bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain-age in midlife is associated with accelerated biological aging and cognitive decline in a longitudinal birth cohort
Authors: Elliott Maxwell L. , Belsky Daniel W. , Knodt Annchen R. , Ireland David , Melzer Tracy R. , Poulton Richie , Ramrakha Sandhya , Caspi Avshalom , Moffitt Terrie E. , Hariri Ahmad R. 
Published: December 2019

AbstractAn individual’s brainAGE is the difference between chronological age and age predicted from machine-learning models of brain-imaging data. BrainAGE has been proposed as a biomarker of age-related deterioration of the brain. Having an older brainAGE has been linked to Alzheimer’s, dementia, and mortality. However, these findings are largely based on cross-sectional associations which can confuse age differences with cohort differences. To illuminate the validity of brainAGE as a biomarker of accelerated brain aging, a study is needed of a large cohort all born in the same year who nevertheless vary on brainAGE. In the Dunedin Study, a population-representative 1972–73 birth cohort, we measured brainAGE at age 45 years, as well as the pace of biological aging and cognitive decline in longitudinal data from childhood to midlife (N = 869). In this cohort, all chronological age 45 years, brainAGE was measured reliably (ICC = 0.81) and ranged from 24 to 72 years. Those with older midlife brainAGEs tended to have poorer cognitive function in both adulthood and childhood, as well as impaired brain health at age 3. Furthermore, those with older brainAGEs had an accelerated pace of biological aging, older facial appearance, and early signs of cognitive decline from childhood to midlife. These findings help to validate brainAGE as a potential surrogate biomarker for midlife intervention studies that seek to measure dementia-prevention efforts in midlife. However, the findings also caution against the assumption that brainAGE scores represent only age-related deterioration of the brain as they may also index central nervous system variation present since childhood.
Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma
Authors: Hazawa Masaharu , Sakai Kie , Kobayashi Akiko , Yoshino Hironori , Iga Yoshihiro , Iwashima Yuki , Lim Kee Sing , Chih-Cheng Voon Dominic , Jiang Yan-Yi , Horike Shin-ichi , Lin De-Chen , Wong Richard W. 
Published: December 2019

AbstractNuclear import, mediated in part by karyopherin-α (KPNA)/importin-α subtypes, regulates transcription factor access to the genome and determines cell fate. However, the cancer-specific changes of KPNA subtypes and the relevancy in cancer biology remain largely unknown. Here, we report that KPNA4, encoding karyopherin-α4 (KPNA4), is exclusively amplified and overexpressed in head and neck of squamous cell carcinoma (HNSCC). Depletion of KPNA4 attenuated nuclear localization signal-dependent transport activity and suppressed malignant phenotypes and induced epidermal differentiation. Mechanistically, KPNA4-mediated nuclear transport of Ras-responsive element-binding protein (RREB1), which sustains Ras/ERK pathway signaling through repressing miR-143/145 expression. Notably, MAPK signaling enhanced trafficking activity of KPNA4 via phosphorylation of KPNA4 at Ser60. These data reveal that KPNA4 establishes a feed-forward cascade that potentiates Ras/ERK signaling in HNSCC.
Performance in delayed non-matching to sample task predicts the diagnosis of obsessive–compulsive disorder
Authors: Maatoug Redwan , Goff Benoît Le , Rotge Jean-Yves , Jaafari Nemat , Guillin Olivier , Millet Bruno 
Published: December 2019

AbstractElectrical stimulation studies have recently evidenced the involvement of orbitofrontal cortex (OFC) in obsessive–compulsive disorder (OCD). In addition, lateral OFC is activated in healthy subjects during delayed non-matching-to-sample task (DNMS). In the present study, we hypothesized that OCD results from a specific defect of lateral OFC processing that can be evidenced via a DNMS task. To this end, we compared the DNMS performances of 20 OCD patients vs 20 demographically matched healthy controls. As predicted, our results showed that OCD patients performed worse than healthy controls at DNMS task. To test for the specificity of this behavioral impairment, we furthermore compared OCD patients and healthy subjects on a different task not involving directly the lateral OFC: the delayed match-to-sample task (DMS). As expected, OCD patients are more impaired for both the DNMS and the DMS task, compared with healthy subjects. Moreover, OCD patients tend statistically to perform worse for the DNMS task than for DMS task. Our results suggest the DNMS task specifically target the malfunctioning areas in OCD, such as the lateral OFC. In light of these results, lateral OFC should therefore be the focus of future therapeutic interventions.
New aspects of amino acid metabolism in cancer
Authors: Vettore Lisa , Westbrook Rebecca L. , Tennant Daniel A. 
Published: December 2019

