bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down‐selecting circumsporozoite protein‐based malaria vaccine: A comparison of malaria sporozoite challenge model
Authors: Amelia Fitri , Iyori Mitsuhiro , Emran Talha Bin , Yamamoto Daisuke S. , Genshi Kento , Otsuka Hiromu , Onoue Yutaro , Yusuf Yenni , Islam Ashekul , Yoshida Shigeto 
Published: March 2019

SummaryPlasmodium falciparum circumsporozoite protein (PfCSP) is the main target antigen in development of pre‐erythrocytic malaria vaccines. To evaluate PfCSP vaccines in animal models, challenge by intravenous sporozoite injection is preferentially used. However, in clinical trials, vaccinated human volunteers are exposed to the bites of malaria‐infected mosquitoes. In this study, we down‐selected Escherichia coli‐produced full‐length PfCSP (PfCSP‐F) and its three truncated PfCSPs based on their abilities to elicit immune response and protection in mice against two challenge models. We showed that immunization with three doses of PfCSP‐F elicited high anti‐PfCSP antibody titres and 100% protection against the bites of infected mosquitoes. Meanwhile, three‐dose truncated PfCSP induced 60%‐70% protection after immunization with each truncated PfCSP. Heterologous prime‐boost immunization regimen with adenovirus‐PfCSP‐F and R32LR greatly induced complete protection against intravenous sporozoite injection. Our results suggest that Abs to both anti‐repeat and anti‐nonrepeat regions induced by PfCSP‐F are required to confer complete protection against challenge by the bites of infected mosquitoes, whereas anti‐repeat Abs play an important role in protection against intravenous sporozoite injection. Our findings provide a potential clinical application that PfCSP‐F vaccine induces potent Abs capable of neutralizing sporozoites in the dermis inoculated by infected mosquitoes and subsequently sporozoites in the blood circulation.
Response of unconfined turbidity current to deep‐water fold and thrust belt topography: Orthogonal incidence on solitary and segmented folds
Authors: Howlett Danielle M. , Ge Zhiyuan , Nemec Wojciech , Gawthorpe Rob L. , Rotevatn Atle , Jackson Christopher A.‐L. 
Published: March 2019

AbstractSea‐floor topography of deep‐water folds is widely considered to have a major impact on turbidity currents and their depositional systems, but understanding the flow response to such features was limited mainly to conceptual notions inspired by small‐scale laboratory experiments. High‐resolution three‐dimensional numerical experiments can compensate for the lack of natural‐scale flow observations. The present study combines numerical modelling of thrusts with fault‐propagation folds by Trishear3D software with computational fluid dynamics simulations of a natural‐scale unconfined turbidity current by MassFlow‐3D™ software. The study reveals the hydraulic and depositional responses of a turbidity current (ca 50 m thick) to typical topographic features that it might encounter in an orthogonal incidence on a sea‐floor deep‐water fold and thrust belt. The supercritical current (ca 10 m sec−1) decelerated and thickened due to the hydraulic jump on the fold backlimb counter‐slope, where a reverse overflow formed through current self‐reflection and a reverse underflow was issued by backward squeezing of a dense near‐bed sediment load. The reverse flows were re‐feeding sediment to the parental current, reducing its waning rate and extending its runout. The low‐efficiency current, carrying sand and silt, outran a downslope distance of >17 km with only modest deposition (<0·2 m) beyond the fold. Most of the flow volume diverted sideways along the backlimb to surround the fold and spread further downslope, with some overspill across the fold and another hydraulic jump at the forelimb toe. In the case of a segmented fold, a large part of the flow went downslope through the segment boundary. Preferential deposition (0·2 to 1·8 m) occurred on the fold backlimb and directly upslope, and on the forelimb slope in the case of a smaller fold. The spatial patterns of sand entrapment revealed by the study may serve as guidelines for assessing the influence of substrate folds on turbiditic sedimentation in a basin.
Therapeutic impact of red blood cell transfusion on anemic outpatients: the RETRO study
Authors: St. Lezin Elizabeth , Karafin Matthew S. , Bruhn Roberta , Chowdhury Dhuly , Qu Lirong , Bialkowski Walter , Merenda Scott , D'Andrea Pamela , McCalla Anne‐Lyne , Anderson Lisa , Keating Sheila M. , Stone Mars , Snyder Edward L. , Brambilla Donald , Murphy Edward L. , Norris Philip J. , Hilton Joan F. , Spencer Bryan R. , Kleinman Steven , Carson Jeffrey L. ,   NHLBI Recipient Epidemiology and Donor Evaluation Study (REDS)‐III Program
Published: March 2019

