bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction of graphene family materials with Listeria monocytogenes and Salmonella enterica
Authors: Kurantowicz Natalia , Sawosz Ewa , Jaworski Sławomir , Kutwin Marta , Strojny Barbara , Wierzbicki Mateusz , Szeliga Jacek , Hotowy Anna , Lipińska Ludwika , Koziński Rafał , Jagiełło Joanna , Chwalibog André
Published: January 2015

Graphene family materials have unique properties, which make them valuable for a range of applications. The antibacterial properties of graphene have been reported; however, findings have been contradictory. This study reports on the antimicrobial proprieties of three different graphene materials (pristine graphene (pG), graphene oxide (GO), and reduced graphene oxide (rGO)) against the food-borne bacterial pathogens Listeria monocytogenes and Salmonella enterica. A high concentration (250 μg/mL) of all the analyzed graphenes completely inhibited the growth of both pathogens, despite their difference in bacterial cell wall structure. At a lower concentration (25 μg/mL), similar effects were only observed with GO, as growth inhibition decreased with pG and rGO at the lower concentration. Interaction of the nanoparticles with the pathogenic bacteria was found to differ depending on the form of graphene. Microscopic imaging demonstrated that bacteria were arranged at the edges of pG and rGO, while with GO, they adhered to the nanoparticle surface. GO was found to have the highest antibacterial activity.
Intraoperative renal near-infrared spectroscopy indicates developing acute kidney injury in infants undergoing cardiac surgery with cardiopulmonary bypass: a case–control study
Authors: Ruf Bettina , Bonelli Vittorio , Balling Gunter , Hörer Jürgen , Nagdyman Nicole , Braun Siegmund Lorenz , Ewert Peter , Reiter Karl
Published: January 2015

Introduction

Acute kidney injury (AKI) is a frequent complication after cardiac surgery with cardiopulmonary bypass in infants. Renal near-infrared spectroscopy (NIRS) is used to evaluate regional oximetry in a non-invasive continuous real-time fashion, and reflects tissue perfusion. The aim of this study was to evaluate the relationship between renal oximetry and development of AKI in the operative and post-operative setting in infants undergoing cardiopulmonary bypass surgery.

Methods

In this prospective study, we enrolled 59 infants undergoing cardiopulmonary bypass surgery for congenital heart disease for univentricular (n = 26) or biventricular (n = 33) repair. Renal NIRS was continuously measured intraoperatively and for at least 24 hours postoperatively and analysed for the intraoperative and first 12 hours, first 24 hours and first 48 hours postoperatively. The renal oximetry values were correlated with the paediatric risk, injury, failure, loss, end (pRIFLE) classification for AKI, renal biomarkers and the postoperative course.

Results

Twenty-eight (48%) infants developed AKI based on pRIFLE classification. Already during intraoperative renal oximetry and further in the first 12 hours, 24 hours and 48 hours postoperatively, significantly lower renal oximetry values in AKI patients compared with patients with normal renal function were recorded (P < 0.05). Of the 28 patients who developed AKI, 3 (11%) needed renal replacement therapy and 2 (7%) died. In the non-AKI group, no deaths occurred. Infants with decreased renal oximetry values developed significantly higher lactate levels 24 hours after surgery. Cystatin C was a late parameter of AKI, and neutrophil gelatinase-associated lipocalin values were not correlated with AKI occurrence.

Conclusion

Our results suggest that prolonged low renal oximetry values during cardiac surgery correlate with the development of AKI and may be superior to conventional biochemical markers. Renal NIRS might be a promising non-invasive tool of multimodal monitoring of kidney function and developing AKI in infants undergoing cardiac surgery with cardiopulmonary bypass.
Bayesian models for syndrome- and gene-specific probabilities of novel variant pathogenicity
Authors: Ruklisa Dace , Ware James S , Walsh Roddy , Balding David J , Cook Stuart A
Published: January 2015

Background

With the advent of affordable and comprehensive sequencing technologies, access to molecular genetics for clinical diagnostics and research applications is increasing. However, variant interpretation remains challenging, and tools that close the gap between data generation and data interpretation are urgently required. Here we present a transferable approach to help address the limitations in variant annotation.

