bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crustal thickness, rift‐drift and potential links to key global events
Authors: Paulsen Timothy , Deering Chad , Sliwinski Jakub , Chatterjee Snehamoy , Bachmann Olivier , Guillong Marcel 
Published: June 2020

AbstractOrogenic crustal thickening leads to increased continental elevation and runoff into the oceans, but there are fundamental uncertainties in the temporal patterns of thickening through Earth history. U‐Pb age and trace element data in detrital zircons from Antarctica are consistent with recent global analyses suggesting two dominant peaks in average crustal thickness from ~2.6 to 2.0 Ga and ~0.8 to 0.5 Ga. Shifts in marine carbonate 87Sr/86Sr ratios show two primary peaks that post‐date these crustal thickness peaks, suggesting significant weathering and erosion of global continental relief. Both episodes correlate well with zircon trace element and isotope proxies indicating enhanced crustal and fluid input into subduction zone magmas. Increased crustal thickness correlates with increased passive margin abundance and overlaps with snowball Earth glaciations and atmospheric oxygenation, suggesting a causal link between continental rift‐drift phases and major transitions in Earth's atmospheric and oceanic evolution.
Primary leaf‐type ferredoxin 1 participates in photosynthetic electron transport and carbon assimilation in rice
Authors: He Lei , Li Man , Qiu Zhennan , Chen Dongdong , Zhang Guangheng , Wang Xiaoqi , Chen Guang , Hu Jiang , Gao Zhenyu , Dong Guojun , Ren Deyong , Shen Lan , Zhang Qiang , Guo Longbiao , Qian Qian , Zeng Dali , Zhu Li 
Published: June 2020

SUMMARYFerredoxins (Fds) play a crucial role in photosynthesis by regulating the distribution of electrons to downstream enzymes. Multiple Fd genes have been annotated in the Oryza sativa L. (rice) genome; however, their specific functions are not well understood. Here, we report the functional characterization of rice Fd1. Sequence alignment, phylogenetic analysis of seven rice Fd proteins and quantitative reverse transcription polymerase chain reaction (qRT‐PCR) analysis showed that rice Fd1 is a primary leaf‐type Fd. Electron transfer assays involving NADP+ and cytochrome c indicated that Fd1 can donate electrons from photosystem I (PSI) to ferredoxin‐NADP+ reductase. Loss‐of‐function fd1 mutants showed chlorosis and seedling lethality at the three‐leaf stage. The deficiency of Fd1 impaired photosynthetic electron transport, which affected carbon assimilation. Exogenous glucose treatment partially restored the mutant phenotype, suggesting that Fd1 plays an important role in photosynthetic electron transport in rice. In addition, the transcript levels of Fd‐dependent genes were affected in fd1 mutants, and the trend was similar to that observed in fdc2 plants. Together, these results suggest that OsFd1 is the primary Fd in photosynthetic electron transport and carbon assimilation in rice.
Optimization of Francis Turbines for Variable Speed Operation Using Surrogate Modeling Approach
Authors: Iliev Igor , Tengs Erik Os , Trivedi Chirag , Dahlhaug Ole Gunnar 
Published: June 2020

Abstract
Previous studies suggested variable speed operation (VSO) of Francis turbines as a measure to improve the efficiency at off-design operating conditions. This is, however, strongly dependent on the hydraulic design and, for an existing turbine, improvements can be expected only with a proper redesign of the hydraulic surfaces. Therefore, an optimization algorithm is proposed and applied to the runner of a low specific speed Francis turbine, with an optimization strategy specifically constructed to improve the variable speed performance. In the constrained design space of the reference turbine, the geometry of the replacement runner is parametrically defined using 15 parameters. Box–Behnken method was used to populate the design space with 421 unique samples, needed to train fully quadratic response surface models of three characteristic efficiencies defined by the proposed objective function. Computational fluid dynamics (CFD) was used to calculate the responses for each sample. The parametric study showed that the anticipated variation of the shape of the hill chart, needed to improve the variable speed performance of the turbine, is limited within a narrow range. The presented method is general and can be applied to any specific speed in the Francis turbine range, for both synchronous speed and variable speed optimization tasks.
Observational study on the current status of thalassaemia in Malaysia: a report from the Malaysian Thalassaemia Registry
Authors: Mohd Ibrahim Hishamshah , Muda Zulaiha , Othman Ida Shahnaz , Mohamed Unni Mohamed Najib , Teh Kok Hoi , Thevarajah Asohan , Gunasagaran Kogilavani , Ong Gek Bee , Yeoh Seoh Leng , Muhammad Rivai Aisyah , Che Mohd Razali Che Hadibiah , Din Nazzlin Dizana , Abdul Latiff Zarina , Jamal Rahman , Mohamad Norsarwany , Mohd Ariffin Hany , Alias Hamidah 
Published: June 2020

