bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK–LKB1 Signaling Axis
Authors: Casimiro Mathew C. , Di Sante Gabriele , Di Rocco Agnese , Loro Emanuele , Pupo Claudia , Pestell Timothy G. , Bisetto Sara , Velasco-Velázquez Marco A. , Jiao Xuanmao , Li Zhiping , Kusminski Christine M. , Seifert Erin L. , Wang Chenguang , Ly Daniel , Zheng Bin , Shen Che-Hung , Scherer Philipp E. , Pestell Richard G. 
Published: May 2017

Abstract
Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1–deficient model, we observed a cyclin D1–mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis. Cancer Res; 77(13); 3391–405. ©2017 AACR.
Expansion of Tumor-Infiltrating CD8+ T cells Expressing PD-1 Improves the Efficacy of Adoptive T-cell Therapy
Authors: Fernandez-Poma Sarita M. , Salas-Benito Diego , Lozano Teresa , Casares Noelia , Riezu-Boj Jose-Ignacio , Mancheño Uxua , Elizalde Edurne , Alignani Diego , Zubeldia Natalia , Otano Itziar , Conde Enrique , Sarobe Pablo , Lasarte Juan Jose , Hervas-Stubbs Sandra 
Published: May 2017

Abstract
Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1+ TILs can be used in adoptive T-cell therapy (ACT). However, no study thus far has evaluated the antitumor activity of PD-1–selected TILs in vivo. In two mouse models of solid tumors, we show that PD-1 allows identification and isolation of tumor-specific TILs without previous knowledge of their antigen specificities. Importantly, despite the high proportion of tumor-reactive T cells present in bulk CD8 TILs before expansion, only T-cell products derived from sorted PD-1+, but not from PD-1− or bulk CD8 TILs, specifically recognized tumor cells. The fold expansion of PD-1+ CD8 TILs was 10 times lower than that of PD-1− cells, suggesting that outgrowth of PD-1− cells was the limiting factor in the tumor specificity of cells derived from bulk CD8 TILs. The highly differentiated state of PD-1+ cells was likely the main cause hampering ex vivo expansion of this subset. Moreover, PD-1 precisely identified marrow-infiltrating, myeloma-specific T cells in a mouse model of multiple myeloma. In vivo, only cells expanded from PD-1+ CD8 TILs contained tumor progression, and their efficacy was enhanced by PDL-1 blockade. Overall, our data provide a rationale for the use of PD-1–selected TILs in ACT. Cancer Res; 77(13); 3672–84. ©2017 AACR.
Estimation of the Number of Women Living with Metastatic Breast Cancer in the United States
Authors: Mariotto Angela B. , Etzioni Ruth , Hurlbert Marc , Penberthy Lynne , Mayer Musa 
Published: May 2017

Abstract
Background: Distant metastatic breast cancer (MBC), including metastases found at diagnosis (de novo) and those occurring later (recurrence), represents the most severe form of the disease, when resource utilization is most intensive. Yet, the number of women living with MBC in the United States is unknown. The objective of this article is to use population-based data to estimate the prevalence of MBC.
Methods: We used a back-calculation method to estimate MBC prevalence from U.S. breast cancer mortality and survival from the Surveillance, Epidemiology and End Results (SEER) registries. On the basis of the illness–death process, this method assumes that each observed breast cancer death is the result of MBC, either de novo or a recurrence with metastatic disease.
Results: We estimate that by January 1, 2017, there will be 154,794 women living with MBC in the United States, three in four initially diagnosed with stage I–III breast cancer who later progressed to MBC.
Median survival and 5-year relative survival for de novo MBC increased over the years, especially in younger women. We estimate a two-fold increase in 5-year relative survival rate from 18% to 36%, for women diagnosed with de novo MBC at age 15–49 between 1992–1994 and 2005–2012, respectively.
Conclusions: This study demonstrates an increasing number of women in the United States living with MBC, likely the result of improvements in treatment and aging of the U.S. population.
Impact: The increasing burden of MBC highlights the importance of documenting recurrence to foster more research into the specific needs of this understudied population. Cancer Epidemiol Biomarkers Prev; 26(6); 809–15. ©2017 AACR.
A Potential Mechanism for ADC-Induced Neutropenia: Role of Neutrophils in Their Own Demise
Authors: Zhao Hui , Gulesserian Sara , Malinao Maria Christina , Ganesan Sathish Kumar , Song James , Chang Mi Sook , Williams Melissa M. , Zeng Zhilan , Mattie Michael , Mendelsohn Brian A. , Stover David R. , Doñate Fernando 
Published: May 2017

