Tales from the EMR: Does a 21st-Century Data Warehouse Facilitate Clinical Research for Pancreatic Cancer?

Background: The importance of an electronic medical record has been highlighted for both clinical care and research. In the current era, data warehouses and repositories have been established to serve the dual function of patient care and investigation. Purpose: The aim of this study was to compare a newly developed institutional clinical data warehouse, linked with the hospital information system (HIS), to a prospectively-maintained departmental database. Methods: A novel HIS-linked institutional clinical data warehouse was queried for 9 primary and secondary ICD-9-CM discharge diagnosis codes for pancreatic cancer. The database captured inpatient and outpatient clinical and billing information from a pool of over 2 million patients evaluated at an academic medical institution and its affiliates since 1995. A cohort was identified; following Institutional Review Board approval, demographic and clinical data was obtained. This data was compared to a manually-entered and prospectively-maintained surgical oncology database of the same institution, tracking 394 patients since 1999. Duplicated patients, and those unique to either dataset, were flagged. Patients with diagnosis dates prior to 1999 were excluded to allow comparison over the same time period. For validation purposes, a 10% random sample of remaining patients unique to each dataset underwent manual review of medical records including clinic notes, admission/discharge notes, diagnostic imaging, and pathology reports. Results: 1107 patients were identified from the HIS-linked dataset with pancreatic neoplasm-associated diagnosis codes dating from 1999 to 2009. Of these, 254 (22.9%) were captured in both datasets, while 853 (77.1%) were only in the HIS-linked dataset. Manual review of the 10% subset of the HIS-only group demonstrated that 55.6% of patients were without identifiable pancreatic pathology, suggesting miscoding, while 31.7% had diagnoses consistent with pancreatic neoplasm, and 12.7% had pseudocyst or pancreatitis. Of the 394 patients tracked by surgical oncology, 254 (64.5%) were captured in both datasets, while 140 (35.5%) had not been captured in the HIS-linked dataset. Manual review of the 10% subset of the non-captured patients demonstrated 93.3% with pancreatic neoplasm and 6.7% with pseudocyst or pancreatitis. Lastly, a review of the 10% subset of the 254 patient overlap demonstrated that 87.5% of patients were with pancreatic neoplasm, 8.3% with pseudocyst or pancreatitis, and 4.2% without pancreatic pathology. Conclusions: While technological advances provide a powerful means to automate institutional-level cohort identification and data collection, a high degree of misclassification may be present if queries are based solely on ICD-9-CM discharge codes. For that reason, careful validation and data cleaning are critical steps prior to research use. These results also suggest cautious interpretation of national-level administrative data utilizing ICD-9-CM diagnosis codes. Our findings suggest that the current state-of-the-art data warehouses continue to require clinical correlation and validation through traditional retrospective mechanisms

Electro-kinetic technology as a low-cost method for dewatering food by-product

Increasing volumes of food waste, intense environmental awareness, and stringent legislation have imposed increased demands upon conventional food waste management. Food byproducts that were once considered to be without value are now being utilized as reusable materials, fuels, and energy in order to reduce waste. One major barrier to the valorization of food by-products is their high moisture content. This has brought about the necessity of dewatering food waste for any potential re-use for certain disposal options. A laboratory system for experimentally characterizing electro-kinetic dewatering of food by-products was evaluated. The bench scale system, which is an augmented filter press, was used to investigate the dewatering at constant voltage. Five food by-products (brewer’s spent grain, cauliflower trimmings, mango peel, orange peel, and melon peel) were studied. The results indicated that electro-kinetic dewatering combined with mechanical dewatering can reduce the percentage of moisture from 78% to 71% for brewer’s spent grain, from 77% to 68% for orange peel, from 80% to 73% for mango peel, from 91% to 74% for melon peel, and from 92% to 80% for cauliflower trimmings. The total moisture reduction showed a correlation with electrical conductivity (R2¼0.89). The energy consumption of every sample was evaluated and was found to be up to 60 times more economical compared to thermal processing

