bluuebunny/crossref_metadata_2025_split huggingface dataset:
TAC1 Gene Products Regulate Pituitary Hormone Secretion and Gene Expression in Prepubertal Grass Carp Pituitary Cells
Authors: Hu Guangfu , He Mulan , Ko Wendy K. W. , Wong Anderson O. L. 
Published: April 2017

AbstractTachykinin-1 (TAC1) is known to have diverse functions in mammals, but similar information is scarce in fish species. Using grass carp as a model, the pituitary actions, receptor specificity and postreceptor signaling of TAC1 gene products, namely substance P (SP) and neurokinin A (NKA), were examined. TAC1 encoding SP and NKA as well as tachykinin receptors NK1R and NK2R were cloned in the carp pituitary. The newly cloned receptors were shown to be functional with properties similar to mammalian counterparts. In carp pituitary cells, SP and NKA could trigger luteinizing hormone (LH), prolactin (PRL), and somatolactin α (SLα) secretion, with parallel rises in PRL and SLα transcripts. Short-term SP treatment (3 hours) induced LH release, whereas prolonged induction (24 hours) could attenuate LHβ messenger RNA (mRNA) expression. At pituitary cell level, LH, PRL, and SLα regulation by TAC1 gene products were mediated by NK1R, NK2R, and NK3R, respectively. Apparently, SP- and NKA-induced LH and SLα secretion and transcript expression were mediated by adenylyl cyclase/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), phospholiphase C (PLC)/inositol 1,4,5-triphosphate/protein kinase C (PKC), and Ca2+/calmodulin (CaM)/CaM-dependent protein kinase-II pathways. The signal transduction for PRL responses was similar, except for the absence of a PKC component. Regarding SP inhibition of LHβ mRNA expression, the cAMP/PKA- and PLC/PKC-dependent (but not Ca2+/CaM-dependent) cascades were involved. These results, as a whole, suggest that TAC1 gene products play a role in LH, PRL, and SLα regulation via overlapping postreceptor signaling coupled to different subtypes of tachykinin receptor expressed in the carp pituitary.
TERT, BRAF, and NRAS in Primary Thyroid Cancer and Metastatic Disease
Authors: Melo Miguel , Gaspar da Rocha Adriana , Batista Rui , Vinagre João , Martins Maria João , Costa Gracinda , Ribeiro Cristina , Carrilho Francisco , Leite Valeriano , Lobo Cláudia , Cameselle-Teijeiro José Manuel , Cavadas Bruno , Pereira Luísa , Sobrinho-Simões Manuel , Soares Paula 
Published: April 2017

Abstract

Context
Little is known about the frequency of key mutations in thyroid cancer metastases and its relationship with the primary tumor genotype.

Objectives
To evaluate the frequency of TERT promoter (TERTp), BRAF, and NRAS mutations in metastatic thyroid carcinomas, analyzing primary thyroid tumors, lymph node metastases (LNMs), and distant metastases.

Design and Patients
Mutation analysis was performed in 437 tissue samples from 204 patients, mainly with papillary thyroid carcinomas (PTCs; n = 180), including 196 LNMs and 56 distant metastases. All the distant metastases included corresponded to radioiodine-refractory metastatic tissue.

Results
We found the following mutation frequency in primary PTCs, LNMs, and distant metastases, respectively: TERTp: 12.9%, 10.5%, and 52.4%; BRAF: 44.6%, 41.7%, and 23.8%; and NRAS: 1.2%, 1.3%, and 14.3%. There was a significant concordance between the primary tumor genotype and the corresponding LNM for all the genes, in particular BRAF-mutated PTC. The overall concordance between primary tumors and respective distant metastases was low. In the group of patients with PTCs, we found a high frequency of TERTp mutations and a low frequency of BRAF mutations in distant metastases, in comparison with the paired primary tumors. When present in distant metastases, BRAF mutations frequently coexisted with TERTp mutations.

Conclusions
When the genotype of primary tumors is compared with the genotype of LNMs, the concordance is high for all the genes studied. On the other hand, distant metastases show an enrichment in TERTp mutations and a decrease in BRAF mutations. TERTp mutations may play a role in distant metastases.
Quantification of Thyroid Cancer and Multinodular Goiter Risk in the DICER1 Syndrome: A Family-Based Cohort Study
Authors: Khan Nicholas E. , Bauer Andrew J. , Schultz Kris Ann P. , Doros Leslie , Decastro Rosamma M. , Ling Alexander , Lodish Maya B. , Harney Laura A. , Kase Ron G. , Carr Ann G. , Rossi Christopher T. , Field Amanda , Harris Anne K. , Williams Gretchen M. , Dehner Louis P. , Messinger Yoav H. , Hill D. Ashley , Stewart Douglas R. 
Published: April 2017

Abstract

Context:
The risk of thyroid cancer and multinodular goiter (MNG) in DICER1 syndrome, a rare tumor-predisposition disorder, is unknown.

