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Sumoylation is a reversible post-translational modification of proteins by small ubiquitin-like modifier (SUMO) that regulates protein function and contributes to cellular response to stress. Sumoylation is an essential pathway for all cells and is involved in diverse processes such as inflammation, DNA damage response, signaling and cell survival/apoptosis. Due to its involvement in such cellular functions, sumoylation intersects with the majority of the hallmarks of cancer. Many cancers display elevated expression of SUMO pathway components, a mechanism co-opted by tumors to survive under stressful conditions. In addition to its tumor intrinsic functions, sumoylation has emerged as a novel target for activating anti-tumor immunity due to its role in regulating type I interferon (IFN) signaling. Targeting sumoylation is a compelling anti-cancer strategy due to the multiple mechanisms of action that may drive anti-tumor activity for cancer patients. We report the discovery of SB-4826, a novel, orally active, covalent small molecule inhibitor of the Sumo Activating Enzyme (SUMO E1), the initiating enzyme of the sumoylation cascade. SB-4826 selectively and irreversibly binds an allosteric pocket of SUMO E1 and drives potent biochemical and cellular activity. SB-4826 inhibits global sumoylation in cells and blocks proliferation across a broad panel (100+) of cancer cell lines. Cysteine-proteome profiling by mass spectrometry indicated that Cys-30 of SUMO E1 was the only cysteine-containing peptide (out of 14,541 measured) that met the criteria for covalent engagement indicating exquisite selectivity across the cellular proteome. In an in vivo pharmacodynamic model measuring IFN signaling SB-4826 treatment led to dose- and time-dependent induction of IFN regulated cytokines. SB-4826 treatment resulted in significant tumor growth inhibition in multiple in vivo models. In a syngeneic A20 lymphoma model SB-4826 led to tumor stasis. In a human RAJI xenograft model, SB-4826 induced near-complete inhibition of tumor growth as a single agent and resulted in tumor regression when combined with rituximab. In a mouse CT-26 colorectal tumor model which is generally refractory to anti-PD-1 treatment, SB-4826 significantly inhibited tumor growth as monotherapy and led to 60% complete tumor responses when combined with anti-PD-1. SB-4826 caused increased CD8+ T cell infiltration in CT-26 tumors supporting the role of SB-4826 in inducing IFN signaling and leading to a tumor microenvironment that is more responsive to immune checkpoint inhibition. SUMO E1 is a clinically validated cancer target as evidenced by recent data showing encouraging responses to TAK-981, an IV-administered, ATP-competitive inhibitor. SB-4826 is a differentiated and optimized SUMO E1 inhibitor that is administered orally and demonstrated improved activity in preclinical models. SB-4826 has favorable properties for development, is a new and promising cancer therapy, and is entering phase 1 clinical studies in 2023. Citation Format: Jude R. Canon, Ashley Callinan, Sarah Bradley, Laurie Wang, Mackenzie Kui, Ariel Wein, Gabriele Sulli, Peter Buchowiecki, Fang-Tsao Hong, Miles Kubota, Mary Walton, Victor J. Cee. SB-4826, a first-in-class oral, covalent inhibitor of SUMO E1 that induces IFN signaling and inhibits tumor growth as monotherapy and in combination with immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB318.

The native prairie of the southern Great Plains has been especially modified by two related forces: conversion of native prairie to agricultural forms of land use and removal of black-tailed prairie dogs (Rodentia: Sciuridae, Cynomys ludovicianus (Ord, 1815)) that act as ecosystem engineers via their burrowing and grazing activities. It is unknown how these changes have affected the native bee community. We surveyed the bee communities in relatively intact native prairie at two National Wildlife Refuges in Texas, quantifying bee community structure as a function of the presence/absence of grazing by prairie dogs. Over a 5-mo sampling period in spring-summer 2013, we found high overall bee diversity (180 species, mostly solitary ground-nesters), with differences detected in diversity between Muleshoe and Buffalo Lake National Wildlife Refuges as well as on and off prairie dog colonies. Although the same three species dominated the bee community at both refuges, most species were represented by relatively few individuals, leading to overall differences in diversity (richness, evenness, and effective number of species) by refuge. Bee diversity differed between sites on and off prairie dog colonies, but in trends that differed by refuge and by index, suggesting that location was more important than prairie dog presence. These results represent a reference fauna against which other regional bee communities in other land-cover types can be compared, but the high spatial heterogeneity we found indicates that detecting effects of landscape change on native bees will be challenging.

