bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib
Authors: Acquaviva Jaime , Smith Donald L. , Jimenez John-Paul , Zhang Chaohua , Sequeira Manuel , He Suqin , Sang Jim , Bates Richard C. , Proia David A. 
Published: January 2014

Abstract
Activating BRAF kinase mutations serve as oncogenic drivers in over half of all melanomas, a feature that has been exploited in the development of new molecularly targeted approaches to treat this disease. Selective BRAFV600E inhibitors, such as vemurafenib, typically induce initial, profound tumor regressions within this group of patients; however, durable responses have been hampered by the emergence of drug resistance. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90, in melanoma lines harboring the BRAFV600E mutation. Ganetespib exposure resulted in the loss of mutant BRAF expression and depletion of mitogen-activated protein kinase and AKT signaling, resulting in greater in vitro potency and antitumor efficacy compared with targeted BRAF and MAP–ERK kinase (MEK) inhibitors. Dual targeting of Hsp90 and BRAFV600E provided combinatorial benefit in vemurafenib-sensitive melanoma cells in vitro and in vivo. Importantly, ganetespib overcame mechanisms of intrinsic and acquired resistance to vemurafenib, the latter of which was characterized by reactivation of extracellular signal-regulated kinase (ERK) signaling. Continued suppression of BRAFV600E by vemurafenib potentiated sensitivity to MEK inhibitors after acquired resistance had been established. Ganetespib treatment reduced, but not abolished, elevations in steady-state ERK activity. Profiling studies revealed that the addition of a MEK inhibitor could completely abrogate ERK reactivation in the resistant phenotype, with ganetespib displaying superior combinatorial activity over vemurafenib. Moreover, ganetespib plus the MEK inhibitor TAK-733 induced tumor regressions in vemurafenib-resistant xenografts. Overall these data highlight the potential of ganetespib as a single-agent or combination treatment in BRAFV600E-driven melanoma, particularly as a strategy to overcome acquired resistance to selective BRAF inhibitors. Mol Cancer Ther; 13(2); 353–63. ©2014 AACR.
Comparison of Probabilistic Statistical Forecast and Trend Adjustment Methods for North American Seasonal Temperatures
Authors: Wilks Daniel S. 
Published: January 2014

AbstractThe three multivariate statistical methods of canonical correlation analysis, maximum covariance analysis, and redundancy analysis are compared with respect to their probabilistic accuracy for seasonal forecasts of gridded North American temperatures. Derivation of forecast error covariance matrices for the methods allows a probabilistic formulation for the forecasts, assuming Gaussian predictive distributions. The three methods perform similarly with respect to probabilistic forecast accuracy as reflected by the ranked probability score, although maximum covariance analysis may be preferred because of its slightly better forecast skill and calibration. In each case the forecast accuracy for North American seasonal temperatures compares favorably to results from previously published studies. In addition, two alternative approaches are compared for alleviating the cold biases in the forecasts that derive from ongoing climate warming. Adding lagging 15-yr means to forecast temperature anomalies improved forecast accuracy and reduced the cold bias in the forecasts, relative to using the more conventional lagging 30-yr mean.
Asymmetries between Wavenumber Spectra of Along- and Across-Track Velocity from Tandem Mission Altimetry
Authors: Wortham Cimarron , Callies Jörn , Scharffenberg Martin G. 
Published: January 2014

Abstract
Satellite altimetry has proven to be one of the most useful oceanographic datasets, providing a continuous, near-global record of surface geostrophic currents, among other uses. One limitation of observations from a single satellite is the difficulty of estimating the full geostrophic velocity field. The 3-yr Jason-1–Ocean Topography Experiment (TOPEX)/Poseidon tandem mission, with two satellites flying parallel tracks, promised to overcome this limitation. However, the wide track separation severely limits the tandem mission’s resolution and reduces the observed velocity variance. In this paper, the effective filter imposed by the track separation is discussed and two important consequences for any application of the tandem mission velocities are explained. First, while across-track velocity is simply low-pass filtered, along-track velocity is attenuated also at wavelengths much longer than the track separation. Second, velocity wavenumber spectral slopes are artificially steepened by a factor of k−2 at wavelengths smaller than the track separation. Knowledge of the effective filter has several applications, including reconstruction of the full velocity spectrum from the heavily filtered observations. Here, the hypothesis that the tandem mission flow field is horizontally nondivergent and isotropic is tested. The effective filter is also used to predict the fraction of the eddy kinetic energy (EKE) that is captured for a given track separation. The EKE captured falls off rapidly for track separations greater than about 20 km.
Continuous Electroencephalogram in Comatose Postcardiac Arrest Syndrome Patients Treated With Therapeutic Hypothermia
Authors: Sadaka Farid , Doerr Danielle , Hindia Jiggar , Lee K. Philip , Logan William 
Published: January 2014

