Protein and epigenetic biomarkers for variability in epidermal growth factor receptor inhibition in cancer treatment and characterization of the inhibitor-induced skin toxicity in an <em>in vitro</em> model

Epidermal growth factor receptor (EGFR) is often over-expressed or over-activated in cells of solid tumors and can be targeted by specific inhibitors (EGFRIs), like erlotinib, gefitinib, cetuximab and panitumumab. Unfortunately, EGFRIs only seem to work in a subset of patients suffering from EGFR-expressing tumors. Efficient biomarkers to reliably select patients who will benefit from an EGFRI therapy and determine their optimal dosage are still needed. One of the most common adverse drug reactions observed during therapy with all approved EGFRIs is the development of a typical skin rash. It has been shown in various studies that occurrence and severity of this EGFRI-induced rash are positively correlated with patient outcome (prolonged overall and progression-free survival). However, the rash usually takes several weeks to manifest and is usually treated with topical or systemic medication. Hence, its severity may be suppressed, rendering it unsuitable as a clinical predictive marker. Therefore, the aim of this study was to identify rapidly determinable predictive biomarkers for the severity of EGFRI-induced skin rash, which would be helpful to allow early preventive treatment of the rash while at the same time still allowing prediction of EGFRI efficacy early on and facilitate optimization of personalized cancer therapy for individual patients. They can also help to prevent exposure of patients to substances which are ineffective but still cause discomforting side effects. Since previous work revealed evidence for genetic, pharmacokinetic and cytokine markers, the intention of this work was to identify functional biomarkers that are able to measure EGFR inhibition variability in the periphery, especially in blood plasma and skin cells. Therefore, molecules that interact with, regulate or functionally modulate EGFR inhibition were selected and their levels determined in plasma samples from patients treated with an EGFRI by enzyme-linked immunosorbent assay (ELISA) and it was checked for correlations with the development of EGFRI-induced skin toxicity. The EGFRI cetuximab, the EGFR ligand amphiregulin (AREG) and the growth factors hepatocyte growth factor (HGF) and 25-OH-vitamin D were selected as candidates following these criteria. Since miRNAs have recently been shown to be very important in the response to cancer therapy, investigating the suitability of specific mature or precursor miRNA molecules as functional, epigenetic biomarkers for the development of EGFRI-induced skin toxicity was of special interest. Therefore, next generation sequencing (NGS) was performed in keratinocyte and fibroblast cultures from healthy donors to compare miRNA profiles between cells previously identified as rather erlotinib-sensitive and those identified as rather erlotinib-insensitive. Results show that plasma levels of the EGFRI cetuximab were not significantly associated with development of EGFRI-induced rash. While the investigated candidates AREG and 25-OH-vitamin D also failed to show a significant correlation with the rash, the plasma concentration of the MET ligand HGF was significantly inversely correlated with severity of EGFRI-induced skin rash. This inverse correlation was also seen with overall survival (OS) in patients who developed EGFRI-induced rash but not in patients with no rash. HGF seems to be a promising biomarker, whose predictive and/or prognostic value should definitely be validated in a larger and well-controlled patient cohort. In this study primary human dermal keratinocytes as well as fibroblasts have proven to be suitable as in vitro models for studying EGFRI-induced skin rash and associated potential biomarkers. Comparison of miRNA profiles between erlotinib-sensitive and rather -insensitive cells combined with a literature review to identify the miRNAs with the most supporting data, led to identification of the precursor miRNAs mir-146a, mir-31, mir-221, mir-520e and mir-944 as most promising predictive biomarkers in keratinocytes, with mir-146a, mir-520e and mir-944 having known targets and a plausible suggested mechanism of action and mir-31 and mir-221 having already been shown to be associated with sensitivity to an EGFRI in at least one previously published study. In fibroblasts the precursor miRNA mir-34a was identified as the by far most promising predictive biomarker with MET reported as direct target and an associated plausible mechanism of action and two confirmatory previous studies. Further identified promising miRNAs in fibroblasts were mir-382, mir-494, mir-520e and mir-7-1, also with plausible suggested targets. Overall, the final conclusion of this study is that it might be possible to develop a kind of "predictive profile" consisting of several different biomarkers which taken together may have a predictive value on individual extent of EGFR inhibition in patients. The results of this study suggest that parameters like the plasma concentration of HGF, the expression of mir-146a and mir-31 in dermal keratinocytes and the expression of mir-34a in dermal fibroblasts might be promising parameters to include in such a predictive profile. However, all suggested parameters need to be further confirmed and validated in clinical settings. Eventually, such a predictive score might be used in the future to predict the requirement for changes in dosage of a specific EGFRI, closer monitoring of therapy efficacy by more frequent tumor imaging or maybe even change in therapy away from using an EGFRI or at least adding an adjuvant drug to the EGFRI for better efficacy

Using futures methods to create transformative spaces: visions of a good Anthropocene in southern Africa