ObjectiveThalassaemia is the most common inherited blood disorder in Malaysia. This study aims to report the current status of thalassaemia in Malaysia and provide a comprehensive understanding of the disease through data obtained from the Malaysian Thalassaemia Registry.DesignData were extracted from the Malaysian Thalassaemia Registry, a web-based system accessible to enrolled users through www.mytalasemia.net.my.SettingThe Malaysian Thalassaemia Registry data was recorded from reports obtained from 110 participating government and university hospitals in Malaysia.ParticipantsThe patients were those attending the 110 participating hospitals for thalassaemia treatment.InterventionData were collected from the Malaysian Thalassaemia Registry from 2007 until the fourth quarter of 2018.Primary outcome measure7984 out of 8681 patients with thalassaemia registered in the Malaysian Thalassaemia Registry were reported alive.ResultsMajority of the patients were reported in the state of Sabah (22.72%); the largest age group affected was 5.0–24.9 years old (64.45%); the largest ethnic group involved was Malay (63.95%); and the major diagnosis was haemoglobin E/β-thalassaemia (34.37%). From the 7984 patients, 56.73% were on regular blood transfusions and 61.72% were on chelation therapy. A small fraction (14.23%) has undergone splenectomy, while the percentage of patients with severe iron overload (serum ferritin ≥5000 µg/L) reduced over time. However, cardiac complications are still the main cause of death in patients with thalassaemia.ConclusionData gathered into the registry can be used to understand the progression of the disorder, to monitor iron overload management and to improve the outcomes of treatment, to enhance preventive strategies, reduce healthcare burden and improve the quality of life. Sustainability of the Malaysian Thalassaemia Registry is important for surveillance of thalassaemia management in the country and help the national health authorities to develop more effective policies.
Variation in tonsillectomy cost and revisit rates: analysis of administrative and billing data from US children’s hospitals
Authors: Mahant Sanjay , Richardson Troy , Keren Ron , Srivastava Rajendu , Meier Jeremy 
Published: June 2020

BackgroundTonsillectomy is one of the most common and cumulatively expensive surgical procedures in children. We determined if substantial variation in resource use, as measured by standardised costs, exists across hospitals for performing tonsillectomy and if higher resource use is associated with better quality of care, as measured by revisits to hospital.MethodsWe conducted a retrospective analysis of children undergoing routine outpatient tonsillectomy between 2011 to 2017 across US children's hospitals using an administrative and billing data source. The primary outcome measures were the hospital tonsillectomy standardised cost and the 30-day revisit rate to hospital. We analysed the interhospital variation in standardised cost by determining the number of outlier hospitals in standardised cost and the intraclass correlation coefficient.Results131 814 children (median age 6 years, IQR: 4,9; female sex 52.5%) underwent tonsillectomy for airway obstruction (62.9%) and infection (23.9%) across 28 hospitals. The median adjusted hospital standardised cost for tonsillectomy was $2392 (IQR: $1827, $2793; range: $1166 to $4222). There was substantial interhospital variation in costs as 11 (40%) hospitals were cost outliers, and the intraclass correlation coefficient was 0.62, suggesting that 62% of the variation in cost was attributable to variation between hospitals. The median hospital revisit rate was 9.5% (IQR: 7.8, 12.1) and higher hospital costs did not correlate with lower revisit rates (rs=0.03, 95% CI −0.36 to 0.41; p=0.87).ConclusionsThere is substantial variation in hospital resource use and standardised costs for routine outpatient tonsillectomy across US children’s hospitals. Higher resource use is not associated with lower revisit rates. Further study is needed to understand the practices of lower resource use hospitals who deliver high quality of care.
Adsorption and dissociation of H2O monomer on ceria(111): Density functional theory calculations
Authors: Wang Shuangxi , Zhang Ping 
Published: June 2020