Objective:
To quantify the risk of thyroid cancer and MNG in individuals with DICER1 syndrome.

Design:
Family-based cohort study.

Setting:
National Institutes of Health (NIH) Clinical Center (CC).

Participants:
The National Cancer Institute DICER1 syndrome cohort included 145 individuals with a DICER1 germline mutation and 135 family controls from 48 families.

Interventions:
Each individual completed a detailed medical history questionnaire. A subset underwent a 3-day evaluation at the NIH CC.

Main Outcome Measures:
The cumulative incidence of MNG (or thyroidectomy) was quantified using the complement of the Kaplan-Meier product limit estimator. We compared the observed number of thyroid cancers in the NCI DICER1 cohort with matched data from the Surveillance, Epidemiology, and End Results (SEER) Program. We performed germline and somatic (thyroid cancer, MNG) DICER1 sequencing.

Results:
By the age of 40 years, the cumulative incidence of MNG or thyroidectomy was 75% in women and 17% in men with DICER1 syndrome compared with 8% of control women (P &lt; 0.001) and 0% of control men (P = 0.0096). During 3937 person-years of observation, individuals with DICER1 syndrome had a 16-fold increased risk of thyroid cancer (95% confidence interval, 4.3 to 41; P &lt; 0.05) compared with the SEER rates. Of 19 MNG nodules and 3 thyroid cancers, 16 (84%) and 3 (100%), respectively, harbored germline and somatic pathogenic DICER1 mutations.

Conclusions:
We propose a model of thyroid carcinogenesis in DICER1 syndrome. Early-onset, familial, or male MNG should prompt consideration of the presence of DICER1 syndrome.
Whole-Exome Sequencing for Diagnosis of Turner Syndrome: Toward Next-Generation Sequencing and Newborn Screening
Authors: Murdock David R. , Donovan Frank X. , Chandrasekharappa Settara C. , Banks Nicole , Bondy Carolyn , Muenke Maximilian , Kruszka Paul 
Published: April 2017

Abstract

Context:
Turner syndrome (TS) is due to a complete or partial loss of an X chromosome in female patients and is not currently part of newborn screening (NBS). Diagnosis is often delayed, resulting in missed crucial diagnostic and therapeutic opportunities.

Objectives:
This study sought to determine if whole-exome sequencing (WES) as part of a potential NBS program could be used to diagnose TS.

Design, Setting, Patients:
Karyotype, chromosomal microarray, and WES were performed on blood samples from women with TS (n = 27) enrolled in the Personalized Genomic Research study at the National Institutes of Health. Female control subjects (n = 37) and male subjects (n = 27) also underwent WES. Copy number variation was evaluated using EXCAVATOR2 and B allele frequency was calculated from informative single nucleotide polymorphisms. Simulated WES data were generated for detection of low-level mosaicism and complex structural chromosome abnormalities.

Results:
We detected monosomy for chromosome X in all 27 TS samples, including 1 mosaic for 45,X/46,XX and another with previously unreported material on chromosome Y. Sensitivity and specificity were both 100% for the diagnosis of TS with no false-positive or false-negative results. Using simulated WES data, we detected isochromosome Xq and low-level mosaicism as low as 5%.

Conclusion:
We present an accurate method of diagnosing TS using WES, including cases with low-level mosaicism, isochromosome Xq, and cryptic Y-chromosome material. Given the potential use of next-generation sequencing for NBS in many different diseases and syndromes, we propose WES can be used as a screening test for TS in newborns.
Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty
Authors: Dauber Andrew , Cunha-Silva Marina , Macedo Delanie B. , Brito Vinicius N. , Abreu Ana Paula , Roberts Stephanie A. , Montenegro Luciana R. , Andrew Melissa , Kirby Andrew , Weirauch Matthew T. , Labilloy Guillaume , Bessa Danielle S. , Carroll Rona S. , Jacobs Dakota C. , Chappell Patrick E. , Mendonca Berenice B. , Haig David , Kaiser Ursula B. , Latronico Ana Claudia 
Published: April 2017

