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

Targeted treatment of advanced and metastaticbreast cancer with lapatinib

Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER-2 and EGFR. Lapatinib is a potent dual inhibitor of HER-2 and EGFR. Preclinical and phase I studies have shown activity with lapatinib in a number of cancers, including breast cancer, and the drug is well tolerated. The main known drug interactions are with paclitaxel and irinotecan. The most significant side-effects of lapatinib are diarrhea and adverse skin events. Rates of cardiotoxicity compare favorably with trastuzumab, a monoclonal antibody against HER-2. This paper focuses on lapatinib in advanced and metastatic breast cancer, which remains an important therapeutic challenge. Phase II and III studies show activity as monotherapy, and in combination with chemotherapy or hormonal agents. Results from these studies suggest that the main benefit from lapatinib is in the HER-2 positive breast cancer population. Combinations of lapatinib and trastuzumab are also being studied and show encouraging results, particularly in trastuzumab-refractory metastatic breast cancer. Lapatinib may have a specific role in treating HER-2 positive CNS metastases. The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated

An Analysis of the Effects of Wing Aspect Ratio and Tail Location on Static Longitudinal Stability Below the Mach Number of Lift Divergence

An analysis is presented of the influence of wing aspect ratio and tail location on the effects of compressibility upon static longitudinal stability. The investigation showed that the use of reduced wing aspect ratios or short tail lengths leads to serious reductions in high-speed stability and the possibility of high-speed instability

miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer

Background: While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. Methods: We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630’s regulation of mRNA, proteins and their phosphorylated forms. Results: We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630’s regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype. Conclusions: Taken together, our findings suggest miR-630 as a key regulator of cancer cell progression in HER2 over-expressing breast cancer, through targeting of IGF1R. This study supports miR-630 as a diagnostic and a predictive biomarker for response to HER-targeted drugs and indicates that the therapeutic addition of miR-630 may enhance and improve patients’ response to HER-targeting drugs

Geologic Mapping Investigations of the Northwest Rim of Hellas Basin, Mars

The Hellas impact basin, spanning 2000+ km in the cratered highlands, is the largest well-preserved impact structure on Mars and its deepest depositional sink. The Hellas region is significant for evaluating Mars hydrogeologic and climate histories, given the nature, diversity, and range in ages of potential water- and ice-related landforms [e.g., 1-2], including possible paleolakes on the basin floor [2-4]. The circum-Hellas highlands are of special interest given recent studies of potential localized fluvial/lacustrine systems [2, 5-17] and evidence for phyllosilicates around and within impact craters north of the basin [18-26]

Evidence for an Ancient Buried Landscape on the NW Rim of Hellas Basin, Mars

Hellas basin is the largest (2000+ km across) well-preserved impact structure on Mars and its deepest depositional sink [e.g., 1]. The Hellas rim and adjacent highlands are of special interest given the possibility of paleolakes on the basin floor [2-4], recent studies of potential localized fluvial/lacustrine systems [2, 5-17], and evidence for phyllosilicates around and within impact craters north of the basin [18-26]. We are producing a 1:1.5M-scale geologic map of eight MTM quadrangles (-25312, -25307, -25302, -25297, -30312, -30307, -30302, -30297) along Hellas NW rim. The map region (22.5-32.5degS, 45- 65degE) includes a transect across the cratered highlands of Terra Sabaea, the degraded NW rim of Hellas, and basin interior deposits of NW Hellas Planitia. No previous mapping studies have focused on this region, although it has been included in earlier global and regional maps [27-29]

In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: a practical guide with case studies

The development of a drug-resistant cell line can take from 3 to 18 months. However, little is published on the methodology of this development process. This article will discuss key decisions to be made prior to starting resistant cell line development; the choice of parent cell line, dose of selecting agent, treatment interval, and optimizing the dose of drug for the parent cell line. Clinically relevant drug-resistant cell lines are developed by mimicking the conditions cancer patients experience during chemotherapy and cell lines display between two- and eight-fold resistance compared to their parental cell line. Doses of drug administered are low, and a pulsed treatment strategy is often used where the cells recover in drug-free media. High-level laboratory models are developed with the aim of understanding potential mechanisms of resistance to chemotherapy agents. Doses of drug are higher and escalated over time. It is common to have difficulty developing stable clinically relevant drug-resistant cell lines. A comparative selection strategy of multiple cell lines or multiple chemotherapeutic agents mitigates this risk and gives insight into which agents or type of cell line develops resistance easily. Successful selection strategies from our research are presented. Pulsed-selection produced platinum or taxane-resistant large cell lung cancer (H1299 and H460) and temozolomide-resistant melanoma (Malme-3M and HT144) cell lines. Continuous selection produced a lapatinib-resistant breast cancer cell line (HCC1954). Techniques for maintaining drug-resistant cell lines are outlined including; maintaining cells with chemotherapy, pulse treating with chemotherapy, or returning to master drug-resistant stocks. The heterogeneity of drug-resistant models produced from the same parent cell line with the same chemotherapy agent is explored with reference to P-glycoprotein. Heterogeneity in drug-resistant cell lines reflects the heterogeneity that can occur in clinical drug resistance

