Phospho-Akt expression is high in a subset of triple negative breast cancer patients

The most commonly used biomarkers to predict the response of breast cancer patients to therapy are oestrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2). Patients positive for these biomarkers are eligible for specific therapies such as anti-oestrogen therapy in the event of ER and PgR positivity, and trastuzumab, a monoclonal antibody, in the case of HER2 positive patients. Patients who are negative for all these three biomarkers, the so-called triple negatives, however, derive little benefit from such therapies. The PI3K/Akt pathway is activated in triple negative breast cancer cases, providing a possible target for therapy. The activation of Akt was investigated in Maltese triple negative breast cancer cases using an antibody detecting Akt phosphorylated at serine 473 (anti-Akt pS473). The study showed that 26\% of triple negative breast cancer patients had an elevated level of Akt (pS473). Furthermore, FTY720, a pharmacological activator of the phosphatase PP2A, was shown to block Akt activation at a concentration of 1\textmu M, in HCC1937 cells subjected to insulin-like growth factor 1 (IGF-1). Our data defined a subset of triple negative breast cancer patients based on high activity of AKT (pS473). This subset would be eligible for treatment using therapies which target the PI3K/Akt pathway, such as kinase inhibitors or phosphatase activators. In support of this, the BRCA1 mutant cells (HCC1937) were sensitive to the PP2a activator, FTY720. This suggests that FTY720 is a potential drug for use in adjuvant therapy in breast cancer cases having a high Akt (pS473).peer-reviewe

Coexistence of 1,3-butadiene conformers in ionisation energies and Dyson orbitals

The minimum-energy structures on the torsional potential-energy surface of 1,3-butadiene have been studied quantum mechanically using a range of models including ab initio Hartree-Fock and second-order Møller-Plesset theories, outer valence Green’s function, and density-functional theory with a hybrid functional and statistical average orbital potential model in order to understand the binding-energy ionization energy spectra and orbital cross sections observed by experiments. The unique full geometry optimization process locates the s-trans-1,3-butadiene as the global minimum structure and the s-gauche-1,3-butadiene as the local minimum structure. The latter possesses the dihedral angle of the central carbon bond of 32.81° in agreement with the range of 30°–41° obtained by other theoretical models. Ionization energies in the outer valence space of the conformer pair have been obtained using Hartree-Fock, outer valence Green’s function, and density-functional statistical average orbital potentials models, respectively. The Hartree-Fock results indicate that electron correlation and orbital relaxation effects become more significant towards the inner shell. The spectroscopic pole strengths calculated in the Green’s function model are in the range of 0.85–0.91, suggesting that the independent particle picture is a good approximation in the present study. The binding energies from the density-functional statisticaly averaged orbital potential model are in good agreement with photoelectron spectroscopy, and the simulated Dyson orbitals in momentum space approximated by the density-functional orbitals using plane-wave impulse approximation agree well with those from experimental electron momentum spectroscopy. The coexistence of the conformer pair under the experimental conditions is supported by the approximated experimental binding-energy spectra due to the split conformer orbital energies, as well as the orbital momentum distributions of the mixed conformer pair observed in the orbital cross sections of electron momentum spectroscopy

Rapid fabrication of annuloplasty rings by electron beam melting

Electron Beam Melting (EBM) is an Additive Manufacturing (AM) technology capable of producing intricate parts by melting powder metal with the aid of an electron beam gun. EBM has facilitated the production of standard and customisable implants. Customizable implants such as orthopaedic implants, cranial implants and dental implants have already been developed and implanted successfully after being fabricated by AM technology. Other medical devices can also benefit from the possibilities offered by AM. An example of such a medical device would be the annuloplasty ring. Standard annuloplasty rings are implanted whenever a patient is diagnosed with mitral valve regurgitation. This problem arises when the mitral valve does not close properly, causing back leakage through the closed valve resulting in blood flowing to the atrium instead of the aorta during systole. The latest designs of annuloplasty rings allow restoration of the mitral annulus configuration to a saddle-shaped shape.peer-reviewe

