A combined biomarker and clinical panel for chronic graft versus host disease diagnosis.

Whilst many chronic graft versus host disease (cGVHD) biomarkers have been previously reported, few have been verified in an independent cGVHD cohort. We aimed to verify the diagnostic accuracy of previously reported markers of cGVHD in a multi-centre Chronic GVHD Consortium. A total of 42 RNA and 18 protein candidate biomarkers were assessed amongst 59 cGVHD cases and 33 matched non-GVHD controls. Total RNA was isolated from PBMC, and RNA markers were quantified using PCR. Serum protein markers were quantified using ELISA. A combined 3 RNA biomarker (IRS2, PLEKHF1 and IL1R2) and 2 clinical variables (recipient CMV serostatus and conditioning regimen intensity) panel accurately (AUC 0.81) segregated cGVHD cases from controls. Other studied RNA and protein markers were not confirmed as accurate cGVHD diagnostic biomarkers. The studied markers failed to segregate higher risk cGVHD (per overall NIH 0-3 score, and overlap versus classic cGVHD status). These data support the need for multiple independent verification studies for the ultimate clinical application of cGVHD diagnostic biomarkers

Dosimetric Comparison of Treatment Techniques: Brachytherapy, Intensity- Modulated Radiation Therapy, and Proton Beam in Partial Breast Irradiation

Purpose: To perform a dosimetric comparison of 3 accelerated partial breast irradiation techniques: catheter-based brachytherapy (BT), intensity-modulated radiation therapy (IMRT), and proton beam therapy (PBT). Patients and Methods: Twelve patients with left-sided breast cancer treated with SAVI (Strut-Adjusted Volume Implant) were selected in this study. The original BT plans were compared with optimum plans using IMRT and PBT for 34 Gy (RBE) with 1.1 RBE in 10 fractions using identical parameters for target and organs at risk. Results: Significant reduction in maximum dose to the ipsilateral breast was observed with PBT and IMRT (mean 108.58% [PBT] versus 107.78% [IMRT] versus 2194.43% [BT], P = .001 for both PBT and IMRT compared to BT). The mean dose to the heart was 0%, 1.38%, and 3.85%, for PBT, IMRT, and BT, respectively (P < .001 and P = .026). The chest wall mean dose was 10.07%, 14.65%, and 29.44% for PBT, IMRT, and BT, respectively (P = .001 and .013 compared to BT). The PBT was superior in reducing the mean ipsilateral lung dose (mean 0.04% versus 2.13% versus 5.4%, P = .025 and P < .001). There was no statistically significant difference in the maximum dose to the ipsilateral lung, chest wall, 3-mm skin rind or in the mean ipsilateral breast V50% among the 3 techniques (P = .168, .405, .067, and .780, respectively). PBT exhibited the greatest mean dose homogeneity index of 4.75 compared to 7.18 for IMRT (P = .001) and 195.82 for BT (P < .001). All techniques resulted in similar dose conformality (P = .143). Conclusion: This study confirms the dosimetric feasibility of PBT and IMRT to lower dose to organs at risk while still maintaining high target dose conformality. Though the results of this comparison are promising, continued clinical research is needed to better define the role of PBT and IMRT in the accelerated partial breast irradiation treatment of early-stage breast cancer

The Neurovascular Relation in Oxygen-induced Retinopathy

Purpose: Longitudinal studies in rat models of retinopathy of prematurity (ROP) have demonstrated that abnormalities of retinal vasculature and function change hand-in-hand. In the developing retina, vascular and neural structures are under cooperative molecular control. In this study of rats with oxygen-induced retinopathy (OIR) models of ROP, mRNA expression of vascular endothelial growth factor (VEGF), semaphorin (Sema), and their neuropilin receptor (NRP) were examined during the course of retinopathy to evaluate their roles in the observed neurovascular congruency. Methods: Oxygen exposures designed to induce retinopathy were delivered to Sprague-Dawley rat pups (n=36) from postnatal day (P) 0 to P14 or from P7 to P14. Room-air-reared controls (n=18) were also studied. Sensitivities of the rod photoreceptors ($S_{rod}$) and the postreceptor cells (Sm) were derived from electroretinographic (ERG) records. Arteriolar tortuosity, $T_A$, was derived from digital fundus images using Retinal Image multi-Scale Analysis (RISA) image analysis software. mRNA expression of $VEGF_{164}$, semaphorin IIIA (Sema3A), and neuropilin-1 (NRP-1) was evaluated by RT–PCR of retinal extracts. Tests were performed at P15–P16, P18–P19, and P25–P26. Relations among ERG, RISA, and PCR parameters were evaluated using linear regression on log transformed data. Results: Sm was low and $T_A$ was high at young ages, then both resolved by P25–P26. $VEGF_{164}$ and Sema3A mRNA expression were also elevated early and decreased with age. Low Sm was significantly associated with high $VEGF_{164}$ and Sema3A expression. Low Srod was also significantly associated with high VEGF164. $S_{rod}$ and Sm were both correlated with $T_A$. NRP-1 expression was little affected by OIR. Conclusions: The postreceptor retina appears to mediate the vascular abnormalities that characterize OIR. Because of the relationships revealed by these data, early treatment that targets the neural retina may mitigate the effects of ROP

Invasive adenoma and pituitary carcinoma: a SEER database analysis

Invasive pituitary adenomas and pituitary carcinomas are clinically indistinguishable until identification of metastases. Optimal management and survival outcomes for both are not clearly defined. The purpose of this study is to use the Surveillance, Epidemiology, and End Results (SEER) database to report patterns of care and compare survival outcomes in a large series of patients with invasive adenomas or pituitary carcinomas. One hundred seventeen patients diagnosed between 1973 and 2008 with pituitary adenomas/adenocarcinomas were included. Eighty-three invasive adenomas and seven pituitary carcinomas were analyzed for survival outcomes. Analyzed prognostic factors included age, sex, race, histology, tumor extent, and treatment. A significant decrease in survival was observed among carcinomas compared to invasive adenomas at 1, 2, and 5 years (p=0.047, 0.001, and 0.009). Only non-white race, male gender, and age ≥65 were significant negative prognostic factors for invasive adenomas (p=0.013, 0.033, and <0.001, respectively). There was no survival advantage to radiation therapy in treating adenomas at 5, 10, 20, or 30 years (p=0.778, 0.960, 0.236, and 0.971). In conclusion, pituitary carcinoma patients exhibit worse overall survival than invasive adenoma patients. This highlights the need for improved diagnostic methods for the sellar phase to allow for potentially more aggressive treatment approaches

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

“Still good life”: On the value of reuse and distributive labor in “depleted” rural Maine

This article explores the production of wealth through distributive labor in Maine\u27s secondhand economy. While reuse is often associated with economic disadvantage, our research complicates that perspective. The labor required to reclaim, repair, redistribute, and reuse secondhand goods provides much more than a means of living in places left behind by international capitalism, but the value generated by this work is persistently discounted by dominant economic logics. On the basis of semistructured interviews, participant observation, and statewide surveys with reuse market participants in Maine, we find that the relational value of reuse, produced through caring, flexible, distributive labor, is especially significant. We argue that paying attention to the practices, politics, and value of distribution is critical for understanding wealth in communities perceived to have been left behind by global capitalist systems, particularly as wage labor opportunities and natural resources grow increasingly scarce