br Conclusion Whilst acknowledging that forensic science cri

Conclusion Whilst acknowledging that forensic science critically needs strategic investment across every domain [27], forensic science needs to bring both ‘hedgehog’ and ‘fox’ approaches together to address the roots of the major challenges the discipline faces. Addressing these challenges in a way that incorporates a holistic understanding of the complex matrix that is forensic science offers huge potential. However, just as a holistic understanding of the whole forensic reconstruction process is critical, the unifying principles of the ‘hedgehog’ and the identification of the range of factors that contribute to the complex landscape we are working within of the ‘fox’, are both fundamental. We lose either approach at our peril.
Introduction Originally discovered in its orthologous form – the wingless gene in Drosophila, the Wnt family of genes has been found to be highly conserved throughout the animal kingdom [1]. Wnt was known to be one of the key gene semagacestat receptor determining patterning during embryonic development [2]. Its role in development of cellular stemness and cancer were subsequently discovered. Initially, the fact that Wnt plays some role in cancer was implied from conducting experiments in mice by transgenic overexpression and activation of Wnt1 (or int1) insertion into Wnt1 locus (mediated by proviral vectors), which resulted in mammary hyperplasias and tumors [[3], [4], [5]]. But then, the discovery of the mutated adenomatous polyposis coli (APC) gene [6,7] and its interaction with β-catenin [8,9], along with the discovery of overactivated T-cell factor 4 (TCF-4)/β-catenin signaling upon its loss of function [10], all studied in human colorectal cancer, substantiated a direct link between the Wnt signaling and cancer. With the advancement in research that followed, many components of the Wnt signaling pathway have been discovered and their functions identified. Comprehensive genetic screening in cancers and high accuracy sequencing methods [11,12] gave way to the evidence that Wnt pathway component mutations frequently occurred in human cancers [[13], [14], [15], [16]], and innumerable studies have been conducted to prove this idea and solidify it. Today, even when we are aware of most of the Wnt signaling pathway components and their functions in the context of cancer biology, it is understood that the said pathway is immensely complex, and a lot more remains to be known regarding its exact role in various cancers as of yet. Moreover, with the advent of knowledge regarding cancer stem cells (CSCs) [17], many studies have been aimed to establish the fact that this Wnt pathway also has a major role to play in origin and maintenance of stemness in cancer cells. Although controversial, but CSCs are proposed to be the main culprit behind treatment failure and cancer relapse [18]. So, researchers have targeted this pathway to remove CSC populations and prevent any recurrence of malignancy [19]. On the other hand, combination therapies are generally prescribed now in aggressive cancers, which employ more than one method, or target more than one key pathway to kill cancer cells or restrict their growth [20]. This stems from the idea that when a therapy is directed towards one particular pathway, the highly mutated and heterogeneous cancer cells shift their focus on other mechanisms to keep themselves alive. Numerous experiments have also proved this fact that when one single pathway is targeted in order to kill cancer cells, components of other pathways are overexpressed, i.e. they become hyperactive. For example, when drugs target cancer cells to cause their apoptosis, the cancer cells have been seen to upregulate Hypoxia-Inducible Factor-1 α (HIF-1α) thus attempting survival via autophagy [20] and associated recycling of nutrients, through the subsequent activation of BCL2/ adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and BNIP3-like protein, resulting in angiogenesis [21]. For example, chloroquine, an autophagy-inhibitor, augmented the effect of vorinostat [22], an HDAC-inhibitor, by increasing cellular death in BCR-ABL-positive chronic myeloid leukemia (CML) cell lines [23,24] which were imatinib-resistant.