The adsorption properties of isolated H2O molecule on stoichiometric and reduced ceria(111) surfaces are theoretically investigated by first-principles calculations and molecular dynamics simulations. We find that the most stable adsorption configurations form two hydrogen bonds between the adsorbate and substrate. The water molecule is very inert on the stoichiometric surface unless up to a high temperature of 600 K. For the reduced surface, we find that the oxygen vacancy enhances the interaction. Moreover, simulations at low temperature of 100 K confirm that it is facilitated for water to dissociate into H and OH species.
Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance
Authors: Uchihara Tomoyuki , Miyake Keisuke , Yonemura Atsuko , Komohara Yoshihiro , Itoyama Rumi , Koiwa Mayu , Yasuda Tadahito , Arima Kota , Harada Kazuto , Eto Kojiro , Hayashi Hiromitsu , Iwatsuki Masaaki , Iwagami Shiro , Baba Yoshifumi , Yoshida Naoya , Yashiro Masakazu , Masuda Mari , Ajani Jaffer A. , Tan Patrick , Baba Hideo , Ishimoto Takatsugu 
Published: June 2020

Abstract

Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAFs impact the aggressive characteristics of gastric cancer cells, the contribution of CAF-EV to gastric cancer progression has not been elucidated. Here, we investigated the molecular mechanism of the changes in gastric cancer characteristics induced by CAF-EV. CAF abundance in gastric cancer tissues was associated with poor prognosis of patients with gastric cancer receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of gastric cancer cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified that Annexin A6 plays a pivotal role in network formation and drug resistance of gastric cancer cells in the ECM via activation of β1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated gastric cancer drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by Annexin A6 in CAF-EV and provide a potential avenue for overcoming gastric cancer drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics.

Significance:
This study elucidates a novel molecular mechanism through which Annexin A6 in CAF-EV activates FAK-YAP by stabilizing β1 integrin at the cell surface of gastric cancer cells and subsequently induces drug resistance.
Traditional Diagnostics versus Disruptive Technology: The Role of the Pathologist in the Era of Liquid Biopsy
Authors: Sholl Lynette M. , Oxnard Geoffrey R. , Paweletz Cloud P. 
Published: June 2020

AbstractPrecision medicine in cancer care is predicated on access to several fundamental pieces of data: (i) a precise tumor diagnosis, (ii) accurate stage classification, and (iii) protein or molecular biomarkers that predict efficacy of targeted therapies. For all patients with cancer, these data points are generated by obtaining a tumor sample and subjecting it to analysis by a pathologist and, when appropriate, a molecular pathologist. While tumor diagnosis and pathologic staging (gross and microscopic examination of the primary tumor and draining lymph nodes) require the infrastructure and expertise of an anatomic pathology program, the advent of “liquid biopsy” has driven a shift in molecular biomarker testing away from local pathology laboratories and into high-throughput, centralized (and often for-profit) laboratories. What does this mean for patient care? How is the role of the pathologist affected? What are the implications for integration of diagnostic information and ultimately for appropriate therapy selection? This article will consider the current testing landscape, address current challenges in the use of liquid biopsy in clinical practice, and consider ways the pathologist should be involved in interpreting liquid biopsy data in the context of the patient's cancer diagnosis and stage.
Lymphatic Vessels in Tumor Dissemination versus Immunotherapy
Authors: Vaahtomeri Kari , Alitalo Kari 
Published: June 2020