Methods

We develop a network of Bayesian logistic regression models that integrate multiple lines of evidence to evaluate the probability that a rare variant is the cause of an individual’s disease. We present models for genes causing inherited cardiac conditions, though the framework is transferable to other genes and syndromes.

Results

Our models report a probability of pathogenicity, rather than a categorisation into pathogenic or benign, which captures the inherent uncertainty of the prediction. We find that gene- and syndrome-specific models outperform genome-wide approaches, and that the integration of multiple lines of evidence performs better than individual predictors. The models are adaptable to incorporate new lines of evidence, and results can be combined with familial segregation data in a transparent and quantitative manner to further enhance predictions.

Though the probability scale is continuous, and innately interpretable, performance summaries based on thresholds are useful for comparisons. Using a threshold probability of pathogenicity of 0.9, we obtain a positive predictive value of 0.999 and sensitivity of 0.76 for the classification of variants known to cause long QT syndrome over the three most important genes, which represents sufficient accuracy to inform clinical decision-making. A web tool APPRAISE [http://www.cardiodb.org/APPRAISE] provides access to these models and predictions.

Conclusions

Our Bayesian framework provides a transparent, flexible and robust framework for the analysis and interpretation of rare genetic variants. Models tailored to specific genes outperform genome-wide approaches, and can be sufficiently accurate to inform clinical decision-making.
Higher gene expression variability in the more aggressive subtype of chronic lymphocytic leukemia
Authors: Ecker Simone , Pancaldi Vera , Rico Daniel , Valencia Alfonso
Published: January 2015

Background

Chronic lymphocytic leukemia (CLL) presents two subtypes which have drastically different clinical outcomes, IgVH mutated (M-CLL) and IgVH unmutated (U-CLL). So far, these two subtypes are not associated to clear differences in gene expression profiles. Interestingly, recent results have highlighted important roles for heterogeneity, both at the genetic and at the epigenetic level in CLL progression.

Methods

We analyzed gene expression data of two large cohorts of CLL patients and quantified expression variability across individuals to investigate differences between the two subtypes using different measures and statistical tests. Functional significance was explored by pathway enrichment and network analyses. Furthermore, we implemented a random forest approach based on expression variability to classify patients into disease subtypes.

Results

We found that U-CLL, the more aggressive type of the disease, shows significantly increased variability of gene expression across patients and that, overall, genes that show higher variability in the aggressive subtype are related to cell cycle, development and inter-cellular communication. These functions indicate a potential relation between gene expression variability and the faster progression of this CLL subtype. Finally, a classifier based on gene expression variability was able to correctly predict the disease subtype of CLL patients.

Conclusions

There are strong relations between gene expression variability and disease subtype linking significantly increased expression variability to phenotypes such as aggressiveness and resistance to therapy in CLL.
Ploidy-Seq: inferring mutational chronology by sequencing polyploid tumor subpopulations
Authors: Malhotra Ankit , Wang Yong , Waters Jill , Chen Ken , Meric-Bernstam Funda , Hall Ira M , Navin Nicholas E
Published: January 2015

Human cancers are frequently polyploid, containing multiple aneuploid subpopulations that differ in total DNA content. In this study we exploit this property to reconstruct evolutionary histories, by assuming that mutational complexity increases with time. We developed an experimental method called Ploidy-Seq that uses flow-sorting to isolate and enrich subpopulations with different ploidy prior to next-generation genome sequencing. We applied Ploidy-Seq to a patient with a triple-negative (ER-/PR-/HER2-) ductal carcinoma and performed whole-genome sequencing to trace the evolution of point mutations, indels, copy number aberrations, and structural variants in three clonal subpopulations during tumor growth. Our data show that few mutations (8% to 22%) were shared between all three subpopulations, and that the most aggressive clones comprised a minority of the tumor mass. We expect that Ploidy-Seq will have broad applications for delineating clonal diversity and investigating genome evolution in many human cancers.
Using inactivating mutations to provide insight into drug action
Authors: Corbin Laura J , Timpson Nicholas J
Published: January 2015

The 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

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

The 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

Sustained 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

Current 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

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.
Programmed pyrolysis (Rock-Eval) data and shale paleoenvironmental analyses: A review
Authors: Hart B. S. , Steen A. S.
Published: January 2015

We use public-domain data from programmed pyrolysis, collected using Rock-Eval or similar apparatuses, to illustrate the utility and challenges of using this method for paleoenvironmental analyses. These data are widely available and commonly collected and analyzed for a variety of purposes in the petroleum industry in the fields of paleo-oceanography and paleoclimate research and elsewhere. We show how factors such as sample condition, mineralogy, organic content, and others can influence the results, leading to potential interpretational complications. We also evaluate ways that the data can be plotted to maximize their utility for interpretation purposes. Four types of organic matter are commonly identified based on programmed pyrolysis results. Type I organic matter has a high (e.g., [Formula: see text]) hydrogen index (HI), is oil-prone and is commonly assumed to represent lacustrine depositional settings. Type II organic matter is also oil-prone (i.e., having an HI between 350 and 700) but is commonly assumed to represent marine organic matter. Type III organic matter has a lower HI ([Formula: see text]), will tend to generate gas, and is commonly assumed to represent terrigenous (e.g., land plants) organic matter. Type IV organic matter has very low HI values and is associated with nongenerative (i.e., inert) organic matter. We show that these simple associations between organic matter type and paleoenvironment were not always valid. Preburial degradation of the organic matter and mixing of different organic matter types are two possibilities that can lead to erroneous paleoenvironmental interpretations. Furthermore, the programmed pyrolysis results characterize the present composition of the organic matter which, especially at high thermal maturities (e.g., dry gas window), can be significantly different to that of the original organic matter. Other types of advanced geochemical and sedimentologic analyses should be integrated with the programmed pyrolysis results during their interpretation.
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 <.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 < .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.
Characterizing alpha helical properties of Ebola viral proteins as potential targets for inhibition of alpha-helix mediated protein-protein interactions
Authors: Chakraborty Sandeep , Rao Basuthkar J. , Asgeirsson Bjarni , Dandekar Abhaya M.
Published: January 2015

Ebola, considered till recently as a rare and endemic disease, has dramatically transformed into a potentially global humanitarian crisis. The genome of Ebola, a member of the Filoviridae family, encodes seven proteins. Based on the recently implemented software (PAGAL) for analyzing the hydrophobicity and amphipathicity properties of alpha helices (AH) in proteins, we characterize the helices in the Ebola proteome. We demonstrate that AHs with characteristically unique features are involved in critical interactions with the host proteins. For example, the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain has an AH with a large hydrophobic moment. The neutralizing antibody (KZ52) derived from a human survivor of the 1995 Kikwit outbreak recognizes a protein epitope on this AH, emphasizing the critical nature of this secondary structure in the virulence of the Ebola virus. Our method ensures a comprehensive list of such `hotspots'. These helices probably are or can be the target of molecules designed to inhibit AH mediated protein-protein interactions. Further, by comparing the AHs in proteins of the related Marburg viruses, we are able to elicit subtle changes in the proteins that might render them ineffective to previously successful drugs. Such differences are difficult to identify by a simple sequence or structural alignment. Thus, analyzing AHs in the small Ebola proteome can aid rational design aimed at countering the `largest Ebola epidemic, affecting multiple countries in West Africa' (http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html).
Capsaicin from chili (Capsicum spp.) inhibits vascular smooth muscle cell proliferation
Authors: Liu Rongxia , Heiss Elke H. , Guo Dean , Dirsch Verena M. , Atanasov Atanas G.
Published: January 2015

Accelerated vascular smooth muscle cell (VSMC) proliferation is implied in cardiovascular disease and significantly contributes to vessel lumen reduction following surgical interventions such as percutaneous transluminal coronary angioplasty or bypass surgery. Therefore, identification and characterization of compounds and mechanisms able to counteract VSMC proliferation is of potential therapeutic relevance. This work reveals the anti-proliferative effect of the natural product capsaicin from Capsicum spp. by quantification of metabolic activity and DNA synthesis in activated VSMC. The observed in vitro activity profile of capsaicin warrants further research on its mechanism of action and potential for therapeutic application.
The curious case of the spinning neuronal mass
Authors: Mitra Shiladitya
Published: January 2015

Rotating cells have been reported in past. Rotation of cells and cell clusters has been associated with migration and development. This observation reports for the first time a rotating cluster of cells isolated from the hippocampi of neonatal mouse pups. The speed of rotation in these clusters is immensely high. Further analysis of such rotating neurons can shed valuable clues on the origin of such cells, their electro-mechanical properties and their role in the development of the brain.
Network Effects in Alternative Fuel Adoption: Empirical Analysis of the Market for Ethanol
Authors: Shriver Scott K.
Published: January 2015

This paper investigates the importance of network effects in the demand for ethanol-compatible vehicles and the supply of ethanol fuel. An indirect network effect, or positive feedback loop, arises in this context due to spatially-dependent complementarities in the availability of ethanol fuel and the installed base of ethanol-compatible vehicles. Marketers and social planners are interested in whether these effects exist, and if so, how policy might accelerate adoption of the ethanol fuel standard within a targeted population. To measure these feedback effects, I develop an econometric framework that considers the simultaneous determination of ethanol-compatible vehicle demand and ethanol fuel supply in local markets. The demand-side model considers the automobile purchase decisions of consumers and fleet operators; the supply-side model considers the ethanol market entry decisions of competing fuel retailers. The framework extends extant market entry models by endogenizing the market size shifting fuel retailer profits. I estimate the model using zip code panel data from four states over a nine-year period. The model estimates provide evidence of a network effect. Under typical market conditions, entry of an additional ethanol fuel retailer leads to a 6% increase in the probability of ethanol-compatible vehicle purchase. The entry model estimates imply that the first entrant requires a local installed base of approximately 300 ethanol-compatible vehicles to be profitable. As an application, I demonstrate that subsidizing fuel retailers to offer ethanol in selective geographic markets can be an effective policy to indirectly increase ethanol-compatible vehicle sales.
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.
Financial analysis of revision knee surgery based on NHS tariffs and hospital costs
Authors: Kallala R. F. , Vanhegan I. S. , Ibrahim M. S. , Sarmah S. , Haddad F. S.
Published: January 2015

Revision total knee arthroplasty (TKA) is a complex procedure which carries both a greater risk for patients and greater cost for the treating hospital than does a primary TKA. As well as the increased cost of peri-operative investigations, blood transfusions, surgical instrumentation, implants and operating time, there is a well-documented increased length of stay which accounts for most of the actual costs associated with surgery.

We compared revision surgery for infection with revision for other causes (pain, instability, aseptic loosening and fracture). Complete clinical, demographic and economic data were obtained for 168 consecutive revision TKAs performed at a tertiary referral centre between 2005 and 2012.

Revision surgery for infection was associated with a mean length of stay more than double that of aseptic cases (21.5 vs 9.5 days, p < 0.0001). The mean cost of a revision for infection was more than three times that of an aseptic revision (£30 011 (sd 4514) vs £9655 (sd 599.7), p < 0.0001).

Current NHS tariffs do not fully reimburse the increased costs of providing a revision knee surgery service. Moreover, especially as greater costs are incurred for infected cases. These losses may adversely affect the provision of revision surgery in the NHS.

Cite this article: Bone Joint J 2015;97-B:197–201.
Social deprivation as a risk factor for fractures in childhood
Authors: Ramaesh R. , Clement N. D. , Rennie L. , Court-Brown C. , Gaston M. S.
Published: January 2015

Paediatric fractures are common and can cause significant morbidity. Socioeconomic deprivation is associated with an increased incidence of fractures in both adults and children, but little is known about the epidemiology of paediatric fractures. In this study we investigated the effect of social deprivation on the epidemiology of paediatric fractures.

We compiled a prospective database of all fractures in children aged < 16 years presenting to the study centre. Demographics, type of fracture, mode of injury and postcode were recorded. Socioeconomic status quintiles were assigned for each child using the Scottish Index for Multiple Deprivation (SIMD).

