Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors

Purpose: NLG207 (formerly CRLX101) is a nanoparticle–drug conjugate (NDC) of the potent topoisomerase I inhibitor, camptothecin (CPT). The present study sought to characterize the complex pharmacokinetics (PK) of NLG207 and better describe CPT release from nanoparticles using a population PK (popPK) model. Methods: From 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 h post-administration of NLG207 during cycle one and six of treatment; samples were also collected at ~ 360 h post-dose. Conjugated and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modeling. Results: The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The typical volumes of distribution of the conjugated CPT central and free CPT central compartments were 3.16 L (BSV CV%; 18.1%) and 21.1 L (CV%; 79.8%), respectively. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h (CV%; 62.6%), which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h (CV%; 33.5%) by ~ 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h (CV%; 42.2%). Conclusion: The popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials

Insights from the management of offshore energy resources: Toward an ecosystem-services based management approach for deep-ocean industries

The deep ocean comprises complex ecosystems made up of numerous community and habitat types that provide multiple services that benefit humans. As the industrialization of the deep sea proceeds, a standardized and robust set of methods and metrics need to be developed to monitor the baseline conditions and any anthropogenic and climate change-related impacts on biodiversity, ecosystem function, and ecosystem services. Here, we review what we have learned from studies involving offshore-energy industries, including state-of-the-art technologies and strategies for obtaining reliable metrics of deep-sea biodiversity and ecosystem function. An approach that includes the detection and monitoring of ecosystem services, with open access to baseline data from multiple sectors, can help to improve our global capacity for the management of the deep ocean

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

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 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

The Role of Alpha 6 Integrin in Prostate Cancer Migration and Bone Pain in a Novel Xenograft Model

Of the estimated 565,650 people in the U.S. who will die of cancer in 2008, almost all will have metastasis. Breast, prostate, kidney, thyroid and lung cancers metastasize to the bone. Tumor cells reside within the bone using integrin type cell adhesion receptors and elicit incapacitating bone pain and fractures. In particular, metastatic human prostate tumors express and cleave the integrin A6, a receptor for extracellular matrix components of the bone, i.e., laminin 332 and laminin 511. More than 50% of all prostate cancer patients develop severe bone pain during their remaining lifetime. One major goal is to prevent or delay cancer induced bone pain. We used a novel xenograft mouse model to directly determine if bone pain could be prevented by blocking the known cleavage of the A6 integrin adhesion receptor. Human tumor cells expressing either the wildtype or mutated A6 integrin were placed within the living bone matrix and 21 days later, integrin expression was confirmed by RT-PCR, radiographs were collected and behavioral measurements of spontaneous and evoked pain performed. All animals independent of integrin status had indistinguishable tumor burden and developed bone loss 21 days after surgery. A comparison of animals containing the wild type or mutated integrin revealed that tumor cells expressing the mutated integrin resulted in a dramatic decrease in bone loss, unicortical or bicortical fractures and a decrease in the ability of tumor cells to reach the epiphyseal plate of the bone. Further, tumor cells within the bone expressing the integrin mutation prevented cancer induced spontaneous flinching, tactile allodynia, and movement evoked pain. Preventing A6 integrin cleavage on the prostate tumor cell surface decreased the migration of tumor cells within the bone and the onset and degree of bone pain and fractures. These results suggest that strategies for blocking the cleavage of the adhesion receptors on the tumor cell surface can significantly prevent cancer induced bone pain and slow disease progression within the bone. Since integrin cleavage is mediated by Urokinase-type Plasminogen Activator (uPA), further work is warranted to test the efficacy of uPA inhibitors for prevention or delay of cancer induced bone pain

Comparative Composition, Diversity and Trophic Ecology of Sediment Macrofauna at Vents, Seeps and Organic Falls

Sediments associated with hydrothermal venting, methane seepage and large organic falls such as whale, wood and plant detritus create deep-sea networks of soft-sediment habitats fueled, at least in part, by the oxidation of reduced chemicals. Biological studies at deep-sea vents, seeps and organic falls have looked at macrofaunal taxa, but there has yet to be a systematic comparison of the community-level attributes of sediment macrobenthos in various reducing ecosystems. Here we review key similarities and differences in the sediment-dwelling assemblages of each system with the goals of (1) generating a predictive framework for the exploration and study of newly identified reducing habitats, and (2) identifying taxa and communities that overlap across ecosystems. We show that deep-sea seep, vent and organic-fall sediments are highly heterogeneous. They sustain different geochemical and microbial processes that are reflected in a complex mosaic of habitats inhabited by a mixture of specialist (heterotrophic and symbiont-associated) and background fauna. Community-level comparisons reveal that vent, seep and organic-fall macrofauna are very distinct in terms of composition at the family level, although they share many dominant taxa among these highly sulphidic habitats. Stress gradients are good predictors of macrofaunal diversity at some sites, but habitat heterogeneity and facilitation often modify community structure. The biogeochemical differences across ecosystems and within habitats result in wide differences in organic utilization (i.e., food sources) and in the prevalence of chemosynthesis-derived nutrition. In the Pacific, vents, seeps and organic-falls exhibit distinct macrofaunal assemblages at broad-scales contributing to ß diversity. This has important implications for the conservation of reducing ecosystems, which face growing threats from human activities

Precision and accuracy of single-molecule FRET measurements - a multi-laboratory benchmark study

Single-molecule Förster resonance energy transfer (smFRET) is increasingly being used to determine distances, structures, and dynamics of biomolecules in vitro and in vivo. However, generalized protocols and FRET standards to ensure the reproducibility and accuracy of measurements of FRET efficiencies are currently lacking. Here we report the results of a comparative blind study in which 20 labs determined the FRET efficiencies (E) of several dye-labeled DNA duplexes. Using a unified, straightforward method, we obtained FRET efficiencies with s.d. between ±0.02 and ±0.05. We suggest experimental and computational procedures for converting FRET efficiencies into accurate distances, and discuss potential uncertainties in the experiment and the modeling. Our quantitative assessment of the reproducibility of intensity-based smFRET measurements and a unified correction procedure represents an important step toward the validation of distance networks, with the ultimate aim of achieving reliable structural models of biomolecular systems by smFRET-based hybrid methods

African Head and Neck Society Clinical Practice guidelines for thyroid nodules and cancer in developing countries and limited resource settings

Background International thyroid nodule and cancer management guidelines generally fail to take into account potential limitations in diagnostic and treatment resources. Methods Thyroid cancer specialists from the African Head and Neck Society and American Head & Neck Society Endocrine Section developed guidelines for diagnosis and management of thyroid nodules and cancer in low resource settings. Recommendations were based on literature review and expert opinion, with level of evidence defined. Results Using the ADAPTE process, diagnostic and treatment algorithms were adapted from the National Comprehensive Cancer Network (NCCN). Low resource settings were simulated by systematically removing elements such as availability of laboratory testing, hormone replacement, imaging, and cytopathology from NCCN guidelines. Conclusions Successful management of thyroid nodules and cancer in low resource settings requires adaptation of treatment methodologies. These guidelines define specific scenarios where either more or less aggressive intervention for thyroid pathology may be advisable based on limited available resources