 510K citations made by approximately 60K open access Computer Science conference or workshop papers that, according to DBLP, do not have a DOI

Novel targeted agents in Her-2 positive and triple negative breast cancer

The development of Her-2 targeted therapies has improved the prognosis for patients with Her-2 positive breast cancer. However, not all Her-2 positive tumours respond to treatment with Her-2 antagonists. Triple negative cancers are resistant to hormone and Her-2 targeted therapies. This project focused on improving response in Her-2 overexpressing breast cancer and on developing effective targeted therapy strategies for triple negative breast cancer. We tested a number of multi-target kinase inhibitors (imatinib, sunitinib, pazopanib and dasatinib) in Her-2 positive and triple negative breast cancer cell lines, alone and in combination with other agents. Two of the Her-2 positive cell lines showed moderate sensitivity to sunitinib malate. Combined treatment with sunitinib and trastuzumab showed improved response compared to either drug alone, in the four Her-2 positive cell lines tested. Dasatinib inhibited growth in 3 of the 5 triple negative but in only 1 of the 4 Her-2 positive cell lines tested. Based on response to the other multi-target kinase inhibitors, which have overlapping target specificities, and the Src,PP2, our results suggest that sensitivity to dasatinib in triple negative breast cancer is due to inhibition of ephrin type A receptors. Consistent with this hypothesis, neither Src expression nor phosphorylation predicted sensitivity to dasatinib, but high levels of Ephrin type A receptor 2 protein correlated with dasatinib sensitivity. High levels of caveolin 1 and caveolin 2 also correlated with dasatinib sensitivity in the panel of cell lines. Dasatinib combined with cisplatin was synergistic in the three dasatinib-sensitive cell lines. Dasatinib, in combination with 5’-deoxy-5’-fluoruridine, displayed synergy or additivity. Moderate synergy was observed with docetaxel in two triple negative cell lines. In conclusion, we have identified dasatinib with cisplatin as a rational combination for testing in triple-negative breast cancer, and have identified a panel of putative predictive biomarkers for dasatinib sensitivity (EphA2, CAV1 and CAV2)

Aromatase Inhibitor-Associated Tendinopathy and Muscle Tendon Rupture: Report of Three Cases of This Exceedingly Rare Adverse Event

Aromatase inhibitors (AIs) are a commonly used antihormonal therapy in the treatment of breast cancer in postmenopausal women, specifically in the treatment of hormone receptor-positive breast cancer. AI-associated tendinopathy and muscle tendon rupture is exceedingly rare. Until now, only one case with AI-associated severe tendinopathy has been reported in the medical literature, and there are no recorded cases of AI-associated muscle tendon rapture. We report three cases of postmenopausal women with hormone receptor-positive breast cancer, who experienced tendinopathy or muscle tendon rupture under antihormonal treatment with letrozole. All of the three women were in the adjuvant setting, and the treatment of tendinopathy or tendon rupture consisted of AI discontinuation, initiation of corticosteroids, or surgical treatment. Diagnosis was made via MRI. Furthermore, in our cases, there were no signs of underlying systemic disease, there was no abnormal physical activity preceding the complaints, and there was no use of other drugs beside letrozole. AIs are one of the most commonly used drugs in antihormonal therapy for hormone receptor-positive breast cancer. In every case of a female patient with hormone receptor-positive breast cancer under treatment with AIs and arthralgia, an MRI should be performed in order to exclude the presence of tendinopathy or muscle tendon rupture

Membrane transport proteins in human melanoma: associations with tumour aggressiveness and metastasis

BACKGROUND: Malignant melanoma, generally described as incurable, is notoriously refractory to chemotherapy. The mechanisms contributing to this have not yet been defined and the contributions of drug efflux pumps, implicated in chemo-resistance of many other cancer types, have not been extensively investigated in melanoma. METHODS: In this study, expression of multi-drug resistant (MDR1/P-gp and MRP-1) proteins was examined, by immunohistochemistry, in archival specimens from 134 melanoma patients. This included 92 primary tumours and 42 metastases. RESULTS: On assessing all specimens, MRP-1 and MDR1/P-gp expression was found to be common, with the majority (81%) of melanomas expressing at least one of these efflux pumps. Although there is significant association between expression of these pumps (P=0.007), MRP-1 was found to be the predominant (67% of cases) form detected. chi(2) analysis showed significant associations between expression of MRP-1 and/or MDR1/P-gp and the aggressive nature of this disease specifically increased Breslow's depth, Clark's level and spread to lymph nodes. This association with aggressiveness and spread is further supported by the observation that a significantly higher percentage of metastases, than primary tumours, express MRP-1 (91% vs 57%; P<0.0001) and MDR1/P-gp (74% vs 50%; P=0.010). CONCLUSION: The predominant expression of these pumps and, in particular, MRP-1 suggests that they may be important contributors to the inherent aggressive and resistant nature of malignant melanoma