101 research outputs found
Actionable pharmacogenetic markers for prediction and prognosis in breast cancer
We would like to thank Professor Christian Scerri for advice and constructive
discussions.Breast cancer is a heterogeneous disease that necessitates proper patient classification to direct surgery,
pharmacotherapy, and radiotherapy. Despite patients within the same subgroup receiving similar pharmacotherapy,
substantial variation in clinical outcomes is observed. Pharmacogenetic variations with direct effect on
pharmacokinetics and pharmacodynamics play a central role in clinical outcomes. Pharmacogenetic markers
associated with clinical outcome are known as biomarkers. They are termed prognostic biomarkers when their
presence is associated with a specific clinical outcome. If the presence of such biomarkers guides treatment,
they are termed predictive biomarkers. A number of pharmacogenetic markers have been described in relation to
breast cancer pharmacotherapy both in the adjuvant and neoadjuvant setting. CYP2D6 allelic variants produce variable
rates of tamoxifen metabolism and are associated with survival outcomes. Other biomarkers have been described in
relation to other forms of endocrine therapy and trastuzumab. In neoadjuvant and adjuvant breast cancer
chemotherapy, specific biomarkers were correlated with clinical outcomes and risk of drug toxicity. This review
highlights key biomarkers in breast cancer pharmacotherapy with the potential of translating such study
outcomes into clinical practice.peer-reviewe
Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma
The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of specific cancers. A recent large systematic review of 24 studies based on meta-analysis of 11,149 patients with prostate cancer showed a significant correlation between obesity and the risk of advanced prostate cancer. Further, a sustained reduction in BMI correlates with a decreased risk of developing aggressive disease. On the other hand, the correlation between consuming different products and prostate cancer occurrence/risk is limited. Here, we review the role of adipose tissue from an endocrine perspective and outline the effect of adipokines on cancer metabolism, with particular focus on leptin. Leptin exerts its physiological and pathological effects through modification of intracellular signalling, most notably activating the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway and recently shown sphingolipid pathway. Both high levels of leptin in circulation and leptin receptor mutation are associated with prostate cancer risk in human patients; however, the in vivo mechanistic evidence is less conclusive. Given the complexity of metabolic cancer pathways, it is possible that leptin may have varying effects on prostate cancer at different stages of its development, a point that may be addressed by further epidemiological studies
The influence of innate and adaptive immunity on Crohn’s disease severity
This article was originally published in a special issue, entitled: "Inflammatory
Bowel Disease", Edited by Nancy Louis, Emory University, USA and Ostanin
Dmitry Vladimirovich, Louisiana State University Health Sciences Center, USAStricturing and penetrating disease are classified as severe Crohn’s disease types and are frequently associated
with an increased risk for bowel surgery. Research has shown that early treatment with aggressive
immunosuppression (including biological and thiopurine therapies – the so-called “top-down approach”) results in a
diminished risk of developing these complicated disease types. However, these therapies carry significant risks and
cost. Being able to predict which patients are at an increased risk of developing severe Crohn’s disease may enable
us to treat patients individually, with the aggressive “top-down approach” started at diagnosis in patients with a
significantly increased risk of developing complicated disease types. Defects of innate and adaptive immunity both
play a role in Crohn’s disease pathophysiology. Identifying whether defects of innate immunity (through gene
mutations) or adaptive immunity (through antibodies to microbial antigens) are associated with stricturing/penetrating
disease types may enable us to predict the course of the disease and therefore decide on who would benefit most
from the “top-down approach”. This review discusses the role of NOD2 and other gene polymorphisms in predicting
Crohn’s disease severity. It also highlights the evidence linking the role of the various antibodies involved in adaptive
immunity (ASCA, OmpC, GM-CSF) and complicated Crohn’s disease types.peer-reviewe
Molecular classification of breast cancer patients using formalin-fixed paraffin-embedded derived RNA samples
The use of archival formalin-fixed paraffin-embedded (FFPE) material to analyse gene expression is limited by
the low quality of extracted RNA. In this paper, we utilised an RNA based assay to quantify expression of luminal
and basal markers, together with ERBB2 probes, in FFPE archival tissue from 2009 to 2010, all of which had clinical
and therapeutic information of more than 5 years. Receptor status of the patients was characterised using the
QuantiGene® Plex assay with 100% concordance to immunohistochemical (IHC) and fluorescence in situ
hybridisation (FISH) results. A panel of molecular markers known to classify luminal and basal tumours were used
and correlated with receptor status of the tumours. As expected, the triple negative breast cancer (TNBC) samples
were classified as basal and oestrogen receptor (ER) positive cases as luminal. In summary, the QuantiGene® Plex
technology provides a platform to quantitate novel panels of biomarkers on archival material. Moreover, multiplex
analysis allows the use of minimal amounts of material providing an opportunity to utilise laser micro-dissected
material. FFPE tissue samples are an invaluable resource for retrospective studies to interrogate current novel
biomarkers, particularly to generate disease free survival and overall survival graphs to measure predictive value
using well annotated retrospective samples with full clinical and pharmacological outcomes.This study was funded by the Faculty of Medicine and Surgery,
University of Malta and the Italia Malta Genome Breast Cancer Cross
Border Risk Surveillance (ImaGenX) project financed under
Operational Program Italia Malta 2007-2013 and co-financed by the
University of Malta.peer-reviewe
Propulsion simulator for magnetically-suspended wind tunnel models
In order to demonstrate the measurement of aerodynamic forces/moments, including the effects of exhaust jets in Magnetic Suspension and Balance System (MSBS) wind tunnels, two propulsion simulator models were developed at Physical Sciences Inc. (PSI). Both the small-scale model (1 in. diameter X 8 in. long) and the large-scale model (2.5 in. diameter X 15 in. long) employed compressed, liquefied carbon dioxide as a propellant. The small-scale simulator, made from a highly magnetizable iron alloy, was demonstrated in the 7 in. MSBS wind tunnel at the University of Southampton. It developed a maximum thrust of approximate 1.3 lbf with a 0.098 in. diameter nozzle and 0.7 lbf with a 0.295 in. diameter nozzle. The Southampton MSBS was able to control the simulator at angles-of attack up to 20 deg. The large-scale simulator was demonstrated to operate in both a steady-state and a pulse mode via a miniaturized solinoid valve. It developed a stable and repeatable thrust of 2.75 lbf over a period of 4s and a nozzle pressure ratio (NPR) of 5
Physical inactivity is a strong risk factor for stroke in the oldest old: Findings from a multi-ethnic population (the Northern Manhattan Study)
Background
The fastest growing segment of the population is those age ≥80 who have the highest stroke incidence. Risk factor management is complicated by polypharmacy-related adverse events.
