Despite a significant increase in the total number of liver transplants (LTs) performed over the last 3 decades, primary biliary cholangitis (PBC) has become an uncommon indication for LT, which ...likely reflects the benefits of earlier diagnosis and available treatment, such as ursodeoxycholic acid (UDCA). Nonetheless, LT remains the only cure for patients with progressive PBC despite medical therapy with survival rates that are among the highest of all indications for LT. Post-LT PBC patients, however, are at increased risk of rejection and disease recurrence.
Primary sclerosing cholangitis (PSC) is a chronic, immune-mediated cholestatic liver disease that often progresses to secondary biliary cirrhosis and end-stage liver disease. Short of liver ...transplantation (LT), there is no effective treatment for PSC. PSC accounts for approximately 5% of total adult LTs in the US and is currently the fifth most common indication for LT. Patient and graft survival for PSC is among the highest for all indications for LT. The main factors that impact outcomes after LT for PSC include biliary strictures, rejection, and recurrence of PSC. Recurrent PSC (rPSC) develops in 20% of LT recipients within 5 years of LT and is associated with negative patient and graft survival. LT is a viable option for recipients who develop rPSC and progress to graft failure.
A phase II trial of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) from the National Cancer Institute showed promising activity in ...untreated diffuse large B-cell lymphoma. The Cancer and Leukemia Group B conducted a study to determine if these results could be reproduced in a multi-institutional setting.
The study included 69 patients with untreated diffuse large B-cell lymphoma at least 18 years of age and at least stage II. Radiaton therapy was not permitted on study. Median age was 58 years (range 23-83) and 40% had high-intermediate or high International Prognostic Index risk. Immunohistochemical biomarkers for cell of origin and proliferation were performed.
With a median follow up of 62 months, time to progression and overall survival were 81% and 84%, respectively, and time to progression was 87%, 92% and 54% for low/low-intermediate, high-intermediate and high International Prognostic Index risk groups, respectively, at 5-years and beyond. The time to progression and event-free survival of germinal center B-cell lymphoma were 100% and 94%, respectively, and non-germinal center B-cell GCB diffuse large B-cell lymphoma were 67% and 58%, respectively, at 62 months (germinal center vs. non-germinal center B cell P=0.008). DA-EPOCH-R was tolerated without significant grade 4 non-hematologic toxicities.
These results provide the first confirmation by a multi-institutional group that DA-EPOCH-R provides high durable remissions in diffuse large B-cell lymphoma and is effective in both germinal center and non-germinal center B-cell subtypes. The trial was registered at ClinicalTrials.Gov (NCT00032019).
Profile-quantitative structure–activity relationship (pQSAR) is a massively multitask, two-step machine learning method with unprecedented scope, accuracy, and applicability domain. In step one, a ...“profile” of conventional single-assay random forest regression models are trained on a very large number of biochemical and cellular pIC50 assays using Morgan 2 substructural fingerprints as compound descriptors. In step two, a panel of partial least squares (PLS) models are built using the profile of pIC50 predictions from those random forest regression models as compound descriptors (hence the name). Previously described for a panel of 728 biochemical and cellular kinase assays, we have now built an enormous pQSAR from 11 805 diverse Novartis (NVS) IC50 and EC50 assays. This large number of assays, and hence of compound descriptors for PLS, dictated reducing the profile by only including random forest regression models whose predictions correlate with the assay being modeled. The random forest regression and pQSAR models were evaluated with our “realistically novel” held-out test set, whose median average similarity to the nearest training set member across the 11 805 assays was only 0.34, comparable to the novelty of compounds actually selected from virtual screens. For the 11 805 single-assay random forest regression models, the median correlation of prediction with the experiment was only r ext 2 = 0.05, virtually random, and only 8% of the models achieved our standard success threshold of r ext 2 = 0.30. For pQSAR, the median correlation was r ext 2 = 0.53, comparable to four-concentration experimental IC50s, and 72% of the models met our r ext 2 > 0.30 standard, totaling 8558 successful models. The successful models included assays from all of the 51 annotated target subclasses, as well as 4196 phenotypic assays, indicating that pQSAR can be applied to virtually any disease area. Every month, all models are updated to include new measurements, and predictions are made for 5.5 million NVS compounds, totaling 50 billion predictions. Common uses have included virtual screening, selectivity design, toxicity and promiscuity prediction, mechanism-of-action prediction, and others. Several such actual applications are described.
Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal ...adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on KrasG12D expression. Transcriptome and metabolomic analyses indicate that KrasG12D serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that KrasG12D drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC.
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▸ Oncogenic KrasG12D is required for PDAC tumor maintenance ▸ KrasG12D reprograms PDAC metabolism by stimulating glucose uptake and glycolysis ▸ KrasG12D drives enhanced glycolytic flux into glycosylation and ribose biogenesis ▸ This metabolic shift is mediated by MEK activation and Myc-dependent transcription
Pancreatic cancers are frequently associated with activated Kras, which is now shown in a genetically engineered mouse model to reprogram tumor metabolism by channeling glucose into several biosynthetic pathways critical for tumor growth and maintenance.
Epigenetic regulation serves as the basis for stem cell differentiation into distinct cell types, but it is unclear how global epigenetic changes are regulated during this process. Here, we tested ...the hypothesis that global chromatin organization affects the lineage potential of stem cells and that manipulation of chromatin dynamics influences stem cell function. Using nuclease sensitivity assays, we found a progressive decrease in chromatin digestion among pluripotent embryonic stem cells (ESCs), multipotent hematopoietic stem cells (HSCs), and mature hematopoietic cells. Quantitative high-resolution microscopy revealed that ESCs contain significantly more euchromatin than HSCs, with a further reduction in mature cells. Increased cellular maturation also led to heterochromatin localization to the nuclear periphery. Functionally, prevention of heterochromatin formation by inhibition of the histone methyltransferase G9A resulted in delayed HSC differentiation. Our results demonstrate global chromatin rearrangements during stem cell differentiation and that heterochromatin formation by H3K9 methylation regulates HSC differentiation.
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•Nuclease sensitivity decreases progressively with stem cell differentiation•Distinct chromatin architecture is apparent in cells of different lineage potential•Stem cell differentiation leads to perinuclear heterochromatin localization•G9a-mediated heterochromatin formation facilitates stem cell differentiation
Forsberg and colleagues use a variety of approaches to investigate global chromatin structure and architecture in pluripotent, multipotent, and differentiated cells. They show that progressive changes in nuclease sensitivity, chromatin condensation, and heterochromatin localization correlate with the lineage potential of embryonic and adult stem cells and committed cells. Functionally, inhibition of heterochromatin formation delayed hematopoietic stem cell differentiation. These data provide new insights on the epigenetic regulation of stem cell lineage potential and differentiation.
While conventional random forest regression (RFR) virtual screening models appear to have excellent accuracy on random held-out test sets, they prove lacking in actual practice. Analysis of 18 ...historical virtual screens showed that random test sets are far more similar to their training sets than are the compounds project teams actually order. A new, cluster-based “realistic” training/test set split, which mirrors the chemical novelty of real-life virtual screens, recapitulates the poor predictive power of RFR models in real projects. The original Profile-QSAR (pQSAR) method greatly broadened the domain of applicability over conventional models by using as independent variables a profile of activity predictions from all historical assays in a large protein family. However, the accuracy still fell short of experiment on realistic test sets. The improved “pQSAR 2.0” method replaces probabilities of activity from naïve Bayes categorical models at several thresholds with predicted IC50s from RFR models. Unexpectedly, the high accuracy also requires removing the RFR model for the actual assay of interest from the independent variable profile. With these improvements, pQSAR 2.0 activity predictions are now statistically comparable to medium-throughput four-concentration IC50 measurements even on the realistic test set. Beyond the yes/no activity predictions from a typical high-throughput screen (HTS) or conventional virtual screen, these semiquantitative IC50 predictions allow for predicted potency, ligand efficiency, lipophilic efficiency, and selectivity against antitargets, greatly facilitating hitlist triaging and enabling virtual screening panels such as toxicity panels and overall promiscuity predictions.
Public, nonprofit and private organisations respond to large‐scale disasters domestically and overseas. Critics of these assistance efforts, as well as those involved, often cite poor ...interorganisational partnering as an obstacle to successful disaster response. Observers frequently call for ‘more’ and ‘better’ partnering. We found important qualitative distinctions existed within partnering behaviours. We identified four different types of interorganisational partnering activities often referred to interchangeably: communication, cooperation, coordination and collaboration—the Four Cs. We derived definitions of the Four Cs from the partnering literature. We then tested them in a case study of the response to the 2010 Haiti earthquake. We suggest that the Four Cs are distinct activities, that organisations are typically strong or weak in one or more for various reasons, and that the four terms represent a continuum of increased interorganisational embeddedness in partnering activities.
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