BACKGROUNDPatients with cancer or other diagnoses associated with chronic anemia often receive red blood cell (RBC) transfusion as outpatients, but the effect of transfusion on functional status is not well demonstrated.STUDY DESIGN AND METHODSTo estimate the effect of transfusion on functional status and quality of life, we measured 6‐minute walk test distance and fatigue‐ and dyspnea‐related quality‐of‐life scores before and 1 week after RBC transfusion in 208 outpatients age ≥50 with at least one benign or malignant hematology/oncology diagnosis. To account for potential confounding effects of cancer treatment, patients were classified into two groups based on cancer treatment within 4 weeks of the study transfusion. Minimum clinically important improvements over baseline were 20 meters in walk test distance, 3 points in fatigue score, and 2 points in dyspnea score.RESULTSThe median improvement in unadjusted walk test distance was 20 meters overall and 30 meters in patients not receiving recent cancer treatment. Fatigue scores improved overall by a median of 3 points and by 4 points in patients without cancer treatment. There was no clinically important change in dyspnea scores. In multiple linear regression analysis, patients who maintained hemoglobin (Hb) levels of 8 g/dL or greater at 1 week posttransfusion, who had not received recent cancer treatment, and who did not require hospitalization during the study showed clinically important increases in mean walk test distance.CONCLUSIONSRed blood cell transfusion is associated with a modest, but clinically important improvement in walk test distance and fatigue score outcomes in adult hematology/oncology outpatients.
Impact of intraoperative high‐volume autologous blood collection on allogeneic transfusion during and after cardiac surgery: a propensity score matched analysis
Authors: Henderson Reney A. , Mazzeffi Michael A. , Strauss Erik R. , Williams Brittney , Wipfli Camron , Dawood Murtaza , Taylor Bradley S. , Tanaka Kenichi A. 
Published: March 2019

BACKGROUNDPerioperative use of allogeneic blood products is associated with higher morbidity, mortality, and hospital costs after cardiac surgery. Blood conservation techniques such as acute normovolemic hemodilution (ANH) report variable success. We hypothesized that large‐volume ANH with limited hemodilution would reduce allogeneic blood transfusion compared to the standard practice.STUDY DESIGN AND METHODSRetrospective observational study of cardiac surgery patients at the University of Maryland Medical Center between January 2014 and September 2017. Using the institutional Society of Thoracic Surgeons database 91 autologous and 981 control patients who underwent coronary artery bypass grafting, aortic valve replacement, or both were identified. After propensity matching of 13 preoperative characteristics, 84 autologous and 84 control patients were evaluated. Our primary endpoint was avoidance of blood transfusion during index hospitalization, and secondary endpoints were postoperative bleeding and major adverse outcomes.RESULTSThe median harvest volumes in the ANH and control groups were 1100 mL and 400 mL, respectively. Of the ANH group, 25% received any transfusion versus 45.2% of the control group after propensity score matching (p < 0.006). When controlling for preoperative platelet count, the transfusion rate ratios for ANH were 0.58 (95% confidence interval, 0.39–0.88) for RBCs and 0.63 (0.44–0.89) for non‐RBC components, which were both found to be statistically significant. There was no difference found in major adverse events.CONCLUSIONThese results suggest that large‐volume ANH is beneficial in reducing both RBC and non‐RBC component usage in cardiac surgery. A further prospective validation is warranted.
Volumetric evaluation of lumbar epidural fat distribution in epidural lipomatosis and back pain in patients who are obese: introducing a novel technique (Fat Finder algorithm)
Authors: Walker Marcus Anthony , Younan Yara , de la Houssaye Christopher , Reimer Nickolas , Robertson Douglas D , Umpierrez Monica , Sharma Gulshan B , Gonzalez Felix M 
Published: March 2019

ObjectiveSpinal epidural lipomatosis (EL) represents an excessive deposition of unencapsulated adipose tissue in the spinal canal that can result in chronic back pain in patients who are obese with and without diabetes. We aim to calculate the total volumetric epidural fat on lumbar spine MRI in a predominately obese population and correlate total epidural fat to lower back pain (LBP) and body mass index (BMI).Research design and methodsWe developed a program (Fat Finder) to quantify volumetric distribution of epidural fat throughout the lumbar spine. Eleven patients with LBP were imaged using two MRI protocols: parallel axial slices and conventional clinical protocol. The distribution of epidural fat per level was analyzed and normalized to the spinal canal size.ResultsOur sample had an average age of 59.9 years and BMI of 31.57 kg/m2. EL subgroup consisted of seven patients. The L2–L5 total fat volume was 3477.6 mm3(1431.1–5595.9) in the EL group versus 1783.8 mm3(815.0–2717.5) in the age-similar non-EL group. A higher percentage of fat volume in the canal was associated with higher LBP scores. The fat percentage was 32.2% among patients with EL versus 15.4% for age-similar non-EL with LBP score of 6.1 and 4.0, respectively.ConclusionsThe Fat Finder is a novel volumetric method to quantify epidural lumbar spinal fat. The epidural fat favors the lower spinal segment with direct proportionality between the fat volume and LBP score, independent of BMI.
Petroleum tectonic comparison of fold and thrust belts: the Zagros of Iraq and Iran, the Pyrenees of Spain, the Sevier of Western USA and the Beni Sub-Andean of Bolivia
Authors: Kendall Jerome , Vergés Jaume , Koshnaw Renas , Louterbach Melanie 
Published: March 2019