AbstractAn abundant supply of amino acids is important for cancers to sustain their proliferative drive. Alongside their direct role as substrates for protein synthesis, they can have roles in energy generation, driving the synthesis of nucleosides and maintenance of cellular redox homoeostasis. As cancer cells exist within a complex and often nutrient-poor microenvironment, they sometimes exist as part of a metabolic community, forming relationships that can be both symbiotic and parasitic. Indeed, this is particularly evident in cancers that are auxotrophic for particular amino acids. This review discusses the stromal/cancer cell relationship, by using examples to illustrate a number of different ways in which cancer cells can rely on and contribute to their microenvironment – both as a stable network and in response to therapy. In addition, it examines situations when amino acid synthesis is driven through metabolic coupling to other reactions, and synthesis is in excess of the cancer cell’s proliferative demand. Finally, it highlights the understudied area of non-proteinogenic amino acids in cancer metabolism and their potential role.
Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin
Authors: Sivalingam Vanitha N. , Latif Ayşe , Kitson Sarah , McVey Rhona , Finegan Katherine G. , Marshall Kay , Lisanti Michael P. , Sotgia Federica , Stratford Ian J. , Crosbie Emma J. 
Published: December 2019

AbstractBackgroundHigh expression of Ki67, a proliferation marker, is associated with reduced endometrial cancer-specific survival. Pre-surgical metformin reduces tumour Ki-67 expression in some women with endometrial cancer. Metformin’s anti-cancer activity may relate to effects on cellular energy metabolism. Since tumour hypoxia and glucose availability are major cellular redox determinants, we evaluated their role in endometrial cancer response to metformin.MethodsEndometrial cancer biopsies from women treated with pre-surgical metformin were tested for the hypoxia markers, HIF-1α and CA-9. Endometrial cancer cell lines were treated with metformin in variable glucose concentrations in normoxia or hypoxia and cell viability, mitochondrial biogenesis, function and energy metabolism were assessed.ResultsIn women treated with metformin (n = 28), Ki-67 response was lower in hypoxic tumours. Metformin showed minimal cytostatic effects towards Ishikawa and HEC1A cells in conventional medium (25 mM glucose). In low glucose (5.5 mM), a dose-dependent cytostatic effect was observed in normoxia but attenuated in hypoxia. Tumours treated with metformin showed increased mitochondrial mass (n = 25), while in cultured cells metformin decreased mitochondrial function. Metformin targets mitochondrial respiration, however, in hypoxic, high glucose conditions, there was a switch to glycolytic metabolism and decreased metformin response.ConclusionsUnderstanding the metabolic adaptations of endometrial tumours may identify patients likely to derive clinical benefit from metformin.
ASCT2 (SLC1A5)-dependent glutamine uptake is involved in the progression of head and neck squamous cell carcinoma
Authors: Zhang Ze , Liu Ruoyan , Shuai Yanjie , Huang Yuting , Jin Rui , Wang Xudong , Luo Jingtao 
Published: December 2019

AbstractBackgroundGlutamine is an abundant and versatile nutrient in cancer cells. Head and neck squamous cell carcinoma (HNSCC) was reported to be dependent on mainly glucose, not glutamine, for producing the energy required for survival and proliferation.MethodsThe roles of ASCT2 (SLC1A5) and associated glutamine metabolism were determined by the MTT, colony formation, glutamine uptake, intracellular glutathione, ROS detection, immunofluorescence, immunohistochemistry, and apoptosis enzyme-linked immunosorbent assays as well as animal studies.ResultsWe found that glutamine is also critical for HNSCC. In this study, ASCT2, an amino acid transporter responsible for glutamine transport, in addition to LAT1 and GLS, is overexpressed in HNSCC and associated with poor survival. Using both in vivo and in vitro models, we found that knocking down ASCT2 by shRNAs or miR-137 or the combination of silencing ASCT2 and pharmacologically inhibiting SNAT2 via a small-molecule antagonist called V-9302 significantly suppressed intracellular glutamine levels and downstream glutamine metabolism, including glutathione production; these effects attenuated growth and proliferation, increased apoptosis and autophagy, and increased oxidative stress and mTORC1 pathway suppression in HNSCC. Additionally, silencing ASCT2 improved the response to cetuximab in HNSCC.ConclusionsIn summary, ASCT2-dependent glutamine uptake and subsequent glutamine metabolism are essential for HNSCC tumorigenesis, and the combination of glutamine uptake inhibitors and cetuximab presents a promising strategy for improving the outcomes of HNSCC patients.
Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma
Authors: Meng Gang , Li Binghua , Chen Anxian , Zheng Meihong , Xu Tiancheng , Zhang Hailin , Dong Jie , Wu Junhua , Yu Decai , Wei Jiwu 
Published: December 2019

Abstract
Background
Oncolytic viro-immunotherapy holds promise for cancer treatment. While immune activation can be robustly triggered by oncolytic viruses, negative feedback is often upregulated in the tumour microenvironment (TME). Lactate accumulation, signal transducer and activator of transcription 3 (STAT3) activation, indoleamine 2,3-dioxygenase 1 (IDO1) expression, and myeloid-derived suppressor cell (MDSC) infiltration coordinate to shape the immunosuppressive TME.

Methods
Representative hepatocellular carcinoma (HCC) cell lines and HCC-bearing mice were treated with oncolytic Newcastle disease virus (NDV), alone or in combination with dichloroacetate (DCA, a pyruvate dehydrogenase kinase (PDK) inhibitor).

Results
We found that infection with oncolytic NDV led to significant induction of the aforementioned suppressive factors. Interestingly, DCA significantly reduced lactate release, STAT3 activation, IDO1 upregulation, and MDSC infiltration in NDV-treated HCC. Consequently, DCA significantly enhanced the antitumour immune responses, leading to improved antitumour efficacy and prolonged survival in mouse models of ascitic and subcutaneous HCC. Furthermore, DCA increased NDV replication in a PDK-1-dependent manner in HCC.

Conclusions
Targeting aerobic glycolysis by DCA improves NDV-mediated viro-immunotherapy in HCC by mitigating immune negative feedback and promoting viral replication. These findings provide a rationale for targeting reprogrammed metabolism together with oncolytic virus-mediated viro-immunotherapy for HCC treatment.
Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response
Authors: Ciccarone Fabio , Di Leo Luca , Lazzarino Giacomo , Maulucci Giuseppe , Di Giacinto Flavio , Tavazzi Barbara , Ciriolo Maria Rosa 
Published: December 2019

Abstract
Background
Deregulation of the tricarboxylic acid cycle (TCA) due to mutations in specific enzymes or defective aerobic metabolism is associated with tumour growth. Aconitase 2 (ACO2) participates in the TCA cycle by converting citrate to isocitrate, but no evident demonstrations of its involvement in cancer metabolism have been provided so far.

Methods
Biochemical assays coupled with molecular biology, in silico, and cellular tools were applied to circumstantiate the impact of ACO2 in the breast cancer cell line MCF-7 metabolism. Fluorescence lifetime imaging microscopy (FLIM) of NADH was used to corroborate the changes in bioenergetics.

Results
We showed that ACO2 levels are decreased in breast cancer cell lines and human tumour biopsies. We generated ACO2- overexpressing MCF-7 cells and employed comparative analyses to identify metabolic adaptations. We found that increased ACO2 expression impairs cell proliferation and commits cells to redirect pyruvate to mitochondria, which weakens Warburg-like bioenergetic features. We also demonstrated that the enhancement of oxidative metabolism was supported by mitochondrial biogenesis and FoxO1-mediated autophagy/mitophagy that sustains the increased ROS burst.

