bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma
Authors: Audenet François , Isharwal Sumit , Cha Eugene K. , Donoghue Mark T.A. , Drill Esther N. , Ostrovnaya Irina , Pietzak Eugene J. , Sfakianos John P. , Bagrodia Aditya , Murugan Paari , Dalbagni Guido , Donahue Timothy F. , Rosenberg Jonathan E. , Bajorin Dean F. , Arcila Maria E. , Hechtman Jaclyn F. , Berger Michael F. , Taylor Barry S. , Al-Ahmadie Hikmat , Iyer Gopa , Bochner Bernard H. , Coleman Jonathan A. , Solit David B. 
Published: October 2018

Abstract

Purpose:
To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors.

Experimental Design:
We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness.

Results:
With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q &lt; 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q &lt; 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness.

Conclusions:
UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.
Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties
Authors: Cao Liangxian , Weetall Marla , Trotta Christopher , Cintron Katherine , Ma Jiyuan , Kim Min Jung , Furia Bansri , Romfo Charles , Graci Jason D. , Li Wencheng , Du Joshua , Sheedy Josephine , Hedrick Jean , Risher Nicole , Yeh Shirley , Qi Hongyan , Arasu Tamil , Hwang Seongwoo , Lennox William , Kong Ronald , Petruska Janet , Moon Young-Choon , Babiak John , Davis Thomas W. , Jacobson Allan , Almstead Neil G. , Branstrom Art , Colacino Joseph M. , Peltz Stuart W. 
Published: October 2018

AbstractPTC299 was identified as an inhibitor of VEGFA mRNA translation in a phenotypic screen and evaluated in the clinic for treatment of solid tumors. To guide precision cancer treatment, we performed extensive biological characterization of the activity of PTC299 and demonstrated that inhibition of VEGF production and cell proliferation by PTC299 is linked to a decrease in uridine nucleotides by targeting dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis. Unlike previously reported DHODH inhibitors that were identified using in vitro enzyme assays, PTC299 is a more potent inhibitor of DHODH in isolated mitochondria suggesting that mitochondrial membrane lipid engagement in the DHODH conformation in situ is required for its optimal activity. PTC299 has broad and potent activity against hematologic cancer cells in preclinical models, reflecting a reduced pyrimidine nucleotide salvage pathway in leukemia cells. Archived serum samples from patients treated with PTC299 demonstrated increased levels of dihydroorotate, the substrate of DHODH, indicating target engagement in patients. PTC299 has advantages over previously reported DHODH inhibitors, including greater potency, good oral bioavailability, and lack of off-target kinase inhibition and myelosuppression, and thus may be useful for the targeted treatment of hematologic malignancies.
Combination Therapy Using Ruxolitinib and Oncolytic HSV Renders Resistant MPNSTs Susceptible to Virotherapy
Authors: Ghonime Mohammed G. , Cassady Kevin A. 
Published: October 2018

Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas resistant to most cancer treatments. Surgical resection remains the primary treatment, but this is often incomplete, ultimately resulting in high mortality and morbidity rates. There has been a resurgence of interest in oncolytic virotherapy because of encouraging preclinical and clinical trial results. Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells, lysing the cell and inducing antitumor immunity. We previously showed that basal interferon (IFN) signaling increases interferon-stimulated gene (ISG) expression, restricting viral replication in almost 50% of MPNSTs. The FDA-approved drug ruxolitinib (RUX) temporarily resets this constitutively active STAT signaling and renders the tumor cells susceptible to oHSV infection in cell culture. In the studies described here, we translated our in vitro results into a syngeneic MPNST tumor model. Consistent with our previous results, murine MPNSTs exhibit a similar IFN- and ISG-mediated oHSV-resistance mechanism, and virotherapy alone provides no antitumor benefit in vivo. However, pretreatment of mice with ruxolitinib reduced ISG expression, making the tumors susceptible to oHSV infection. Ruxolitinib pretreatment improved viral replication and altered the oHSV-induced immune-mediated response. Our results showed that this combination therapy increased CD8+ T-cell activation in the tumor microenvironment and that this population was indispensable for the antitumor benefit that follows from the combination of RUX and oHSV. These data suggest that JAK inhibition prior to oncolytic virus treatment augments both oHSV replication and the immunotherapeutic efficacy of oncolytic herpes virotherapy.
Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell–Effector Responses
Authors: Clancy-Thompson Eleanor , Devlin Christine A. , Tyler Paul M. , Servos Mariah M. , Ali Lestat R. , Ventre Katherine S. , Bhuiyan M. Aladdin , Bruck Patrick T. , Birnbaum Michael E. , Dougan Stephanie K. 
Published: October 2018