Abstract
During the growth of various cancers, primary tumors can escape antitumor immune responses of their host and eventually disseminate into distant organs. Peritumoral lymphatic vessels connect the primary tumor to lymph nodes, facilitating tumor entry into lymph nodes, systemic circulation, and metastasis. Lymph node metastases that occur frequently provide sites of tumor cell spread, whereas tumor antigen transfer into and presentation in tumor-draining lymph nodes induce activation of tumor-specific T-lymphocyte responses that can result in cytolytic targeting of the tumor. Here, we discuss the recently emerged controversial role of the lymphatic vessels in tumor dissemination and cancer immunotherapy.
KRASQ61H Preferentially Signals through MAPK in a RAF Dimer-Dependent Manner in Non–Small Cell Lung Cancer
Authors: Zhou Zhi-Wei , Ambrogio Chiara , Bera Asim K. , Li Qing , Li Xing-Xiao , Li Lianbo , Son Jieun , Gondi Sudershan , Li Jiaqi , Campbell Emily , Jin Hua , Okoro Jeffrey J. , Xu Cheng-Xiong , Janne Pasi A. , Westover Kenneth D. 
Published: June 2020

Abstract

Assembly of RAS molecules into complexes at the cell membrane is critical for RAS signaling. We previously showed that oncogenic KRAS codon 61 mutations increase its affinity for RAF, raising the possibility that KRASQ61H, the most common KRAS mutation at codon 61, upregulates RAS signaling through mechanisms at the level of RAS assemblies. We show here that KRASQ61H exhibits preferential binding to RAF relative to PI3K in cells, leading to enhanced MAPK signaling in in vitro models and human NSCLC tumors. X-ray crystallography of KRASQ61H:GTP revealed that a hyperdynamic switch 2 allows for a more stable interaction with switch 1, suggesting that enhanced RAF activity arises from a combination of absent intrinsic GTP hydrolysis activity and increased affinity for RAF. Disruption of KRASQ61H assemblies by the RAS oligomer–disrupting D154Q mutation impaired RAF dimerization and altered MAPK signaling but had little effect on PI3K signaling. However, KRASQ61H oligomers but not KRASG12D oligomers were disrupted by RAF mutations that disrupt RAF–RAF interactions. KRASQ61H cells show enhanced sensitivity to RAF and MEK inhibitors individually, whereas combined treatment elicited synergistic growth inhibition. Furthermore, KRASQ61H tumors in mice exhibited high vulnerability to MEK inhibitor, consistent with cooperativity between KRASQ61H and RAF oligomerization and dependence on MAPK signaling. These findings support the notion that KRASQ61H and functionally similar mutations may serve as predictive biomarkers for targeted therapies against the MAPK pathway.

Significance:
These findings show that oncogenic KRASQ61H forms a cooperative RAS–RAF ternary complex, which renders RAS-driven tumors vulnerable to MEKi and RAFi, thus establishing a framework for evaluating RAS biomarker-driven targeted therapies.
MRI Distinguishes Tumor Hypoxia Levels of Different Prognostic and Biological Significance in Cervical Cancer
Authors: Hillestad Tiril , Hompland Tord , Fjeldbo Christina S. , Skingen Vilde E. , Salberg Unn Beate , Aarnes Eva-Katrine , Nilsen Anja , Lund Kjersti V. , Evensen Tina S. , Kristensen Gunnar B. , Stokke Trond , Lyng Heidi 
Published: June 2020

Abstract

Tumor hypoxia levels range from mild to severe and have different biological and therapeutical consequences but are not easily assessable in patients. Here we present a method based on diagnostic dynamic contrast enhanced (DCE) MRI that reflects a continuous range of hypoxia levels in patients with tumors of cervical cancer. Hypoxia images were generated using an established approach based on pixel-wise combination of DCE-MRI parameters νe and Ktrans, representing oxygen consumption and supply, respectively. Using two tumor models, an algorithm to retrieve surrogate measures of hypoxia levels from the images was developed and validated by comparing the MRI-defined levels with hypoxia levels reflected in pimonidazole-stained histologic sections. An additional indicator of hypoxia levels in patient tumors was established on the basis of expression of nine hypoxia-responsive genes; a strong correlation was found between these indicator values and MRI-defined hypoxia levels in 63 patients. Chemoradiotherapy outcome of 74 patients was most strongly predicted by moderate hypoxia levels, whereas more severe or milder levels were less predictive. By combining gene expression profiles and MRI-defined hypoxia levels in cancer hallmark analysis, we identified a distribution of levels associated with each hallmark; oxidative phosphorylation and G2–M checkpoint were associated with moderate hypoxia, epithelial-to-mesenchymal transition, and inflammatory responses with significantly more severe levels. At the mildest levels, IFN response hallmarks together with HIF1A protein expression by IHC appeared significant. Thus, our method visualizes the distribution of hypoxia levels within patient tumors and has potential to distinguish levels of different prognostic and biological significance.

Significance:
These findings present an approach to image a continuous range of hypoxia levels in tumors and demonstrate the combination of imaging with molecular data to better understand the biology behind these different levels.
Radiation with STAT3 Blockade Triggers Dendritic Cell–T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy
Authors: Ott Martina , Kassab Cynthia , Marisetty Anantha , Hashimoto Yuuri , Wei Jun , Zamler Daniel , Leu Jia-Shiun , Tomaszowski Karl-Heinz , Sabbagh Aria , Fang Dexing , Gupta Pravesh , Priebe Waldemar , Zielinski Rafal J. , Burks Jared K. , Long James P. , Kong Ling-Yuan , Fuller Gregory N. , DeGroot John , Sulman Erik P. , Heimberger Amy B. 
Published: June 2020

Abstract

Purpose:
Patients with central nervous system (CNS) tumors are typically treated with radiotherapy, but this is not curative and results in the upregulation of phosphorylated STAT3 (p-STAT3), which drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of STAT3 and whole-brain radiotherapy (WBRT) in a murine model of glioma.

Experimental Design:
C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood–brain barrier–penetrant inhibitor of the STAT3 pathway, or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune-incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and NanoString gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment.

Results:
The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy in the GL261 glioma model (combination vs. control P &lt; 0.0001). Immunologic memory appeared to be induced, because mice were protected during subsequent tumor rechallenge. The therapeutic effect of the combination was completely lost in immune-incompetent animals. NanoString analysis and immunofluorescence revealed immunologic reprograming in the CNS tumor microenvironment specifically affecting dendritic cell antigen presentation and T-cell effector functions.

Conclusions:
This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the CNS by inducing dendritic cell and T-cell interactions in the CNS tumor.
Addition of Antiestrogen Treatment in Patients with Malignant PEComa Progressing to mTOR Inhibitors
Authors: Sanfilippo Roberta , Fabbroni Chiara , Fucà Giovanni , Fumagalli Elena , Morosi Carlo , Sbaraglia Marta , Gronchi Alessandro , Collini Paola , Dei Tos Angelo P. , Casali Paolo G. 
Published: June 2020

Abstract

Purpose:
Perivascular epithelioid cell tumors (PEComa) are rare mesenchymal neoplasms. mTOR inhibitors are the most active agents in PEComa and in patients progressing to mTOR inhibitors, other available therapies have limited benefit. Preclinical evidences showed a cross-talk between the mTOR pathway and estrogen receptor signaling. This provided a rationale for adding an antiestrogen treatment in female patients becoming resistant to mTOR inhibitors.

Experimental Design:
Since April 2018, female patients with advanced/metastatic PEComa progressing to mTOR inhibitors were treated with a combination of sirolimus and exemestane with or without LHRH analogue (based on menopausal status). This case series was retrospectively reviewed. Survival analyses were performed using the Kaplan–Meier method.

Results:
A total of seven consecutive patients treated with the combination of sirolimus and antiestrogen treatment were retrospectively reviewed. Six (86%) received a combination of sirolimus and exemestane, whereas one patient (14%) received a combination of sirolimus, exemestane, and triptorelin since in premenopausal status. After a median follow-up of 13.1 months, three patients (43%) experienced a partial response, three patients (43%) experienced a stabilization of disease, and one patient (14%) had disease progression with an overall response rate of 43% and a disease control rate of 86%.

Conclusions:
In this small retrospective case series, the addition of antiestrogen treatment in female patients with advanced PEComa progressing to mTOR inhibitors resulted in a remarkable clinical benefit in a setting where no other options are available.