Abstract
The genetic analysis of fold and thrust belts is facilitated by tracking the evolution of their organic endowment (petroleum tectonics). Petroleum tectonic analysis of convergent orogenic systems provides an audit of the processes that control the deformation and kinematics of orogenic belts. The distribution and deformation paths of the organic endowment intervals are key factors in determining the petroleum system evolution of fold and thrust belts. This comparison of orogenic systems illustrates the importance of flexural v. dynamic processes, orogenic wedge taper, mechanical stratigraphy and inherited architecture on the creation, preservation and destruction of petroleum accumulations. The Zagros, Pyrenees, Sevier and Beni Sub-Andean convergent systems share key characteristics of fold and thrust belts, with major differences in scale, degree of incorporation of organic endowment in evolution of the fold and thrust belt and its foreland, and preservation of fold and thrust belt wedge-top deposits.
The Zagros is an orogen dominated by flexural processes that is a perfect storm for hydrocarbon generation and preservation. Its multiple stacked sources ensure continuous hydrocarbon generation while stacked detachments foster a low taper and thick wedge-top basins. The Pyrenees is also a flexurally dominated orogen, but the early consumption of its source rocks led to minimal survival of hydrocarbon accumulations during exhumation in a long lasting, high-taper orogenic wedge. The Sevier was initially a flexural orogen that was later dominated by dynamic uplift of the fold and thrust belt and distal foreland subsidence with foreland deformation. The consumption of its pre-orogenic sources during the early low-taper phase indicates a probable robust petroleum system at that time. However, the late high-taper phase exhumed and destroyed much of the early petroleum system. The addition of syntectonic foreland sources to be matured by both local and dynamic subsidence created an additional later set of petroleum systems. Post-orogenic events have left only remnants of world-class petroleum systems. The Beni segment of the Sub-Andean Orogen is a flexural system with probable dynamic overprints. Its most robust petroleum system probably occurred during its early low-taper flexural phase, with dynamic subsidence enhancement. Its late high-taper phase with possible dynamic uplift shuts down and stresses the petroleum systems. Comparison of these orogenic systems illustrates the importance of flexural v. dynamic processes, orogenic wedge taper kinematics, mechanical stratigraphy, distribution of source rocks relative to shortening and inherited architecture on the creation, preservation and destruction of petroleum accumulations in fold and thrust belts.
An HK2 Antisense Oligonucleotide Induces Synthetic Lethality in HK1−HK2+ Multiple Myeloma
Authors: Xu Shili , Zhou Tianyuan , Doh Hanna M. , Trinh K Ryan , Catapang Art , Lee Jason T. , Braas Daniel , Bayley Nicholas A. , Yamada Reiko E. , Vasuthasawat Alex , Sasine Joshua P. , Timmerman John M. , Larson Sarah M. , Kim Youngsoo , MacLeod A. Robert , Morrison Sherie L. , Herschman Harvey R. 
Published: March 2019

Abstract

Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1+HK2+ cancers, HK1−HK2+ cancer subsets are sensitive to cytostasis induced by HK2shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human multiple myeloma cell lines are HK1−HK2+. Here we describe an antisense oligonucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human multiple myeloma cell cultures and human multiple myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in multiple myeloma cells in culture and prevented HK1−HK2+ multiple myeloma tumor xenograft progression. DPI was replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2 (mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine multiple myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1−HK2+ multiple myeloma.

Significance:
A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in in vivo, presenting an effective, tolerated combination therapy for preventing progression of HK1−HK2+ multiple myeloma tumors.
Hyperspectral Imaging for Resection Margin Assessment during Cancer Surgery
Authors: Kho Esther , de Boer Lisanne L. , Van de Vijver Koen K. , van Duijnhoven Frederieke , Vrancken Peeters Marie-Jeanne T.F.D. , Sterenborg Henricus J.C.M. , Ruers Theo J.M. 
Published: March 2019

Abstract

Purpose:
Complete tumor removal during cancer surgery remains challenging due to the lack of accurate techniques for intraoperative margin assessment. This study evaluates the use of hyperspectral imaging for margin assessment by reporting its use in fresh human breast specimens.

Experimental Design:
Hyperspectral data were first acquired on tissue slices from 18 patients after gross sectioning of the resected breast specimen. This dataset, which contained over 22,000 spectra, was well correlated with histopathology and was used to develop a support vector machine classification algorithm and test the classification performance. In addition, we evaluated hyperspectral imaging in clinical practice by imaging the resection surface of six lumpectomy specimens. With the developed classification algorithm, we determined if hyperspectral imaging could detect malignancies in the resection surface.