Abstract
Neutropenia is a common adverse event in cancer patients treated with antibody–drug conjugates (ADC) and we aimed to elucidate the potential mechanism of this toxicity. To investigate whether ADCs affect neutrophil production from bone marrow, an in vitro assay was developed in which hematopoietic stem cells (HSC) were differentiated to neutrophils. Several antibodies against targets absent in HSCs and neutrophils were conjugated to MMAE via a cleavable valine-citrulline linker (vcMMAE-ADC) or MMAF via a noncleavable maleimidocaproyl linker (mcMMAF-ADC), and their cytotoxicity was tested in the neutrophil differentiation assay. Results showed that HSCs had similar sensitivity to vcMMAE-ADCs and mcMMAF-ADCs; however, vcMMAE-ADCs were more cytotoxic to differentiating neutrophils than the same antibody conjugated to mcMMAF. This inhibitory effect was not mediated by internalization of ADC either by macropinocytosis or FcγRs. Our results suggested that extracellular proteolysis of the cleavable valine-citrulline linker is responsible for the cytotoxicity to differentiating neutrophils. Mass spectrometry analyses indicated that free MMAE was released from vcMMAE-ADCs in the extracellular compartment when they were incubated with differentiating neutrophils or neutrophil conditioned medium, but not with HSC-conditioned medium. Using different protease inhibitors, our data suggested that serine, but not cysteine proteases, were responsible for the cleavage. In vitro experiments demonstrated that the purified serine protease, elastase, was capable of releasing free MMAE from a vcMMAE-ADC. Here we propose that ADCs containing protease cleavable linkers can contribute to neutropenia via extracellular cleavage mediated by serine proteases secreted by differentiating neutrophils in bone marrow. Mol Cancer Ther; 16(9); 1866–76. ©2017 AACR.
See related article by Zhao et al., p. 1877
Histone H3.3K27M Represses p16 to Accelerate Gliomagenesis in a Murine Model of DIPG
Authors: Cordero Francisco J. , Huang Zhiqing , Grenier Carole , He Xingyao , Hu Guo , McLendon Roger E. , Murphy Susan K. , Hashizume Rintaro , Becher Oren J. 
Published: May 2017

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor genetically distinguished from adult GBM by the high prevalence of the K27M mutation in the histone H3 variant H3.3 (H3F3A). This mutation reprograms the H3K27me3 epigenetic landscape of DIPG by inhibiting the H3K27-specific histone methyltransferase EZH2. This globally reduces H3K27me2/3, critical repressive marks responsible for cell fate decisions, and also causes focal gain of H3K27me3 throughout the epigenome. To date, the tumor-driving effects of H3.3K27M remain largely unknown. Here, it is demonstrated that H3.3K27M cooperates with PDGF-B in vivo, enhancing gliomagenesis and reducing survival of p53 wild-type (WT) and knockout murine models of DIPG. H3.3K27M expression drives increased proliferation of tumor-derived murine neurospheres, suggesting that cell-cycle deregulation contributes to increased malignancy in mutant tumors. RNA sequencing on tumor tissue from H3.3K27M-expressing mice indicated global upregulation of PRC2 target genes, and a subset of newly repressed genes enriched in regulators of development and cell proliferation. Strikingly, H3.3K27M induced targeted repression of the p16/ink4a (CDKN2A) locus, a critical regulator of the G0–G1 to S-phase transition. Increased levels of H3K27me3 were observed at the p16 promoter; however, pharmacologic reduction of methylation at this promoter did not rescue p16 expression. Although DNA methylation is also present at this promoter, it is not K27M dependent. Intriguingly, inhibition of DNA methylation restores p16 levels and is cytotoxic against murine tumor cells. Importantly, these data reveal that H3.3K27M-mediated p16 repression is an important mechanism underlying the proliferation of H3.3K27M tumor cells, as in vivo cdkn2a knockout eliminates the survival difference between H3.3K27M and H3.3WT tumor-bearing mice.
Implications: This study shows that H3.3K27M mutation and PDGF signaling act in concert to accelerate gliomagenesis in a genetic mouse model and identifies repression of p16 tumor suppressor as a target of H3.3K27M, highlighting the G1–S cell-cycle transition as a promising therapeutic avenue. Mol Cancer Res; 15(9); 1243–54. ©2017 AACR.
Greater Frequency of Fruit and Vegetable Consumption Is Associated With Lower Prevalence of Peripheral Artery Disease
Authors: Heffron Sean P. , Rockman Caron B. , Adelman Mark A. , Gianos Eugenia , Guo Yu , Xu Jin Feng , Berger Jeffrey S. 
Published: May 2017

Objective—
Although fruit and vegetable (F&V) consumption is associated with lower risk of coronary heart disease and stroke, its association with peripheral artery disease (PAD) is less certain. We, thus, sought to characterize F&V intake and investigate the association between F&V consumption and presence of PAD in a large community sample.

