bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reparameterization of PAM50 Expression Identifies Novel Breast Tumor Dimensions and Leads to Discovery of a Genome-Wide Significant Breast Cancer Locus at 12q15
Authors: Madsen Michael J. , Knight Stacey , Sweeney Carol , Factor Rachel , Salama Mohamed , Stijleman Inge J. , Rajamanickam Venkatesh , Welm Bryan E. , Arunachalam Sasi , Jones Brandt , Rachamadugu Rakesh , Rowe Kerry , Cessna Melissa H. , Thomas Alun , Kushi Lawrence H. , Caan Bette J. , Bernard Philip S. , Camp Nicola J. 
Published: April 2018

Abstract
Background: Breast tumor subtyping has failed to provide impact in susceptibility genetics. The PAM50 assay categorizes breast tumors into: Luminal A, Luminal B, HER2-enriched and Basal-like. However, tumors are often more complex than simple categorization can describe. The identification of heritable tumor characteristics has potential to decrease heterogeneity and increase power for gene finding.
Methods: We used 911 sporadic breast tumors with PAM50 expression data to derive tumor dimensions using principal components (PC). Dimensions in 238 tumors from high-risk pedigrees were compared with the sporadic tumors. Proof-of-concept gene mapping, informed by tumor dimension, was performed using Shared Genomic Segment (SGS) analysis.
Results: Five dimensions (PC1-5) explained the majority of the PAM50 expression variance: three captured intrinsic subtype, two were novel (PC3, PC5). All five replicated in 745 TCGA tumors. Both novel dimensions were significantly enriched in the high-risk pedigrees (intrinsic subtypes were not). SGS gene-mapping in a pedigree identified a 0.5 Mb genome-wide significant region at 12q15. This region segregated through 32 meioses to 8 breast cancer cases with extreme PC3 tumors (P = 2.6 × 10−8).
Conclusions: PC analysis of PAM50 gene expression revealed multiple independent, quantitative measures of tumor diversity. These tumor dimensions show evidence for heritability and potential as powerful traits for gene mapping.
Impact: Our study suggests a new approach to describe tumor expression diversity, provides new avenues for germline studies, and proposes a new breast cancer locus. Similar reparameterization of expression patterns may inform other studies attempting to model the effects of tumor heterogeneity. Cancer Epidemiol Biomarkers Prev; 27(6); 644–52. ©2018 AACR.
Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer
Authors: Yoda Satoshi , Lin Jessica J. , Lawrence Michael S. , Burke Benjamin J. , Friboulet Luc , Langenbucher Adam , Dardaei Leila , Prutisto-Chang Kylie , Dagogo-Jack Ibiayi , Timofeevski Sergei , Hubbeling Harper , Gainor Justin F. , Ferris Lorin A. , Riley Amanda K. , Kattermann Krystina E. , Timonina Daria , Heist Rebecca S. , Iafrate A. John , Benes Cyril H. , Lennerz Jochen K. , Mino-Kenudson Mari , Engelman Jeffrey A. , Johnson Ted W. , Hata Aaron N. , Shaw Alice T. 
Published: April 2018

Abstract
The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4–ALK. Under comparable conditions, N-ethyl-N-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4–ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.
Significance: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. Cancer Discov; 8(6); 714–29. ©2018 AACR.
This article is highlighted in the In This Issue feature, p. 663
Lymphatic Vasculature Requires Estrogen Receptor-α Signaling to Protect From Lymphedema
Authors: Morfoisse Florent , Tatin Florence , Chaput Benoit , Therville Nicole , Vaysse Charlotte , Métivier Raphael , Malloizel-Delaunay Julie , Pujol Francoise , Godet Anne-Claire , De Toni Fabienne , Boudou Frederic , Grenier Katia , Dubuc David , Lacazette Eric , Prats Anne-Catherine , Guillermet-Guibert Julie , Lenfant Francoise , Garmy-Susini Barbara 
Published: April 2018

Objective—
Estrogens exert beneficial effect on the blood vascular system. However, their role on the lymphatic system has been poorly investigated. We studied the protective effect of the 17β estradiol—the most potent endogenous estrogen—in lymphedema—a lymphatic dysfunction, which results in a massive fluid and fat accumulation in the limb.

Approach and Results—

Screening of DNA motifs able to mobilize ERs (estrogen receptors) and quantitative real-time polymerase chain reaction analysis revealed that estradiol promotes transcriptional activation of lymphangiogenesis-related gene expression including VEGF (vascular endothelial growth factor)-D, VEGFR (VEGF receptor)-3, lyve-1, and HASs (hyaluronan synthases). Using an original model of secondary lymphedema, we observed a protective effect of estradiol on lymphedema by reducing dermal backflow—a representative feature of the pathology. Blocking ERα by tamoxifen—the selective estrogen modulator—led to a remodeling of the lymphatic network associated with a strong lymphatic leakage. Moreover, the protection of lymphedema by estradiol treatment was abrogated by the endothelial deletion of the receptor ERα in Tie2-Cre; ERα
lox/lox
mice, which exhibit dilated lymphatic vessels. This remodeling correlated with a decrease in lymphangiogenic gene expression. In vitro, blocking ERα by tamoxifen in lymphatic endothelial cells decreased cell–cell junctions, inhibited migration and sprouting, and resulted in an inhibition of Erk but not of Akt phosphorylation.

Conclusions—
Estradiol protection from developing lymphedema is mediated by an activation of its receptor ERα and is antagonized by tamoxifen. These findings reveal a new facet of the estrogen influence in the management of the lymphatic system and provide more evidence that secondary lymphedema is worsened by hormone therapy.
Cardiovascular Genetic Risk Testing for Targeting Statin Therapy in the Primary Prevention of Atherosclerotic Cardiovascular Disease
Authors: Jarmul Jamie , Pletcher Mark J. , Hassmiller Lich Kristen , Wheeler Stephanie B. , Weinberger Morris , Avery Christy L. , Jonas Daniel E. , Earnshaw Stephanie , Pignone Michael 
Published: April 2018

Background:
It is unclear whether testing for novel risk factors, such as a cardiovascular genetic risk score (cGRS), improves clinical decision making or health outcomes when used for targeting statin initiation in the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Our objective was to estimate the cost-effectiveness of cGRS testing to inform clinical decision making about statin initiation in individuals with low-to-intermediate (2.5%–7.5%) 10-year predicted risk of ASCVD.

Methods and Results:
We evaluated the cost-effectiveness of testing for a 27-single-nucleotide polymorphism cGRS comparing 4 test/treat strategies: treat all, treat none, test/treat if cGRS is high, and test/treat if cGRS is intermediate or high. We tested a set of clinical scenarios of men and women, aged 45 to 65 years, with 10-year ASCVD risks between 2.5% and 7.5%. Our primary outcome measure was cost per quality-adjusted life-year gained. Under base case assumptions for statin disutility and cost, the preferred strategy is to treat all patients with ASCVD risk >2.5% without cGRS testing. For certain clinical scenarios, such as a 57-year-old man with a 10-year ASCVD risk of 7.5%, cGRS testing can be cost-effective under a limited set of assumptions; for example, when statins cost $15 per month and statin disutility is 0.013 (ie, willing to trade 3 months of life in perfect health to avoid 20 years of statin therapy), the preferred strategy (using a willingness-to-pay threshold of $50 000 per quality-adjusted life-year gained) is to test and treat if cGRS is intermediate or high. Overall, the results were not sensitive to assumptions about statin efficacy and harms.

