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Requirements analysis and specification for a molecular tumor board platform based on cBioPortal
(2020)
Clinicians in molecular tumor boards (MTB) are confronted with a growing amount of genetic high-throughput sequencing data. Today, at German university hospitals, these data are usually handled in complex spreadsheets from which clinicians have to obtain the necessary information. The aim of this work was to gather a comprehensive list of requirements to be met by cBioPortal to support processes in MTBs according to clinical needs. Therefore, oncology experts at nine German university hospitals were surveyed in two rounds of interviews. To generate an interview guideline a scoping review was conducted. For visual support in the second round, screenshot mockups illustrating the requirements from the first round were created. Requirements that cBioPortal already meets were skipped during the second round. In the end, 24 requirements with sometimes several conceivable options were identified and 54 screenshot mockups were created. Some of the identified requirements have already been suggested to the community by other users or are currently being implemented in cBioPortal. This shows, that the results are in line with the needs expressed by various disciplines. According to our findings, cBioPortal has the potential to significantly improve the processes and analyses of an MTB after the implementation of the identified requirements.
Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5′ splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted.
Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.