bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying the preferable rheumatoid arthritis subgroups for intervention with the anti-RANKL antibody denosumab to reduce progression of joint destruction
Authors: Tanaka Yoshiya , Soen Satoshi , Ishiguro Naoki , Yamanaka Hisashi , Yoneda Toshiyuki , Tanaka Sakae , Ohira Takeshi , Nitta Takaya , Okubo Naoki , Genant Harry , van der Heijde Desirée , Takeuchi Tsutomu 
Published: July 2020

ObjectivesTo clarify which rheumatoid arthritis (RA) patients benefit most from the anti-receptor activator of nuclear factor-κB ligand antibody denosumab to reduce the progression of joint destruction.MethodsWe pooled patient data from the 12-month, double-blind, placebo-controlled DRIVE (phase II) and DESIRABLE (phase III) studies. In DRIVE, concomitant treatment was limited to methotrexate, salazosulfapyridine and bucillamine. In DESIRABLE, patients could receive any disease-modifying antirheumatic drug. RA patients were randomised to denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or placebo. Efficacy was assessed by van der Heijde-modified total Sharp score (mTSS), bone erosion score (ES) and joint space narrowing score (JSNS). Change in mTSS was assessed in subgroups stratified by risk factors for radiographic damage if the interaction factor was significant.ResultsThe pooled analysis included 909 patients. Denosumab reduced worsening of mTSS (mean (SD)) at 12 months in the Q6M (0.88 (3.30), p=0.0024) and Q3M (0.66 (2.16), p=0.0002) groups versus placebo (1.50 (3.73)). This reduction in mTSS progression was due to the change in ES (Q6M, 0.44 (1.89), p=0.0006; Q3M, 0.20 (0.86), p<0.0001) versus placebo (0.98 (2.54)); no effect was observed on JSNS. Anti-cyclic citrullinated peptide (CCP) antibodies, glucocorticoid use and baseline ES showed a significant interaction. Denosumab was particularly effective in patients who were anti-CCP antibody positive (p<0.05). Changes in mTSS versus placebo were observed in all denosumab dose groups, regardless of glucocorticoid use and baseline ES.ConclusionsDenosumab broadly reduced the progression of joint destruction in RA patients with risk factors for radiographic damage such as especially anti-CCP antibody positivity.
Forage type and transportation stress effects on gut microbial counts and meat quality in goats
Authors: Mechineni A. , Kommuru D.S. , Terrill T.H. , Kouakou B. , Lee J.H. , Gujja S. , Burke J.M. , Kannan G. 
Published: July 2020

An experiment was conducted to determine the effects of feeding highly condensed tannin legume (sericea lespedeza, SL; Lespedeza cuneata) forage on gastrointestinal tract microbial counts and meat quality in goats. Intact male Spanish kids were kept in 0.40 ha paddocks of SL, bermudagrass (BG; Cynodon dactylon; control), or a combination of SL + BG (n = 10 goats per treatment group) for 8 wk. All goats were supplemented with a commercial feed pellet at 0.45 kg·head−1·d−1 for the first 4 wk and 0.23 kg·head−1·d−1 for the final 4 wk of the trial. At the end of the experiment, half the goats from each paddock were subjected to 3 h transportation stress, then all animals were humanely slaughtered. Diet or stress did not have a significant effect on skin Escherichia coli, coliform, or aerobic plate counts, and carcass, rumen, and fecal bacterial counts. Muscle pH at 24 h postmortem tended (P = 0.06) to be higher in transported compared with non-transported goats. The results indicate that SL consumption by goats for 8 wk did not significantly affect gastrointestinal tract, skin, and carcass microbial counts or meat quality, although preslaughter stress could influence meat quality due to changes in the course of postmortem pH decline.
The Collins asymmetry in electroproduction of Kaon at the electron ion colliders within TMD factorization
Authors: Xue Shi-Chen , Wang Xiaoyu , Li De-Min , Lu Zhun 
Published: July 2020