Purpose: Therapeutic Hypothermia (TH) is the only therapeutic intervention proven to significantly improve survival and neurologic outcome in comatose postcardiac arrest patients and is now considered standard of care. When we discuss prognostication with regard to comatose survivors postcardiac arrest, we should look for tools that are both reliable and accurate and that achieve a false-positive rate (FPR) equal to or very closely approaching zero. Methods: We retrospectively reviewed data that were prospectively collected on all cardiac arrest patients admitted to our ICU. Continuous electroencephalogram (cEEG) monitoring was performed as part of our protocol for therapeutic hypothermia in comatose postcardiac arrest patients. The primary outcome measure was the best score on hospital discharge on the 5-point Glasgow-Pittsburgh cerebral performance category (CPC) scores. Results: A total of 58 patients were included in this study. Twenty five (43%) patients had a good neurologic outcome (CPC score of 1-2). Three (5.2%) patients had nonconvulsive status epilepticus, all of whom had poor outcome (CPC = 5). Seventeen (29%) patients had burst suppression (BS); all had poor outcome. Both nonconvuslsive seizures (NCS) and BS had a specificity of 100% (95% confidence interval [CI], 84%-100%), positive predictive values of 100% (95% CI, 31%-100%), and 100% (95% CI, 77%-100%), respectively. Both NCS and BS had FPRs of zero (95% CI, 0.0-0.69, and 0.0-0.23, respectively). Conclusions: In comatose postcardiac arrest patients treated with hypothermia, EEG during the maintenance and rewarming phase of hypothermia can contribute to prediction of neurologic outcome. Pending large multicenter prospective studies evaluating the role of cEEG in prognostication, our study adds to the existing evidence that cEEG can play a potential role in prediction of outcome in postcardiac arrest patients treated with hypothermia.
Methotrexate in systemic lupus erythematosus: a systematic review of its efficacy
Authors: Sakthiswary R , Suresh E 
Published: January 2014

Objective The objective of this review is to evaluate the evidence for efficacy of methotrexate (MTX) in systemic lupus erythematosus (SLE). Methods A comprehensive, computerized search was performed in MEDLINE (PubMed), EMBASE and the Cochrane Controlled Trials registry to screen for studies that examined the efficacy of MTX in adult SLE patients. The Jadad scoring system was used to assess study quality, and data were pooled using the random effects model. Results Of the 53 articles that were identified, 44 were excluded. Nine studies (including three randomized controlled and six observational) were eligible for inclusion. All of the included studies predominantly involved patients with arthritis or mucocutaneous features. There was significant reduction of the SLE Disease Activity Index (SLEDAI) among MTX-treated patients when compared with controls ( p = 0.001, odds ratio (OR) 0.444, 95% confidence interval (CI) 0.279 to 0.707). There was also significant reduction in the average dose of corticosteroids among MTX-treated patients when compared with controls ( p = 0.001, OR 0.335, 95% CI 0.202 to 0.558). The effect of MTX on laboratory and serological markers, including erythrocyte sedimentation rate, anti-dsDNA and complement levels (C3 and C4), could not be determined because of the limited numbers of controlled trials. Conclusion The use of MTX is associated with significant reductions in SLEDAI and the average dose of corticosteroids in adult patients with SLE.
Novel association of rectal evacuation disorder and rumination syndrome: Diagnosis, comorbidities, and treatment
Authors: Vijayvargiya Priya , Iturrino Johanna , Camilleri Michael , Shin Andrea , Vazquez-Roque Maria , Katzka David A , Snuggerud Jill R , Seime Richard J 
Published: January 2014