We found a correlation between increasing deprivation and the incidence of fractures (r = 1.00, p < 0.001). In the most deprived group the incidence was 2420/100 000/yr, which diminished to 1775/100 000/yr in the least deprived group.

The most deprived children were more likely to suffer a fracture as a result of a fall (odds ratio (OR) = 1.5, p < 0.0001), blunt trauma (OR = 1.5, p = 0.026) or a road traffic accident (OR = 2.7, p < 0.0001) than the least deprived.

These findings have important implications for public health and preventative measures.

Cite this article: Bone Joint J 2015;97-B:240–5.
The effect of orientation of the acetabular component on outcome following total hip arthroplasty with small diameter hard-on-soft bearings
Authors: Grammatopoulos G. , Thomas G. E. R. , Pandit H. , Beard D. J. , Gill H. S. , Murray D. W.
Published: January 2015

We assessed the orientation of the acetabular component in 1070 primary total hip arthroplasties with hard-on-soft, small diameter bearings, aiming to determine the size and site of the target zone that optimises outcome. Outcome measures included complications, dislocations, revisions and ΔOHS (the difference between the Oxford Hip Scores pre-operatively and five years post-operatively). A wide scatter of orientation was observed (2sd 15°). Placing the component within Lewinnek’s zone was not associated withimproved outcome. Of the different zone sizes tested (± 5°, ± 10° and ± 15°), only ± 15° was associated with a decreased rate of dislocation. The dislocation rate with acetabular components inside an inclination/anteversion zone of 40°/15° ± 15° was four times lower than those outside. The only zone size associated with statistically significant and clinically important improvement in OHS was ± 5°. The best outcomes (ΔOHS > 26) were achieved with a 45°/25° ± 5° zone.

This study demonstrated that with traditional technology surgeons can only reliably achieve a target zone of ±15°. As the optimal zone to diminish the risk of dislocation is also ±15°, surgeons should be able to achieve this. This is the first study to demonstrate that optimal orientation of the acetabular component improves the functional outcome. However, the target zone is small (± 5°) and cannot, with current technology, be consistently achieved.

Cite this article: Bone Joint J 2015;97-B:164–72.
Cemented versus cementless Oxford unicompartmental knee arthroplasty using radiostereometric analysis
Authors: Kendrick B. J. L. , Kaptein B. L. , Valstar E. R. , Gill H. S. , Jackson W. F. M. , Dodd C. A. F. , Price A. J. , Murray D. W.
Published: January 2015

The most common reasons for revision of unicompartmental knee arthroplasty (UKA) are loosening and pain. Cementless components may reduce the revision rate. The aim of this study was to compare the fixation and clinical outcome of cementless and cemented Oxford UKAs.

A total of 43 patients were randomised to receive either a cemented or a cementless Oxford UKA and were followed for two years with radiostereometric analysis (RSA), radiographs aligned with the bone–implant interfaces and clinical scores.

The femoral components migrated significantly during the first year (mean 0.2 mm) but not during the second. There was no significant difference in the extent of migration between cemented and cementless femoral components in either the first or the second year. In the first year the cementless tibial components subsided significantly more than the cemented components (mean 0.28 mm (sd 0.17) vs. 0.09 mm (sd 0.19 mm)). In the second year, although there was a small amount of subsidence (mean 0.05 mm) there was no significant difference (p = 0.92) between cemented and cementless tibial components. There were no femoral radiolucencies. Tibial radiolucencies were narrow (< 1 mm) and were significantly (p = 0.02) less common with cementless (6 of 21) than cemented (13 of 21) components at two years. There were no complete radiolucencies with cementless components, whereas five of 21 (24%) cemented components had complete radiolucencies. The clinical scores at two years were not significantly different (p = 0.20).

As second-year migration is predictive of subsequent loosening, and as radiolucency is suggestive of reduced implant–bone contact, these data suggest that fixation of the cementless components is at least as good as, if not better than, that of cemented devices.

Cite this article: Bone Joint J 2015; 97-B:185–91.