Trastuzumab: Updated Mechanisms of Action and Resistance in Breast Cancer

HER2-positive breast cancer accounts for 20–30% of all breast cancers and has the second-poorest prognosis among breast cancer subtypes. The approval of trastuzumab in 1998 has significantly improved patients’ outcomes and paved the way for the beginning of advent of targeted approaches in breast cancer treatment. However, primary or acquired resistance to trastuzumab has been increasingly recognized as a major obstacle in the clinical management of this disease. In addition, in clinical practice, there are currently no conclusive biomarkers for patient response to trastuzumab. Therefore, understanding the molecular mechanism of trastuzumab and the development of resistance to this drug are of interest. Such understanding will provide the guidance critically needed for the design of better combination therapy and will allow the appropriate selection of patients who are responsive to trastuzumab-based strategies. In line with that, our review highlights the well-accepted mechanisms of action and resistance to the therapy and discusses the progress that has been made toward successfully overcoming this resistance

Authentic assessment for student learning: an ontological conceptualisation

Authentic assessment has been proposed as having potential to enhance student learning for a changing world. Conventionally, assessment is seen to be authentic when the tasks are real-to-life or have real-life value. Drawing on Martin Heidegger's work, we challenge this conceptualisation as narrow and limited. We argue that authenticity need not be an attribute of tasks but, rather, is a quality of educational processes that engage students in becoming more fully human. Adopting the mode of authenticity involves calling things into question, challenging public assumptions and striving to take a stand in the situations encountered. In addition to assessing student achievement, then, authentic assessment can enhance integration of what students know and how they act with who they are becoming

JAB1 NEGATIVELY REGULATES PTEN AND PROMOTES RESISTANCE TO TRASTUZUMAB IN HER2-POSITIVE BREAST CANCER

HER2-positive breast cancer, which is characterized by the over-expression of the HER2 onco-protein, accounts for approximately 20% of all breast cancer cases. Trastuzumab (Herceptin), the first targeted therapy approved for HER2-positive disease, potently prevents the activation of signaling pathways downstream of HER2 and significantly improves patients’ outcomes. However, resistance to trastuzumab is inevitable; such resistance can occur through reduced expression of PTEN protein. Jab1 is over-expressed in 50% of primary cancers and 90% of metastatic tumors. Our lab previously showed that depletion of Jab1 in combination with trastuzumab treatment up-regulated PTEN in mouse xenografts refractory to trastuzumab. PTEN was not detected in the control Jab1 knockdown. However, how Jab1 modulated trastuzumab responses and affected PTEN function was incompletely understood. The overall goal of my project was to identify the role of Jab1 in regulating PTEN and in contributing to trastuzumab resistance in HER2-positive breast cancer. I demonstrated that Jab1 mediated the post-translational regulation of PTEN by associating with PTEN and facilitating its degradation. I also found that the C-terminal end of Jab1 was required for Jab1 to induce degradation of PTEN. Furthermore, I showed that proteasome inhibitors failed to prevent PTEN degradation induced by Jab1 over-expression in breast cancer cells. Instead, the combination of lysosomal protease inhibitors - E64D and pepstatin A - significantly impaired the ability of Jab1 to degrade PTEN. Further, I showed that silencing Jab1 increased trastuzumab’s inhibitory effects on cell proliferation. In contrast, the introduction of Jab1 into breast cancer cells conferred resistance to trastuzumab. Taken together, my findings suggest that Jab1 negatively regulates PTEN and promotes trastuzumab resistance in HER2-positive breast cancer

Inlet morpho-dynamics during a storm event inferred from tidal records: a case study of the Brunswick River, NSW, Australia

A 24.5h moving window is used to analyse storm effects on the tidal dynamics. Compared to earlier studies using window lengths varying between 2h (for tsunami analysis) to 14 days for tidal inlet analysis, the present method provides good resolution of variations of hydraulic efficiency during storms or floods. The importance of de-trending before carrying out the harmonics analysis has been studied and it was found to be highly important. De-trending involved removing the 24.5h mean before harmonic analysis. The main results are the morphodynamic timescale Tmorph and the varying response functions F1 and F2 of the diurnal and semi-diurnal tidal constituents through a storm event at the Brunswick River, Australia. Tmorph is inferred from time series of primary semi-diurnal gain G2(t) = |F2 | with an exp(-t/Tmorph) curve fit. The results show only insignificant morphological change. Thus, the changes in tidal response for this medium sized catchment are mainly due to hydraulic effects. These include the influence of river flow Qf via the non-linear friction term and increased estuary surface area during the flood. The traces of both F1(t) and F2(t) in the complex plane show an equilibrium before the storm, dynamic change during the storm and relaxation mimicked by exp(-t/Tmorph) after the storm

Morphology of coastal lagoon entrances: waves versus tides

Lagoon inlets and river entrances on sandy coasts are shaped by waves, tides and freshwater outflows interacting subject to geological constraints. In dimensionless terms the relative importance of fresh water discharge Q versus peak tidal discharge Q is quantified simply by Q/Q, where the tidal peak discharge may be taken either as the actual Q = ωaA corresponding to the actual bay tidal amplitude aB or the potential Q = ωaA, which is based on the ocean tide amplitude aO. ω is the tidal angular frequency and A is the bay surface area at mid tide. The quantification of the relative strength of waves versus tides is less obvious and has not previously been clearly resolved. The case is made here for it being quantified by (Equation presented), where tidal dominance resulting in the canonical funnel shaped estuary occurs for (Equation presented) and, at the other end of the spectrum, intermittently open/closed systems (ICOLLS) occur for (Equation presented) denotes the average offshore significant wave height and g is acceleration due to gravity. More comprehensive data may lead to the inclusion of the wave period as well as the wave height in future formulations