AbstractWe apply the transverse momentum dependent factorization formalism to investigate the transverse single spin dependent Collins asymmetry with a $$\sin (\phi _h+\phi _s)$$sin(ϕh+ϕs) modulation in the semi-inclusive production of Kaon meson in deep inelastic scattering process. The asymmetry is contributed by the convolutions of the transversity distribution function $$h_1(x)$$h1(x) of the target proton and the Collins function of the Kaon in the final state. We adopt the available parametrization of $$h_1(x)$$h1(x) as well as the recent extracted result for the Kaon Collins function. To perform the transverse momentum dependent evolution, the parametrization of the nonperturbative Sudakov form factor of the proton and final state Kaon are utilized. We numerically predict the Collins asymmetry for charged Kaon production at the electron ion colliders within the accuracy of next-to-leading-logarithmic order. It is found that the asymmetry is sizable and could be measured. We emphasize the importance of planned electron ion colliders in the aspect of constraining sea quark distribution functions as well as accessing the information of the nucleon spin structure and the hadronization mechanism.
How to excite reader interest
Authors: Yaffe Philip 
Published: July 2020

Each "Communication Corner" essay is self-contained; however, they build on each other. For best results, before reading this essay and doing the exercise, go to the first essay "How an Ugly Duckling Became a Swan," then read each succeeding essay.
Unless under duress, such as a school assignment or work assignment, people will read only what they want to. However, many will read at least the first couple lines before saying yes or no. Here are five techniques that greatly increase the chances they will say yes.
Ablation of the Brca1–Palb2 Interaction Phenocopies Fanconi Anemia in Mice
Authors: Park Dongju , Bergin Stephen M. , Jones Dan , Ru Peng , Koivisto Christopher S. , Jeon Young-Jun , Sizemore Gina M. , Kladney Raleigh D. , Hadjis Ashley , Shakya Reena , Ludwig Thomas 
Published: July 2020

Abstract

Heterozygous mutations in the BRCA1 gene predispose women to breast and ovarian cancer, while biallelic BRCA1 mutations are a cause of Fanconi anemia (FA), a rare genetic disorder characterized by developmental abnormalities, early-onset bone marrow failure, increased risk of cancers, and hypersensitivity to DNA-crosslinking agents. BRCA1 is critical for homologous recombination of DNA double-strand breaks (DSB). Through its coiled-coil domain, BRCA1 interacts with an essential partner, PALB2, recruiting BRCA2 and RAD51 to sites of DNA damage. Missense mutations within the coiled-coil domain of BRCA1 (e.g., L1407P) that affect the interaction with PALB2 have been reported in familial breast cancer. We hypothesized that if PALB2 regulates or mediates BRCA1 tumor suppressor function, ablation of the BRCA1–PALB2 interaction may also elicit genomic instability and tumor susceptibility. We generated mice defective for the Brca1–Palb2 interaction (Brca1 L1363P in mice) and established MEF cells from these mice. Brca1L1363P/L1363P MEF exhibited hypersensitivity to DNA-damaging agents and failed to recruit Rad51 to DSB. Brca1L1363P/L1363P mice were viable but exhibited various FA symptoms including growth retardation, hyperpigmentation, skeletal abnormalities, and male/female infertility. Furthermore, all Brca1L1363P/L1363P mice exhibited macrocytosis and died due to bone marrow failure or lymphoblastic lymphoma/leukemia with activating Notch1 mutations. These phenotypes closely recapitulate clinical features observed in patients with FA. Collectively, this model effectively demonstrates the significance of the BRCA1–PALB2 interaction in genome integrity and provides an FA model to investigate hematopoietic stem cells for mechanisms underlying progressive failure of hematopoiesis and associated development of leukemia/lymphoma, and other FA phenotypes.