Aims
To characterize the impact of physical inactivity for stroke by age in a multi-ethnic prospective cohort study (NOMAS, n = 3298).
Methods
Leisure time physical activity was assessed by a validated questionnaire and our primary exposure was physical inactivity (PI). Participants were followed annually for incident stroke. We fit Cox-proportional hazard models to calculate hazard ratios and 95% confidence intervals (HR 95% CI) for the association of PI and other risk factors with risk of stroke including two-way interaction terms between the primary exposures and age (<80 vs. ≥80).
Results
The mean age was 69 ± 10.3 years and 562 (17%) were ≥80 at enrolment. PI was common in the cohort (40.8%). Over a median of 14 years, we found 391 strokes. We found a significant interaction of age ≥80 on the risk of stroke with PI (p = 0.03). In stratified models, PI versus any activity (adjusted HR 1.60, 95%CI 1.05–2.42) was associated with an increased risk of stroke among those ≥80.
Conclusion
Physical inactivity is a treatable risk factor for stroke among those older than age 80. Improving activity may reduce the risk of stroke in this segment of the population
Disease-free survival in molecular subtypes of breast cancer in Malta
Introduction: Breast cancer is the commonest incident
tumour in the Maltese islands. The disease is heterogeneous
and exhibits diverse clinical prognosis and survival rates.
Proper patient classification helps stratify breast cancer groups
to ascertain
likely prognostic ontcome and select treatment.
Breast cancer survival has commonly been described in terms
of disease-
free survival and five-year overall survival. The aim
of this study is to determine disease-free survival together with
site of metastasis while stratifying clinical outcomes with
known prognostic
markers and novel genetic markers.peer-reviewe
Leptomeningeal carcinomatosis as the primary presentation of relapse in breast cancer
Leptomeningeal metastasis (LM) is an uncommon presentation of relapse in breast cancer, which is associated with poor clinical outcomes and poor prognosis. Notably, LM most commonly occurs in breast cancer. The aim of the present review was to investigate the occurrence of LM as the primary presentation of relapse following remission in breast cancer patients and to determine whether specific histological subtypes are predisposed to meningeal metastases. In addition, the present review evaluated whether patients presenting with LM as the primary site of relapse exhibit differences in survival when compared with patients exhibiting metastasis to other sites. Cross-sectional studies have demonstrated that LM is commonly associated with other sites of distant metastasis including lung, liver and bone metastases. The histological breast cancer subtype most commonly associated with LM was invasive lobular carcinoma, while triple-negative breast cancer patients appear to be predisposed to the development of LM when considering the overall prevalence of histological breast cancer subtypes. At present, data regarding LM as the primary site of relapse are limited due to its rarity as the first site of metastasis in breast cancer. Case-controlled studies are required to investigate the incidence of LM as the primary site of recurrence in breast cancer patients as this would enable treatment standardization and identification of prognostic factors for improved survival
Quantification of titanium dioxide (TiO2) anatase and rutile polymorphs in binary mixtures by Raman spectroscopy: an interlaboratory comparison
This article presents an interlaboratory comparison (ILC) on Raman spectroscopy as a technique for relative quantification of the two most common polymorphs of titanium dioxide (TiO2)-anatase and rutile-in binary mixtures. Some standard methods are currently employed internationally for the determination of TiO2 content in samples (ISO 591-1, ASTM D3720-90), but require extensive sample preparation, do not distinguish between the two polymorphs or are accurate only for small fractions of either polymorph. Raman spectroscopy is a well-suited characterization technique for measuring and differentiating TiO2 in a fast, non-invasive way, while requiring no particular reagent or sample preparation. Eleven international participants conducted the study under the framework of Versailles Project on Advanced Materials and Standards. The collected data was analyzed by means of partial least squares regression after spectral preprocessing. The resulting models all show discrepancies of lower than 2% from the nominal values in the quantitative analysis over the concentration range of 5%-95% mixture fractions, with many datasets showing substantial improvement margins on this figure. The results of this ILC provide validation of Raman spectroscopy as a reliable method for quantification of TiO2 phases
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