White spotting phenotypes in horses may be caused by developmental alterations impairing melanoblast differentiation, survival, migration and/or proliferation. Candidate genes for white-spotting phenotypes in horses include EDNRB, KIT, MITF, PAX3 and TRPM1. We investigated a German Riding Pony with a sabino-like phenotype involving extensive white spots on the body together with large white markings on the head and almost completely white legs. We obtained whole genome sequence data from this horse. The analysis revealed a heterozygous 1273-bp deletion spanning parts of intron 2 and exon 3 of the equine KIT gene (Chr3: 79 579 925-79 581 197). We confirmed the breakpoints of the deletion by PCR and Sanger sequencing. Knowledge of the functional impact of similar KIT variants in horses and other species suggests that this deletion represents a plausible candidate causative variant for the white-spotting phenotype. We propose the designation W28 for the mutant allele.

Recent experience with damage and failure due to graphitization in electric power plant piping of carbon (C) and carbon-molybdenum (C-Mo) steel suggests that the previously developed time-temperature curves for graphitization prediction, first published over two decades ago, merit review. Recent data were combined with an exhaustive review of available literature. As with the earlier research, available experience data with reported approximate extent of graphitization and nominal service exposure conditions were analyzed for the predictions. When the data were combined, the database consisted of 281 data points. The data are in contrast to the roughly 40 points used in the prior research. The nature of the expanded C steel weldment database was such that the analysis could not effectively discriminate between all of the five graphitization levels used in previous research efforts. In this analysis, it was found that the level of graphitization as a function of time and temperature could be categorized into three broad “risk” ranges—defined as low, moderate, and significant, and that the curves delineating these ranges could be developed in a statistically conservative manner. These conservative time-temperature prediction curves are offered as an update to the previous time-temperature curves. Although the data for C-Mo steel base metal and weldments and on C steel base metal were inadequate for a full quantitative analysis, the experience with these materials cases is presented within the context of the C steel weldment risk curves and preliminary time-temperature conditions warranting concern for graphitization are offered. Finally, a partial validation of the risk curves is presented in examination of power plant piping that had operated for over 400,000 h.

Catherine H Yu,1,2 Giuliana Guarna,1 Pamela Tsao,3 Jude R Jesuthasan,1 Adrian NC Lau,3,4 Ferhan S Siddiqi,1 Julie Anne Gilmour,3 Danyal Ladha,1 Henry Halapy,5 Andrew Advani1–3 1Li Ka Shing Knowledge Institute, St Michael’s Hospital, 2Division of Endocrinology and Metabolism, Department of Medicine, StMichael’s Hospital, University of Toronto, 3Department of Medicine, Faculty of Medicine, University of Toronto, 4Division of Endocrinology, Department of Medicine, University Health Network, 5Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada Purpose: For emerging adults with chronic medical diseases, the transition from pediatric to adult health care is often a time of great upheaval, commonly associated with unhealthy self-management choices, loss to follow-up, and adverse outcomes. We conducted a systematic review to examine the use of incentive strategies to promote positive health-related behaviors in young adults with chronic medical diseases.Methods: The Medline, CINAHL, Embase, PsycInfo, and Cochrane databases were searched through June 2014. Studies of any design where an incentive was used to achieve a target behavior or outcome in a pediatric or emerging adult population (age

We intensively sampled fishes from two reaches of the Rio Grande within the Albuquerque Basin (Albuquerque and Belen valleys) during 1998–2001, compared our findings with those from 1984, and compiled a list of all fishes known from the two reaches. Structure of assemblages (richness, diversity, abundance distributions–taxon dominance versus rank abundance) was similar between reaches in 1998–2001, but the faunas had low taxonomic similarity. The nonnative white sucker (Catostomus commersonii), western mosquitofish (Gambusia affinis), and native red shiner (Cyprinella lutrensis) dominated the Albuquerque Valley. Faunal change in the Albuquerque Valley between 1984 and 1998–2001 indicated all native fishes besides the red shiner declined, particularly the Rio Grande silvery minnow (Hybognathus amarus) and longnose dace (Rhinichthys cataractae). In contrast, the red shiner alone dominated the Belen Valley, nonnative fishes were less dominant, and aside from the Rio Grande silvery minnow and longnos...

We report the diagnosis and outcome of a fetus with an unusual left ventricular wall defect. A 34-week fetus presented for echocardiographic evaluation because of an irregular cardiac rhythm. Fetal echocardiography revealed frequent ventricular ectopy and an “accessory” ventricular chamber diagnosed as a left ventricular diverticulum (LVD). The ectopy resolved in utero but recurred after delivery. Angiography revealed a “bifid” LVD. Inderal therapy suppressed the ventricular ectopy. The association between ventricular ectopy and LVD is unusual, but the prognosis of LVD even with arrhythmia is excellent.