BackgroundPatients with disorders of gastrointestinal function may undergo unnecessary treatment if misdiagnosed as motility disorders.ObjectiveTo report on clinical features, medical, surgical, and psychiatric comorbidities, and prior treatments of a patient cohort diagnosed concurrently with nonpsychogenic rumination syndrome and pelvic floor dysfunction (also termed rectal evacuation disorder).MethodsFrom a consecutive series (1994–2013) of 438 outpatients with rectal evacuation disorders in the practice of a single gastroenterologist at a tertiary care centre, 57 adolescents or adults were diagnosed with concomitant rumination syndrome. All underwent formal psychological assessment or completed validated questionnaires.ResultsAll 57 patients (95% female) fulfilled Rome III criteria for rumination syndrome; rectal evacuation disorder was confirmed by testing of anal sphincter pressures and rectal balloon evacuation. Prior to diagnosis, most patients underwent multiple medical and surgical treatments (gastrostomy, gastric fundoplication, other gastric surgery, ileostomy, colectomy) for their symptoms. Psychological comorbidity was identified in 93% of patients. Patients were managed predominantly with psychological and behavioural approaches: diaphragmatic breathing for rumination and biofeedback retraining for pelvic floor dysfunction.ConclusionsAwareness of concomitant rectal evacuation disorder and rumination syndrome and prompt identification of psychological comorbidity are keys to instituting behavioural and psychological methods to avoid unnecessary treatment.
Prevalence and factors associated with low bone mineral density in Saudi women: a community based survey
Authors: AlQuaiz AlJohara M , Kazi Ambreen , Tayel Salwa , Shaikh Shaffi Ahamed , Al-Sharif Abdullah , Othman Saleh , Habib Fawzia , Fouda Mona , Sulaimani Riad 
Published: January 2014

Abstract

Background
Low bone mineral density (BMD) is a public health issue in Saudi Arabia. This study measured the prevalence and factors associated with low BMD in Saudi women in Riyadh, Saudi Arabia.

Methods
A cross sectional study using two stage cluster sampling technique was conducted in Riyadh, 2009. Thirty clusters, each comprising of 300 houses were randomly chosen and from each cluster 38–40 households were selected to identify 1150 women of >40 years. Women were invited to primary health care center for filling of self-administered questionnaire (n = 1069) comprising of sociodemographic, health, diet and physical activity variables. 1008 women underwent screening for low BMD using the quantitative ultrasound technique. 535 (53%) women with positive screening test were referred to King Khalid Hospital for Dual X-ray Energy absorptiometry (DXA).

Results
362 women underwent DXA and 212 (39.6%) were screened low BMD either at lumbar spine or femur neck. Mean age of women was 55.26(±8.84) years. Multivariate logistic analysis found; being aged 61 to 70 years (OR 2.75, 95% CI: 1.32-1.48), no literacy (OR 2.97, 95% CI:1.44 - 6.12) or primary education (OR 4.12, 95% CI:2.05-8.29), history of fractures (OR 2.20, 95% CI:1.03- 4.69) and not drinking laban(diluted yogurt) (OR 2.81, 95% CI:1.47- 5.37) significantly associated with low BMD.

Conclusions
Women with low level of education, who do not drink laban and had history of fractures were at high risk of low BMD.
Initial and Cyclic Recruitment of Ovarian Follicles*
Authors: McGee Elizabeth A. , Hsueh Aaron J. W. 
Published: January 2014

AbstractMammalian ovaries consist of follicles as basic functional units. The total number of ovarian follicles is determined early in life, and the depletion of this pool leads to reproductive senescence. Each follicle develops to either ovulate or, more likely, to undergo degeneration. The dynamics of ovarian follicle development have interested endocrinologists and developmental biologists for many years. With the advent of assisted reproductive techniques in humans, the possibility of regulating follicle development in vivo and in vitro has gained clinical relevance. In this review, we focus upon key branching points during the development of ovarian follicles as well as factors involved in determining the eventual destiny of individual follicles. We discuss inconsistencies in the literature regarding the definitions of follicle recruitment and selection and propose to name the two major steps of follicle development as initial and cyclic recruitment, respectively. Because some of these disparities have arisen due to differences in the animal systems studied, we also compare the development of the ovarian follicles of both humans and rats. We also review the status of knowledge of several puzzling clinical issues that may provide important clues toward unlocking the mechanisms of follicle development.
Endocrine Dysfunction in Prader-Willi Syndrome: A Review with Special Reference to GH
Authors: Burman Pia , Ritzén E. Martin , Lindgren Ann Christin 
Published: January 2014

AbstractPrader-Willi syndrome is a genetic disorder occurring in 1 in 10,000–16,000 live-born infants. In the general population, approximately 60 people in every 1,000,000 are affected. The condition is characterized by short stature, low lean body mass, muscular hypotonia, mental retardation, behavioral abnormalities, dysmorphic features, and excessive appetite with progressive obesity. Furthermore, morbidity and mortality are high, probably as a result of gross obesity. Most patients have reduced GH secretory capacity and hypogonadotropic hypogonadism, suggesting hypothalamic-pituitary dysfunction. Replacement of GH and/or sex hormones may therefore be beneficial in Prader-Willi syndrome, and several clinical trials have now evaluated GH replacement therapy in affected children. Results of GH treatment have been encouraging: improved growth, increased lean body mass, and reduced fat mass. There was also some evidence of improvements in respiratory function and physical activity. The long-term benefits of GH treatment are, however, still to be established. Similarly, the role of sex hormone replacement therapy needs to be clarified as few data exist on its efficacy and potential benefits. In summary, Prader-Willi syndrome is a disabling condition associated with GH deficiency and hypogonadism. More active treatment of these endocrine disorders is likely to benefit affected individuals.
Hypoglycemia from IGF2 Overexpression Associated with Activation of Fetal Promoters and Loss of Imprinting in a Metastatic Hemangiopericytoma
Authors: Lawson Elizabeth A. , Zhang Xun , Crocker Jonathan T. , Wang Wei-Lien , Klibanski Anne 
Published: January 2014

ABSTRACT

Context
The mechanism of IGF2 overexpression in non-islet-cell tumor hypoglycemia is not understood.

Objective
We investigated the imprinting control and promoter usage for IGF2 expression to identify a mechanism for increased IGF-II production in non-islet-cell tumor hypoglycemia.

Patient and Methods
A patient with metastatic hemangiopericytoma was studied. Tissue from the original hemangiopericytoma, metastatic tumor, and uninvolved liver was analyzed for IGF-II immunohistochemistry. IGF2, a paternally imprinted gene, shares a control region with maternally imprinted H19, a putative tumor suppressor. IGF-II and H19 mRNA expression was compared in metastatic tumor and uninvolved liver by quantitative RT-PCR. Imprinting of IGF2/H19 genes and IGF2 promoter usage in metastatic tumor was investigated by RT-PCR and sequence analysis, and the methylation pattern in the IGF2/H19 imprinting control region was analyzed.

Results
IGF-II protein expression was increased in metastatic tumor vs. uninvolved liver and original tumor. In the metastatic tumor, IGF-II mRNA was increased 60-fold, but H19 mRNA was comparable to uninvolved liver; loss of imprinting of IGF2, but not H19, was identified; no major change in methylation of the IGF2/H19 imprinting control regions was observed; and transcripts from four different IGF2 promoters were detected, compared to two in uninvolved liver.

Conclusions
IGF-2 overexpression, newly acquired in the metastatic tumor, was associated with loss of IGF2 gene imprinting and different promoter usage. The imprinting control mechanism governing the IGF2/H19 locus was intact, as evidenced by normal levels of H19, maintenance of H19 imprinting, and no major change in methylation of the imprinting control regions.
Physiological Thyroid Hormone Levels Regulate Numerous Skeletal Muscle Transcripts
Authors: Visser W. Edward , Heemstra Karen A. , Swagemakers Sigrid M. A. , Özgür Zeliha , Corssmit Eleonora P. , Burggraaf Jacobus , van Ijcken Wilfred F. J. , van der Spek Peter J. , Smit Johannes W. A. , Visser Theo J. 
Published: January 2014

ABSTRACT

Context
Skeletal muscle is an important target tissue for thyroid hormone (TH). It is currently unknown which genes are regulated by physiological TH levels.

Objective
We examined the effects of l-thyroxine on human skeletal muscle transcriptome.

Design
Microarray analysis of transcript levels was performed using skeletal muscle biopsies from patients under euthyroid and hypothyroid conditions.

Setting
The study was conducted in a university hospital laboratory.

Patients
We studied skeletal muscle obtained from 10 thyroidectomized patients with differentiated thyroid carcinoma on and after 4 wk off l-thyroxine replacement.

Mean Outcome Measures
Gene expression changes were measured using microarrays. Results were analyzed using dedicated statistical methods.

Results
We detected 607 differentially expressed genes on l-thyroxine treatment, of which approximately 60% were positively and approximately 40% were negatively regulated. Representative genes were validated by quantitative PCR. Genes involved in energy and fuel metabolism were overrepresented among the up-regulated genes, of which a large number were newly associated with thyroid state. l-thyroxine therapy induced a large down-regulation of the primary transcripts of the noncoding microRNA pair miR-206/miR-133b.

Conclusion
We demonstrated that physiological levels of TH regulate a myriad of genes in human skeletal muscle. The identification of novel putatively TH-responsive genes may provide the molecular basis of clinical effects in subjects with different TH status. The observation that TH regulates microRNAs reveals a new layer of complexity by which TH influences cellular processes.
Subcutaneous Injection of Kisspeptin-54 Acutely Stimulates Gonadotropin Secretion in Women with Hypothalamic Amenorrhea, But Chronic Administration Causes Tachyphylaxis
Authors: Jayasena Channa N. , Nijher Gurjinder K. , Chaudhri Owais B. , Murphy Kevin G. , Ranger Amita , Lim Adrian , Patel Daksha , Mehta Amrish , Todd Catriona , Ramachandran Radha , Salem Victoria , Stamp Gordon W. , Donaldson Mandy , Ghatei Mohammad A. , Bloom Stephen R. , Dhillo Waljit S. 
Published: January 2014

ABSTRACT

Background
Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown.

Aim
The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA.

Methods
We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed.

Results
On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 ± 3.5 IU/liter; FSH, 9.1 ± 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 ± 2.2 IU/liter, P &lt; 0.05; FSH, 0.5 ± 0.5 IU/liter, P &lt; 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed.

Conclusion
Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.
Activation of the Aryl-Hydrocarbon Receptor Inhibits Invasive and Metastatic Features of Human Breast Cancer Cells and Promotes Breast Cancer Cell Differentiation
Authors: Hall Julie M. , Barhoover Melissa A. , Kazmin Dmitri , McDonnell Donald P. , Greenlee William F. , Thomas Russell S. 
Published: January 2014

ABSTRACT
The current statistics associated with breast cancer continue to show a relatively high recurrence rate together with a poor survival for aggressive metastatic disease. These findings reflect, in part, the pharmaceutical intractability of processes involved in the metastatic process and highlight the need to identify additional drug targets for the treatment of late-stage disease. In the current study, we report that ligand activation of the aryl-hydrocarbon receptor (AhR) inhibits multiple aspects of the metastatic process in a panel of breast cancer cell lines that represent the major breast cancer subtypes. Specifically, it was observed that treatment with exogenous AhR agonists significantly inhibited cell invasiveness and motility in the Boyden chamber assay and inhibited colony formation in soft agar regardless of estrogen receptor (ER), progesterone receptor, or human epidermal growth factor receptor 2 status. Knockdown of the AhR using small interfering RNA duplexes demonstrated that the inhibition of invasiveness was receptor dependent and that endogenous receptor activity was protective in each cell type examined. The inhibition of invasiveness and anchorage-independent growth correlated with the ability of exogenous AhR agonists to promote differentiation. Finally, exogenous AhR agonists were able to promote differentiation in a putative mammary cancer stem cell line. Cumulatively, these results suggest that the AhR plays an important role in mammary epithelial differentiation and, as such, represent a promising therapeutic target for a range of phenotypically distinct human breast cancers.