The unique challenges posed by the Anthropocene require creative ways of engaging with the future and bringing about transformative change. Envisioning positive futures is a first step in creating a shared understanding and commitment that enables radical transformations toward sustainability in a world defined by complexity, diversity, and uncertainty. However, to create a transformative space in which truly unknowable futures can be explored, new experimental approaches are needed that go beyond merely extrapolating from the present into archetypal scenarios of the future. Here, we present a process of creative visioning where participatory methods and tools from the field of futures studies were combined in a novel way to create and facilitate a transformative space, with the aim of generating positive narrative visions for southern Africa. We convened a diverse group of participants in a workshop designed to develop radically different scenarios of good Anthropocenes, based on existing “seeds” of the future in the present. These seeds are innovative initiatives, practices, and ideas that are present in the world today, but are not currently widespread or dominant. As a result of a carefully facilitated process that encouraged a multiplicity of perspectives, creative immersion, and grappling with deeply held assumptions, four radical visions for southern Africa were produced. Although these futures are highly innovative and exploratory, they still link back to current real-world initiatives and contexts. The key learning that arose from this experience was the importance of the imagination for transformative thinking, the need to capitalize on diversity to push boundaries, and finally, the importance of creating a space that enables participants to engage with emotions, beliefs, and complexity. This method of engagement with the future has the potential to create transformative spaces that inspire and empower people to act toward positive Anthropocene visions despite the complexity of the sustainability challenge

Seeds of good anthropocenes: developing sustainability scenarios for Northern Europe

Scenario development helps people think about a broad variety of possible futures; however, the global environmental change community has thus far developed few positive scenarios for the future of the planet and humanity. Those that have been developed tend to focus on the role of a few common, large-scale external drivers, such as technology or environmental policy, even though pathways of positive change are often driven by surprising or bottom-up initiatives that most scenarios assume are unchanging. We describe an approach, pioneered in Southern Africa and tested here in a new context in Northern Europe, to developing scenarios using existing bottom-up transformative initiatives to examine plausible transitions towards positive, sustainable futures. By starting from existing, but marginal initiatives, as well as current trends, we were able to identify system characteristics that may play a key role in sustainability transitions (e.g., gender issues, inequity, governance, behavioral change) that are currently under-explored in global environmental scenarios. We suggest that this approach could be applied in other places to experiment further with the methodology and its potential applications, and to explore what transitions to desirables futures might be like in different places

Bright spots: seeds of a good Anthropocene

The scale, rate, and intensity of humans’ environmental impact has engendered broad discussion about how to find plausible pathways of development that hold the most promise for fostering a better future in the Anthropocene. However, the dominance of dystopian visions of irreversible environmental degradation and societal collapse, along with overly optimistic utopias and business‐as‐usual scenarios that lack insight and innovation, frustrate progress. Here, we present a novel approach to thinking about the future that builds on experiences drawn from a diversity of practices, worldviews, values, and regions that could accelerate the adoption of pathways to transformative change (change that goes beyond incremental improvements). Using an analysis of 100 initiatives, or “seeds of a good Anthropocene”, we find that emphasizing hopeful elements of existing practice offers the opportunity to: (1) understand the values and features that constitute a good Anthropocene, (2) determine the processes that lead to the emergence and growth of initiatives that fundamentally change human–environmental relationships, and (3) generate creative, bottom‐up scenarios that feature well‐articulated pathways toward a more positive future

High cable forces deteriorate pinch force control in voluntary-closing body-powered prostheses

It is generally asserted that reliable and intuitive control of upper-limb prostheses requires adequate feedback of prosthetic finger positions and pinch forces applied to objects. Body-powered prostheses (BPPs) provide the user with direct proprioceptive feedback. Currently available BPPs often require high cable operation forces, which complicates control of the forces at the terminal device. The aim of this study is to quantify the influence of high cable forces on object manipulation with voluntary-closing prostheses. Able-bodied male subjects were fitted with a bypass-prosthesis with low and high cable force settings for the prehensor. Subjects were requested to grasp and transfer a collapsible object as fast as they could without dropping or breaking it. The object had a low and a high breaking force setting. Subjects conducted significantly more successful manipulations with the low cable force setting, both for the low (33 % more) and high (50 %) object’s breaking force. The time to complete the task was not different between settings during successful manipulation trials. In conclusion: high cable forces lead to reduced pinch force control during object manipulation. This implies that low cable operation forces should be a key design requirement for voluntary-closing BPPs

Global trends 2025

The original publication is available at http://www.hichert.co.za/global-trends-2025/The National Intelligence Council's (NIC) 2025 Global Trends report deals with how key global trends might develop over the next 15 years to influence world events. It contains a range of possibilities and potential discontinuities, amongst others in the form of four global scenarios and 2025 Global Landscape 'certainties' and 'uncertainties'. An overview of the report is provided with content highlights, extracts from the 2025 Global Landscape and selected commentary about sub-Saharan Africa

Planning and strategising during turbulence

The original publication is available at http://www.hichert.co.za/planning-and-strategising-during-turbulance/The business landscape (organisations’ contextual environment) is characterised by turbulence which describes conditions which are uncertain, complex and volatile. Standard forecasting and planning tools as well as standard winning strategies are inadequate in these conditions. Scenario planning and collaborative value-building strategies are described as alternatives

The future of management

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The greening of business

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Innovations for a sustainable economy: Steps for business

Please help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected] En BestuurswetenskappeInstituut Vir Toekomsnavorsin