Conclusions
This work identifies ACO2 as a relevant gene in cancer metabolic rewiring of MCF-7 cells, promoting a different utilisation of pyruvate and revealing the potential metabolic vulnerability of ACO2-associated malignancies.
High-resolution imaging mass spectrometry combined with transcriptomic analysis identified a link between fatty acid composition of phosphatidylinositols and the immune checkpoint pathway at the primary tumour site of breast cancer
Authors: Kawashima Masahiro , Tokiwa Mariko , Nishimura Tomomi , Kawata Yukiko , Sugimoto Masahiro , Kataoka Tatsuki R. , Sakurai Takaki , Iwaisako Keiko , Suzuki Eiji , Hagiwara Masatoshi , Harris Adrian L. , Toi Masakazu 
Published: December 2019

Abstract
Background
The fatty acid (FA) composition of phosphatidylinositols (PIs) is tightly regulated in mammalian tissue since its disruption impairs normal cellular functions. We previously found its significant alteration in breast cancer by using matrix-assisted laser desorption and ionisation imaging mass spectrometry (MALDI-IMS).

Methods
We visualised the histological distribution of PIs containing different FAs in 65 primary breast cancer tissues using MALDI-IMS and investigated its association with clinicopathological features and gene expression profiles.

Results
Normal ductal cells (n = 7) predominantly accumulated a PI containing polyunsaturated FA (PI-PUFA), PI(18:0/20:4). PI(18:0/20:4) was replaced by PIs containing monounsaturated FA (PIs-MUFA) in all non-invasive cancer cells (n = 12). While 54% of invasive cancer cells (n = 27) also accumulated PIs-MUFA, 46% of invasive cancer cells (n = 23) accumulated the PIs-PUFA, PI(18:0/20:3) and PI(18:0/20:4). The accumulation of PI(18:0/20:3) was associated with higher incidence of lymph node metastasis and activation of the PD-1-related immune checkpoint pathway. Fatty acid-binding protein 7 was identified as a putative molecule controlling PI composition.

Conclusions
MALDI-IMS identified PI composition associated with invasion and nodal metastasis of breast cancer. The accumulation of PI(18:0/20:3) could affect the PD-1-related immune checkpoint pathway, although its precise mechanism should be further validated.
Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin
Authors: Lord Simon R. , Collins Jennifer M. , Cheng Wei-Chen , Haider Syed , Wigfield Simon , Gaude Edoardo , Fielding Barbara A. , Pinnick Katherine E. , Harjes Ulrike , Segaran Ashvina , Jha Pooja , Hoefler Gerald , Pollak Michael N. , Thompson Alastair M. , Roy Pankaj G. , English Ruth. , Adams Rosie F. , Frezza Christian , Buffa Francesca M. , Karpe Fredrik , Harris Adrian L. 
Published: December 2019

AbstractBackgroundEpidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy.MethodsThirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment.ResultsMultiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation.ConclusionsWe propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations.Clinical Trial RegistrationNCT01266486.
Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy
Authors: Harris Adrian L. 
Published: December 2019

AbstractCancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.
The epigenomic landscape of transposable elements across normal human development and anatomy
Authors: Pehrsson Erica C. , Choudhary Mayank N. K. , Sundaram Vasavi , Wang Ting 
Published: December 2019

