Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Closing the Gap Between Mammalian and Invertebrate Peripheral Nerve Injury: Protocol for a Novel Nerve Repair

Background: Outcomes after peripheral nerve injuries are poor despite current nerve repair techniques. Currently, there is no conclusive evidence that mammalian axons are capable of spontaneous fusion after transection. Notably, certain invertebrate species are able to auto-fuse after transection. Although mammalian axonal auto-fusion has not been observed experimentally, no mammalian study to date has demonstrated regenerating axolemmal membranes contacting intact distal segment axolemmal membranes to determine whether mammalian peripheral nerve axons have the intrinsic mechanisms necessary to auto-fuse after transection.Objective: This study aims to assess fusion competence between regenerating axons and intact distal segment axons by enhancing axon regeneration, delaying Wallerian degeneration, limiting the immune response, and preventing myelin obstruction. Methods: This study will use a rat sciatic nerve model to evaluate the effects of a novel peripheral nerve repair protocol on behavioral, electrophysiologic, and morphologic parameters. This protocol consists of a variety of preoperative, intraoperative, and postoperative interventions. Fusion will be assessed with electrophysiological conduction of action potentials across the repaired transection site. Axon-axon contact will be assessed with transmission electron microscopy. Behavioral recovery will be analyzed with the sciatic functional index. A total of 36 rats will be used for this study. The experimental group will use 24 rats and the negative control group will use 12 rats. For both the experimental and negative control groups, there will be both a behavior group and another group that will undergo electrophysiological and morphological analysis. The primary end point will be the presence or absence of action potentials across the lesion site. Secondary end points will include behavioral recovery with the sciatic functional index and morphological analysis of axon-axon contact between regenerating axons and intact distal segment axons. Results: The author is in the process of grant funding and institutional review board approval as of March 2020. The final follow-up will be completed by December 2021. Conclusions: In this study, the efficacy of the proposed novel peripheral nerve repair protocol will be evaluated using behavioral and electrophysiologic parameters. The author believes this study will provide information regarding whether spontaneous axon fusion is possible in mammals under the proper conditions. This information could potentially be translated to clinical trials if successful to improve outcomes after peripheral nerve injury

Indigenous Protocol and Artificial Intelligence Position Paper

This position paper on Indigenous Protocol (IP) and Artificial Intelligence (AI) is a starting place for those who want to design and create AI from an ethical position that centers Indigenous concerns. Each Indigenous community will have its own particular approach to the questions we raise in what follows. What we have written here is not a substitute for establishing and maintaining relationships of reciprocal care and support with specific Indigenous communities. Rather, this document offers a range of ideas to take into consideration when entering into conversations which prioritize Indigenous perspectives in the development of artificial intelligence. It captures multiple layers of a discussion that happened over 20 months, across 20 time zones, during two workshops, and between Indigenous people (and a few non-Indigenous folks) from diverse communities in Aotearoa, Australia, North America, and the Pacific. Indigenous ways of knowing are rooted in distinct, sovereign territories across the planet. These extremely diverse landscapes and histories have influenced different communities and their discrete cultural protocols over time. A single ‘Indigenous perspective’ does not exist, as epistemologies are motivated and shaped by the grounding of specific communities in particular territories. Historically, scholarly traditions that homogenize diverse Indigenous cultural practices have resulted in ontological and epistemological violence, and a flattening of the rich texture and variability of Indigenous thought. Our aim is to articulate a multiplicity of Indigenous knowledge systems and technological practices that can and should be brought to bear on the ‘question of AI.’ To that end, rather than being a unified statement this position paper is a collection of heterogeneous texts that range from design guidelines to scholarly essays to artworks to descriptions of technology prototypes to poetry. We feel such a somewhat multivocal and unruly format more accurately reflects the fact that this conversation is very much in an incipient stage as well as keeps the reader aware of the range of viewpoints expressed in the workshops

Kaʻina Hana ʻŌiwi a me ka Waihona ʻIke Hakuhia Pepa Kūlana

He wahi hoʻomaka kēia pepa kuana no ke Kaʻina Hana ʻŌiwi (KHʻO) a me ka Waihona ʻike Hakuhia (WʻIH) no ka poʻe e ake nei e haku a hana he WʻIK mai ke kuanaʻike kūpono e hoʻokele ʻia nei e ka manaʻo ʻŌiwi. He kiʻina hana ko kēlā a me kēia kaiāulu ʻŌiwi i nā nīnau a mākou e ui aʻe ai. ʻAʻole kēia mea a mākou i kākau ai he pani i ke kūkulu a mālama ʻana i ka pilina kākoʻo kekahi i kekahi me kekahi mau kaiāulu ʻŌiwi. Eia naʻe, hāpai aʻe kēia palapala i kekahi mau manaʻo e noʻonoʻo ai ke komo i kēia mau kamaʻilio ʻana ʻo ka hoʻomaka koho ʻana i ke kuanaʻike ʻŌiwi i ka haku ʻana he waihona ʻike hakuhia. He hoʻāʻo kēia wahi pepa kūlana e hōʻiliʻili i nā ʻano kamaʻilio like ʻole no 20 mahina, no 20 kāʻei hola, no ʻelua hālāwai hoʻonaʻauao, a ma waena hoʻi o kekahi mau poʻe ʻŌiwi (a ʻŌiwi ʻole hoʻi) no nā kaiāulu like ʻole i Aotearoa, Nū Hōlani, ʻAmelika ʻĀkau a me ka Pākīpika. ʻO ke kia nō naʻe, ʻaʻole ʻo ka hoʻolōkahi ʻana he leo. Paʻa nō ka ʻike ʻŌiwi i kekahi mau ʻāina a aupuni kikoʻī a puni ka honua. Hoʻohuli aku kēia mau ʻāina a mōʻaukala like ʻole i nā kaiāulu ʻokoʻa a me ko lākou mau kaʻina hana ʻŌiwi i ke au o ka manawa. ʻAʻohe “kuanaʻike ʻŌiwi hoʻokahi”, a hoʻomau a haku ʻia nā kālaikuhiʻike e ka hoʻokumu ʻana o kekahi mau kaiāulu kikoʻī i loko o kahi mau ʻāina. Ma mua, he hopena ulūlu o ke kālaikuhiʻike a kālaikuhikanaka ko ka loina naʻauao i hoʻāʻo e naʻi a hoʻohilimia i ka loina ʻŌiwi, a hoʻohāiki ʻia ke ʻano o ka manaʻo a kuanaʻike ʻŌiwi. ʻO ko mākou pahuhopu ke kālele ʻana i nā ʻōnaehana ʻike ʻŌiwi like ʻole a me ke ʻano o ka ʻenehana e hāpai i ka nīnau ʻo ka WʻIH. Ma muli o ia palena, a ma kahi o ka hoʻokuʻikuʻi ʻana he manaʻo lōkahi, he hōʻiliʻili kēia pepa kūlana o kēlā ʻano kēia ʻano o ka moʻokalaleo: ʻo nā manaʻo hoʻokele hakulau ʻoe,, ʻo ka ʻatikala akeakamai ʻoe, ʻo ka wehewehena o ka mana ʻenehana mua ʻoe , a ʻo ka poema ʻoe. I ko mākou manaʻo, he ʻolokeʻa kūpono maoli nā leo a kuanaʻike ʻokoʻa i ka ʻoiaʻiʻo he pae kinohi maoli nō kēia kamaʻilio ʻana, a he hōʻike i ka mea heluhelu no nā kuanaʻike i kupu mai i loko o nā hālāwai hoʻonaʻauao

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead