Using action understanding to understand the left inferior parietal cortex in the human brain

Published in final edited form as: Brain Res. 2014 September 25; 1582: 64–76. doi:10.1016/j.brainres.2014.07.035.Humans have a sophisticated knowledge of the actions that can be performed with objects. In an fMRI study we tried to establish whether this depends on areas that are homologous with the inferior parietal cortex (area PFG) in macaque monkeys. Cells have been described in area PFG that discharge differentially depending upon whether the observer sees an object being brought to the mouth or put in a container. In our study the observers saw videos in which the use of different objects was demonstrated in pantomime; and after viewing the videos, the subject had to pick the object that was appropriate to the pantomime. We found a cluster of activated voxels in parietal areas PFop and PFt and this cluster was greater in the left hemisphere than in the right. We suggest a mechanism that could account for this asymmetry, relate our results to handedness and suggest that they shed light on the human syndrome of apraxia. Finally, we suggest that during the evolution of the hominids, this same pantomime mechanism could have been used to ‘name’ or request objects.We thank Steve Wise for very detailed comments on a draft of this paper. We thank Rogier Mars for help with identifying the areas that were activated in parietal cortex and for comments on a draft of this paper. Finally, we thank Michael Nahhas for help with the imaging figures. This work was supported in part by the NIH grant RO1NS064100 to LMV. (RO1NS064100 - NIH)Accepted manuscrip

Healthcare Empowerment and HIV Viral Control: Mediating Roles of Adherence and Retention in Care

Introduction: This study assessed longitudinal relationships between patient healthcare empowerment, engagement in care, and viral control in the Women's Interagency HIV Study, a prospective cohort study of U.S. women living with HIV. Methods: From April 2014 to March 2016, four consecutive 6-month visits were analyzed among 973 women to assess the impact of Time 1 healthcare empowerment variables (Tolerance for Uncertainty and the state of Informed Collaboration Committed Engagement) on Time 2 reports of ≥95% HIV medication adherence and not missing an HIV primary care appointment since last visit; and on HIV RNA viral control across Times 3 and 4, controlling for illicit drug use, heavy drinking, depression symptoms, age, and income. Data were analyzed in 2017. Results: Adherence of ≥95% was reported by 83% of women, 90% reported not missing an appointment since the last study visit, and 80% were categorized as having viral control. Logistic regression analyses revealed a significant association between the Informed Collaboration Committed Engagement subscale and viral control, controlling for model covariates (AOR=1.08, p=0.04), but not for the Tolerance for Uncertainty subscale and viral control (AOR=0.99, p=0.68). In separate mediation analyses, the indirect effect of Informed Collaboration Committed Engagement on viral control through adherence (β=0.04, SE=0.02, 95% CI=0.02, 0.08), and the indirect effect of Informed Collaboration Committed Engagement on viral control through retention (β=0.01, SE=0.008, 95% CI=0.001, 0.030) were significant. Mediation analyses with Tolerance for Uncertainty as the predictor did not yield significant indirect effects. Conclusions: The Informed Collaboration Committed Engagement healthcare empowerment component is a promising pathway through which to promote engagement in care among women living with HIV

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

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

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

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

Patient Health Literacy and Communication with Providers Among Women Living with HIV: A Mixed Methods Study

In this mixed-methods study, we examine the relationship between provider communication and patient health literacy on HIV continuum of care outcomes among women living with HIV in the United States. We thematically coded qualitative data from focus groups and interviews (N = 92) and conducted mediation analyses with quantitative survey data (N = 1455) collected from Women’s Interagency HIV Study participants. Four qualitative themes related to provider communication emerged: importance of respect and non-verbal cues; providers’ expressions of condescension and judgement; patient health literacy; and unclear, insufficient provider communication resulting in diminished trust. Quantitative mediation analyses suggest that higher health literacy is associated with higher perceived patient–provider interaction quality, which in turn is associated with higher levels of trust in HIV providers, improved antiretroviral medication adherence, and reduced missed clinical visits. Findings indicate that enhancing provider communication and bolstering patient health literacy could have a positive impact on the HIV continuum of care

Osteopontin induces growth of metastatic tumors in a preclinical model of non-small lung cancer

Osteopontin (OPN), also known as SPP1 (secreted phosphoprotein), is an integrin binding glyco-phosphoprotein produced by a variety of tissues. In cancer patients expression of OPN has been associated with poor prognosis in several tumor types including breast, lung, and colorectal cancers. Despite wide expression in tumor cells and stroma, there is limited evidence supporting role of OPN in tumor progression and metastasis. Using phage display technology we identified a high affinity anti-OPN monoclonal antibody (hereafter AOM1). The binding site for AOM1 was identified as SVVYGLRSKS sequence which is immediately adjacent to the RGD motif and also spans the thrombin cleavage site of the human OPN. AOM1 efficiently inhibited OPNa binding to recombinant integrin αvβ3 with an IC50 of 65 nM. Due to its unique binding site, AOM1 is capable of inhibiting OPN cleavage by thrombin which has been shown to produce an OPN fragment that is biologically more active than the full length OPN. Screening of human cell lines identified tumor cells with increased expression of OPN receptors (αvβ3 and CD44v6) such as mesothelioma, hepatocellular carcinoma, breast, and non-small cell lung adenocarcinoma (NSCLC). CD44v6 and αvβ3 were also found to be highly enriched in the monocyte, but not lymphocyte, subset of human peripheral blood mononuclear cells (hPBMCs). In vitro, OPNa induced migration of both tumor and hPBMCs in a transwell migration assay. AOM1 significantly blocked cell migration further validating its specificity for the ligand. OPN was found to be enriched in mouse plasma in a number of pre-clinical tumor model of non-small cell lung cancers. To assess the role of OPN in tumor growth and metastasis and to evaluate a potential therapeutic indication for AOM1, we employed a KrasG12D-LSLp53fl/fl subcutaneously implanted in vivo model of NSCLC which possesses a high capacity to metastasize into the lung. Our data indicated that treatment of tumor bearing mice with AOM1 as a single agent or in combination with Carboplatin significantly inhibited growth of large metastatic tumors in the lung further supporting a role for OPN in tumor metastasis and progression