Approach and Results—
Self-referred participants at >20 000 US sites who completed medical and lifestyle questionnaires were evaluated by screening ankle brachial indices for PAD (ankle brachial index ≤0.9). Among 3 696 778 individuals, mean age was 64.1±10.2 years and 64.1% were female. Daily consumption of ≥3 servings of F&V was reported by 29.2%. Increasing age, female sex, white race, never smoking, being currently married, physical activity, increasing income, and frequent consumption of fish, nuts, and red meat were positively associated with daily consumption of F&V. After multivariable adjustment, there was a stepwise inverse association between F&V intake and PAD. Participants reporting daily intake of ≥3 servings of F&V had 18% lower odds of PAD than those reporting less than monthly consumption. In unadjusted and multivariable-adjusted models, the inverse association with F&V became stronger as ankle brachial index decreased. When stratified by smoking status, the association was present only among those subjects who currently or formerly smoked tobacco.

Conclusions—
Our study demonstrates an inverse association of F&V consumption with prevalent PAD and overall low F&V consumption. These observations suggest the need to further efforts to increase F&V consumption and for more rigorous evaluation of the role of F&V in PAD prevention.
Apolipoprotein A-I Mimetic Peptides
Authors: Ditiatkovski Michael , Palsson Jonatan , Chin-Dusting Jaye , Remaley Alan T. , Sviridov Dmitri 
Published: May 2017

Objective—
Apolipoprotein A-I (apoA-I) mimetic peptides have antiatherogenic properties of high-density lipoprotein in vitro and have been shown to inhibit atherosclerosis in vivo. It is unclear, however, if each in vitro antiatherogenic property of these peptides translates to a corresponding activity in vivo, and if so, which of these contributes most to reduce atherosclerosis.

Approach and Results—
The effect of 7 apoA-I mimetic peptides, which were developed to selectively reproduce a specific component of the antiatherogenic properties of apoA-I, on the development of atherosclerosis was investigated in apolipoprotein E–deficient mice fed a high-fat diet for 4 or 12 weeks. The peptides include those that selectively upregulate cholesterol efflux, or are anti-inflammatory, or have antioxidation properties. All the peptides studied effectively inhibited the in vivo development of atherosclerosis in this model to the same extent. However, none of the peptides had the same selective effect in vivo as they had exhibited in vitro. None of the tested peptides affected plasma lipoprotein profile; capacity of plasma to support cholesterol efflux was increased modestly and similarly for all peptides.

Conclusions—
There is a discordance between the selective in vitro and in vivo functional properties of apoA-I mimetic peptides, and the in vivo antiatherosclerotic effect of apoA-I-mimetic peptides is independent of their in vitro functional profile. Comparing the properties of apoA-I mimetic peptides in plasma rather than in the lipid-free state is better for predicting their in vivo effects on atherosclerosis.
Circulating MicroRNA-125b Predicts the Presence and Progression of Uremic Vascular Calcification
Authors: Chao Chia-Ter , Liu You-Pi , Su Sheng-Fang , Yeh Hsiang-Yuan , Chen Hsuan-Yu , Lee Pei-Jung , Chen Wan-Jiun , Lee Yee-Ming , Huang Jenq-Wen , Chiang Chih-Kang , Hung Kuan-Yu , Chen Huei-Wen 
Published: May 2017

Objective—
Vascular calcification (VC) is a major cause of mortality in patients with end-stage renal diseases. Biomarkers to predict the progression of VC early are in urgent demand.

Approach and Results—

We identified circulating, cell-free microRNAs as potential biomarkers using in vitro VC models in which both rat and human aortic vascular smooth muscle cells were treated with high levels of phosphate to mimic uremic hyperphosphatemia. Using an Affymetrix microRNA array, we found that miR-125b and miR-382 expression levels declined significantly as biomineralization progressed, but this decline was only observed for miR-125b in the culture medium. A time-dependent decrease in aortic tissue and serum miR-125b levels was also found in both ex vivo and in vivo renal failure models. We examined the levels of circulating, cell-free miR-125b in sera from patients with end-stage renal diseases (n=88) and found an inverse association between the severity of VC and the circulating miR-125b level, irrespective of age or mineral-related hormones (odds ratio, 0.71;
P
=0.03). Furthermore, serum miR-125b levels on enrollment can predict VC progression years later (for high versus low, odds ratio, 0.14;
P
<0.01; for the highest versus lowest tertile and middle versus lowest tertile, odds ratio, 0.55 and 0.13;
P
=0.3 and <0.01, respectively). The uremic VC prediction efficacy using circulating miR-125b levels was also observed in an independent cohort (n=135).

