bluuebunny/crossref_metadata_2025_split huggingface dataset:
A model combining clinical and genomic factors to predict response to PD-1/PD-L1 blockade in advanced urothelial carcinoma
Authors: Nassar Amin H. , Mouw Kent W. , Jegede Opeyemi , Shinagare Atul B. , Kim Jaegil , Liu Chia-Jen , Pomerantz Mark , Harshman Lauren C. , Van Allen Eliezer M. , Wei Xiao X. , McGregor Bradley , Choudhury Atish D. , Preston Mark A. , Dong Fei , Signoretti Sabina , Lindeman Neal I. , Bellmunt Joaquim , Choueiri Toni K. , Sonpavde Guru , Kwiatkowski David J. 
Published: December 2019

Abstract
Background
In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features associated with response to ICIs in mUC.

Methods
Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology.

Results
Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01–1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01–0.43) and single-nucleotide variant (SNV) count < 10 (OR = 0.04, 95% CI, 0.006–0.27) were identified as independent predictors of NCB to ICI in multivariable analysis (c-statistic = 0.90). None of the 16 variables were associated with clinical benefit in the taxane cohort.

Conclusions
This three-factor model includes genomic (SNV count >9) and clinical (NLR <5, lack of visceral metastasis) variables predictive for benefit to ICI but not taxane therapy for mUC. External validation of these hypothesis-generating results is warranted to enable use in routine clinical care.
TAS-116 inhibits oncogenic KIT signalling on the Golgi in both imatinib-naïve and imatinib-resistant gastrointestinal stromal tumours
Authors: Saito Yurina , Takahashi Tsuyoshi , Obata Yuuki , Nishida Toshirou , Ohkubo Shuichi , Nakagawa Fumio , Serada Satoshi , Fujimoto Minoru , Ohkawara Tomoharu , Nishigaki Takahiko , Sugase Takahito , Koh Masahiro , Ishida Tomo , Tanaka Koji , Miyazaki Yasuhiro , Makino Tomoki , Kurokawa Yukinori , Nakajima Kiyokazu , Yamasaki Makoto , Hirota Seiichi , Naka Tetsuji , Mori Masaki , Doki Yuichiro 
Published: December 2019

Abstract
Background
Despite the effectiveness of imatinib mesylate (IM), most gastrointestinal stromal tumours (GISTs) develop IM resistance, mainly due to the additional kinase-domain mutations accompanied by concomitant reactivation of KIT tyrosine kinase. Heat-shock protein 90 (HSP90) is one of the chaperone molecules required for appropriate folding of proteins such as KIT.

Methods
We used a novel HSP90 inhibitor, TAS-116, which showed specific binding to HSP90α/β with low toxicity in animal models. The efficacy and mechanism of TAS-116 against IM-resistant GIST were evaluated by using IM-naïve and IM-resistant GIST cell lines. We also evaluated the effects of TAS-116 on the other HSP90 client protein, EGFR, by using lung cell lines.

Results
TAS-116 inhibited growth and induced apoptosis in both IM-naïve and IM-resistant GIST cell lines with KIT activation. We found KIT was activated mainly in intracellular compartments, such as trans-Golgi cisternae, and TAS-116 reduced autophosphorylated KIT in the Golgi apparatus. In IM-resistant GISTs in xenograft mouse models, TAS-116 caused tumour growth inhibition. We found that TAS-116 decreased phosphorylated EGFR levels and inhibited the growth of EGFR-mutated lung cancer cell lines.

Conclusion
TAS-116 may be a novel promising drug to overcome tyrosine kinase inhibitor-resistance in both GIST and EGFR-mutated lung cancer.
Higher cholesterol levels, not statin use, are associated with a lower risk of hepatocellular carcinoma
Authors: Yi Sang-Wook , Kim Se Hwa , Han Ki Jun , Yi Jee-Jeon , Ohrr Heechoul 
Published: December 2019