Conclusions:
Testing for a 27-single-nucleotide polymorphism cGRS is generally not a cost-effective approach for targeting statin therapy in the primary prevention of ASCVD for low- to intermediate-risk patients.
Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles
Authors: Zuo Hui , Svingen Gard F. T. , Tell Grethe S. , Ueland Per M. , Vollset Stein E. , Pedersen Eva R. , Ulvik Arve , Meyer Klaus , Nordrehaug Jan E. , Nilsen Dennis W. T. , Bønaa Kaare H. , Nygård Ottar 
Published: April 2018

Background
Although choline metabolism has been associated with atherosclerotic heart disease, less research attention has been paid to the associations of choline and its oxidative metabolite betaine with cardiac arrhythmias.

Methods and Results

We evaluated associations of plasma concentrations and dietary intakes of choline and betaine with long‐term atrial fibrillation (
AF
) risk in a community‐based cohort, HUSK ([the Hordaland Health Study] n=6949), and validated the findings in 2 patient cohorts: the Western Norway Coronary Angiography Cohort (n=4164) and the NORVIT (Norwegian B‐Vitamin) Trial (n=3733). Information on
AF
was obtained from the
CVDNOR
(Cardiovascular Disease in Norway) project. In
HUSK
,
WECAC
(Western Norway Coronary Angiography Cohort), and
NORVIT
, 552, 411, and 663
AF
cases were identified during a median follow‐up time of 10.9, 7.3, and, 8.7 years, respectively. Plasma concentrations of choline and betaine were significantly positively associated with later
AF
risk after multivariable adjustments in
HUSK
. Such associations were independently replicated in the 2 external prospective patient cohorts. The pooled hazard ratio was 1.13 (95% confidence interval 1.08‐1.19,
P
<0.001) and 1.16 (95% confidence interval 1.10‐1.22,
P
<0.001) per
SD
increment for log‐transformed choline and betaine, respectively. Moreover, dietary intake of choline was marginally associated with
AF
risk (pooled hazard ratio 1.29, 95% confidence interval 1.01‐1.66, fifth versus first quintile), whereas no significant association was observed between dietary betaine and
AF
risk.

Conclusions

Our findings indicate that plasma concentrations as well as dietary intake of choline, but not betaine, are associated with subsequent risk of
AF
, suggesting a potential role of choline metabolism in the pathogenesis of
AF
.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov.Unique
identifier:
NCT
00671346.
Christus unicus ille episcopus universalis
Authors: de Boer Erik A. 
Published: April 2018

Abstract
In their critique of the hierarchy in the Roman Catholic Church most reformers in the sixteenth century did not argue for retaining the office of bishop. In the English Reformation, led by the king, the bishopric was reformed, and in Hungary, too, the office of bishop survived. Did reformers like John Calvin fundamentally reject this office, or did they primarily attack its abuse? Investigation of the early work of Calvin shows a focus on the meaning of the biblical term ‘overseer’ and on preaching as the primary function of the episcopacy. While the title of bishop is reserved for the one head of the church, the office of the preacher is brought to a higher level. As moderator of the Company of Pastors in Geneva, Calvin would have a standing in the city comparable to the ousted bishop.
Application of NICE guideline NG12 to the initial assessment of patients with lower gastrointestinal symptoms: not FIT for purpose?
Authors: Quyn Aaron J , Steele Robert JC , Digby Jayne , Strachan Judith A , Mowat Craig , McDonald Paula J , Carey Francis A , Godber Ian M , Younes Hakim B , Fraser Callum G 
Published: April 2018