Linear α-olefins (LAOs) find industrial use as high-value chemical intermediates. Most of the LAO production is based on ethylene oligomerization and does not yield a market-related product distribution. Various non-ethylene-based LAO production routes have been evaluated and it was found that a process based on boron chemistry was the most likely to be successfully commercialized. Process flow diagrams for a low-temperature (150−200 °C) continuous boron-based process to produce LAOs from linear internal olefins are presented, showing that it can be designed with or without a solvent in the boron cycle. Experimental data are presented to illustrate progress made in understanding the chemistry associated with such a process. It is shown that (a) solvent exchange competes with hydroboration and is rate-controlling by regulating borane availability, (b) reactivity of substituted boranes is determined by the availability of the empty pz orbital of boron, (c) steric effects influence the rate of hydroboration ...

As a poet, novelist, and playwright, Sebastian Barry has established his reputation, in recent years, as one of Ireland's young literary stars. Particularly through his efforts for the stage and through his 1995 breakout play, The Steward of Christendom, Barry finds himself today compared to and associated with that host of Irish playwrights — including Brian Friel, Fr;nk McGUinness, Tom Murphy, Marina Carr, and Martin McDonagh — who have revitalized Irish theatre in the last few decades. Barry also shares a common goal with these playwrights: restaging Ireland.

Despite the critical role that shear is hypothesized to play in the damage modes that limit the performance of total hip and knee replacements, the shear behavior of ultra-high molecular weight polyethylene (UHMWPE) remains poorly understood, especially after oxidative degradation or radiation crosslinking. In the present study, we developed the miniature specimen (0.5 mm thickness×6.4 mm diameter) shear punch test to evaluate the shear behavior of UHMWPE used in total joint replacement components. We investigated the shear punch behavior of virgin and crosslinked stock materials, as well as of UHMWPE from tibial implants that were gamma-irradiated in air and shelf aged for up to 8.5 years. Finite element analysis, scanning electron microscopy, and interrupted testing were conducted to aid in the interpretation of the shear punch load–displacement curves. The shear punch load–displacement curves exhibited similar distinctive features. Following toe-in, the load–displacement curves were typically bilinear, and characterized by an initial stiffness, a transition load, a hardening stiffness, and a peak load. The finite element analysis established that the initial stiffness was proportional to the elastic modulus of the UHMWPE, and the transition load of the bilinear curve reflected the development of a plastically deforming zone traversing through the thickness of the sample. Based on our observations, we propose two interpretations of the peak load during the shear punch test: one theory is based on the initiation of crystalline plasticity, the other based on the transition from shear to tension during the tests. Due to the miniature specimen size, the shear punch test offers several potential advantages over bulk test methods, including the capability to directly measure shear behavior, and quite possibly infer ultimate uniaxial behavior as well, from shelf aged and retrieved UHMWPE components. Thus, the shear punch test represents an effective and complementary new tool in the armamentarium of miniature specimen mechanical testing methods for UHMWPE used in total joint replacement components.

This case study describes a bilobed or bipartite placenta followed by serial ultrasound. Incidence of occurrence is reported by Fujikura et al as 4.2% in a study of 8505 deliveries,or approximately 1 in 357 deliveries. The diagnosis of an anomalous placenta is important for patient management at time of delivery. Specifically,the bilobed placenta can be associated with first-trimester bleeding,polyhydramnios,abruption,and retained placenta. Care ful attention to the cord insertion is also required for optimal fetal management. The authors describe the sonographic features and evolution of a bilobed placenta and its relationship to the pregnancy outcome.

Recent, brittle fracture in Grade 23 power plant components at relatively low temperatures has increased the need to assess the cracking behavior of this material. Time-dependent cracking in the heat-affected zone of Grade 23 weldments was assessed using crack growth testing of subsize compact tension specimens at a temperature (482°C, 900°F) characteristic of the upper portion of a furnace wall in supercritical boilers. Results of additional testing at a higher, typical design temperature (566°C, 1050°F) for superheater and reheater tubing and headers will be reported later. Post-test metallurgical evaluation of the cracking morphology was conducted using traditional light microscopy and laser microscopy. Although large-scale creep deformation is absent under these lower test temperature conditions, significant weldment heat-affected zone intergranular cracking was documented. An example of application of the data to the inservice integrity and life assessment of a furnace tube is also described, providing preliminary perspective on the factors controlling lifetime and manageability of integrity. Paper published with permission.

The small punch test was developed to investigate the mechanical behavior of polyethylene using miniature specimens (< 14 mg) measuring 0.5 mm in thickness and 6.4 mm in diameter. The objective of this study was to demonstrate the feasibility and reproducibility of the small punch test when applied to clinically relevant polyethylenes. Mechanical behavior was characterized during 66 tests performed on GUR4150HP and GUR4120 specimens following alternate sterilization methods and 4 weeks of accelerated aging at 80 degrees C. The small punch test was found to be highly reproducible with regard to characterizing the ductility, ultimate strength, and fracture resistance of sterilized and aged polyethylene. In the future, the small punch test can be used to directly measure mechanical properties near the articulating surface of retrieved components.