Is pancreatic cancer palliatable? A national study

Background: Pancreatic cancer is frequently diagnosed at advanced stages where potentially curative resection is no longer possible. Palliative procedures can be performed; however, results on a national level are unknown. This study examines pancreatic cancer patients who underwent potentially palliative procedures including gastric bypass, biliary bypass surgery, celiac block, biliary stent, gastrostomy or jejunostomy, and examines post-intervention complications and 30-day mortality. Methods: SEER-Medicare 1991-2005 was used to identify patients with Stage 3-4 pancreatic cancer. Complication rates were calculated including post-op infection, myocardial infarction, aspiration pneumonia, DVT/PE, pulmonary compromise, gastric bleed, acute renal failure, and reoperation. Kaplan-Meier survival analysis was performed. Finally, Cox proportional hazards modeling was used to control for the effects of age, sex, race, stage, and resection. Results: Of 22,314 pancreatic cancer patients, 858 (3.9%) patients were Stage 3, and 11,149 (50.0%) stage 4. Post-procedure median survival for all patients is approximately two months, with longest survival for biliary bypass patients (3.2mo, 95% CI(2.9-3.7), and lowest survival for jejunostomy 1.3 mo (1.2-1.5) and gastrostomy 1.5 mo (1.4-1.8). Post-procedure 30-day mortality was highest for gastrostomy patients at 41.5%; followed by jejunostomy (39.1%), celiac plexus block (30.0%), gastric bypass (23.8%), biliary bypass (17.8%), and biliary stent (21.2%). The rate of complications averaged 40%, with highest rate for gastrostomy (47.4%) and gastric bypass (45.3%) and lowest for celiac plexus block (29.3%). Stage 4 disease was an independent predictor of death for patients undergoing five out of six procedures. Conclusion: We found that morbidity and mortality of palliative procedures in unresectable pancreatic cancer is high, especially in stage 4 patients. Further studies need to be conducted to identify patients who will have sufficient expected post-procedure survival to benefit from these palliative interventions

Cold Atmospheric Plasma Stimulates Clathrin-Dependent Endocytosis to Repair Oxidised Membrane and Enhance Uptake of Nanomaterial in Glioblastoma Multiforme Cells

peer-reviewedCold atmospheric plasma (CAP) enhances uptake and accumulation of nanoparticles and promotes synergistic cytotoxicity against cancer cells. However, the mechanisms are not well understood. In this study, we investigate the enhanced uptake of theranostic nanomaterials by CAP. Numerical modelling of the uptake of gold nanoparticle into U373MG Glioblastoma multiforme (GBM) cells predicts that CAP may introduce a new uptake route. We demonstrate that cell membrane repair pathways play the main role in this stimulated new uptake route, following non-toxic doses of dielectric barrier discharge CAP. CAP treatment induces cellular membrane damage, mainly via lipid peroxidation as a result of reactive oxygen species (ROS) generation. Membranes rich in peroxidised lipids are then trafficked into cells via membrane repairing endocytosis. We confirm that the enhanced uptake of nanomaterials is clathrin-dependent using chemical inhibitors and silencing of gene expression. Therefore, CAP-stimulated membrane repair increases endocytosis and accelerates the uptake of gold nanoparticles into U373MG cells after CAP treatment. We demonstrate the utility of CAP to model membrane oxidative damage in cells and characterise a previously unreported mechanism of membrane repair to trigger nanomaterial uptake. This knowledge will underpin the development of new delivery strategies for theranostic nanoparticles into cancer cells