AbstractWe aimed to examine whether statin users have a lower risk of hepatocellular carcinoma (HCC) after careful consideration of prevalent statin use and cholesterol levels. During a mean prospective follow-up of 8.4 years in 400,318 Koreans, 1686 individuals were diagnosed with HCC. When prevalent users were included, HCC risk was reduced by >50% in statin users, regardless of adjustment for total cholesterol (TC). When prevalent users were excluded, new users who initiated statins within 6 months after baseline had a 40% lower risk of HCC (hazard ratio [HR] = 0.59) in a TC-unadjusted analysis. However, this relationship disappeared (HR = 1.16, 95% CI = 0.80–1.69) after adjusting for TC levels measured within 6 months before statin initiation. TC levels had strong inverse associations with HCC in each model. High cholesterol levels at statin initiation, not statin use, were associated with reduced risk of HCC. Our study suggests no protective effect of statins against HCC.
HnRNP F/H associate with hTERC and telomerase holoenzyme to modulate telomerase function and promote cell proliferation
Authors: Xu Chenzhong , Xie Nan , Su Yuanyuan , Sun Zhaomeng , Liang Yao , Zhang Na , Liu Doudou , Jia Shuqin , Xing Xiaofang , Han Limin , Li Guodong , Tong Tanjun , Chen Jun 
Published: December 2019

AbstractHuman telomerase RNA component hTERC comprises multiple motifs that contribute to hTERC biogenesis, holoenzyme activity, and enzyme recruitment to telomeres. hTERC contains several guanine tracts (G-tracts) at its 5′-end, but its associated proteins and potential roles in telomerase function are still poorly understood. The heterogeneous nuclear ribonucleoproteins F, H1, and H2 (hnRNP F/H) are splicing factors that preferentially bind to poly(G)-rich sequences RNA. Here, we demonstrate that hnRNP F/H associate with both hTERC and telomerase holoenzyme to regulate telomerase activity. We reveal hnRNP F/H bind to the 5′-end region of hTERC in vitro and in vivo, and identify the first three G-tracts of hTERC and qRRM1 domain of hnRNP F/H are required for their interaction. Furthermore, hnRNP F/H also directly interact with telomerase holoenzyme. Functionally, we show that hnRNP F/H plays important roles in modulating telomerase activity and telomere length. Moreover, hnRNP F/H deletion greatly impair cancer and stem cell proliferation, and induce stem cell senescence, while hnRNP F/H overexpression delay stem cell senescence. Collectively, our findings unveil a novel role of hnRNP F/H as the binding partners of hTERC and telomerase holoenzyme to regulate telomerase function.
The impact of oncogenic RAS on redox balance and implications for cancer development
Authors: Lim Jonathan K. M. , Leprivier Gabriel 
Published: December 2019

AbstractThe RAS family of proto-oncogenes comprises HRAS, KRAS, and NRAS, which are among the most mutated genes in human cancers. The RAS family genes encode small GTPases that coordinate key signaling pathways in response to growth factors. Mutations in RAS result in a constitutively active form of the protein that supports cellular transformation and tumorigenesis. The mechanisms of oncogenic RAS-mediated transformation encompass uncontrolled proliferation and inhibition of cell death through overactivation of the RAF-MEK-ERK and the PI3K-AKT pathways, respectively. In addition, the control of redox balance by RAS has also been proposed to play a role in its oncogenic properties. However, the exact role of redox balance in mediating mutant RAS transformation is still under debate. Here, we present, on one hand, the involvement of pro-oxidant components in oncogenic RAS transformation, such as NADPH oxidases and mitochondrial reactive oxygen species, and how these promote transformation. On the other hand, we describe the contribution of antioxidant components to mutant RAS transformation, including Nrf2, glutathione biosynthesis and xCT, as well as the mechanisms by which antioxidant programs drive transformation. Finally, we aim to reconcile the seemingly opposite effects of oncogenic RAS on redox balance and discuss a model for the complementary role of both pro-oxidant and antioxidant pathways in mutant RAS-driven tumor progression.
Breathing chromium spinels: a showcase for a variety of pyrochlore Heisenberg Hamiltonians
Authors: Ghosh Pratyay , Iqbal Yasir , Müller Tobias , Ponnaganti Ravi T. , Thomale Ronny , Narayanan Rajesh , Reuther Johannes , Gingras Michel J. P. , Jeschke Harald O. 
Published: December 2019

AbstractWe address the long-standing problem of the microscopic origin of the richly diverse phenomena in the chromium breathing pyrochlore material family. Combining electronic structure and renormalization group techniques we resolve the magnetic interactions and analyze their reciprocal-space susceptibility. We show that the physics of these materials is principally governed by long-range Heisenberg Hamiltonian interactions, a hitherto unappreciated fact. Our calculations uncover that in these isostructural compounds, the choice of chalcogen triggers a proximity of the materials to classical spin liquids featuring degenerate manifolds of wave-vectors of different dimensions: A Coulomb phase with three-dimensional degeneracy for LiInCr4O8 and LiGaCr4O8, a spiral spin liquid with two-dimensional degeneracy for CuInCr4Se8 and one-dimensional line degeneracies characteristic of the face-centered cubic antiferromagnet for LiInCr4S8, LiGaCr4S8, and CuInCr4S8. The surprisingly complex array of prototypical pyrochlore behaviors we discovered in chromium spinels may inspire studies of transition paths between different semi-classical spin liquids by doping or pressure.
Shift rotation, circadian misalignment and excessive body weight influence psychomotor performance: a prospective and observational study under real life conditions
Authors: Rosa Dayane Eusenia , Marot Luisa Pereira , de Mello Marco Túlio , Narciso Fernanda Veruska , Gonçalves Bruno da Silva Brandão , Marqueze Elaine Cristina , Crispim Cibele Aparecida 
Published: December 2019

AbstractWe aimed to evaluate the influence of shift work rotation, circadian misalignment and being overweight/obese on psychomotor performance throughout a complete shift rotation schedule. The study was conducted with 30 males working rotating shifts from a mining company under real life conditions. Individuals were evaluated over seven days in a shift schedule carried out as follow: two shifts in the morning (D1 and D2), two shifts in the afternoon (D3 and D4), 24 hour free day (D5) and two shifts at night (D6 and D7). Work performance was evaluated by psychomotor vigilance task tests (PVT), and actigraphy was used to characterise the rest-activity rhythm based on intradaily variability (IV) and interdaily stability (IS) of nonparametric functions. We found a significant effect of the shift, body mass index (BMI), IS and IV on lapses in attention. More lapses occurred on D7 than D1, D2, D3 and D4 of the schedule shift. The obese group presented a higher number of lapses in attention than eutrophic. The interaction between day and IS showed that less synchronised individuals presented a higher number of lapses in attention on D7 than D1 and, for the interaction between day and IV, more fragmented individuals presented a higher number of lapses in attention on D7 than D6. We conclude that higher BMI, lower synchronisation and higher fragmentation of the rest-activity pattern influenced lapses in attention throughout the shift rotation.
Mesenchymal Stromal Cells Induce Podocyte Protection in the Puromycin Injury Model
Authors: Ornellas Felipe Mateus , Ramalho Rodrigo J. , Fanelli Camilla , Garnica Margoth Ramos , Malheiros Denise M. A. C. , Martini Sabrina Vargas , Morales Marcelo Marcos , Noronha Irene L. 
Published: December 2019

AbstractPodocytes are specialized cells with a limited capacity for cell division that do not regenerate in response to injury and loss. Insults that compromise the integrity of podocytes promote proteinuria and progressive renal disease. The aim of this study was to evaluate the potential renoprotective and regenerative effects of mesenchymal stromal cells (mSC) in a severe form of the podocyte injury model induced by intraperitoneal administration of puromycin, aggravated by unilateral nephrectomy. Bone derived mSC were isolated and characterized according to flow cytometry analyses and to their capacity to differentiate into mesenchymal lineages. Wistar rats were divided into three groups: Control, PAN, and PAN+ mSC, consisting of PAN rats treated with 2 × 105 mSC. PAN rats developed heavy proteinuria, hypertension, glomerulosclerosis and significant effacement of the foot process. After 60 days, PAN rats treated with mSC presented a significant amelioration of all these abnormalities. In addition, mSC treatment recovered WT1 expression, improved nephrin, podocin, synaptopodin, podocalyxin, and VEGF expression, and downregulated proinflammatory Th1 cytokines in the kidney with a shift towards regulatory Th2 cytokines. In conclusion, mSC administration induced protection of podocytes in this experimental PAN model, providing new perspectives for the treatment of renal diseases associated with podocyte damage.
Exploring genetic architecture of grain yield and quality traits in a 16-way indica by japonica rice MAGIC global population
Authors: Zaw Hein , Raghavan Chitra , Pocsedio Arnel , Swamy B. P. Mallikarjuna , Jubay Mona Liza , Singh Rakesh Kumar , Bonifacio Justine , Mauleon Ramil , Hernandez Jose E. , Mendioro Merlyn S. , Gregorio Glenn B. , Leung Hei 
Published: December 2019

