bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical outcomes of prexasertib monotherapy in recurrentBRCAwild-type high-grade serous ovarian cancer involve innate and adaptive immune responses
Authors: Lampert Erika J , Cimino-Mathews Ashley , Lee Joo Sang , Nair Jayakumar , Lee Min-Jung , Yuno Akira , An Daniel , Trepel Jane B , Ruppin Eytan , Lee Jung-Min 
Published: July 2020

BackgroundPreclinical data suggest cell cycle checkpoint blockade may induce an immunostimulatory tumor microenvironment. However, it remains elusive whether immunomodulation occurs in the clinical setting. To test this, we used blood and fresh tissue samples collected at baseline and post therapy from a phase II trial of the cell cycle checkpoint 1 inhibitor (CHK1i) prexasertib in recurrent ovarian cancer.MethodsPaired blood samples and fresh core biopsies, taken before treatment was started at baseline (cycle 1 day 1 (C1D1)) and post second dose on day 15 of cycle 1 (C1D15), were collected. To evaluate changes in the immune responses after treatment, multiparametric flow cytometry for DNA damage markers and immune cell subsets was performed on paired blood samples. RNA sequencing (RNAseq) of paired core biopsies was also analyzed. Archival tissue immune microenvironment was evaluated with immunohistochemistry. All correlative study statistical analyses used two-sided significance with a cut-off of p=0.05.ResultsFlow cytometric analysis showed significantly increased γ-H2AX staining after CHK1i treatment, accompanied by increased monocyte populations, suggestive of an activated innate immune response (median 31.6% vs 45.6%, p=0.005). Increased expressions of immunocompetence marker HLA-DR (Human Leukocyte Antigen DR antigen) on monocytes and ofTBK1,a marker of STING (stimulator of interferon genes) pathway activation, in biopsies were associated with improved progression-free survival (PFS) (9.25 vs 3.5 months, p=0.019; 9 vs 3 months, p=0.003, respectively). Computational analysis of RNAseq data indicated increased infiltration of tumor niches by naïve B-cells and resting memory T-cells, suggestive of a possibly activated adaptive immune response, and greater T-reg infiltration after treatment correlated with worse PFS (9.25 vs 3.5 months, p=0.007). An immunosuppressive adaptive immune response, perhaps compensatory, was also observed on flow cytometry, including lymphodepletion of total peripheral CD4+ and CD8+T cells after CHK1i and an increase in the proportion of T-regs among these T-cells. Additionally, there was a trend of improved PFS with greater tumor-infiltrating lymphocytes (TILs) in archival tissues (13.7 months >30% TILs vs 5.5 months ≤30% TILs, p=0.05).ConclusionOur study demonstrates that a favorable clinical response in high-grade serous ovarian carcinoma patients treated with CHK1i is possibly associated with enhanced innate and adaptive immunity, requiring further mechanistic studies. It is supportive of current efforts for a clinical development strategy for therapeutic combinations with immunotherapy in ovarian cancer.
Baseline metabolic tumor volume as a strong predictive and prognostic biomarker in patients with non-small cell lung cancer treated with PD1 inhibitors: a prospective study
Authors: Chardin David , Paquet Marie , Schiappa Renaud , Darcourt Jacques , Bailleux Caroline , Poudenx Michel , Sciazza Aurélie , Ilie Marius , Benzaquen Jonathan , Martin Nicolas , Otto Josiane , Humbert Olivier 
Published: July 2020

