https://cdr.lib.unc.edu/downloads/02870x81q

Genomic Classification of Cutaneous Melanoma

Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held perception that RAS proteins are 'undruggable'. However, recent data from the laboratory and the clinic have renewed our hope for the development of RAS-inhibitory molecules. In this Review, we summarize the progress and the promise of five key approaches. Firstly, we focus on the prospects of using direct inhibitors of RAS. Secondly, we address the issue of whether blocking RAS membrane association is a viable approach. Thirdly, we assess the status of targeting RAS downstream effector signalling, which is arguably the most favourable current approach. Fourthly, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, RAS-mediated changes in cell metabolism have recently been described and we discuss whether these changes could be exploited for new therapeutic directions. We conclude with perspectives on how additional complexities, which are not yet fully understood, may affect each of these approaches.

/pdf/drugging-the-undruggable-ras-mission-possible-25j0sc44dt.pdf

Drugging the undruggable Ras: mission possible?

Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here, we describe two independent mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined. These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, and in reporter assays, the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.

/pdf/highly-recurrent-tert-promoter-mutations-in-human-melanoma-40df2vy3gb.pdf

Highly Recurrent TERT Promoter Mutations in Human Melanoma

https://www.cell.com/cell/pdf/S0092-8674(13)00288-2.pdf

Lessons from the cancer genome.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

/pdf/whole-genome-landscapes-of-major-melanoma-subtypes-x5vjnn3ziz.pdf

Whole-genome landscapes of major melanoma subtypes

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 92% of sun-exposed melanomas This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit

http://www.bouwt.avl.nl/media/326848/Artikel%20John%20Haanen%20(Melanoom).pdf

Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma.

The ability of liquid metals (LMs) to recover from repeated stretching and deformation is a particularly attractive attribute for soft bioelectronics. In addition to their high electrical and thermal conductivity, LMs can be actuated, potentially enabling highly durable electro-mechanical and microfluidics systems for applications such as cooling, drug delivery, or reconfigurable electronics. In particular, continuous electrowetting (CEW) phenomena can actuate liquid metal at relatively low voltage and affordable power requirements for wearable systems (~ < 10 V, ~ 10 – 100 µW) by inducing a surface tension gradient across the LM. However, sustaining LM actuation remains challenging due to factors such as electrolyte depletion, polarity changes in multi-electrode systems, and limitations related to LM composition. Here, we demonstrate LM actuation in a circular conduit for prolonged durations of at least nine hours. We enabled sustained actuation by sequentially applying short, direct current (DC) pulses through a multi-electrode system based on the dynamics of LM actuation. As a proof of concept, we also demonstrated the ability of LM to transport electrically conducting, non-conducting, and magnetic materials within a microchannel and show the liquid metal actuation system can be potentially miniaturized to the size of a wearable device. We envision that with further miniaturization of the device architectures, our CEW platform can enable future integration of low-voltage electro-mechanical systems into a broad range of wearable form factors. We achieved prolonged LM actuation in a circular conduit of at least nine hours. We enabled sustained actuation by sequentially applying short, direct current (DC) pulses through a multi-electrode system based on the dynamics of LM actuation. The platform can also transport electrically conductive, insulating, and magnetic composite cargos in a channel. We achieved prolonged LM actuation in a circular conduit of at least nine hours. We enabled sustained actuation by sequentially applying short, direct current (DC) pulses through a multi-electrode system based on the dynamics of LM actuation. The platform can also transport electrically conductive, insulating, and magnetic composite cargos in a channel.

The continuous actuation of liquid metal with a 3D-printed electrowetting device

We study the dissipative bi-stable Duffing oscillator with equal energy wells and observe fractal patterns in the parameter space of driving frequency, forcing amplitude, and damping ratio. Our numerical investigation reveals the Hausdorff fractal dimension of the boundaries that separate the oscillator's intra-well and inter-well behaviors. Furthermore, we categorize the inter-well behaviors as three steady-state types: switching, reverting, and vacillating. While fractal patterns in the phase space are well-known and heavily studied, our results point to a new research direction about fractal patterns in the parameter space. Another implication of this study is that the vibration of a continuous bi-stable system modeled using a single-mode approximation also manifests fractal patterns in the parameter space. In addition, our findings can guide the design of next-generation bi-stable and multi-stable mechanical metamaterials.

pdf/fractal-patterns-in-the-parameter-space-of-bi-stable-duffing-142j3xwa.pdf

Fractal Patterns in the Parameter Space of Bi-stable Duffing Oscillator

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Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma.

The continuous actuation of liquid metal with a 3D-printed electrowetting device

Fractal Patterns in the Parameter Space of Bi-stable Duffing Oscillator