Significance:
A new Brca1 mouse model for Fanconi anemia (FA) complementation group S provides a system in which to study phenotypes observed in human FA patients including bone marrow failure.
See related commentary by Her and Bunting, p. 4044
Ovarian Cancer Risk Factor Associations by Primary Anatomic Site: The Ovarian Cancer Cohort Consortium
Authors: Fortner Renée T. , Rice Megan S. , Knutsen Synnove F. , Orlich Michael J. , Visvanathan Kala , Patel Alpa V. , Gaudet Mia M. , Tjønneland Anne , Kvaskoff Marina , Kaaks Rudolf , Trichopolou Antonia , Pala Valeria , Onland-Moret N. Charlotte , Gram Inger T. , Amiano Pilar , Idahl Annika , Allen Naomi E. , Weiderpass Elisabete , Poynter Jenny N. , Robien Kim , Giles Graham G. , Milne Roger L. , Setiawan Veronica W. , Merritt Melissa A. , van den Brandt Piet A. , Zeleniuch-Jacquotte Anne , Arslan Alan A. , O'Brien Katie M. , Sandler Dale P. , Wolk Alicja , Håkansson Niclas , Harris Holly R. , Trabert Britton , Wentzensen Nicolas , Tworoger Shelley S. , Schouten Leo J. 
Published: July 2020

Abstract

Background:
Epithelial ovarian, fallopian tube, and primary peritoneal cancers have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites.

Methods:
We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests.

Results:
Most associations did not vary by tumor site (Phet ≥ 0.05). Associations between first pregnancy (Phet = 0.04), tubal ligation (Phet = 0.01), and early-adult (age 18–21 years) body mass index (BMI; Phet = 0.02) and risk differed between ovarian and peritoneal cancers. The association between early-adult BMI and risk further differed between peritoneal and fallopian tube cancer (Phet = 0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases.

Conclusions:
Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site.

Impact:
Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.
Pathway Analysis of Renal Cell Carcinoma Genome-Wide Association Studies Identifies Novel Associations
Authors: Purdue Mark P. , Song Lei , Scélo Ghislaine , Houlston Richard S. , Wu Xifeng , Sakoda Lori C. , Thai Khanh , Graff Rebecca E. , Rothman Nathaniel , Brennan Paul , Chanock Stephen J. , Yu Kai 
Published: July 2020

Abstract

Background:
Much of the heritable risk of renal cell carcinoma (RCC) associated with common genetic variation is unexplained. New analytic approaches have been developed to increase the discovery of risk variants in genome-wide association studies (GWAS), including multi-locus testing through pathway analysis.

Methods:
We conducted a pathway analysis using GWAS summary data from six previous scans (10,784 cases and 20,406 controls) and evaluated 3,678 pathways and gene sets drawn from the Molecular Signatures Database. To replicate findings, we analyzed GWAS summary data from the UK Biobank (903 cases and 451,361 controls) and the Genetic Epidemiology Research on Adult Health and Aging cohort (317 cases and 50,511 controls).

Results:
We identified 14 pathways/gene sets associated with RCC in both the discovery (P &lt; 1.36 × 10−5, the Bonferroni correction threshold) and replication (P &lt; 0.05) sets, 10 of which include components of the PI3K/AKT pathway. In tests across 2,035 genes in these pathways, associations (Bonferroni corrected P &lt; 2.46 × 10−5 in discovery and replication sets combined) were observed for CASP9, TIPIN, and CDKN2C. The strongest SNP signal was for rs12124078 (PDiscovery = 2.6 × 10−5; PReplication = 1.5 × 10−4; PCombined = 6.9 × 10−8), a CASP9 expression quantitative trait locus.

Conclusions:
Our pathway analysis implicates genetic variation within the PI3K/AKT pathway as a source of RCC heritability and identifies several promising novel susceptibility genes, including CASP9, which warrant further investigation.

Impact:
Our findings illustrate the value of pathway analysis as a complementary approach to analyzing GWAS data.
Racial/Ethnic Differences in Ovarian Cancer Risk: Results from the Multiethnic Cohort Study
Authors: Sarink Danja , Wu Anna H. , Le Marchand Loïc , White Kami K. , Park Song-Yi , Setiawan V. Wendy , Hernandez Brenda Y. , Wilkens Lynne R. , Merritt Melissa A. 
Published: July 2020

Abstract

Background:
Incidence rates of epithelial ovarian cancer (EOC) vary across racial/ethnic groups, yet little is known about the impact of hormone-related EOC risk factors in non-Whites.

Methods:
Among 91,625 female Multiethnic Cohort Study participants, 155 incident EOC cases were diagnosed in Whites, 93 in African Americans, 57 in Native Hawaiians, 161 in Japanese Americans, and 141 in Latinas. We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between race/ethnicity and EOC risk and between hormone-related factors and EOC risk across racial/ethnic groups.