AbstractContext:Central precocious puberty (CPP) results from premature activation of the hypothalamic–pituitary–gonadal axis. Few genetic causes of CPP have been identified, with the most common being mutations in the paternally expressed imprinted gene MKRN3.Objective:To identify the genetic etiology of CPP in a large multigenerational family.Design:Linkage analysis followed by whole-genome sequencing was performed in a family with five female members with nonsyndromic CPP. Detailed phenotyping was performed at the time of initial diagnosis and long-term follow-up, and circulating levels of Delta-like 1 homolog (DLK1) were measured in affected individuals. Expression of DLK1 was measured in mouse hypothalamus and in kisspeptin-secreting neuronal cell lines in vitro.Setting:Endocrine clinic of an academic medical center.Patients:Patients with familial CPP were studied.Results:A complex defect of DLK1 (∼14-kb deletion and 269-bp duplication) was identified in this family. This deletion included the 5′ untranslated region and the first exon of DLK1, including the translational start site. Only family members who inherited the defect from their father have precocious puberty, consistent with the known imprinting of DLK1. The patients did not demonstrate additional features of the imprinted disorder Temple syndrome except for increased fat mass. Serum DLK1 levels were undetectable in all affected individuals. Dlk1 was expressed in mouse hypothalamus and in kisspeptin neuron-derived cell lines.Conclusion:We identified a genomic defect in DLK1 associated with isolated familial CPP. MKRN3 and DLK1 are both paternally expressed imprinted genes. These findings suggest a role of genomic imprinting in regulating the timing of human puberty.
A Randomized Phase 2 Study of Long-Acting TransCon GH vs Daily GH in Childhood GH Deficiency
Authors: Chatelain Pierre , Malievskiy Oleg , Radziuk Klaudziya , Senatorova Ganna , Abdou Magdy O. , Vlachopapadopoulou Elpis , Skorodok Yulia , Peterkova Valentina , Leff Jonathan A. , Beckert Michael ,   the TransCon GH Working Group
Published: April 2017

Abstract

Context:
TransCon Growth Hormone (GH) (Ascendis Pharma) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency (GHD).

Objective:
To compare the pharmacokinetics, pharmacodynamics, safety, and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD.

Design:
Randomized, open-label, active-controlled study of three doses of weekly TransCon GH versus daily Genotropin (Pfizer).

Setting:
Thirty-eight centers in 14 European countries and Egypt.

Patients:
Prepubertal male and female treatment-naïve children with GHD (n = 53).

Interventions:
Subjects received one of three TransCon GH doses (0.14, 0.21, or 0.30 mg GH/kg/wk) or Genotropin 0.03 mg GH/kg/d for 26 weeks.

Main Outcome Measures:
GH and insulinlike growth factor-1 (IGF-1) levels, growth, adverse events, and immunogenicity.

Results:
Both GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses. A dose response was observed, with IGF-1 standard deviation scores increasing into the normal range for all three TransCon GH doses. Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm, which was not statistically different from 11.6 cm for Genotropin. Adverse events were mild to moderate, and most were unrelated to the study drug. Injection site tolerance was good. One TransCon GH subject developed a low-titer, nonneutralizing antibody response to GH.

Conclusions:
The results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH (pharmacokinetics) and IGF-1 (pharmacodynamics) levels, safety, and efficacy and support advancement into phase 3 development.
Persistent Reduction of Circulating Myeloid Calcifying Cells in Acromegaly: Relevance to the Bone–Vascular Axis
Authors: Fadini Gian Paolo , Dassie Francesca , Cappellari Roberta , Persano Mariasara , Vigili de Kreutzenberg Saula , Martini Chiara , Parolin Matteo , Avogaro Angelo , Vettor Roberto , Maffei Pietro 
Published: April 2017

Abstract

Context:
Acromegaly is a systemic disease characterized by persistent bone pathology and excess cardiovascular mortality. Despite multiple concomitant risk factors, atherosclerosis does not seem to be accelerated in acromegaly.

Objective:
To compare the levels of circulating myeloid calcifying cells (MCCs), which promote ectopic calcification and inhibit angiogenesis, in individuals with and without acromegaly.

Design:
Cross-sectional case-control study.

Setting:
Tertiary ambulatory referral endocrinology center.

Patients:
44 acromegalic patients (25 active; 19 inactive), 44 control subjects matched by age, sex, risk factors, and medications, and 8 patients cured of acromegaly.

Intervention:
MCCs were measured using flow cytometry based on the expression of osteocalcin (OC) and bone alkaline phosphatase (BAP) on monocytes and circulating CD34+ stem cells.