Background The National Institute for Health and Care Excellence (NICE) published NG12 in 2015. The referral criteria for suspected colorectal cancer (CRC) caused controversy, because tests for occult blood in faeces were recommended. Faecal immunochemical tests for haemoglobin (FIT), which estimate faecal haemoglobin concentrations (f-Hb), might more than fulfil the intentions. Our aim was to compare the utility of f-Hb as the initial investigation with the NICE NG12 symptom-based guidelines. Methods Data from three studies were included. Patients had sex, age, symptoms, f-Hb and colonoscopy and histology data recorded. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of f-Hb and NG12 were calculated for all significant colorectal disease (SCD: CRC, higher risk adenoma and inflammatory bowel disease). Overall diagnostic accuracy was also estimated by the area under the receiver operating characteristic curve (AUC). Results A total of 1514 patients were included. At a cut-off of ≥10  µg Hb/g faeces, the sensitivity of f-Hb for CRC was 93.3% (95% confidence interval (CI): 80.7–98.3) with NPV of 99.7% (95%CI: 99.2–99.9). The sensitivity and NPV for SCD were 63.2% (95%CI: 56.6–69.4) and 96.0% (95%CI: 91.4–94.4), respectively. The NG12 sensitivity and NPV for SCD were 58.4% (95%CI: 51.8–64.8) and 87.6% (95%CI: 85.0–89.8), respectively. The AUC for CRC was 0.85 (95% CI: 0.87–0.90) for f-Hb versus 0.65 (95%CI: 0.58–0.73) for NG12 ( P < 0.005). For SCD, the AUC was 0.73 (95%CI: 0.69–0.77) for f-Hb versus 0.56 (95%CI: 0.52–0.60) for NG12 ( P < 0.0005). Conclusion f-Hb provides a good rule-out test for SCD and has significantly higher overall diagnostic accuracy than NG12.
Effects of mirror therapy on walking ability, balance and lower limb motor recovery after stroke: a systematic review and meta-analysis of randomized controlled trials
Authors: Li Yi , Wei Qingchuan , Gou Wei , He Chengqi 
Published: April 2018

Objective: To investigate the effects of mirror therapy on walking ability, balance and lower limb motor recovery in patients with stroke. Method: MEDLINE, EMBASE, Web of Science, CENTRAL, PEDro Database, CNKI, VIP, Wan Fang, ClinicalTrials.gov, Current controlled trials and Open Grey were searched for randomized controlled trials that investigated the effects of mirror therapy on lower limb function through January 2018. The primary outcomes included were walking speed, mobility and balance function. Secondary outcomes included lower limb motor recovery, spasticity and range of motion. Quality assessments were performed with the PEDro scale. Results: A total of 13 studies ( n = 572) met the inclusion criteria. A meta-analysis demonstrated a significant effect of mirror therapy on walking speed (mean difference (MD) 0.1 m/s, 95% confidence interval (CI): 0.08 to 0.12, P < 0.00001), balance function (standard mean difference (SMD) 0.66, 95% CI: 0.43 to 0.88, P < 0.00001), lower limb motor recovery (SMD 0.83, 95% CI: 0.62 to 1.05, P < 0.00001) and passive range of motion of ankle dorsiflexion (MD 2.07°, 95% CI: 082 to 3.32, P = 0.001), without improving mobility (SMD 0.43, 95% CI: −0.12 to 0.98, P = 0.12) or spasticity of ankle muscles (MD −0.14, 95% CI: −0.43 to 0.15, P = 0.35). Conclusion: The systematic review demonstrates that the use of mirror therapy in addition to some form of rehabilitation appears promising for some areas of lower limb function, but there is not enough evidence yet to suggest when and how to approach this therapy.
Postoperative New-Onset Pseudoparalysis: A Retrospective Analysis of 430 Consecutive Arthroscopic Repairs for Large to Massive Rotator Cuff Tears
Authors: Jeong Hyeon Jang , Rhee Sung Min , Oh Joo Han 
Published: April 2018

Background: The authors have sometimes encountered postoperative new-onset pseudoparalysis (PONP) after arthroscopic repair for large to massive rotator cuff tear (ARCR). As there are insufficient data regarding PONP, the authors aimed to determine whether such a condition is characterized by obvious risk factors, as well as to assess the conditions under which it can be reversed. Purpose: To evaluate the predictors of PONP development after ARCR and its reversal and to integrate these predictors into a scoring system that can be applied in clinical practice. Study Design: Case-control study; Level of evidence, 3. Methods: The authors retrospectively analyzed 430 consecutive ARCRs performed between March 2010 and May 2016. Patients were stratified according to the occurrence of PONP. To determine the risk factors of PONP, the authors compared the PONP and control groups (patients who did not experience PONP) in terms of demographic, clinical, and operative characteristics. Results were expressed in terms of odds ratios (ORs). Results: The incidence of PONP was 6.0% (26 of 430). Predictors of PONP included torn subscapularis (OR, 7.875; 95% CI, 1.780-34.956; P = .007), ≥30-mm retraction of the torn supraspinatus (OR, 4.657; 95% CI, 1.537-14.203; P = .007), age ≥65 years (OR, 3.865; 95% CI, 1.465-10.040; P = .006), and preoperative stiffness (OR, 2.954; 95% CI, 1.212-7.159; P = .017). The reversal rate of PONP was 65.4% (17 of 26), and the mean time to PONP reversal was 10 months. The occurrence and reversal of PONP were not related to retear. Fatty infiltration of the supraspinatus lower than Goutallier grade 3 was the sole predictor of reversal (OR, 22.000; 95% CI, 1.857-260.648; P = .014). Conclusion: Although the incidence of PONP after ARCR was low (6.0%), the risk of PONP was higher in patients with a torn subscapularis, larger supraspinatus tear size, older age, and preoperative stiffness. The mean time from PONP onset to reversal was 10 months, and PONP reversal was affected solely by fatty infiltration of the supraspinatus. Therefore, surgeons should consider the risk for PONP and attempt to identify high-risk patients before rotator cuff repair.
Using Two-Eyed Seeing to Explore Interagency Collaboration
Authors: Whiting Cheryl , Cavers Stephanie , Bassendowski Sandra , Petrucka Pammla 
Published: April 2018

Background Health-care environments influence service delivery; approaches need to be more wholistic and culturally competent requiring effective interagency collaboration to bridge traditional Indigenous and mainstream health services. Despite considerable research on collaboration, the concept remains misunderstood, at worst, and formative, at best. Within the nexus of these two diverse health services, there is limited information on how collaborations could be created and sustained effectively. Purpose To explore the perspectives/experiences of collaboration of select Saskatchewan health professionals practicing across these diverse services to understand the concept from their perspectives. Methods This qualitative study explored collaboration through observation and interviews to elicit perspectives (two-eyed seeing) of health professionals working within the context of a traditional–mainstream health services partnership. Results Individual- and system-level factors and accountabilities are needed for successful cross-cultural collaboration and can be enabled by embedding the virtues of Indigenous and values of mainstream health services along with building and maintaining relationships, valuing difference, creating supportive environments and wholistic approaches, having the right people at the table, and making a change for impactful outcomes. Conclusion Findings support the need for implementing contextually relevant collaborative practice models for productive, wholistic health services. Two-eyed seeing provides the ability to capture and catalyze the tremendous value and strengths of both worlds, potentiating complementary aspects to meet the needs of clients and communities.
Autogenous Bone Graft Versus Bovine Bone Graft in Association With Platelet-Rich Plasma for the Reconstruction of Alveolar Clefts: A Pilot Study
Authors: Bezerra Bruno Torres , Pinho John Nadson Andrade , Figueiredo Fabrício Eneas Diniz , Brandão José Renato Moraes Carvalho Barreto , Ayres Lucas Celestino Guerzet , da Silva Luiz Carlos Ferreira 
Published: April 2018

Objective: To compare the outcomes of 2 different bone graft materials: autogenous bone grafts from mandibular symphysis and bovine bone grafts associated with platelet-rich plasma (PRP). Methods: Twenty individuals met the inclusion criteria and accepted to participate in the study. Group A patients underwent alveolar bone grafting using autologous bone and group B patients using a bovine bone graft associated with PRP. Cone beam computed tomography scans were taken and reconstructed 3-dimensionally for all patients preoperatively and 1 year postoperatively. Results: A significant reduction was detected for area and volume within group A and group B. Between groups, no significant difference was found for area or volume. Conclusions: Bovine grafts associated with PRP are a good option for the reconstruction of alveolar clefts and provide good results such as autologous bone grafts.