AbstractT-cell priming occurs when a naïve T cell recognizes cognate peptide–MHC complexes on an activated antigen-presenting cell. The circumstances of this initial priming have ramifications on the fate of the newly primed T cell. Newly primed CD8+ T cells can embark onto different trajectories, with some becoming short-lived effector cells and others adopting a tissue resident or memory cell fate. To determine whether T-cell priming influences the quality of the effector T-cell response to tumors, we used transnuclear CD8+ T cells that recognize the melanoma antigen TRP1 using TRP1high or TRP1low TCRs that differ in both affinity and fine specificity. From a series of altered peptide ligands, we identified a point mutation (K8) in a nonanchor residue that, when analyzed crystallographically and biophysically, destabilized the peptide interaction with the MHC binding groove. In vitro, the K8 peptide induced robust proliferation of both TRP1high and TRP1low CD8+ T cells but did not induce expression of PD-1. Cytokine production from K8-stimulated TRP1 cells was minimal, whereas cytotoxicity was increased. Upon transfer into B16 tumor–bearing mice, the reference peptide (TRP1-M9)- and K8-stimulated TRP1 cells were equally effective at controlling tumor growth but accomplished this through different mechanisms. TRP1-M9–stimulated cells produced more IFNγ, whereas K8-stimulated cells accumulated to higher numbers and were more cytotoxic. We, therefore, conclude that TCR recognition of weakly binding peptides during priming can skew the effector function of tumor-specific CD8+ T cells.
Atriplex retusa, the correct name for A. deserticola (Chenopodiaceae; Amaranthaceae sensu APG)
Authors: BÖHNERT TIM , LUEBERT FEDERICO , WEIGEND MAXIMILIAN 
Published: October 2018

The genus Atriplex Linnaeus (1753: 1052) (Chenopodiaceae Vent.; placed in Amaranthaceae Juss. s. l. in APG IV 2016) comprises about 300 species distributed mainly in subtropical, temperate, and subarctic regions of the world and is mostly adapted to dry conditions on often saline soils (Sukhorukov & Danin 2009, Kadereit et al. 2010, Iamonico 2013, APG IV 2016). The genus is highly diverse in Eurasia, Australia and North America. South America is another centre of diversity with ca. 55 species, 45 of which are considered as native (Brignone et al. 2016). A recent and exhaustive taxonomical synopsis of Atriplex for South America was published by Brignone et al. (2016), but there are also regional taxonomic revisions, e.g., for Chile by Rosas (1989), or Argentina by Múlgura de Romero (1981, 1982 & 1984).
SMITHSONIAN SOLAR CONSTANT VALUES
Authors: Kimball H. H. 
Published: October 2018

A critical study of the values published during the past 20 years leads to profound respect for the skill, energy, and devotion to science evidenced in connection with their determination. The mean of these values is generally accepted as correct within the limits of the accuracy of the observations. This paper has to do principally with the two following sources of error, and their probable effect upon the day-to-day variations in the solar constant values:(1) Pyrheliometer readings. Numerous comparisons between different instruments indicate a probable error in the readings of one, provided both are equally good, of about ±0.30 per cent. For Montezuma, Chili, Dr. Abbot computes the error to be ±0.20 per cent, and since a solar constant value depends upon the readings of two instruments, the error would be onlyThis enters directly into the determination of the solar constant values.(2) The difficulties of extrapolating pyrheliometer readings to the outer limit of the atmosphere, which is accomplished through determinations of atmospheric transmissibility for monochromatic radiation, (a), by the bolometer, or (b) by the pyranometer. An examination of individual determinations made at Montezuma and Harqua Hala on days having not less than 6 determinations at the two stations, gives probable errors of from ±0.2,3 per cent to ±0.74 per cent, and the day-to-day variability seems to be a function of the number of determinations upon which the daily values are based.
Since the probable error, or the probable variability, in the day-to-day values of the solar constant derived from determinations at these two stations is less than ±0.5 per cent, it is seen that solar variability, if it exists, is of the same order of magnitude as the probable error of the determinations. Therefore, this fact must be taken into account in attempting to correlate solar constant values with weather and other phenomena.
Indo-Western Pacific Climate Variability: ENSO Forcing and Internal Dynamics in a Tropical Pacific Pacemaker Simulation
Authors: Wang Chuan-Yang , Xie Shang-Ping , Kosaka Yu 
Published: October 2018