OvMark: a user-friendly system for the identification of prognostic biomarkers in publically available ovarian cancer gene expression datasets

Background: Ovarian cancer has the lowest survival rate of all gynaecologic cancers and is characterised by a lack of early symptoms and frequent late stage diagnosis. There is a paucity of robust molecular markers that are independent of and complementary to clinical parameters such as disease stage and tumour grade. METHODS: We have developed a user-friendly, web-based system to evaluate the association of genes/miRNAs with outcome in ovarian cancer. The OvMark algorithm combines data from multiple microarray platforms (including probesets targeting miRNAs) and correlates them with clinical parameters (e.g. tumour grade, stage) and outcomes (disease free survival (DFS), overall survival). In total, OvMark combines 14 datasets from 7 different array platforms measuring the expression of ~17,000 genes and 341 miRNAs across 2,129 ovarian cancer samples. RESULTS: To demonstrate the utility of the system we confirmed the prognostic ability of 14 genes and 2 miRNAs known to play a role in ovarian cancer. Of these genes, CXCL12 was the most significant predictor of DFS (HR = 1.42, p-value = 2.42x10-6). Surprisingly, those genes found to have the greatest correlation with outcome have not been heavily studied in ovarian cancer, or in some cases in any cancer. For instance, the three genes with the greatest association with survival are SNAI3, VWA3A and DNAH12. CONCLUSIONS/IMPACT: OvMark is a powerful tool for examining putative gene/miRNA prognostic biomarkers in ovarian cancer (available at http://glados.ucd.ie/OvMark/index.html). The impact of this tool will be in the preliminary assessment of putative biomarkers in ovarian cancer, particularly for research groups with limited bioinformatics facilities

Serological Qualitative Diagnoses of Helicobacter pylori in Patients Accessing Care at the Bingham University Teaching Hospital Jos, Nigeria

The widespread Helicobacter pylori infection is a substantial global health problem affecting approximately 50% of the worldwide population, with 50% infection rates in developed countries and 80% in developing countries, mainly concentrating in resource-limited settings. The mode of transmission is through the faecal-oral route, contamination of food and water, where inadequate sanitation practices, low socioeconomic status and overcrowdedness seem to relate to the high prevalence of H. pylori infections. This study sought to serologically determine the prevalence of H. pylori and the disease-associated burden in patients accessing care in a Tertiary Hospital. This hospital-based cross-sectional study was conducted at the Bingham University Teaching Hospital, North-Central Nigeria, for four months (September to December 2022). There, 551 blood specimens were collected from the patients into plain tubes and spun to obtain serum for the serological qualitative analysis. Out of the 551 screened specimens for H. pylori, 79% (n=437) were 58.4% reactive female and 41.6% male. Ages 15-49 had 62%, 50-70 yrs had 26.5%, and less than 14 yrs had 11.4% respectively. Furthermore, 64.3% of female patients presented with burning pains, nausea/vomiting, and trouble breathing.In comparison, 35.5% of the male counterparts presented symptoms of dyspepsia, and 32.1% had either taken one of the Nonsteroidal-inflammatory drugs. 86.7% of the suspected patients were hand washed after using the toilet, 83.3% had a loss of appetite, 55.4% reported alcohol intake and 35.9% smoked instead. 47.7% ate from mama-put, 30.1% from street-vended foods and 22.2% from classified restaurants, while 94.7% got their drinking water from sachet, bottled, borehole or tap, and well water, respectively.Serum antibody detection of H. pylori infection was higher in female than male patients accessing care at the Bingham University Teaching Hospital, Jos. This revealed that gender could be considered a potential risk factor. Thus, early risk identification factors, such as other transmission routes, are urgently needed in defining clinical and epidemiological characteristics to facilitate appropriate supportive care and prompt treatment