Results:
The diagnostic performance of hyperspectral imaging on the tissue slices was high; invasive carcinoma, ductal carcinoma in situ, connective tissue, and adipose tissue were correctly classified as tumor or healthy tissue with accuracies of 93%, 84%, 70%, and 99%, respectively. These accuracies increased with the size of the area, consisting of one tissue type. The entire resection surface was imaged within 10 minutes, and data analysis was performed fast, without the need of an experienced operator. On the resection surface, hyperspectral imaging detected 19 of 20 malignancies that, according to the available histopathology information, were located within 2 mm of the resection surface.

Conclusions:
These findings show the potential of using hyperspectral imaging for margin assessment during breast-conserving surgery to improve surgical outcome.
Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism
Authors: Valli Alessandro , Morotti Matteo , Zois Christos E. , Albers Patrick K. , Soga Tomoyoshi , Feldinger Katharina , Fischer Roman , Frejno Martin , McIntyre Alan , Bridges Esther , Haider Syed , Buffa Francesca M. , Baban Dilair , Rodriguez Miguel , Yanes Oscar , Whittington Hannah J. , Lake Hannah A. , Zervou Sevasti , Lygate Craig A. , Kessler Benedikt M. , Harris Adrian L. 
Published: March 2019

AbstractHypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1α is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways. We analyzed pathways that allow cells to survive hypoxic stress in the absence of HIF1α, using the HCT116 colon cancer cell line with deleted HIF1α versus control. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, and proteomic analysis and integrated the results. These showed surprisingly that in three-dimensional growth, a key regulatory step of glycolysis is Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained in hypoxia through upregulation of GLUT14, not previously recognized in this role. Finally, there was a marked adaptation and change of phosphocreatine energy pathways, which made the cells susceptible to inhibition of creatine metabolism in hypoxic conditions. Overall, our studies show a complex adaptation to hypoxia that can bypass HIF1α, but it is targetable and it provides new insight into the key metabolic pathways involved in cancer growth.Implications:Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting.
HDAC (Histone Deacetylase) Inhibitor Valproic Acid Attenuates Atrial Remodeling and Delays the Onset of Atrial Fibrillation in Mice
Authors: Scholz Beatrix , Schulte Jan Sebastian , Hamer Sabine , Himmler Kirsten , Pluteanu Florentina , Seidl Matthias Dodo , Stein Juliane , Wardelmann Eva , Hammer Elke , Völker Uwe , Müller Frank Ulrich 
Published: March 2019

Background:
A structural, electrical and metabolic atrial remodeling is central in the development of atrial fibrillation (AF) contributing to its initiation and perpetuation. In the heart, HDACs (histone deacetylases) control remodeling associated processes like hypertrophy, fibrosis, and energy metabolism. Here, we analyzed, whether the HDAC class I/IIa inhibitor valproic acid (VPA) is able to attenuate atrial remodeling in CREM-IbΔC-X (cAMP responsive element modulator isoform IbΔC-X) transgenic mice, a mouse model of extensive atrial remodeling with age-dependent progression from spontaneous atrial ectopy to paroxysmal and finally long-lasting AF.

Methods:
VPA was administered for 7 or 25 weeks to transgenic and control mice. Atria were analyzed macroscopically and using widefield and electron microscopy. Action potentials were recorded from atrial cardiomyocytes using patch-clamp technique. ECG recordings documented the onset of AF. A proteome analysis with consecutive pathway mapping identified VPA-mediated proteomic changes and related pathways.

Results:

VPA attenuated many components of atrial remodeling that are present in transgenic mice, animal AF models, and human AF. VPA significantly (
P
<0.05) reduced atrial dilatation, cardiomyocyte enlargement, atrial fibrosis, and the disorganization of myocyte’s ultrastructure. It significantly reduced the occurrence of atrial thrombi, reversed action potential alterations, and finally delayed the onset of AF by 4 to 8 weeks. Increased histone H4-acetylation in atria from VPA-treated transgenic mice verified effective in vivo HDAC inhibition. Cardiomyocyte-specific genetic inactivation of HDAC2 in transgenic mice attenuated the ultrastructural disorganization of myocytes comparable to VPA. Finally, VPA restrained dysregulation of proteins in transgenic mice that are involved in a multitude of AF relevant pathways like oxidative phosphorylation or RhoA (Ras homolog gene family, member A) signaling and disease functions like cardiac fibrosis and apoptosis of muscle cells.

Conclusions:
Our results suggest that VPA, clinically available, well-tolerated, and prescribed to many patients for years, has the therapeutic potential to delay the development of atrial remodeling and the onset of AF in patients at risk.