Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy1,2,3. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes1,3. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1)1,3,4. Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.This work was supported by an Alex's Lemonade Stand Young Investigator Award (S.C.M.), The CIHR Banting Fellowship (S.C.M.), The Cancer Prevention Research Institute of Texas (S.C.M., RR170023), Sibylle Assmus Award for Neurooncology (K.W.P.), the DKFZ-MOST (Ministry of Science, Technology & Space, Israel) program in cancer research (H.W.), James S. McDonnell Foundation (J.N.R.) and NIH grants: CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). R.C.G. is supported by NIH grants T32GM00725 and F30CA217065. M.D.T. is supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Pediatric Brain Tumour Foundation, Grand Challenge Award from CureSearch for Children’s Cancer, the National Institutes of Health (R01CA148699, R01CA159859), The Terry Fox Research Institute and Brainchild. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113)

230 mW of blue light from a thulium-doped upconversion fiber laser

We demonstrate a powerful diode-pumped blue laser source, consisting of a 7W diode at 807nm that pumps a Nd:YAG laser giving 1.6W with good beam quality at 1123nm, and a thulium-doped upconversion fiber laser. The maximum output power achieved at 481nm is 230mW. We also describe the behavior of a reversible loss which is generated in the fluoride fiber during high power operation

Vertical-external-cavity semiconductor lasers

Surface-emitting semiconductor lasers can make use of external cavities and optical pumping techniques to achieve a combination of high continuous-wave output power and near-diffraction-limited beam quality that is not matched by any other type of semiconductor source. The ready access to the laser mode that the external cavity provides has been exploited for applications such as intra-cavity frequency doubling and passive mode-locking. The purpose of this Topical Review is to outline the operating principles of these versatile lasers and summarize the capabilities of devices that have been demonstrated so far. Particular attention is paid to the generation of near-transform-limited sub-picosecond pulses in passively mode-locked surface-emitting lasers, which are potentially of interest as compact sources of ultrashort pulses at high average power that can be operated readily at repetition rates of many gigahertz

Thulium-doped upconversion fibre-laser with 230mW of 480nm blue output

Blue laser sources are required for a number of applications such as colour displays, printing and data recording. Three main approaches are currently pursued. Blue emitting laser diodes have recently been demonstrated, albeit with a number of limitations at present regarding power lifetime and operating temperature. Another approach is frequency doubling of an infrared source; for example 49mW of 473nm light have recently been obtained by frequency doubling the output of a diode-pumped 946nm Nd:YAG laser in a single pass through a periodically poled LiNbO3 crystal. The third approach is upconversion lasing, for which the highest reported power to date, at blue wavelengths, was 106mW from a diode-pumped Tm:ZBLAN upconversion fibre laser. In this paper we report a blue output of up to 230mW, achieved by using a more powerful pump laser and a Tm:ZBLAN fibre with a modified composition, which has allowed higher power operation. Long term operation at the highest power is not yet possible however due to an optically induced loss in the fibre as observed in earlier work. The pump laser was a Nd:YAG laser operating at 1123nm and pumped by a 7W diode-bar. This laser produced 1.6W in a circular Gaussian-beam of M2 < 1.1. The high beam quality allowed overall launch efficiencies into the fibre of between 50 and 60%. The Tm-doped fibre used, produced by Le Verre Fluoré, had a Tm concentration of 1000ppm (by weight), a NA of 0.2, a core diameter of 3µm and length of 2.2m. To form the cavity, dielectric mirrors were dry butted against both ends of the fibre. The input mirror had high reflectivity for blue light, and a transmission of 90% for the 1123nm pump, which was launched through this mirror using an aspheric lens. The output coupler had a transmission of 37% for the blue. This laser had a threshold of 100mW of incident pump power, and a slope efficiency of 18.5%, again with respect to incident power. For high pump powers the slope efficiency rolled off, and the maximum output obtained was 230mW for 1.6W of incident power. It was noted that this output power could not be sustained. Instead, at a constant pump power, the output would gradually decrease to some sustainable level. Around 140mW was the highest sustainable power achieved. The underlying cause of this effect was an induced loss in the fibre at blue wavelengths, thus increasing the threshold and decreasing the slope efficiency. Further tests revealed that this loss is not permanent and it can be entirely removed by operation of the fibre laser at low powers for a time of the order of an hour. It is hoped that an understanding of the loss mechanism and its relation to material composition could lead to upconversion lasers with even higher sustainable powers

230 mW of blue light from thulium:ZBLAN upconversion fibre laser

230 mW at 481 nm have been obtained from a Tm:ZBLAN upconversion fibre laser, pumped by a Nd:YAG laser with 1.6W at 1123nm. The fibre developed a strong loss which however appeared to be fully reversible