Body distribution of dextrin and D-2-S and evaluation of their potential as novel polymeric-drug carriers.

Water soluble polymers, including natural polymers (e.g. polyamino acids and polysaccharides) and synthetic polymers (e.g. polyethyleneglycol (PEG)) and N-(2- hydroxypropyl)methacrylamide (HPMA) copolymers) are finding increasing use as polymer therapeutics. Dextrin and dextrin-2-Sulphate (D-2-S) are poly(1-4 glucose) polymers that have entered into clinical use: dextrin as a peritoneal dialysis solution and D-2-S as an anti-HIV treatment. The aim of this study was (1) to quantitate the biodistribution of dextrin and D-2-S and (2) to evaluate the potential of these polymers for use as drug carriers. First, pendant groups were introduced by succinoylation (1-60 mol%). To study biodistribution (after s.c., i.v. or i.p. administration) probes were then synthesised containing either -TyrNH2 or -DTPA (~1 mol%) to allow labelling with 125I iodine or 111In indium respectively. After i.p. administration 125I-labelled D-2-S remained longer in the peritoneal cavity (~27 times) than 125I-labelled dextrin (t1/2 = 2.3 h and 5 min respectively). Maximum tissue accumulation was seen in the liver, for 125I-labelled dextrin approximately 20% administered dose (2 min) and for 125I-labelled D-2-S (15.3% administered dose (24 h). Gamma camera images obtained using 111In-labelled polymers were consistent with the data obtained using 125I-labelled compounds. Using the succinoylated intermediate, dextrin- and D-2-S-amphotericin B conjugates (AmpB) were prepared containing 0.01-3.50 wt% and 0.01-16.0 wt% AmpB respectively. Conjugation increased drug solubility approximately 10 fold. Preliminary in vitro testing showed IC50 values for AmpB, dextrin- and D-2-S-AmpB (IC50 of 11.0 >50, and >50 μg/ml respectively) and haemolytic activity at 24 h (Hb50 of 0.06 mg/ml, >50 μg/ml and 8.0 μg/ml respectively). Additionally, experiments were carried out with dextrin-doxorubicin (Dox) (9 wt%, Dox-equiv) to ascertain its tumour targeting potential and antitumour activity. Whereas free Dox was inactive (T/C= 105%) in a s.c. B16F10 tumour model dextrin- Dox had a T/C = 144%. Dextrin and D-2-S have shown that they have potential for further development as water soluble drug carriers

University of Nebraska – Lincoln Libraries Workflow and Organizational Analysis

Libraries everywhere are undergoing tremendous transformation in staffing, services, and collections. With the need to create new programs and services, it is critical that resources are deployed in the most efficient way possible. Library workforces across the country are aging and succession planning is important for libraries to thrive. The University of Nebraska at Lincoln Libraries invited us to review staffing, examine the organizational structure, communication pathways, and general workflows in the DARM and to make recommendations for changes that would improve and enhance service quality, improve productivity, and best align library faculty and staff with organizational priorities and needs. Our experience with a broad array of academic libraries of many types and sizes informs our consulting work, thus enabling us to provide insight and recommendations on best practices. Without exception, the people that we spoke with were frank and open. In February 2016, we spent one and a half days meeting with the Libraries’ administration, the Interim Chair of the Discovery and Resource Maintenance Department (DARM), DARM faculty and Staff, the newly formed Collection Strategies Committee, Library Systems, and the stakeholders who are served by DARM. Our analysis has benefited enormously from the ideas and comments offered by UNL library faculty and staff. These recommendations are interrelated because all aspects of the collections and technical services workflows must work successfully together. However, because we were only on site 1.5 days, we did not have the opportunity to delve deeply into the workflows. As a result, many our suggestions involve establishing a working group or a team to follow up on a process we feel needs closer examination. Like most large research libraries, the content purchased by the UNL Libraries has shifted significantly from print to electronic. However, most of the human resources are still heavily devoted to the print workflows rather than the digital ones. As a very lean organization, making an appropriate transformation from print to digital will be needed in order for the UNL Libraries to operate at peak efficiency and effectiveness

Creating a New Collections Allocation Model for These Changing Times: Challenges, Opportunities, and Data

This presentation focuses on the development of a formula for potential use in allocating the collections budget for Penn State and the questions that arose during the process. The Associate Dean for Collections, Information, and Access Services charged a Collections Allocations Team to examine the development and use of a collections allocation formula. The team used a variety of methods to guide the development of the formula including a literature review, a survey of ARL Chief Collection Development Officers, and discussions with fellow selectors within the University Libraries. In addition, the Team developed other recommendations related to the allocation of the collections budget, especially focusing on the process of collection development, duplication of materials across the University Libraries, and the rewriting of collection development policies

Ensuring Reliable and Predictable Behavior of IEEE 802.1CB Frame Replication and Elimination