Results:
Compared with Whites, African Americans and Japanese Americans had a lower multivariable-adjusted EOC risk; Native Hawaiians had a suggestive higher risk. Parity and oral contraceptive (OC) use were inversely associated with EOC risk (Pint race/ethnicity ≥ 0.43); associations were strongest among Japanese Americans (e.g., ≥4 vs. 0 children; HR = 0.45; CI, 0.26–0.79). Age at natural menopause and postmenopausal hormone (PMH) use were not associated with EOC risk in the overall population, but were positively associated with risk in Latinas (e.g., ≥5 years vs. never PMH use; HR = 2.13; CI, 1.30–3.49).

Conclusions:
We observed strong associations with EOC risk for parity and OC use in Japanese Americans and PMH use and age at natural menopause in Latinas. However, differences in EOC risk among racial/ethnic groups were not fully explained by established hormone-related risk factors.

Impact:
Our study indicates there are racial/ethnic differences in EOC risk and risk factors, and could help improve prevention strategies for non-White women.
Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer
Authors: Crosby Erika J. , Acharya Chaitanya R. , Haddad Anthony-Fayez , Rabiola Christopher A. , Lei Gangjun , Wei Jun-Ping , Yang Xiao-Yi , Wang Tao , Liu Cong-Xiao , Wagner Kay U. , Muller William J. , Chodosh Lewis A. , Broadwater Gloria , Hyslop Terry , Shepherd Jonathan H. , Hollern Daniel P. , He Xiaping , Perou Charles M. , Chai Shengjie , Ashby Benjamin K. , Vincent Benjamin G. , Snyder Joshua C. , Force Jeremy , Morse Michael A. , Lyerly Herbert K. , Hartman Zachary C. 
Published: July 2020

Abstract

Purpose:
Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers.

Experimental Design:
Our models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti–PD-1, alone and in combination.

Results:
We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2.

Conclusions:
Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).
X- and Y-Linked Chromatin-Modifying Genes as Regulators of Sex-Specific Cancer Incidence and Prognosis
Authors: Tricarico Rossella , Nicolas Emmanuelle , Hall Michael J. , Golemis Erica A. 
Published: July 2020

Abstract
Biological sex profoundly conditions organismal development and physiology, imposing wide-ranging effects on cell signaling, metabolism, and immune response. These effects arise from sex-specified differences in hormonal exposure, and from intrinsic genetic and epigenetic differences associated with the presence of an XX versus XY chromosomal complement. In addition, biological sex is now recognized to be a determinant of the incidence, presentation, and therapeutic response of multiple forms of cancer, including cancers not specifically associated with male or female anatomy. Although multiple factors contribute to sex-based differences in cancer, a growing body of research emphasizes a role for differential activity of X- and Y-linked tumor-suppressor genes in males and females. Among these, the X-linked KDM6A/UTX and KDM5C/JARID1C/SMCX, and their Y-linked paralogs UTY/KDM6C and KDM5D/JARID1D/SMCY encode lysine demethylases. These epigenetic modulators profoundly influence gene expression, based on enzymatic activity in demethylating H3K27me3 and H3K4me3, and nonenzymatic scaffolding roles for large complexes that open and close chromatin for transcription. In a growing number of cases, mutations affecting these proteins have been recognized to strongly influence cancer risk, prognosis, and response to specific therapies. However, sex-specific patterns of mutation, expression, and activity of these genes, coupled with tissue-specific requirement for their function as tumor suppressors, together exemplify the complex relationship between sex and cancer vulnerabilities. In this review, we summarize and discuss the current state of the literature on the roles of these proteins in contributing to sex bias in cancer, and the status of clinical agents relevant to their function.
Protective Role of C3aR (C3a Anaphylatoxin Receptor) Against Atherosclerosis in Atherosclerosis-Prone Mice
Authors: Wei Lin-Lin , Ma Ning , Wu Kun-Yi , Wang Jia-Xing , Diao Teng-Yue , Zhao Shu-Juan , Bai Liang , Liu Enqi , Li Zong-Fang , Zhou Wuding , Chen Daxin , Li Ke 
Published: July 2020

Objective:
Emerging evidence suggests that C3aR (C3a anaphylatoxin receptor) signaling has protective roles in various inflammatory-related diseases. However, its role in atherosclerosis has been unknown. The purpose of the study was to investigate the possible protective role of C3aR in aortic atherosclerosis and explore molecular and cellular mechanisms involved in the protection.