Main Outcome Measure:
Differences in MCCs between patients and controls.

Results:
OC+BAP+ MCCs were severely reduced in acromegalic compared with control patients (0.17% ± 0.02% vs 1.00% ± 0.24%; P &lt; 0.001), as were the total OC+ and BAP+ monocytic cells. Patients with inactive acromegaly and those cured of acromegaly displayed persistently reduced levels of MCCs. In the controls, but not acromegalic patients, MCCs were increased in the presence of diabetes or cardiovascular disease. A direct correlation was noted between MCCs and parathyroid hormone (r = 0.61; P &lt; 0.0001), supporting a link between bone biology and MCCs.

Conclusions:
In patients with acromegaly, the levels of MCCs are reduced and remain low, even years after a complete cure. This finding might be related to low atherosclerotic calcification and the persistence of bone pathology after acromegaly remission or cure.
Archer fish jumping prey capture: kinematics and hydrodynamics
Authors: Shih Anna M. , Mendelson Leah , Techet Alexandra H. 
Published: April 2017

ABSTRACT
Smallscale archer fish, Toxotes microlepis, are best known for spitting jets of water to capture prey, but also hunt by jumping out of the water to heights of up to 2.5 body lengths. In this study, high-speed imaging and particle image velocimetry were used to characterize the kinematics and hydrodynamics of this jumping behavior. Jumping used a set of kinematics distinct from those of in-water feeding strikes and was segmented into three phases: (1) hovering to sight prey at the surface, (2) rapid upward thrust production and (3) gliding to the prey once out of the water. The number of propulsive tail strokes positively correlated with the height of the bait, as did the peak body velocity observed during a jump. During the gliding stage, the fish traveled ballistically; the kinetic energy when the fish left the water balanced with the change in potential energy from water exit to the maximum jump height. The ballistic estimate of the mechanical energy required to jump was comparable with the estimated mechanical energy requirements of spitting a jet with sufficient momentum to down prey and subsequently pursuing the prey in water. Particle image velocimetry showed that, in addition to the caudal fin, the wakes of the anal, pectoral and dorsal fins were of nontrivial strength, especially at the onset of thrust production. During jump initiation, these fins were used to produce as much vertical acceleration as possible given the spatial constraint of starting directly at the water's surface to aim.
Reduction in activity by noxious chemical stimulation is ameliorated by immersion in analgesic drugs in zebrafish
Authors: Lopez-Luna Javier , Al-Jubouri Qussay , Al-Nuaimy Waleed , Sneddon Lynne U. 
Published: April 2017

ABSTRACT
Research has recently demonstrated that larval zebrafish show similar molecular responses to nociception to those of adults. Our study explored whether unprotected larval zebrafish exhibited altered behaviour after exposure to noxious chemicals and screened a range of analgesic drugs to determine their efficacy to reduce these responses. This approach aimed to validate larval zebrafish as a reliable replacement for adults as well as providing a high-throughput means of analysing behavioural responses. Zebrafish at 5 days post-fertilization were exposed to known noxious stimuli: acetic acid (0.01%, 0.1% and 0.25%) and citric acid (0.1%, 1% and 5%). The behavioural response of each was recorded and analysed using novel tracking software that measures time spent active in 25 larvae at one time. Subsequently, the efficacy of aspirin, lidocaine, morphine and flunixin as analgesics after exposure to 0.1% acetic acid was tested. Larvae exposed to 0.1% and 0.25% acetic acid spent less time active, whereas those exposed to 0.01% acetic acid and 0.1–5% citric acid showed an increase in swimming activity. Administration of 2.5 mg l−1 aspirin, 5 mg l−1 lidocaine and 48 mg l−1 morphine prevented the behavioural changes induced by acetic acid. These results suggest that larvae respond to a noxious challenge in a similar way to adult zebrafish and other vertebrates and that the effect of nociception on activity can be ameliorated by using analgesics. Therefore, adopting larval zebrafish could represent a direct replacement of a protected adult fish with a non-protected form in pain- and nociception-related research.
How High Should We Go? Determining Reservation Values to Negotiate Successfully for Composite Software Services
Authors: Sun Sherry X. , Zhao Jing , Sarkar Sumit 
Published: April 2017