For over three decades, the long seam-welded low alloy steel, Grades 11 and 22, high energy piping in fossil power plants has been considered at risk of premature damage and failure. The experience with piping damage and failures has been documented and extensively studied, but there remains a lack of perspective on how the overall experience with such piping, including that of the large “survivor” population, compares with what one may expect with the design rules used in their construction. Such a perspective can be useful in helping decide on suitable design rules for this class of piping. This paper focuses on an aggregate, global, semi-quantitative evaluation of the damage and failure experience in fossil plant low alloy steel long seam-welded piping in terms of a rate of failure measured against the performance of the overall population. A key aspect of the evaluation is the consideration of the survivor population, particularly important since the documented cases of failure and damage represent a very small fraction of the population of relevant components. The damage and failure rates have been derived from the Electric Power Research Institute database, using an exposure parameter represented by the product of operating time and length of piping. The rates are viewed against the backdrop of the statistical scatter band of base metal stress rupture data used in development of the ASME Code design allowable stresses and against the weld strength reduction factors recently adopted by the ASME Boiler Pressure Vessel Code, Section I and the Power Piping Code, B31.1.Copyright © 2011 by ASME

The small punch (miniature disk bend) test was used to estimate conventional tensile and fracture properties of the reactor pressure vessel A 533B plate steel provided by ASTM for its Cross-Comparison Exercise on Determination of Material Properties Through the Use of Miniature Mechanical Testing Techniques. The test procedures followed those developed over the last six years mainly through support of the Electric Power Research Institute. The small punch, disk-shaped specimen of 6.35 mm (0.25 in.) diameter and 0.5 mm (0.020 in.) thickness is loaded by a 2.54 mm (0.1 in.) diameter hemispherical head punch at a constant displacement rate of typically 0.25 mm (0.01 in.) per minute. The room-temperature material fracture toughness (K I c ) and uniaxial tensile stress-strain curve and properties estimated from three separate small punch tests at room temperature show good reproducibility and agreement with the conventionally-measured, large specimen values. A series of small punch tests exhibited well-defined temperature-dependent energy transition behavior and potential for estimation of standard Chatpy transition temperatures from such data.

Short hairpin RNAs (shRNAs) and short interfering RNAs (siRNAs) probably enter different stages of the microRNA (miRNA) pathway for depletion of mRNA and suppression of protein translation. Primary and secondary structural characteristics that are shared between endogenous primary miRNA transcripts (pri-miRNAs) may contribute toward efficient biogenesis and potent silencing. This study investigates known miRNA transcripts for characteristics that are conserved between miRNAs and that distinguish them from random hairpins with similar lengths. The primary structure is conserved, as demonstrated by a significant presence or absence of certain bases at specific positions in the miRNA precursors and their flanking regions. The secondary structure is also conserved between miRNAs, as internal loops and bulges commonly appear in specific positions in the miRNA stem. The conservation of base-pairing continues past the mature duplex and 13 bases into the primary stem, with no detectable conservation of secondary structure beyond this region. Based on these observations, we have designed a hairpin construct that incorporates the most important characteristics present in endogenous miRNAs. Preliminary experiments suggest that this construct may rescue the efficacy of shRNA triggers that cannot be used with a miR-30-based hairpin, and vice versa.

Three identical 85 MW combustion turbines experienced cracking and failure of several first stage compressor stator (S1) blades. The root cause analysis involved the following distinct stages: 1. Examination of failed blades including fractography and analyses of the mechanics of their fracture; 2. Blade vibration analysis to determine the modes of vibration and corresponding resonant frequencies; 3. Inlet plenum flow and acoustical analysis to identify possible sources of excitation. This paper summarizes the methodology and results of the root cause analysis investigation and outlines the convergence of results obtained from the independently conducted mechanical and acoustical analyses.Copyright © 2005 by ASME

The identification of the PWSCC (Primary Water Stress Corrosion Cracking) mechanism responsible for leakage from an Alloy 600 nozzle tube of a PWR RPV (pressurized water reactor reactor pressure vessel) head more than a decade ago led to a significant body of research into understanding the phenomenon and to development of bases for safely managing primary pressure boundary integrity. However, the relatively recent experience at Davis-Besse, wherein penetration leakage resulted in significant vessel head material wastage, led to the heretofore unconsidered issue of vessel failure risk due to head rupture. This paper addresses, in preliminary fashion, one key input to determining the risk associated with head material wastage and potential rupture — the local environmental and fluid conditions associated with a range of leak paths. The results indicate a need for rigorous prediction of fluid conditions for a range of leak situations to help establish criteria for addressing penetration leaks.