Ocean driven flooding of a coastal lake

Analysis of Lake Conjola flooding in April 2006, provided in this paper, attributes it to waves pumping water over a 300 m long beach berm and into Lake Conjola. This overwash, generated by the medium wave height swell occurring during this flooding, was able to lift the lake levels near the entrance, persistently over several tidal cycles, to well above the ocean water levels . The wave pump model was used to model this flooding. Lake Conjola water storage and dynamics were modelled by using a two-node continuity based model that a change in storage in time is driven by the net inflow to a node and these nodes and the ocean are linked by log-law. The extents of these two nodes were established from previous water surface measurements. While the qualitative flood behavior was reproduced by this remarkably simple model, the peak flood level was not satisfactorily predicted when using literature values for model turning parameters. One reason for this mismatch was that the waves pumped against a head including critical flow on the beach berm. Based on recent images of Lake Conjola wave overwash events, it may be concluded that pumping against critical flow is too harsh. Removing this from the model has halved the gap between the measurements and predictions. However, more research is definitely required to establish what components should be included in the hydraulic head pumped against

FTKHUIM: A fast and efficient method for mining top-k high-utility itemsets

High-utility itemset mining (HUIM) is an important task in the field of knowledge data discovery. The large search space and huge number of HUIs are the consequences of applying HUIM algorithms with an inappropriate user-defined minimum utility threshold value. Determining a suitable threshold value to obtain the expected results is not a simple task and requires spending a lot of time. For common users, it is difficult to define a minimum threshold utility for exploring the right number of HUIs. On the one hand, if the threshold is set too high then the number of HUIs would not be enough. On the other hand, if the threshold is set too low, too many HUIs will be mined, thus wasting both time and memory. The top-k HUIs mining problem was proposed to solve this issue, and many effective algorithms have since been introduced by researchers. In this research, a novel approach, namely FTKHUIM (Fast top k HUI Mining), is introduced to explore the top-k HUIs. One new threshold-raising strategy called RTU, a transaction utility (TU)-based threshold-raising strategy, has also been shown to rapidly increase the speed of top-k HUIM. The study also proposes a global structure to store utility values in the process of applying raising-threshold strategies to optimize these strategies. The results of experiments on various datasets prove that the FTKHUIM algorithm achieves better results with regard to both the time and search space needed.Web of Science1110480510478

The Association Between Ambient Temperatures and Hospital Admissions Due to Respiratory Diseases in the Capital City of Vietnam

This study aimed to examine the short-term effects of ambient temperature on hospital admissions due to respiratory diseases among Hanoi residents. We collected 34,653 hospital admissions for 365 days (November 1, 2017, to November 31, 2018) from two hospitals in Hanoi. A quasi-Poisson regression model with time series analysis was used to explore the temperature-health outcome relationship's overall pattern. The non-linear curve indicated the temperatures with the lowest risk range from 22 degrees (Celcius) to 25 degrees (Celcius). On average, cold temperatures showed a higher risk than hot temperatures across all genders and age groups. Hospital admissions risk was highest at 13 degrees (Celcius) (RR = 1.39; 95% CI = 1.26–1.54) for cold effects and at 33 degrees (Celcius) (RR = 1.21, 95% CI = 1.04–1.39) for the hot effects. Temporal pattern analysis showed that the most effect on respiratory diseases occurred at a lag of 0 days for hot effect and at a lag of 1 day for cold effect. The risk of changing temperature among women and people over 5 years old was higher than other groups. Our results suggest that the risk of respiratory admissions was greatest when the temperature was low. Public health prevention programs should be enhanced to improve public awareness about the health risks of temperature changes, especially respiratory diseases risked by low temperatures

Depression, anxiety and stress among healthcare workers in the context of the COVID-19 pandemic: a cross-sectional study in a tertiary hospital in Northern Vietnam

IntroductionThe outbreak of coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) had significant effects on the mental well-being in general, particularly for healthcare professionals. This study examined the prevalence of depression, anxiety, and stress, and identified the associated risk factors amongst healthcare workers during the COVID-19 outbreak in a tertiary hospital located in Vietnam.MethodsWe conducted a cross-sectional study at a tertiary-level hospital, where the Depression Anxiety and Stress Scale 21 (DASS-21) web-based questionnaire was employed. We analyzed the determinant factors by employing multivariate logistic models.ResultsThe prevalence of depression, anxiety, and stress symptoms were 19.2%, 24.7%, and 13.9%, respectively. Factors such as engaging in shift work during the pandemic, taking care of patients with COVID-19, and staff’s health status were associated with mental health issues among health professionals. In addition, having alternate rest periods was likely to reduce the risk of stress.ConclusionThe prevalence of mental health problems in healthcare workers during the COVID-19 pandemic was relatively high. Having resting periods could potentially mitigate the development of stress among health professionals. Our findings could be taken into account for improving mental health of the health professional population