Conclusions—
The results suggest that serum miR-125b levels are associated with VC severity and serve as a novel predictive marker for the risk of uremia-associated calcification progression.
Loop-mediated isothermal amplification (LAMP) for detection of the red ring nematode, Bursaphelenchus cocophilus
Authors: Ide Tatsuya , Kanzaki Natsumi , Parra Giraldo Pedro Pablo , Giblin-Davis Robin M. 
Published: May 2017

As a first step in developing a quick, accurate and simple method for the diagnosis of red ring disease, the loop-mediated isothermal amplification (LAMP)-based identification procedure was applied to the causative agent,Bursaphelenchuscocophilus. Two LAMP primer sets were designed using two loci of ribosomal RNA genes,i.e., D2-D3 expansion segments of the large subunit (D2-D3 LSU), and internal transcribed spacers (ITS). Within those two sets of primers, the D2-D3 LSU primer set successfully yielded amplicons fromB. cocophilusnematode lysate prepared from 3-year-old DESS-fixed specimens. The specificity of the primers was examined using 18 species of confamilial Aphelenchoididae nematodes and primer sensitivity was tested using a diluted series ofB. cocophiluslysate. The primer set did not amplify the DNA from other aphelenchoidids, and sensitivity was achieved by ‘1:100 diluted’B. cocophilusDNA (roughly 1/1500 of total DNA from a single third-stage juvenile).
TV Weathercasters’ Views of Climate Change Appear to Be Rapidly Evolving
Authors: Maibach Edward , Mazzone Raphael , Drost Robert , Myers Teresa , Seitter Keith , Hayhoe Katharine , Ryan Bob , Witte Joe , Gardiner Ned , Hassol Susan , Lazo Jeffrey K. , Placky Bernadette , Sublette Sean , Cullen Heidi 
Published: May 2017

AbstractFindings from the most recent surveys of TV weathercasters—which are methodologically superior to prior surveys in a number of important ways—suggest that weathercasters’ views of climate change may be rapidly evolving. In contrast to prior surveys, which found many weathercasters who were unconvinced of climate change, newer results show that approximately 80% of weathercasters are convinced of human-caused climate change. A majority of weathercasters now indicate that climate change has altered the weather in their media markets over the past 50 years, and many feel there have also been harmful impacts to water resources, agriculture, transportation resources, and human health. Nearly all weathercasters—89%—believe their viewers are at least slightly interested in learning about local impacts. The majority of weathercasters are interested in reporting on local impacts, including extreme precipitation and flooding, drought and water shortages, extreme heat events, air quality, and harm to local wildlife, crops and livestock, and human health; and nearly half had reported on the local impacts in at least one channel over the past 12 months. Thus, it appears that a strong majority of weathercasters are now convinced that human-caused climate change is happening, many feel they are already witnessing harmful impacts in their communities, and many are beginning to explore ways of educating their viewers about these local impacts of global climate change. We believe that the role of local climate educator will soon become a normative practice for broadcast meteorologists—adding a significant and important new role to their job descriptions.
Malnutrition, Critical Illness Survivors, and Postdischarge Outcomes: A Cohort Study
Authors: Mogensen Kris M. , Horkan Clare M. , Purtle Steven W. , Moromizato Takuhiro , Rawn James D. , Robinson Malcolm K. , Christopher Kenneth B. 
Published: May 2017