AbstractIdentification of Quantitative Trait Loci (QTL) has been a challenge for complex traits due to the use of populations with narrow genetic base. Most of QTL mapping studies were carried out from crosses made within the subspecies, either indica × indica or japonica × japonica. In this study we report advantages of using Multi-parent Advanced Generation Inter-Crosses global population, derived from a combination of eight indica and eight japonica elite parents, in QTL discovery for yield and grain quality traits. Genome-wide association study and interval mapping identified 38 and 34 QTLs whereas Bayesian networking detected 60 QTLs with 22 marker-marker associations, 32 trait-trait associations and 65 marker-trait associations. Notably, nine known QTLs/genes qPH1/OsGA20ox2, qDF3/OsMADS50, PL, QDg1, qGW-5b, grb7-2, qGL3/GS3, Amy6/Wx gene and OsNAS3 were consistently identified by all approaches for nine traits whereas qDF3/OsMADS50 was co-located for both yield and days-to-flowering traits on chromosome 3. Moreover, we identified a number of candidate QTLs in either one or two analyses but further validations will be needed. The results indicate that this new population has enabled identifications of significant QTLs and interactions for 16 traits through multiple approaches. Pyramided recombinant inbred lines provide a valuable source for integration into future breeding programs.
Ultrastructural modeling of small angle scattering from photosynthetic membranes
Authors: Jakubauskas Dainius , Kowalewska Łucja , Sokolova Anna V. , Garvey Christopher J. , Mortensen Kell , Jensen Poul Erik , Kirkensgaard Jacob J. K. 
Published: December 2019

AbstractThe last decade has seen a range of studies using non-invasive neutron and X-ray techniques to probe the ultrastructure of a variety of photosynthetic membrane systems. A common denominator in this work is the lack of an explicitly formulated underlying structural model, ultimately leading to ambiguity in the data interpretation. Here we formulate and implement a full mathematical model of the scattering from a stacked double bilayer membrane system taking instrumental resolution and polydispersity into account. We validate our model by direct simulation of scattering patterns from 3D structural models. Most importantly, we demonstrate that the full scattering curves from three structurally typical cyanobacterial thylakoid membrane systems measured in vivo can all be described within this framework. The model provides realistic estimates of key structural parameters in the thylakoid membrane, in particular the overall stacking distance and how this is divided between membranes, lumen and cytoplasmic liquid. Finally, from fitted scattering length densities it becomes clear that the protein content in the inner lumen has to be lower than in the outer cytoplasmic liquid and we extract the first quantitative measure of the luminal protein content in a living cyanobacteria.
Computational discovery of hidden breaks in 28S ribosomal RNAs across eukaryotes and consequences for RNA Integrity Numbers
Authors: Natsidis Paschalis , Schiffer Philipp H. , Salvador-Martínez Irepan , Telford Maximilian J. 
Published: December 2019

AbstractIn some eukaryotes, a ‘hidden break’ has been described in which the 28S ribosomal RNA molecule is cleaved into two subparts. The break is common in protostome animals (arthropods, molluscs, annelids etc.), but a break has also been reported in some vertebrates and non-metazoan eukaryotes. We present a new computational approach to determine the presence of the hidden break in 28S rRNAs using mapping of RNA-Seq data. We find a homologous break is present across protostomes although it has been lost in a small number of taxa. We show that rare breaks in vertebrate 28S rRNAs are not homologous to the protostome break. A break is found in just 4 out of 331 species of non-animal eukaryotes studied and, in three of these, the break is located in the same position as the protostome break suggesting a striking instance of convergent evolution. RNA Integrity Numbers (RIN) rely on intact 28S rRNA and will be consistently underestimated in the great majority of animal species with a break.
Tailings microbial community profile and prediction of its functionality in basins of tungsten mine
Authors: Chung Ana Paula , Coimbra Carina , Farias Pedro , Francisco Romeu , Branco Rita , Simão Francisco V. , Gomes Elsa , Pereira Alcides , Vila Maria C. , Fiúza António , Mortensen Martin S. , Sørensen Søren J. , Morais Paula V. 
Published: December 2019