Ultra-reliable and low-latency communication has received significant research attention. A key part of this evolution are the Time-Sensitive Networking (TSN) standards, which extend Ethernet with real-time mechanisms. To guarantee high reliability, the standard IEEE 802.1CB-2017 Frame Replication and Elimination for Reliability enables redundant communication over disjoint paths. While this mechanism is essential for time-critical applications, the standard contains some fundamental limitations that can compromise safety. Although some of these limitations have been addressed, none of the previous works provide solutions to these problems. This paper presents solutions to four main limitations of the IEEE 802.1CB-2017 standard. These are 1) choosing match versus vector recovery algorithm, 2) defining the length of the sequence history, 3) setting a timer to reset the sequence history, and 4) dimensioning the burst size in case of link failures. We show how these challenges can be solved by using best- and worst-case path delays of the network. We have performed simulations to illustrate the impact of the limitations and prove the correctness of our solutions. Thereby, we demonstrate how our solutions can improve reliability in TSN networks and propose these methods as guidance for users of the IEEE 802.1CB standard

Approval Plan Profile Assessment in Two Large ARL Libraries: University of Illinois at Urbana-Champaign and Pennsylvania State University

Two Association of Research Libraries member libraries, the University of Illinois at Urbana–Champaign (UIUC) and Pennsylvania State University (Penn State), evaluated their monograph acquisition approval plan profiles to answer basic questions concerning use, cost effectiveness, and coverage. Data were collected in tandem from vendors and local online systems to track book receipt, item circulation, and overlap between plans. The study period was fiscal year 2005 (July 1, 2004–June 30, 2005) for the approval plan purchasing data, and circulation use data were collected from July 1, 2004, through March 31, 2007, for both UIUC and Penn State. Multiple data points were collected for each title, including author, title, ISBN, publisher, Library of Congress classification number, purchase price, and circulation data. Results of the study measured the cost-effectiveness of each plan by subject and publisher, analyzed similarities and differences in use, and examined the overlap between the two approval plans. The goals were to establish a benchmark for consistently evaluating approval plan profile effectiveness and to provide a reproducible method with baseline data that will allow other libraries to collect comparable data and conduct their own studies

Genome-wide MicroRNA profiling of mantle cell lymphoma reveal a distinct subgroup with poor prognosis

MicroRNA (miRNA) deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1- positive MCL (n=30) and cyclin D1-negative MCL (n=7) and compared them with small lymphocytic leukemia/lymphoma (SLL, n=12), aggressive B-cell lymphomas (n=138), normal B-cell subsets and stromal cells. We identified a 19-miRNA classifier which included six upregulated miRNAs (miR-135a, miR-708, miR-150, miR-363, miR-184, miR-342-5p) and 13 downregulated miRNAs, that was able to distinguish MCL from other aggressive lymphomas with \u3e90% probability. Some of these upregulated miRNAs are highly expressed in naïve B-cells. MicroRNA classifier showed consistent results in FFPE tissues and was able to distinguish cyclin D1-negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from SLL, dominated by 23 upregulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL cases demonstrated a cluster characterized by high expression of miRNAs from polycistronic miR17~92 cluster and its paralogs miR-106a-363 and miR-106b-25, which was distinct from the other clusters showing enrichment of stroma associated miRNAs. The corresponding gene-expressionprofiling (GEP) data showed that the former cluster of MCL had significantly higher proliferation genesignature (PS), while the other subsets had higher expression of stroma associated genes. Clinical outcome analysis suggests that miRNAs can serve as prognosticators

From the Trenches: A Cross-Sectional Study Applying the GRADE Tool in Systematic Reviews of Healthcare Interventions

Background: GRADE was developed to address shortcomings of tools to rate the quality of a body of evidence. While much has been published about GRADE, there are few empirical and systematic evaluations. Objective: To assess GRADE for systematic reviews (SRs) in terms of inter-rater agreement and identify areas of uncertainty. Design: Cross-sectional, descriptive study. Methods: We applied GRADE to three SRs (n = 48, 66, and 75 studies, respectively) with 29 comparisons and 12 outcomes overall. Two reviewers graded evidence independently for outcomes deemed clinically important a priori. Inter-rater reliability was assessed using kappas for four main domains (risk of bias, consistency, directness, and precision) and overall quality of evidence. Results: For the first review, reliability was: k = 0.41 for risk of bias; 0.84 consistency; 0.18 precision; and 0.44 overall quality. Kappa could not be calculated for directness as one rater assessed all items as direct; assessors agreed in 41 % of cases. For the second review reliability was: 0.37 consistency and 0.19 precision. Kappa could not be assessed for other items; assessors agreed in 33 % of cases for risk of bias; 100 % directness; and 58 % overall quality. For the third review, reliability was: 0.06 risk of bias; 0.79 consistency; 0.21 precision; and 0.18 overall quality. Assessors agreed in 100 % of cases for directness. Precision created the most uncertainty due to difficulties in identifying ‘‘optimal’ ’ information size and ‘‘clinica

Loss of signalling via Gα13 in germinal center B-cell-derived lymphoma

Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined1,2. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells3,4. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Gα13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Gα13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Gα13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Gα13. These findings identify a Gα13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma

Genome-wide miRNAprofiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis

miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1–positive MCL (n = 30) and cyclin D1–negative MCL (n =7) and compared them with small lymphocytic leukemia/ lymphoma (n =12), aggressive B-cell lymphomas (n =138), normal B-cell subsets, and stromal cells.We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNAclassifier showed consistent results in formalinfixed paraffin-embedded tissues and was able to distinguish cyclin D1–negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma-associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators