bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using inactivating mutations to provide insight into drug action
Authors: Corbin Laura J , Timpson Nicholas J 
Published: January 2015

AbstractThe role of ezetimibe in lowering plasma cholesterol has been established; however, controversy remains about its clinical benefit. A recent study utilizes naturally occurring genetic variation within the NPC1-like 1 gene (NPC1L1) to demonstrate the potential for pharmacologic inhibition of the protein to reduce the risk of coronary heart disease. This research demonstrates the application of the concept of genocopy to a population-based validation of NPC1L1 as a therapeutic target.
Golimumab in patients with active rheumatoid arthritis after treatment with tumor necrosis factor α inhibitors: findings with up to five years of treatment in the multicenter, randomized, double-blind, placebo-controlled, phase 3 GO-AFTER study
Authors: Smolen Josef S , Kay Jonathan , Doyle Mittie , Landewé Robert , Matteson Eric L , Gaylis Norman , Wollenhaupt Jürgen , Murphy Frederick T , Xu Stephen , Zhou Yiying , Hsia Elizabeth C 
Published: January 2015

Abstract
Introduction
The aim of this study was to assess long-term golimumab therapy in rheumatoid arthritis (RA) patients who discontinued previous tumor necrosis factor-α (TNF)-inhibitor(s).

Methods
Patients enrolled into this multicenter, randomized, double-blind, placebo-controlled study of active RA (≥4 tender, ≥4 swollen joints) received placebo (Group 1) or golimumab 50 mg (Group 2) or 100 mg (Group 3) injections every 4 weeks. Patients in Groups 1 and 2 with inadequate response at week 16 escaped to golimumab 50 and 100 mg, respectively. At week 24, Group 1 patients crossed-over to golimumab 50 mg, Group 2 continued golimumab 50/100 mg per escape status, and Group 3 maintained dosing. During the long-term-extension (LTE), golimumab 50 mg could be increased to 100 mg, and 100 mg could be decreased to 50 mg. Data through 5 years are reported for all patients (safety) and patients using methotrexate (efficacy, intention-to-treat (ITT) analysis with last-observation-carried-forward for missing data and non-responder imputation for unsatisfactory efficacy discontinuations).

Results
In total, 459 of 461 randomized patients received the study agent, 304 of whom were methotrexate-treated and included in efficacy analyses. Through week 256, the proportions of methotrexate-treated patients achieving American-College-of-Rheumatology (ACR) responses were 37.6% to 47.0% for ACR20, 21.4% to 35.0% for ACR50, and 7.8% to 17.0% for ACR70 response across randomized groups. Golimumab safety through week 268 was generally consistent with that at week 24 and week 160 and other anti-TNF agents.

Conclusions
In some patients with active RA discontinuing previous TNF-antagonist therapy, golimumab safety and efficacy, assessed conservatively with ITT analyses, was confirmed through 5 years.

Trial registration
Clinicaltrials.gov NCT00299546. Registered 03 March 2006.
Non-canonical NF-κB signaling in rheumatoid arthritis: Dr Jekyll and Mr Hyde?
Authors: Noort Ae R , Tak Paul P , Tas Sander W 
Published: January 2015

AbstractThe nuclear factor-κB (NF-κB) family of transcription factors is essential for the expression of pro-inflammatory cytokines, but can also induce regulatory pathways. NF-κB can be activated via two distinct pathways: the classical or canonical pathway, and the alternative or non-canonical pathway. It is well established that the canonical NF-κB pathway is essential both in acute inflammatory responses and in chronic inflammatory diseases, including rheumatoid arthritis (RA). Although less extensively studied, the non-canonical NF-κB pathway is not only central in lymphoid organ development and adaptive immune responses, but is also thought to play an important role in the pathogenesis of RA. Importantly, this pathway appears to have cell type-specific functions and, since many different cell types are involved in the pathogenesis of RA, it is difficult to predict the net overall contribution of the non-canonical NF-κB pathway to synovial inflammation. In this review, we describe the current understanding of non-canonical NF-κB signaling in various important cell types in the context of RA and consider the relevance to the pathogenesis of the disease. In addition, we discuss current drugs targeting this pathway, as well as future therapeutic prospects.
Parietal and intravascular innate mechanisms of vascular inflammation
Authors: Ramirez Giuseppe A , Rovere-Querini Patrizia , Sabbadini Maria Grazia , Manfredi Angelo A 
Published: January 2015

AbstractSustained inflammation of the vessel walls occurs in a large number of systemic diseases (ranging from atherosclerosis to systemic vasculitides, thrombotic microangiopathies and connective tissue diseases), which are ultimately characterized by ischemia and end-organ failure. Cellular and humoral innate immunity contribute to a common pathogenic background and comprise several potential targets for therapeutic intervention. Here we discuss some recent advances in the effector and regulatory action of neutrophils and in the outcome of their interaction with circulating platelets. In parallel, we discuss novel insights into the role of humoral innate immunity in vascular inflammation. All these topics are discussed in light of potential clinical and therapeutic implications in the near future.
Proteasome inhibitors as experimental therapeutics of autoimmune diseases
Authors: Verbrugge Sue Ellen , Scheper Rik J , Lems Willem F , de Gruijl Tanja D , Jansen Gerrit 
Published: January 2015

AbstractCurrent treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies. Therapeutic application of PIs in an autoimmune disease setting is much less explored, despite a clear rationale of (immuno) proteasome involvement in (auto)antigen presentation, and PIs harboring the capacity to inhibit the activation of nuclear factor-κB and suppress the release of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6. Here, we review the clinical positioning of (immuno) proteasomes in autoimmune diseases, in particular RA, systemic lupus erythematosus, Sjögren’s syndrome and sclerodema, and elaborate on (pre)clinical data related to the impact of BTZ and next generation PIs on immune effector cells (T cells, B cells, dendritic cells, macrophages, osteoclasts) implicated in their pathophysiology. Finally, factors influencing long-term efficacy of PIs, their current (pre)clinical status and future perspectives as anti-inflammatory and anti-arthritic agents are discussed.
Patterns of health care utilization related to initiation of amitriptyline, duloxetine, gabapentin, or pregabalin in fibromyalgia
Authors: Kim Seoyoung C , Landon Joan E , Lee Yvonne C 
Published: January 2015

Abstract
Introduction
Several pharmacologic treatments are available for fibromyalgia, but little is known about the comparative effectiveness of these treatments on health care utilization.

Methods
Using US commercial insurance claims data (covering 2007 to 2009), we conducted a cohort study to examine the comparative effectiveness of amitriptyline, duloxetine, gabapentin, and pregabalin on health care utilization in patients with fibromyalgia. We measured patients’ medication adherence using the proportion of days covered (PDC) and estimated multivariable rate ratios (RRs) for outpatient visits, prescriptions, hospitalization, and emergency department (ED) visits in propensity score (PS)–matched cohorts.

Results
Cohorts of 8,269 amitriptyline, 9,941 duloxetine, and 18,613 gabapentin initiators were compared with their PS-matched pregabalin initiators. During the baseline 180-day period, patients had, on average, seven to nine physician visits, including six to eight specialist visits, and received eight prescription drugs. The mean PDC up to 180 days varied from 38.6% to 67.7%. The number of outpatient visits, prescriptions, and hospitalizations decreased slightly after initiating one of the study drugs, but the number of ED visits increased after treatment initiation. Compared to pregabalin, duloxetine was associated with decreased outpatient visits (RR, 0.94; 95% confidence interval (CI), 0.88 to 1.00), prescriptions (RR, 0.94; 95% CI, 0.90 to 0.98), hospitalizations (RR, 0.75; 95% CI, 0.68 to 0.83), and ED visits (RR, 0.85; 95% CI, 0.79 to 0.91). Little difference in health care utilization rates was noted among amitriptyline and gabapentin initiators compared to those who were started on pregabalin.

Conclusions
Fibromyalgia patients had high health care utilization before and after initiation of amitriptyline, duloxetine, gabapentin, or pregabalin. Medication adherence was suboptimal. Overall, fibromyalgia treatment had little impact on reducing health care utilization, but duloxetine initiators had less health care utilization than those started on pregabalin.
Model for Individualized Prediction of Breast Cancer Risk After a Benign Breast Biopsy
Authors: Pankratz V. Shane , Degnim Amy C. , Frank Ryan D. , Frost Marlene H. , Visscher Daniel W. , Vierkant Robert A. , Hieken Tina J. , Ghosh Karthik , Tarabishy Yaman , Vachon Celine M. , Radisky Derek C. , Hartmann Lynn C. 
Published: January 2015

Purpose Optimal early detection and prevention for breast cancer depend on accurate identification of women at increased risk. We present a risk prediction model that incorporates histologic features of biopsy tissues from women with benign breast disease (BBD) and compare its performance to the Breast Cancer Risk Assessment Tool (BCRAT). Methods We estimated the age-specific incidence of breast cancer and death from the Mayo BBD cohort and then combined these estimates with a relative risk model derived from 377 patient cases with breast cancer and 734 matched controls sampled from the Mayo BBD cohort to develop the BBD–to–breast cancer (BBD-BC) risk assessment tool. We validated the model using an independent set of 378 patient cases with breast cancer and 728 matched controls from the Mayo BBD cohort and compared the risk predictions from our model with those from the BCRAT. Results The BBD-BC model predicts the probability of breast cancer in women with BBD using tissue-based and other risk factors. The concordance statistic from the BBD-BC model was 0.665 in the model development series and 0.629 in the validation series; these values were higher than those from the BCRAT (0.567 and 0.472, respectively). The BCRAT significantly underpredicted breast cancer risk after benign biopsy (P = .004), whereas the BBD-BC predictions were appropriately calibrated to observed cancers (P = .247). Conclusion We developed a model using both demographic and histologic features to predict breast cancer risk in women with BBD. Our model more accurately classifies a woman's breast cancer risk after a benign biopsy than the BCRAT.
Phase III, Randomized, Double-Blind, Multicenter Trial Comparing Orteronel (TAK-700) Plus Prednisone With Placebo Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer That Has Progressed During or After Docetaxel-Based Therapy: ELM-PC 5
Authors: Fizazi Karim , Jones Robert , Oudard Stephane , Efstathiou Eleni , Saad Fred , de Wit Ronald , De Bono Johann , Cruz Felipe Melo , Fountzilas George , Ulys Albertas , Carcano Flavio , Agarwal Neeraj , Agus David , Bellmunt Joaquim , Petrylak Daniel P. , Lee Shih-Yuan , Webb Iain J. , Tejura Bindu , Borgstein Niels , Dreicer Robert 
Published: January 2015

Purpose Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. Patients and Methods In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory–Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. Results The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). Conclusion Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.
Prospective Approach to Breast Cancer Risk Prediction in African American Women: The Black Women's Health Study Model
Authors: Boggs Deborah A. , Rosenberg Lynn , Adams-Campbell Lucile L. , Palmer Julie R. 
Published: January 2015

Purpose Breast cancer risk prediction models have underestimated risk for African American women, contributing to lower recruitment rates in prevention trials. A model previously developed for African American women was found to underestimate risk in the Black Women's Health Study (BWHS). Methods We developed a breast cancer risk model for African American women using relative risks derived from 10 years of follow-up of BWHS participants age 30 to 69 years at baseline. Using the subsequent 5 years of follow-up data, we evaluated calibration as the ratio of expected to observed number of breast cancers and assessed discriminatory accuracy using the concordance statistic. Results The BWHS model included family history, previous biopsy, body mass index at age 18 years, age at menarche, age at first birth, oral contraceptive use, bilateral oophorectomy, estrogen plus progestin use, and height. There was good agreement between predicted and observed number of breast cancers overall (expected-to-observed ratio, 0.96; 95% CI, 0.88 to 1.05) and in most risk factor categories. Discriminatory accuracy was higher for women younger than age 50 years (area under the curve [AUC], 0.62; 95% CI, 0.58 to 0.65) than for women age ≥ 50 years (AUC, 0.56; 95% CI, 0.53 to 0.59). Using a 5-year predicted risk of 1.66% or greater as a cut point, 2.8% of women younger than 50 years old and 32.2% of women ≥ 50 years old were classified as being at elevated risk of invasive breast cancer. Conclusion The BWHS model was well calibrated overall, and the predictive ability was best for younger women. The proportion of women predicted to meet the 1.66% cut point commonly used to determine eligibility for breast cancer prevention trials was greatly increased relative to previous models.
Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non–Small-Cell Lung Cancer and Brain Metastases
Authors: Costa Daniel B. , Shaw Alice T. , Ou Sai-Hong I. , Solomon Benjamin J. , Riely Gregory J. , Ahn Myung-Ju , Zhou Caicun , Shreeve S. Martin , Selaru Paulina , Polli Anna , Schnell Patrick , Wilner Keith D. , Wiltshire Robin , Camidge D. Ross , Crinò Lucio 
Published: January 2015

Purpose Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non–small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied. Patients and Methods Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1). Results At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases. Conclusion Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.
Circulating Fibroblast Growth Factor 21 Levels Predict Progressive Kidney Disease in Subjects With Type 2 Diabetes and Normoalbuminuria
Authors: Lee C. H. , Hui E. Y. L. , Woo Y. C. , Yeung C. Y. , Chow W. S. , Yuen M. M. A. , Fong C. H. Y. , Xu A. , Lam K. S. L. 
Published: January 2015

Background:
Elevated fibroblast growth factor 21 (FGF21) levels have been suggested, from cross-sectional studies, as an indicator of subclinical diabetic nephropathy. We investigated whether serum FGF21 was predictive of the development of diabetic nephropathy.

Method:
Baseline serum FGF21 levels were measured in 1136 Chinese type 2 diabetic subjects recruited from the Hong Kong West Diabetes Registry. The role of serum FGF21 in predicting decline in estimated glomerular filtration rate (eGFR) over a median follow-up of 4 years was analyzed using Cox regression analysis.

Results:
At baseline, serum FGF21 levels increased progressively with eGFR category (P for trend &lt;.001). Among 1071 subjects with baseline eGFR ≥ 30 mL/min/1.73 m2, serum FGF21 levels were significantly higher in those with eGFR decline during follow-up (n = 171) than those without decline (n = 900) (P &lt; .001). In multivariable Cox regression analysis, baseline serum FGF21 was independently associated with eGFR decline (hazard ratio, 1.21; 95% confidence interval [CI], 1.01–1.43; P = .036), even after adjustment for baseline eGFR. In a subgroup of 559 subjects with baseline eGFR ≥60 mL/min/1.73 m2 and normoalbuminuria, serum FGF21 level remained an independent predictor of eGFR decline (hazard ratio, 1.36; 95% CI, 1.06–1.76; P = .016). Integrated discrimination improvement (IDI) suggested that the inclusion of baseline serum FGF21 significantly improved the prediction of eGFR decline (IDI, 1%; 95% CI, 0.1–3.0; P = .013) in this subgroup, but not in the initial cohort involving all subjects.

Conclusions:
Elevated serum FGF21 levels may be a useful biomarker for predicting kidney disease progression, especially in the early stages of diabetic nephropathy.
MEN1 Mutations in Hürthle Cell (Oncocytic) Thyroid Carcinoma
Authors: Kasaian Katayoon , Chindris Ana-Maria , Wiseman Sam M. , Mungall Karen L. , Zeng Thomas , Tse Kane , Schein Jacqueline E. , Rivera Michael , Necela Brian M. , Kachergus Jennifer M. , Casler John D. , Mungall Andrew J. , Moore Richard A. , Marra Marco A. , Copland John A. , Thompson E. Aubrey , Smallridge Robert C. , Jones Steven J. M. 
Published: January 2015

Context and Objective:Oncocytic thyroid carcinoma, also known as Hürthle cell thyroid carcinoma, accounts for only a small percentage of all thyroid cancers. However, this malignancy often presents at an advanced stage and poses unique challenges to patients and clinicians. Surgical resection of the tumor accompanied in some cases by radioactive iodine treatment, radiation, and chemotherapy are the established modes of therapy. Knowledge of the perturbed oncogenic pathways can provide better understanding of the mechanism of disease and thus opportunities for more effective clinical management.Design and Patients:Initially, two oncocytic thyroid carcinomas and their matched normal tissues were profiled using whole genome sequencing. Subsequently, 72 oncocytic thyroid carcinomas, one cell line, and five Hürthle cell adenomas were examined by targeted sequencing for the presence of mutations in the multiple endocrine neoplasia I (MEN1) gene.Results:Here we report the identification of MEN1 loss-of-function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma. Whole genome sequence data also revealed large regions of copy number variation encompassing nearly the entire genomes of these tumors.Conclusion:Menin, a ubiquitously expressed nuclear protein, is a well-characterized tumor suppressor whose loss is the cause of MEN1 syndrome. Menin is involved in several major cellular pathways such as regulation of transcription, control of cell cycle, apoptosis, and DNA damage repair pathways. Mutations of this gene in a subset of Hürthle cell tumors point to a potential role for this protein and its associated pathways in thyroid tumorigenesis.
Repeated Auctions with Budgets in Ad Exchanges: Approximations and Design
Authors: Balseiro Santiago R. , Besbes Omar , Weintraub Gabriel Y. 
Published: January 2015

Ad exchanges are emerging Internet markets where advertisers may purchase display ad placements, in real time and based on specific viewer information, directly from publishers via a simple auction mechanism. Advertisers join these markets with a prespecified budget and participate in multiple second-price auctions over the length of a campaign. This paper studies the competitive landscape that arises in ad exchanges and the implications for publishers’ decisions. The presence of budgets introduces dynamic interactions among advertisers that need to be taken into account when attempting to characterize the bidding landscape or the impact of changes in the auction design. To this end, we introduce the notion of a fluid mean-field equilibrium (FMFE) that is behaviorally appealing and computationally tractable, and in some important cases, it yields a closed-form characterization. We establish that an FMFE approximates well the rational behavior of advertisers in these markets. We then show how this framework may be used to provide sharp prescriptions for key auction design decisions that publishers face in these markets. In particular, we show that ignoring budgets, a common practice in this literature, can result in significant profit losses for the publisher when setting the reserve price. This paper was accepted by Dimitris Bertsimas, optimization.