Recovery, rehabilitation and follow-up services following critical illness: an updated UK national cross-sectional survey and progress report.

OBJECTIVE: To comprehensively update and survey the current provision of recovery, rehabilitation and follow-up services for adult critical care patients across the UK. DESIGN: Cross-sectional, self-administered, predominantly closed-question, electronic, online survey. SETTING: Institutions providing adult critical care services identified from national databases. PARTICIPANTS: Multiprofessional critical care clinicians delivering services at each site. RESULTS: Responses from 176 UK hospital sites were included (176/242, 72.7%). Inpatient recovery and follow-up services were present at 127/176 (72.2%) sites, adopting multiple formats of delivery and primarily delivered by nurses (n=115/127, 90.6%). Outpatient services ran at 130 sites (73.9%), predominantly as outpatient clinics. Most services (n=108/130, 83.1%) were co-delivered by two or more healthcare professionals, typically nurse/intensive care unit (ICU) physician (n=29/130, 22.3%) or nurse/ICU physician/physiotherapist (n=19/130, 14.6%) teams. Clinical psychology was most frequently lacking from inpatient or outpatient services. Lack of funding was consistently the primary barrier to service provision, with other barriers including logistical and service prioritisation factors indicating that infrastructure and profile for services remain inadequate. Posthospital discharge physical rehabilitation programmes were relatively few (n=31/176, 17.6%), but peer support services were available in nearly half of responding institutions (n=85/176, 48.3%). The effects of the COVID-19 pandemic resulted in either increasing, decreasing or reformatting service provision. Future plans for long-term service transformation focus on expansion of current, and establishment of new, outpatient services. CONCLUSION: Overall, these data demonstrate a proliferation of recovery, follow-up and rehabilitation services for critically ill adults in the past decade across the UK, although service gaps remain suggesting further work is required for guideline implementation. Findings can be used to enhance survivorship for critically ill adults, inform policymakers and commissioners, and provide comparative data and experiential insights for clinicians designing models of care in international healthcare jurisdictions

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

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

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

Ena/VASP proteins have an anti-capping independent function in filopodia formation

Author Posting. © American Society for Cell Biology, 2007. This article is posted here by permission of American Society for Cell Biology for personal use, not for redistribution. The definitive version was published in Molecular Biology of the Cell 18 (2007): 2579-2591, doi:10.1091/mbc.E06-11-0990.Filopodia have been implicated in a number of diverse cellular processes including growth-cone path finding, wound healing, and metastasis. The Ena/VASP family of proteins has emerged as key to filopodia formation but the exact mechanism for how they function has yet to be fully elucidated. Using cell spreading as a model system in combination with small interfering RNA depletion of Capping Protein, we determined that Ena/VASP proteins have a role beyond anticapping activity in filopodia formation. Analysis of mutant Ena/VASP proteins demonstrated that the entire EVH2 domain was the minimal domain required for filopodia formation. Fluorescent recovery after photobleaching data indicate that Ena/VASP proteins rapidly exchange at the leading edge of lamellipodia, whereas virtually no exchange occurred at filopodial tips. Mutation of the G-actin–binding motif (GAB) partially compromised stabilization of Ena/VASP at filopodia tips. These observations led us to propose a model where the EVH2 domain of Ena/VASP induces and maintains clustering of the barbed ends of actin filaments, which putatively corresponds to a transition from lamellipodial to filopodial localization. Furthermore, the EVH1 domain, together with the GAB motif in the EVH2 domain, helps to maintain Ena/VASP at the growing barbed ends.This work was supported in part by National Institutes of Health Grants GM7542201 to D.A.A., GM58801 to F.B.G., and GM62431 to G.G.B. and by Cell Migration Consortium Grants GM64346 to D.A.A and G.G.B

Recovery, rehabilitation and follow-up services following critical illness: an updated UK national cross-sectional survey and progress report

Objective: To comprehensively update and survey the current provision of recovery, rehabilitation and follow-up services for adult critical care patients across the UK. Design: Cross-sectional, self-administered, predominantly closed-question, electronic, online survey. Setting: Institutions providing adult critical care services identified from national databases. Participants: Multiprofessional critical care clinicians delivering services at each site. Results: Responses from 176 UK hospital sites were included (176/242, 72.7%). Inpatient recovery and follow-up services were present at 127/176 (72.2%) sites, adopting multiple formats of delivery and primarily delivered by nurses (n=115/127, 90.6%). Outpatient services ran at 130 sites (73.9%), predominantly as outpatient clinics. Most services (n=108/130, 83.1%) were co-delivered by two or more healthcare professionals, typically nurse/intensive care unit (ICU) physician (n=29/130, 22.3%) or nurse/ICU physician/physiotherapist (n=19/130, 14.6%) teams. Clinical psychology was most frequently lacking from inpatient or outpatient services. Lack of funding was consistently the primary barrier to service provision, with other barriers including logistical and service prioritisation factors indicating that infrastructure and profile for services remain inadequate. Posthospital discharge physical rehabilitation programmes were relatively few (n=31/176, 17.6%), but peer support services were available in nearly half of responding institutions (n=85/176, 48.3%). The effects of the COVID-19 pandemic resulted in either increasing, decreasing or reformatting service provision. Future plans for long-term service transformation focus on expansion of current, and establishment of new, outpatient services. Conclusion: Overall, these data demonstrate a proliferation of recovery, follow-up and rehabilitation services for critically ill adults in the past decade across the UK, although service gaps remain suggesting further work is required for guideline implementation. Findings can be used to enhance survivorship for critically ill adults, inform policymakers and commissioners, and provide comparative data and experiential insights for clinicians designing models of care in international healthcare jurisdictions

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

SummaryWe describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers

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