AbstractBackground: We hypothesized that preexisting malnutrition in patients who survived critical care would be associated with adverse outcomes following hospital discharge. Methods: We performed an observational cohort study in 1 academic medical center in Boston. We studied 23,575 patients, aged ≥18 years, who received critical care between 2004 and 2011 and survived hospitalization. Results: The exposure of interest was malnutrition determined at intensive care unit (ICU) admission by a registered dietitian using clinical judgment and on data related to unintentional weight loss, inadequate nutrient intake, and wasting of muscle mass and/or subcutaneous fat. The primary outcome was 90‐day postdischarge mortality. Secondary outcome was unplanned 30‐day hospital readmission. Adjusted odds ratios were estimated by logistic regression models adjusted for age, race, sex, Deyo‐Charlson Index, surgical ICU, sepsis, and acute organ failure. In the cohort, the absolute risk of 90‐day postdischarge mortality was 5.9%, 11.7%, 15.8%, and 21.9% in patients without malnutrition, those at risk of malnutrition, nonspecific malnutrition, and protein‐energy malnutrition, respectively. The odds of 90‐day postdischarge mortality in patients at risk of malnutrition, nonspecific malnutrition, and protein‐energy malnutrition fully adjusted were 1.77 (95% confidence interval [CI], 1.23–2.54), 2.51 (95% CI, 1.36–4.62), and 3.72 (95% CI, 2.16–6.39), respectively, relative to patients without malnutrition. Furthermore, the presence of malnutrition is a significant predictor of the odds of unplanned 30‐day hospital readmission. Conclusions: In patients treated with critical care who survive hospitalization, preexisting malnutrition is a robust predictor of subsequent mortality and unplanned hospital readmission.
Dynamic alterations in cerebral, celiac and renal flows resulting from ascending aorta, subclavian artery and femoral artery cannulations of extracorporeal devices
Authors: Iscan Sahin , Cakir Habib , Eygi Bortecin , Yurekli Ismail , Donmez Koksal , Ayvat Pınar Unde , Pekel Derya Sarıkaya , Kestelli Mert 
Published: May 2017

Introduction: The aim of this study was to assess the relationships among cardiac output, extracorporeal blood flow, cannulation site, right (RCa) and left carotid (LCa), celiac (Ca) and renal artery (Ra) flows during extracorporeal circulation. Methods: A mock circulatory circuit was assembled, based on a compliant anatomical aortic model. The ascending aorta, right subclavian and femoral artery cannulations were created and flow was provided by a centrifugal pump (Cp); cardiac output was provided by a roller pump (Rp). Five volume flow rates were tested. The Rp was set at 4 L/min with no Cp flow (R4-C0) and the basic volume flow rates of the vessels were measured. The flow of the Cp was increased while the Rp flow was decreased for other measurements; R3-C1, R2-C2, R1-C3 and R0-C4. Measurements were repeated for all cannulation sites. Results: The RCa flow rate at R4-C0 was higher compared to the R3-C1, R2-C2, R1-C3 and R0-C4 RCa flows with subclavian cannulation. The RCa flow decreased as the Cp flow increased (p<0.05). The RCa flow with ascending aortic and femoral cannulation was higher compared to subclavian cannulation. Higher flows were obtained with subclavian cannulation in the LCa compared to the others (p<0.05). R4-C0 Ca and Ra flows were higher compared to other Ca and Ra flows with femoral cannulation. Ca and Ra flows decreased as Cp flow increased. Flows of the Ca and Ra with ascending and subclavian cannulations were not lower compared to the R4-C0 flow (p<0.05). Conclusion: This study shows that prolonged extracorporeal circulation may develop flow decrease and ischemia in cerebral and abdominal organs with both subclavian and femoral cannulations.
Foetal responses to dexmedetomidine in parturients undergoing caesarean section: a systematic review and meta-analysis
Authors: Zhang Jian , Zhou Haibin , Sheng Kaihua , Tian Tian , Wu Anshi 
Published: May 2017

Objective This current meta-analysis was conducted to evaluate effects of dexmedetomidine on neonatal maternal factors. Methods The electronic databases of PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. The primary outcomes were neonatal parameters, including umbilical blood gases and Apgar scores. The secondary outcomes were maternal parameters. Results We identified six randomized controlled trials (RCTs). No differences in neonatal umbilical blood gases, and Apgar scores at 1 min (WMD: −0.09; 95% CI: −0.21 to 0.04; I2 = 0%) and 5 min (weighted mean difference (WMD): 0.03; 95% CI: −0.05 to 0.11; I2 = 37%) were observed with dexmedetomidine. For maternal parameters, characteristics of motor and sensory block and postoperative analgesia (standard mean difference (SMD): 3.99; 95% CI: 2.85 to 5.12; I2 = 78%) were significantly improved after dexmedetomidine treatment. Adverse events, including nausea/vomiting and shivering (risk ratio (RR): 0.26; 95% CI: 0.11 to 0.60; I2 = 0%), were lower after dexmedetomidine treatment. Conclusion This meta-analysis shows that dexmedetomidine is safe for neonates who are delivered by caesarean section. Moreover, dexmedetomidine used in neuraxial anaesthesia can improve the characteristics of motor and sensory block and prolong the maternal pain-free period. Dexmedetomidine can also reduce the maternal incidence of postoperative adverse effects.