AbstractEl Niño–Southern Oscillation (ENSO) peaks in boreal winter but its impact on Indo-western Pacific climate persists for another two seasons. Key ocean–atmosphere interaction processes for the ENSO effect are investigated using the Pacific Ocean–Global Atmosphere (POGA) experiment with a coupled general circulation model, where tropical Pacific sea surface temperature (SST) anomalies are restored to follow observations while the atmosphere and oceans are fully coupled elsewhere. The POGA shows skills in simulating the ENSO-forced warming of the tropical Indian Ocean and an anomalous anticyclonic circulation pattern over the northwestern tropical Pacific in the post–El Niño spring and summer. The 10-member POGA ensemble allows decomposing Indo-western Pacific variability into the ENSO forced and ENSO-unrelated (internal) components. Internal variability is comparable to the ENSO forcing in magnitude and independent of ENSO amplitude and phase. Random internal variability causes apparent decadal modulations of ENSO correlations over the Indo-western Pacific, which are high during epochs of high ENSO variance. This is broadly consistent with instrumental observations over the past 130 years as documented in recent studies. Internal variability features a sea level pressure pattern that extends into the north Indian Ocean and is associated with coherent SST anomalies from the Arabian Sea to the western Pacific, suggestive of ocean–atmosphere coupling.
Energy Loss from Transient Eddies due to Lee Wave Generation in the Southern Ocean
Authors: Yang Luwei , Nikurashin Maxim , Hogg Andrew M. , Sloyan Bernadette M. 
Published: October 2018

ABSTRACTObservations suggest that enhanced turbulent dissipation and mixing over rough topography are modulated by the transient eddy field through the generation and breaking of lee waves in the Southern Ocean. Idealized simulations also suggest that lee waves are important in the energy pathway from eddies to turbulence. However, the energy loss from eddies due to lee wave generation remains poorly estimated. This study quantifies the relative energy loss from the time-mean and transient eddy flow in the Southern Ocean due to lee wave generation using an eddy-resolving global ocean model and three independent topographic datasets. The authors find that the energy loss from the transient eddy flow (0.12 TW; 1 TW = 1012 W) is larger than that from the time-mean flow (0.04 TW) due to lee wave generation; lee wave generation makes a larger contribution (0.12 TW) to the energy loss from the transient eddy flow than the dissipation in turbulent bottom boundary layer (0.05 TW). This study also shows that the energy loss from the time-mean flow is regulated by the transient eddy flow, and energy loss from the transient eddy flow is sensitive to the representation of anisotropy in small-scale topography. It is implied that lee waves should be parameterized in eddy-resolving global ocean models to improve the energetics of resolved flow.
A 20-year follow-up evaluation of total hip arthroplasty in patients younger than 50 using a custom cementless stem
Authors: Dessyn Edouard , Flecher Xavier , Parratte Sebastien , Ollivier Matthieu , Argenson Jean-Noël 
Published: October 2018

Aim: The purpose of this study is to report the 20-year follow-up of a continuous series of 232 total hip arthroplasties (THAs) performed in patients aged less than 50 at the index surgery. Patients and methods: This is a retrospective monocentric study which reports the clinical, radiographical and survival results of 232 THAs performed with a custom cementless femoral stem in 212 patients evaluated at follow-up ranging from 14 to 27 years. Results: At the time of follow-up, the mean Harris Hip Score was 94.1 (range 48–100). The Hip disability and Osteoarthritis Outcome Score was >80 points in all 5 categories for 146 patients (68.9%). 18 hips (8.5%) showed radiographical femoral abnormalities. 23 hips (10.8%) underwent revision of the implants. 13 were isolated cup revisions. 3 more hips had bipolar revisions for aseptic loosening at 15, 20 and 21 years. Taking stem revision for aseptic loosening as an endpoint, survivorship was 96.8% at 20 years (95% confidence interval, 95.1–98.5; patients at risk 76) and 94.5% at 25 years (91.7–97.3; patients at risk 12). Conclusions: The results of this study confirm that THA using this custom-designed stem can provide excellent clinical and radiographical outcomes at a mean follow-up of 20 years in patients younger than 50. The individual 3D femoral stem and prosthetic neck has been able to restore extra- and intramedullary functional anatomy in this young and active cohort of patients.
Total finger joint arthroplasty with a costal osteochondral autograft: up to 11 years of follow-up
Authors: Sato Kazuki , Iwamoto Takuji , Matsumura Noboru , Suzuki Taku , Nishiwaki Yuji , Nakamura Toshiyasu 
Published: October 2018

The purpose of this study was to evaluate the mid- to long-term clinical outcomes of total finger joint arthroplasty using a costal osteochondral autograft for joint ankylosis. Twenty-three joints (three metacarpophalangeal joints, 20 proximal interphalangeal joints) in 23 patients (19 men and four women) were treated with a costal osteochondral autograft and were evaluated after a mean follow-up of 77 months (60–138). Mean age was 33 years (18 to 55). Significant improvement in active finger extension/flexion was seen from a preoperative mean of −24°/26° (arc: 2°) to −13°/75° (arc: 63°) at latest follow-up. Mean preoperative Japanese Society for Surgery of the Hand version of the Disability of the Arm, Shoulder and Hand score was initially 24 and improved significantly to 5 at latest follow-up. Conclusion: total finger arthroplasty using a costal osteochondral autograft gave an anatomical and biological reconstruction and provided stable improvement at a mean follow-up of 77 months. Level of evidence: IV
Clinical characteristics and unlicensed applications of licensed psychotropic drugs within a regional tertiary service for patients with affective disorders
Authors: Tiwari Nupur , Baldwin David S. 
Published: October 2018