AbstractIn a circular economy concept, where more than 300 million tons of mining and quarrying wastes are produced annually, those are valuable resources, supplying metals that are extracted today by other processes, if innovative methods and processes for efficient extraction of these elements are applied. This work aims to assess microbiological and chemical spatial distribution within two tailing basins from a tungsten mine, using a MiSeq approach targeting the 16S rRNA gene, to relate microbial composition and function with chemical variability, thus, providing information to enhance the efficiency of the exploitation of these secondary sources. The tailings sediments core microbiome comprised members of family Anaerolineacea and genera Acinetobacter, Bacillus, Cellulomonas, Pseudomonas, Streptococcus and Rothia, despite marked differences in tailings physicochemical properties. The higher contents of Al and K shaped the community of Basin 1, while As-S-Fe contents were correlated with the microbiome composition of Basin 2. The predicted metabolic functions of the microbiome were rich in genes related to metabolism pathways and environmental information processing pathways. An in-depth understanding of the tailings microbiome and its metabolic capabilities can provide a direction for the management of tailings disposal sites and maximize their potential as secondary resources.
Locking Two Rigid-body Bundles in an Outward-Facing Conformation: The Ion-coupling Mechanism in a LeuT-fold Transporter
Authors: Li Jing , Zhao Zhiyu , Tajkhorshid Emad 
Published: December 2019

AbstractSecondary active transporters use electrochemical gradient of ions to fuel the “uphill” translocation of the substrate following the alternating-access model. The coupling of ions to conformational dynamics of the protein remains one of the least characterized aspects of the transporter function. We employ extended molecular dynamics (MD) simulations to examine the Na+-binding effects on the structure and dynamics of a LeuT-fold, Na+-coupled secondary transporter (Mhp1) in its major conformational states, i.e., the outward-facing (OF) and inward-facing (IF) states, as well as on the OF ↔ IF state transition. Microsecond-long, unbiased MD simulations illustrate that Na+stabilizes an OF conformation favorable for substrate association, by binding to a highly conserved site at the interface between the two helical bundles and restraining their relative position and motion. Furthermore, a special-protocol biased simulation for state transition suggests that Na+binding hinders the OF ↔ IF transition. These synergistic Na+-binding effects allosterically couple the ion and substrate binding sites and modify the kinetics of state transition, collectively increasing the lifetime of an OF conformation with high substrate affinity, thereby facilitating substrate recruitment from a low-concentration environment. Based on the similarity between our findings for Mhp1 and experimental reports on LeuT, we propose that this model may represent a general Na+-coupling mechanism among LeuT-fold transporters.
Characterizing the maximum number of layers in chemically exfoliated graphene
Authors: Szirmai Péter , Márkus Bence G. , Chacón-Torres Julio C. , Eckerlein Philipp , Edelthalhammer Konstantin , Englert Jan M. , Mundloch Udo , Hirsch Andreas , Hauke Frank , Náfrádi Bálint , Forró László , Kramberger Christian , Pichler Thomas , Simon Ferenc 
Published: December 2019

AbstractAn efficient route to synthesize macroscopic amounts of graphene is highly desired and bulk characterization of such samples, in terms of the number of layers, is equally important. We present a Raman spectroscopy-based method to determine the typical upper limit of the number of graphene layers in chemically exfoliated graphene. We utilize a controlled vapour-phase potassium intercalation technique and identify a lightly doped stage, where the Raman modes of undoped and doped few-layer graphene flakes coexist. The spectra can be unambiguously distinguished from alkali doped graphite, and modeling with the typical upper limit of the layers yields an upper limit of flake thickness of five layers with a significant single-layer graphene content. Complementary statistical AFM measurements on individual few-layer graphene flakes find a consistent distribution of the layer numbers.