Widespread Site-Dependent Buffering of Human Regulatory Polymorphism

The average individual is expected to harbor thousands of variants within non-coding genomic regions involved in gene regulation. However, it is currently not possible to interpret reliably the functional consequences of genetic variation within any given transcription factor recognition sequence. To address this, we comprehensively analyzed heritable genome-wide binding patterns of a major sequence-specific regulator (CTCF) in relation to genetic variability in binding site sequences across a multi-generational pedigree. We localized and quantified CTCF occupancy by ChIP-seq in 12 related and unrelated individuals spanning three generations, followed by comprehensive targeted resequencing of the entire CTCF–binding landscape across all individuals. We identified hundreds of variants with reproducible quantitative effects on CTCF occupancy (both positive and negative). While these effects paralleled protein–DNA recognition energetics when averaged, they were extensively buffered by striking local context dependencies. In the significant majority of cases buffering was complete, resulting in silent variants spanning every position within the DNA recognition interface irrespective of level of binding energy or evolutionary constraint. The prevalence of complex partial or complete buffering effects severely constrained the ability to predict reliably the impact of variation within any given binding site instance. Surprisingly, 40% of variants that increased CTCF occupancy occurred at positions of human–chimp divergence, challenging the expectation that the vast majority of functional regulatory variants should be deleterious. Our results suggest that, even in the presence of “perfect” genetic information afforded by resequencing and parallel studies in multiple related individuals, genomic site-specific prediction of the consequences of individual variation in regulatory DNA will require systematic coupling with empirical functional genomic measurements

Genome-Wide Association Study in Asian Populations Identifies Variants in ETS1 and WDFY4 Associated with Systemic Lupus Erythematosus

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33×10−11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10−12, OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3′-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved

Co-regulation map of the human proteome enables identification of protein functions

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordData availability: All mass spectrometry raw files generated in-house have been deposited in the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository36 with the dataset identifier PXD008888. The co-regulation map is hosted on our website at www.proteomeHD.net, and pair-wise co-regulation scores are available through STRING (https://string-db.org). A network of the top 0.5% co-regulated protein pairs can be explored interactively on NDEx (https://doi.org/10.18119/N9N30Q).Code availability: Data analysis was performed in R 3.5.1. R scripts and input files required to reproduce the results of this manuscript are available in the following GitHub repository: https://github.com/Rappsilber-Laboratory/ProteomeHD. R scripts related specifically to the benchmarking of the treeClust algorithm using synthetic data are available in the following GitHub repository: https://github.com/Rappsilber-Laboratory/treeClust-benchmarking. The R package data.table was used for fast data processing. Figures were prepared using ggplot2, gridExtra, cowplot and viridis.Note that the title of the AAM is different from the published versionThe annotation of protein function is a longstanding challenge of cell biology that suffers from the sheer magnitude of the task. Here we present ProteomeHD, which documents the response of 10,323 human proteins to 294 biological perturbations, measured by isotope-labelling mass spectrometry. We reveal functional associations between human proteins using the treeClust machine learning algorithm, which we show to improve protein co-regulation analysis due to robust selectivity for close linear relationships. Our co-regulation map identifies a functional context for many uncharacterized proteins, including microproteins that are difficult to study with traditional methods. Co-regulation also captures relationships between proteins which do not physically interact or co-localize. For example, co-regulation of the peroxisomal membrane protein PEX11β with mitochondrial respiration factors led us to discover a novel organelle interface between peroxisomes and mitochondria in mammalian cells. The co-regulation map can be explored at www.proteomeHD.net .Biotechnology & Biological Sciences Research Council (BBSRC)European Commissio

phi-Meson production at forward rapidity in p-Pb collisions at root s(NN)=5.02 TeV and in pp collisions at root s=2.76 TeV

The first study of phi-meson production in p-Pb collisions at forward and backward rapidity, at a nucleonnucleon centre-of-mass energy root s(NN)= 5.02 TeV, has been performed with the ALICE apparatus at the LHC. The phi-mesons have been identified in the dimuon decay channel in the transverse momentum (p(T)) range 1 <p(T) <7GeV/c, both in the p-going (2.03 <y <3.53) and the Pb-going (-4.46 <y <-2.96) directions - where ystands for the rapidity in the nucleon-nucleon centre-of-mass - the integrated luminosity amounting to 5.01 +/- 0.19nb(-1) and 5.81 +/- 0.20nb(-1), respectively, for the two data samples. Differential cross sections as a function of transverse momentum and rapidity are presented. The forward-backward ratio for f-meson production is measured for 2.96Peer reviewe