Background: Referral to tertiary services is recommended when patients with mood and anxiety disorders have not responded to multiple treatments in primary or secondary care. Within specialist services, some patients undergo treatment with licensed psychotropic medications outside the narrow terms of their market authorization (‘unlicensed applications’). We examined the demographic and clinical characteristics of patients referred to a regional specialist service to determine the extent of and factors associated with recommendations for unlicensed (‘off label’) prescriptions. Methods: Retrospective examination of demographic and clinical characteristics and treatment recommendations in patients seen within a 5-year period. Patients were allocated to three broad diagnostic clusters (unipolar depressive disorders, bipolar disorder, anxiety disorders), and two groups (with or without comorbid disorders). We compared patients in whom all treatment recommendations were for licensed applications with patients in whom at least one treatment was for an unlicensed application, across a range of variables reflecting illness ‘burden’ (duration, inpatient treatment, electroconvulsive therapy, nonfatal self-harm, psychosis). Results: From 177 new referrals, 148 patients (91 females, 57 males) could be placed within one of the three clusters. Many patients with bipolar disorder had not undergone treatment with lithium or formal psychological interventions in secondary care. Treatment recommendations involving unlicensed applications of medications were common (approximately 50%) in all clusters, but there were no significant differences in measures of illness burden between groups of patients, categorized according to licensed or unlicensed prescriptions. Limitations: Retrospective examination of notes recorded for other purposes, within a single service, in which treatment recommendations might reflect idiosyncratic practice is a limitation of our findings. Also, examined variables could not provide a comprehensive indication of illness severity or functional impairment. Conclusion: Our findings confirm that ‘off label’ prescribing is common in psychiatric practice. Treatment decisions relating to unlicensed applications appear to be influenced by factors other than overall illness burden.
Molecular pathophysiology of the myelodysplastic syndromes: insights for targeted therapy
Authors: Aleshin Alex , Greenberg Peter L. 
Published: October 2018

AbstractThe clinical heterogeneity of the myelodysplastic syndromes (MDSs) relates to the recently discerned panoply of molecular abnormalities extant within this disease spectrum. Despite increasing recognition of these biologic abnormalities, very limited therapeutic options exist to exploit our increasing understanding of the molecular pathophysiology of MDS, with only 1 therapy (lenalidomide) particularly focused on a specific clinical patient subset (del(5q) cytogenetics) and 2 epigenetic modulators (azacitidine and decitabine) having been approved for treating these patients. This article will review the mutational and biologic landscape of these disorders, as well as the targeted therapeutics currently in clinical trials that are focused on attacking these features. Given the molecular complexity of these disorders and the limited repertoire of effective therapeutic agents, we will also discuss novel approaches attempting to determine potentially effective and personalized treatment options through complementary chemosensitivity and computerized signaling network screening for these disparate MDS patient subsets. Translational use of such resources, combined with the rapidly evolving next-generation molecular technologies, should prove useful in effectuating improved and more selective options for therapy.
A three-phase decision making approach for self-adaptive systems using web services
Authors: AL-Kafaf Dhrgam , Kim Dae-Kyoo , Lu Lunjin 
Published: October 2018

AbstractA self-adaptive system adapts itself to changes in a dynamic environment. The core in self-adaptive systems is making an adaptation decision. The current practice focuses on a single layer of decision making using either a local knowledge base or a shared knowledge base shared by multiple units through a network. While the use of a local knowledge base is efficient, it suffers from its limited maturity. A shared knowledge base can address the maturity problem, but it is inefficient in adaptation due to communication overheads. In this work, we present a three-phase decision making approach for self-adaptive systems to improve precision while being competitive for efficiency. The approach consists of three phases for making a decision. The first phase uses the local knowledge base of the self-adaptive unit to identify an object. If the object cannot be identified locally, the unit sends a request to shared knowledge bases through web services in the second and third phases. The approach makes use of B-kNN for object identification and web services for accessing shared knowledge bases. We conducted quantitative validation in terms of accuracy, precision, recall, and F-measure using a set of scenarios. The results show that 99.58% of accuracy, 94.01% of recall, 94.04% of precision, and 94.01% of F-measure can be achieved. We also conducted comparative analysis by comparing the presented approach with the traditional approach and the cloud-based approach. The results show that the presented approach improves 45% in object identification with an increase of 0.66 s over the traditional approach and the same performance in object identification with a decrease of 0.95 s over the cloud-based approach.