In the paradigm of service-centric computing, new value-added applications can be developed dynamically and flexibly by combining and integrating existing services. While software applications are traditionally specified and implemented as a set of functions uniform to all users, this new paradigm allows the same software service to be delivered with a different price, response time, availability, and other nonfunctional attributes to accommodate different modes of use. These nonfunctional attributes together are referred to as Quality of Service (QoS). When creating a new composite service, negotiation makes it possible for a service provider to offer the service with the QoS properties customized to the needs of a user. Automated negotiation tactics require the specification of reservation values for the QoS attributes. We present a methodology that determines the reservation values a user (or broker) should use for each component service based on the user’s minimum requirements for the composite service. Our methodology maximizes the chance of reaching a successful negotiation outcome while staying within the user’s reservation values for the composite service. We show that the problem of determining the user’s reservation values for component services can be modeled as a multiobjective optimization problem and then transformed to a single-objective optimization problem using a max-min approach. The formulation can incorporate providers' different QoS preferences to increase the chance of negotiation success. We identify problem instances for which closed-form solutions can be found for the reservation values. We show how the method of setting reservation values can be incorporated into a negotiation process that uses extant concession and trade-off tactics. Simulation experiments demonstrate the effectiveness of the proposed approach. If some providers accept offers before the negotiation process deadline, we show that dynamically changing the reservation values for the remaining providers makes the overall negotiation process more likely to succeed. The online appendix is available at https://doi.org/10.1287/isre.2016.0678 .
Pharmacy Dashboard: An Innovative Process for Pharmacy Workload and Productivity
Authors: Kinney Ashley , Bui Quyen , Hodding Jane , Le Jennifer 
Published: April 2017

Background Innovative approaches, including LEAN systems and dashboards, to enhance pharmacy production continue to evolve in a cost and safety conscious health care environment. Furthermore, implementing and evaluating the effectiveness of these novel methods continues to be challenging for pharmacies. Objective To describe a comprehensive, real-time pharmacy dashboard that incorporated LEAN methodologies and evaluate its utilization in an inpatient Central Intravenous Additives Services (CIVAS) pharmacy. Methods Long Beach Memorial Hospital (462 adult beds) and Miller Children's and Women's Hospital of Long Beach (combined 324 beds) are tertiary not-for-profit, community-based hospitals that are served by one CIVAS pharmacy. Metrics to evaluate the effectiveness of CIVAS were developed and implemented on a dashboard in real-time from March 2013 to March 2014. Results The metrics that were designed and implemented to evaluate the effectiveness of CIVAS were quality and value, financial resilience, and the department's people and culture. Using a dashboard that integrated these metrics, the accuracy of manufacturing defect-free products was ≥99.9%, indicating excellent quality and value of CIVAS. The metric for financial resilience demonstrated a cost savings of $78,000 annually within pharmacy by eliminating the outsourcing of products. People and value metrics on the dashboard focused on standard work, with an overall 94.6% compliance to the workflow. Conclusion A unique dashboard that incorporated metrics to monitor 3 important areas was successfully implemented to improve the effectiveness of CIVAS pharmacy. These metrics helped pharmacy to monitor progress in real-time, allowing attainment of production goals and fostering continuous quality improvement through LEAN work.
Clinical Feasibility of Monitoring Enoxaparin Anti-Xa Concentrations: Are We Getting it Right?
Authors: Kufel Wesley D. , Seabury Robert W. , Darko William , Probst Luke A. , Miller Christopher D. 
Published: April 2017

Background Anti-Xa monitoring is utilized to measure the extent of anticoagulation in certain patient populations receiving enoxaparin. It is essential to accurately obtain this pharmacodynamic marker for safe and effective anticoagulation management. Objectives To determine the frequency of correctly drawn anti-Xa concentrations in accordance with predefined institutional criteria and to determine the number of dose adjustments implemented based on incorrectly drawn anti-Xa concentrations. Methods This was a retrospective, single-center, cohort study among adult patients who received treatment doses of enoxaparin with measured anti-Xa concentrations. Patients were excluded if they were pregnant, on hemodialysis, or received prophylactic dosing. Anti-Xa levels were defined as correctly measured if they were drawn 3 to 5 hours after the dose during steady state concentrations. Descriptive statistics were performed and analyzed via SPSS software. Results Overall, 203 patients were reviewed and 59 patients with 74 anti-Xa levels were included. The majority of anti-Xa levels (57/74; 77%) were drawn incorrectly and often resulted in collection of repeat anti-Xa samples. There were 12 documented dose adjustments and approximately 42% (5/12) were based on incorrectly drawn anti-Xa levels. Anti-Xa levels were within target range approximately 45% of the time. Conclusions Enoxaparin anti-Xa concentrations are frequently drawn incorrectly and dose adjustments are often performed based on these unsupported anti-Xa levels. This may present a potential risk to compromise patient safety.