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

Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase II study

The purpose of the study was to investigate the toxicity and efficacy of the combination of gemcitabine and docetaxel in untreated advanced urothelial carcinoma. Patients with previously untreated, locally advanced/recurrent or metastatic urothelial carcinoma stage-IV disease were eligible. Patients with Performance status: PS ECOG >3 or age >75 years or creatinine clearance <50 ml min−1 were excluded. Study treatment consisted of docetaxel 75 mg m−2 (day 8) and gemcitabine 1000 mg m−2 (days 1+8), every 21 days for a total of six to nine cycles. A total of 31 patients with urothelial bladder cancer, 25 men and six women, aged 42–74 (median 64) years were enrolled. The majority of patients had a good PS (51.6%; PS 0). In all, 15 (48.3%) patients had locally advanced or recurrent disease only and 16 (54.8%) presented with distant metastatic spread, with multiple site involvement in 22.5%. Toxicity was primarily haematologic, and the most frequent grade 3–4 toxicities were anaemia 11 (6.7%) thrombocytopenia eight (4.9%), and neutropenia 45 (27.6%), with 10 (6.1%) episodes of febrile neutropenia. No toxic deaths occurred. A number of patients had some cardiovascular morbidity (38.7%). Nonhaematological toxicities except alopecia (29 patients) were mild. Overall response rate was 51.6%, including four complete responses (12.9%) and 12 partial responses (38.7%), while a further five patients had disease stabilisation (s.d. 16.1%). The median time to progression was 8 months (95% CI 5.1–9.2 months) and the median overall survival was 15 months (95% CI 11.2–18.5 months), with 1-year survival rate of 60%. In conclusion, this schedule of gemcitabine and docetaxel is very active and well tolerated as a first-line treatment for advanced/relapsing or metastatic urothelial carcinoma. Although its relative efficacy and tolerance as compared to classic MVAC should be assessed in a phase III setting, the favourable toxicity profile of this regimen may offer an interesting alternative, particularly in patients with compromised renal function or cardiovascular disease

Cyber threat intelligence sharing: Survey and research directions

Cyber Threat Intelligence (CTI) sharing has become a novel weapon in the arsenal of cyber defenders to proactively mitigate increasing cyber attacks. Automating the process of CTI sharing, and even the basic consumption, has raised new challenges for researchers and practitioners. This extensive literature survey explores the current state-of-the-art and approaches different problem areas of interest pertaining to the larger field of sharing cyber threat intelligence. The motivation for this research stems from the recent emergence of sharing cyber threat intelligence and the involved challenges of automating its processes. This work comprises a considerable amount of articles from academic and gray literature, and focuses on technical and non-technical challenges. Moreover, the findings reveal which topics were widely discussed, and hence considered relevant by the authors and cyber threat intelligence sharing communities

Greek Hotels&rsquo; Web Traffic: A Comparative Study Based on Search Engine Optimization Techniques and Technologies

Currently, websites rely heavily on digital marketing, notably search engine optimization (SEO), for success. In the COVID-19 era, hotels have to employ every feasible means to stay afloat despite the bleak business and travel conditions. Many of them have already invested in digital marketing, especially SEO, by applying SEO techniques to their websites to attract more visitors and bookings. This research examines hotels&rsquo; websites regarding the SEO techniques they have applied and their impact on web traffic to their websites. During a one-year observation period (February 2021&ndash;February 2022), we collected and analyzed web data from 309 top-listed Greek hotels using our own-developed software. By creating and following a specific methodology, we came to valuable conclusions. In addition, we used fuzzy cognitive mapping to develop an exploratory model. From the descriptive analysis and technical SEO perspective, we have concluded that hotels websites&rsquo; traffic and, by extension, their long-term viability are inextricably intertwined. Existing and future SEO marketers may benefit from our research&rsquo;s time-accurate insights on hotel SEO tactics

Greek Hotels’ Web Traffic: A Comparative Study Based on Search Engine Optimization Techniques and Technologies

Currently, websites rely heavily on digital marketing, notably search engine optimization (SEO), for success. In the COVID-19 era, hotels have to employ every feasible means to stay afloat despite the bleak business and travel conditions. Many of them have already invested in digital marketing, especially SEO, by applying SEO techniques to their websites to attract more visitors and bookings. This research examines hotels’ websites regarding the SEO techniques they have applied and their impact on web traffic to their websites. During a one-year observation period (February 2021–February 2022), we collected and analyzed web data from 309 top-listed Greek hotels using our own-developed software. By creating and following a specific methodology, we came to valuable conclusions. In addition, we used fuzzy cognitive mapping to develop an exploratory model. From the descriptive analysis and technical SEO perspective, we have concluded that hotels websites’ traffic and, by extension, their long-term viability are inextricably intertwined. Existing and future SEO marketers may benefit from our research’s time-accurate insights on hotel SEO tactics.</jats:p

Activity of dasatinib with chemotherapy in triple-negative breast cancer cells

e14605 Background: Triple-negative breast cancers (TNBC) lack expression of oestrogen, progesterone, and are HER-2 normal. TNBC cell lines have displayed greater sensitivity to growth inhibition by the multi-target kinase inhibitor, dasatinib, than luminal or HER- 2 positive breast cancer cell lines. The aim of this study was to assess the direct anti-tumor effects of dasatinib in combination with chemotherapy in TNBC. Methods: Four TNBC cell lines (MDA-MB-231, HCC-1143, HCC-1937, MDA-MB-468) were treated with dasatinib in combination with docetaxel, cisplatin or 5'-5' DFUR. IC50 values were calculated for each drug alone by determining response in a 5-day proliferation (acid phosphatase) assay. Combination index (CI) values were determined, using CalcuSyn, to assess the interaction between drugs. Results: Three of the cell lines (MDA-MB-231, HCC- 1143, HCC-1937) were sensitive to dasatinib (IC50 &lt; 1 μM) whereas MDA-MB-468 was resistant (IC50 &gt; 1 μM) (Table). In MDA-MB-231 and HCC-1143 cells, combined treatment with dasatinib and 5'-5'-DFUR displayed synergy (CI&lt;1.0), whereas the combination was additive in HCC-1937 cells (CI=0.98). Combined treatment with dasatinib and cisplatin was synergistic in the three dasatinib sensitive cell lines (CI&lt;1.0). Dasatinib in combination with docetaxel displayed moderate synergy in MDA-MB-231 and HCC-1937 cells (CI&lt;1.0), but was antagonistic in HCC-1143 cells (CI&gt;1.0). Conclusions: Our findings show that the combination of dasatinib with either 5'-5'-DFUR or cisplatin is synergistic in TNBC cell lines, and suggest that combinations of dasatinib with chemotherapy may improve response in triple negative breast cancer patients. [Table: see text] No significant financial relationships to disclose. </jats:p