AbstractTransposable elements (TEs) have deposited functional regulatory elements throughout the human genome. Although most are silenced, certain TEs have been co-opted by the host. However, a comprehensive, multidimensional picture of the contribution of TEs to normal human gene regulation is still lacking. Here, we quantify the epigenomic status of TEs across human anatomy and development using data from the Roadmap Epigenomics Project. We find that TEs encompass a quarter of the human regulatory epigenome, and 47% of elements can be in an active regulatory state. We demonstrate that SINEs are enriched relative to other classes for active and transcribed marks, that TEs encompass a higher proportion of enhancer states in the hematopoietic lineage, and that DNA methylation of Alu elements decreases with age, corresponding with a loss of CpG islands. Finally, we identify TEs that may perform an evolutionarily conserved regulatory function, providing a systematic profile of TE activity in normal human tissue.
Efficient sky-blue perovskite light-emitting diodes via photoluminescence enhancement
Authors: Wang Qi , Wang Xiaoming , Yang Zhi , Zhou Ninghao , Deng Yehao , Zhao Jingjing , Xiao Xun , Rudd Peter , Moran Andrew , Yan Yanfa , Huang Jinsong 
Published: December 2019

AbstractThe efficiencies of green and red perovskite light-emitting diodes (PeLEDs) have been increased close to their theoretical upper limit, while the efficiency of blue PeLEDs is lagging far behind. Here we report enhancing the efficiency of sky-blue PeLEDs by overcoming a major hurdle of low photoluminescence quantum efficiency in wide-bandgap perovskites. Blending phenylethylammonium chloride into cesium lead halide perovskites yields a mixture of two-dimensional and three-dimensional perovskites, which enhances photoluminescence quantum efficiency from 1.1% to 19.8%. Adding yttrium (III) chloride into the mixture further enhances photoluminescence quantum efficiency to 49.7%. Yttrium is found to incorporate into the three-dimensional perovskite grain, while it is still rich at grain boundaries and surfaces. The yttrium on grain surface increases the bandgap of grain shell, which confines the charge carriers inside grains for efficient radiative recombination. Record efficiencies of 11.0% and 4.8% were obtained in sky-blue and blue PeLEDs, respectively.
Metabolic balancing by miR-276 shapes the mosquito reproductive cycle and Plasmodium falciparum development
Authors: Lampe Lena , Jentzsch Marius , Kierszniowska Sylwia , Levashina Elena A. 
Published: December 2019

AbstractThe blood-feeding behavior of Anopheles females delivers essential nutrients for egg development and drives parasite transmission between humans. Plasmodium growth is adapted to the vector reproductive cycle, but how changes in the reproductive cycle impact parasite development remains unclear. Here, we show that the bloodmeal-induced miR-276-5p fine-tunes the expression of branched-chain amino acid transferase to terminate the reproductive cycle. Silencing of miR-276 prolongs high rates of amino acid (AA) catabolism and increases female fertility, suggesting that timely termination of AA catabolism restricts mosquito investment into reproduction. Prolongation of AA catabolism in P. falciparum-infected females also compromises the development of the transmissible sporozoite forms. Our results suggest that Plasmodium sporogony exploits the surplus mosquito resources available after reproductive investment and demonstrate the crucial role of the mosquito AA metabolism in within-vector parasite proliferation and malaria transmission.
Tropical carbon sink accelerated by symbiotic dinitrogen fixation
Authors: Levy-Varon Jennifer H. , Batterman Sarah A. , Medvigy David , Xu Xiangtao , Hall Jefferson S. , van Breugel Michiel , Hedin Lars O. 
Published: December 2019

AbstractA major uncertainty in the land carbon cycle is whether symbiotic nitrogen fixation acts to enhance the tropical forest carbon sink. Nitrogen-fixing trees can supply vital quantities of the growth-limiting nutrient nitrogen, but the extent to which the resulting carbon–nitrogen feedback safeguards ecosystem carbon sequestration remains unclear. We combine (i) field observations from 112 plots spanning 300 years of succession in Panamanian tropical forests, and (ii) a new model that resolves nitrogen and light competition at the scale of individual trees. Fixation doubled carbon accumulation in early succession and enhanced total carbon in mature forests by ~10% (~12MgC ha−1) through two mechanisms: (i) a direct fixation effect on tree growth, and (ii) an indirect effect on the successional sequence of non-fixing trees. We estimate that including nitrogen-fixing trees in Neotropical reforestation projects could safeguard the sequestration of 6.7 Gt CO2 over the next 20 years. Our results highlight the connection between functional diversity of plant communities and the critical ecosystem service of carbon sequestration for mitigating climate change.