Livestock vocalisation classification in farm soundscapes

Livestock vocalisations have been shown to contain information related to animal welfare and behaviour. Automated sound detection has the potential to facilitate a continuous acoustic monitoring system, for use in a range Precision Livestock Farming (PLF) applications. There are few examples of automated livestock vocalisation classification algorithms, and we have found none capable of being easily adapted and applied to different species' vocalisations. In this work, a multi-purpose livestock vocalisation classification algorithm is presented, utilising audio-specific feature extraction techniques, and machine learning models. To test the multi-purpose nature of the algorithm, three separate data sets were created targeting livestock-related vocalisations, namely sheep, cattle, and Maremma sheepdogs. Audio data was extracted from continuous recordings conducted on-site at three different operational farming enterprises, reflecting the conditions of real deployment. A comparison of Mel-Frequency Cepstral Coefficients (MFCCs) and Discrete Wavelet Transform-based (DWT) features was conducted. Classification was determined using a Support Vector Machine (SVM) model. High accuracy was achieved for all data sets (sheep: 99.29%, cattle: 95.78%, dogs: 99.67%). Classification performance alone was insufficient to determine the most suitable feature extraction method for each data set. Computational timing results revealed the DWT-based features to be markedly faster to produce (14.81 - 15.38% decrease in execution time). The results indicate the development of a highly accurate livestock vocalisation classification algorithm, which forms the foundation for an automated livestock vocalisation detection system

Biomarkers of pituitary adenoma behaviour

The pathological behaviour of pituitary adenomas (PAs) is complex and difficult to predict. In this study, the proliferation marker, Ki-67, pituitary tumour transforming gene (PTTG), vascular endothelial growth factor (VEGF), cyclin D1, c-MYC and pituitary adenylate cyclase-activating peptide (PACAP) protein expression were analyzed using immunohistochemistry in 74 PA samples (48 non-functional PAs, 26 functional PAs) and correlated with tumour characteristics including size, extension and tumour behaviour patterns. Correlation of protein marker expression with clinical characteristics yielded significant results. A correlation between PTTG expression and age at diagnosis, tumour size, tumour regrowth and Ki-67 was observed. Cyclin D1 and c-MYC also showed significant correlations with gender, tumour size, age at diagnosis and other protein markers. Significant differences in protein expression in the chosen markers were also observed between different tumour types, between patients treated pre-operatively with somatostatin analogues and in tumours with different intensity on MR imaging). Significant correlations were also observed between the markers themselves, with a possible direct link between two of the studied markers which substantiate data from other in vitro studies. Differences in protein localization were also analyzed to identify possible differences in biological behaviour arising in relation to nuclear vs cytoplasmic localization of the studied biomarkers. VEGF and PACAP similarly appeared interesting but exhibited few statistically significant correlations on detailed analysis. In conclusion, interesting and novel observations on the differences in expression of tumour markers studied are reported. Specifically, Ki-67 and PTTG appear to be very strongly correlated to tumour regrowth/recurrence and may be considered useful tools in predicting the proliferative potential of the resected tumours. Further data on the differential role of Cyclin D1 and cMYC in pituitary tumorigenesis and possibly tumour prognosis are presented.Principal author (MG, JV) was funded by the University of Malta Research funds (MEDRP02-05) and the Faculty of Medicine and Surgery (MDSIN08-22).RF is funded by the REACH HIGH Scholars Programme – Post-Doctoral Grant. The Research work disclosed in this publication is partially funded by the REACH HIGH Scholars Programme – Post Doctoral Grants. The grant is part-financed by the European Union, Operational Programme II – Cohesion Policy 2014 – 2020 “Investing in human capital to create more opportunities and promote the wellbeing of society” – European Social Fund.peer-reviewe

Modelling the effect of short-course multidrug-resistant tuberculosis treatment in Karakalpakstan, Uzbekistan

Background: Multidrug-resistant tuberculosis (MDR-TB) is a major threat to global TB control. MDR-TB treatment regimens typically have a high pill burden, last 20 months or more and often lead to unsatisfactory outcomes. A 9-11 month regimen with seven antibiotics has shown high success rates among selected MDR-TB patients in different settings and is conditionally recommended by the World Health Organization. Methods: We construct a transmission-dynamic model of TB to estimate the likely impact of a shorter MDR-TB regimen when applied in a low HIV prevalence region of Uzbekistan (Karakalpakstan) with high rates of drug resistance, good access to diagnostics and a well-established community-based MDR-TB treatment programme providing treatment to around 400 patients. The model incorporates acquisition of additional drug resistance and incorrect regimen assignment. It is calibrated to local epidemiology and used to compare the impact of shorter treatment against four alternative programmatic interventions. Results: Based on empirical outcomes among MDR-TB patients and assuming no improvement in treatment success rates, the shorter regimen reduced MDR-TB incidence from 15.2 to 9.7 cases per 100,000 population per year and MDR-TB mortality from 3.0 to 1.7 deaths per 100,000 per year, achieving comparable or greater gains than the alternative interventions. No significant increase in the burden of higher levels of resistance was predicted. Effects are probably conservative given that the regimen is likely to improve success rates. Conclusions: In addition to benefits to individual patients, we find that shorter MDR-TB treatment regimens also have the potential to reduce transmission of resistant strains. These findings are in the epidemiological setting of treatment availability being an important bottleneck due to high numbers of patients being eligible for treatment, and may differ in other contexts. The high proportion of MDR-TB with additional antibiotic resistance simulated was not exacerbated by programmatic responses and greater gains may be possible in contexts where the regimen is more widely applicable

Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis

BACKGROUND: Paediatric multidrug-resistant (MDR) tuberculosis is a public health challenge of growing concern, accounting for an estimated 15% of all global cases of MDR tuberculosis. Clinical management is especially challenging, and recommendations are based on restricted evidence. We aimed to assess existing evidence for the treatment of MDR tuberculosis in children. METHODS: We did a systematic review and meta-analysis of published and unpublished studies reporting treatment outcomes for children with MDR tuberculosis. We searched PubMed, Ovid, Embase, Cochrane Library, PsychINFO, and BioMedCentral databases up to Oct 31, 2011. Eligible studies included five or more children (aged ≤16 years) with MDR tuberculosis within a defined treatment cohort. The primary outcome was treatment success, defined as a composite of cure and treatment completion. RESULTS: We identified eight studies, which reported treatment outcomes for a total of 315 patients. We recorded much variation in the characteristics of patients and programmes. Time to appropriate treatment varied from 2 days to 46 months. Average duration of treatment ranged from 6 months to 34 months, and duration of follow-up ranged from 12 months to 37 months. The pooled estimate for treatment success was 81·67% (95% CI 72·54-90·80). Across all studies, 5·9% (95% CI 1·3-10·5) died, 6·2% (2·3-10·2) defaulted, and 39·1% (28·7-49·4) had an adverse event. The most common drug-related adverse events were nausea and vomiting. Other serious adverse events were hearing loss, psychiatric effects, and hypothyroidism. INTERPRETATION: The treatment of paediatric MDR tuberculosis has been neglected, but when children are treated outcomes can be achieved that are at least as good as those reported for adults. Programmes should be encouraged to report outcomes in children to improve the knowledge base for care, especially as new drugs become available. FUNDING: None

Mutational analysis of c-KIT and PDGFRA in GIST cases diagnosed locally

Introduction: The pathogenesis of most gastrointestinal stromal tumours (GISTs) is associated with activating mutations of the proto-oncogene tyrosine kinase KIT (c-KIT). Activating mutations are also found in the homologous tyrosine kinase platelet-derived growth factor receptor a (PDGFRA). Accurate diagnosis of GIST is essential due to the availability of targeted therapy. Immunohistochemistry (IHC) for CD117 (c-KIT receptor) is routinely performed in the diagnostic workup, however, it does not provide complete sensitivity, as there are nearly 5% of GISTs that are CD117 negative. The aim of this study was to identify cKIT and PDGFRA mutations present in GIST cases diagnosed locally.peer-reviewe

The distribution and prevalence of HPV genotype in Maltese women diagnosed with CIN 3 and cervical cancer

Introduction: The Human papilloma virus (HPV) is the causative agent of cervical carcinoma in women. There is a global variation of HPV genotypes that are highly carcinogenic. The aim of this study was to estimate the prevalence and type - specific distribution of HPV genotype in Maltese patients who were previously diagnosed with cervical intraepithelial neoplasia 3 (CIN 3) or cervical carcinoma.peer-reviewe

Mutational analysis of c-KIT and PDGFRA receptors in gastrointestinal stromal tumours

Introduction: The pathogenesis of gastrointestinal stromal tumors (GISTs) is generally associated with activating mutations of the proto-oncogene tyrosine-protein kinase Kit (c-KIT). However, about 15% of GISTs do not harbour c-KIT mutations. It is estimated that 5% of these GISTs have mutations in the platelet-derived growth factor receptor α (PDGFRA). Accurate diagnosis of GIST has become very important since the availability of targeted therapy with tyrosine kinase inhibitors, such as imatinib mesylate. The routine workup for GIST diagnosis includes immunohistochemistry for CD117 (c-KIT polyclonal antibody), as it is estimated that 95% of GIST cases show positive immunoreactivity. However, it can be observed that the routinely used immunohistochemical analysis does not provide complete sensitivity for GIST diagnosis, as there are nearly 5% of GISTs that are negative for c-KIT immunohistochemistry. Mutational analysis for c-KIT and PDGFRA can confirm the diagnosis of GIST, particularly in CD117-negative suspect GIST. Moreover, specific mutations have a prognostic and/or a predictive value for response to therapy.peer-reviewe