Approach and Results:

C3ar
−/−
/Apoe
−/−
mice were generated by cross-breeding of atherosclerosis-prone
Apoe
−/−
mice and
C3ar
−/−
mice.
C3ar
−/−
/Apoe
−/−
mice and
Apoe
−/−
mice (as a control) underwent high-fat diet for 16 weeks were assessed for (1) atherosclerotic plaque burden, (2) aortic tissue inflammation, (3) recruitment of CD11b
+
leukocytes into atherosclerotic lesions, and (4) systemic inflammatory responses. Compared with
Apoe
−/−
mice,
C3ar
−/−
/Apoe
−/−
mice developed more severe atherosclerosis. In addition,
C3ar
−/−
/Apoe
−/−
mice have increased local production of proinflammatory mediators (eg, CCL2 [chemokine (C-C motif) ligand 2], TNF [tumor necrosis factor]-α) and infiltration of monocyte/macrophage in aortic tissue, and their lesional macrophages displayed an M1-like phenotype. Local pathological changes were associated with enhanced systemic inflammatory responses (ie, elevated plasma levels of CCL2 and TNF-α, increased circulating inflammatory cells). In vitro analyses using peritoneal macrophages showed that C3a stimulation resulted in upregulation of M2-associated signaling and molecules, but suppression of M1-associated signaling and molecules, supporting the roles of C3a/C3aR axis in mediating anti-inflammatory response and promoting M2 macrophage polarization.

Conclusions:
Our findings demonstrate a protective role for C3aR in the development of atherosclerosis and suggest that C3aR confers the protection through C3a/C3aR axis–mediated negative regulation of proinflammatory responses and modulation of macrophage toward the anti-inflammatory phenotype.
Screening for Intracranial Aneurysms in Coarctation of the Aorta
Authors: Pickard Sarah S. , Prakash Ashwin , Newburger Jane W. , Malek Adel M. , Wong John B. 
Published: July 2020

Background:
Patients with coarctation of the aorta have a high prevalence of intracranial aneurysms (IA) and suffer subarachnoid hemorrhage (SAH) at younger ages than the general population. American Heart Association/American College of Cardiology guidelines recommend IA screening, but appropriate age and interval of screening and its effectiveness remain a critical knowledge gap.

Methods and Results:
To evaluate the benefits and cost-effectiveness of magnetic resonance angiography screening for IA in patients with coarctation of the aorta, we developed and calibrated a Markov model to match published IA prevalence estimates. The primary outcome was the incremental cost-effectiveness ratio. Secondary outcomes included lifetime cumulative incidence of prophylactic IA treatment and mortality and SAH deaths prevented. Using a payer perspective, a lifetime horizon, and a willingness-to-pay of $150 000 per quality-adjusted life-year gained, we applied a 3% annual discounting rate to costs and effects and performed 1-way, 2-way, and probabilistic sensitivity analyses. In a simulated cohort of 10 000 patients, no screening resulted in a 10.1% lifetime incidence of SAH and 183 SAH-related deaths. Screening at ages 10, 20, and 30 years led to 978 prophylactic treatments for unruptured aneurysms, 19 procedure-related deaths, and 65 SAH-related deaths. Screening at ages 10, 20, and 30 years was cost-effective compared with screening at ages 10 and 20 years (incremental cost-effectiveness ratio $106 841/quality-adjusted life-year). Uncertainty in the outcome after aneurysm treatment and quality of life after SAH influenced the preferred screening strategy. In probabilistic sensitivity analysis, screening at ages 10, 20, and 30 years was cost-effective in 41% of simulations and at ages 10 and 20 in 59% of simulations.

Conclusions:
Our model supports the American Heart Association/American College of Cardiology recommendation to screen patients with coarctation of the aorta for IA and suggests screening at ages 10 and 20 or at 10, 20, and 30 years would extend life and be cost-effective.