BackgroundReliable predictive and prognostic markers are still lacking for patients treated with programmed death receptor 1 (PD1) inhibitors for non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the prognostic and predictive values of different baseline metabolic parameters, including metabolic tumor volume (MTV), from 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET/CT) scans in patients with NSCLC treated with PD1 inhibitors.MethodsMaximum and peak standardized uptake values, MTV and total lesion glycolysis (TLG), as well as clinical and biological parameters, were recorded in 75 prospectively included patients with NSCLC treated with PD1 inhibitors. Associations between these parameters and overall survival (OS) were evaluated as well as their accuracy to predict early treatment discontinuation (ETD).ResultsA high MTV and a high TLG were significantly associated with a lower OS (p<0.001). The median OS in patients with MTV above the median (36.5 cm3) was 10.5 months (95% CI: 6.2 to upper limit: unreached), while the median OS in patients with MTV below the median was not reached. Patients with no prior chemotherapy had a poorer OS than patients who had received prior systemic treatment (p=0.04). MTV and TLG could reliably predict ETD (area under the receiver operating characteristic curve=0.76, 95% CI: 0.65 to 0.87 and 0.72, 95% CI: 0.62 to 0.84, respectively).ConclusionMTV is a strong prognostic and predictive factor in patients with NSCLC treated with PD1 inhibitors and can be easily determined from routine 18F-FDG PET/CT scans. MTV, could help to personalize immunotherapy and be used to stratify patients in future clinical studies.
Biological activities of commercial bovine lactoferrin sources
Authors: Lönnerdal Bo , Du Xiaogu , Jiang Rulan 
Published: July 2020

Lactoferrin (Lf) samples from several manufacturers were evaluated in vitro. The purity and protein form of each Lf were examined by SDS–PAGE, Western blot, and proteomics analysis. Assays were conducted to evaluate uptake of Lfs and iron from Lfs by enterocytes as well as Lf bioactivities, including effects on intestinal cell proliferation and differentiation, IL-18 secretion, TGF-β1 transcription, and growth of enteropathogenic Escherichia coli (EPEC). Composition of the Lfs varies; some only contain a major Lf band (∼80 kDa), and some also contain minor forms. All Lfs and iron from the Lfs were absorbed by Caco-2 cells, with various efficiencies. The bioactivities of the Lfs varied considerably, but there was no consistent trend. All Lfs promoted intestinal cell proliferation, secretion of IL-18, and transcription of TGF-β1. Some Lfs exhibited pro-differentiation effects on Caco-2 cells. Effects of pasteurization (62.5 °C for 30 min, 72 °C for 15 s, or 121 °C for 5 min) on integrity, uptake, and bioactivities were examined using Dicofarm, Tatua, and native bovine Lfs. Results show that pasteurization did not affect protein integrity, but variously affected uptake of Lf and its effects on intestinal proliferation, differentiation, and EPEC growth. To choose a Lf source for a clinical trial, assessment of bioactivities is recommended.
Structural and thermal properties of Cu1.75−xMxTe crystals
Authors: Aliyev Y. I. , Asadov Y. G. , Rustamova L. B. , Dashdemirov A. O. , Ismayilova N. A. , Ayubov A. A. , Jabarov S. H. 
Published: July 2020

Single crystals of Cu[Formula: see text]Te, Cu[Formula: see text]Zn[Formula: see text]Te and Cu[Formula: see text]Cd[Formula: see text]Te compounds were synthesized by Brijmen method and their crystal structure was studied by X-ray diffraction. The hexagonal, orthorhombic aand cubic structure phases of these compounds have been determined at room-temperature. Phase transitions at high-temperatures were observed. Lattice parameters for hexagonal, orthorhombic and cubic phases have been determined in the temperature range of [Formula: see text]–1073 K. From the temperature dependences of the lattice parameters, the coefficients of thermal expansion of the existing modifications in the main crystallographic directions were calculated.
Ranking and selecting fault models using flow-indicator fault properties and simple streamline simulations
Authors: Wilson Paul , Smith Stewart , Povey Danny , Harris Simon 
Published: July 2020

Fault zones in porous sandstones are commonly divided into two parts: a fault core and a damage zone. Both fault-zone elements could influence subsurface fluid flow and should be incorporated in a geologically realistic model. The fault core can be implemented in the model as a transmissibility multiplier (TM), while the damage zone can be implemented by modifying the grid permeability in the cells adjacent to the model faults. Each of the input parameters used in calculating the TM and damage-zone permeability modification is subject to geological uncertainty. Here an iterative workflow is employed to define probability distribution functions for each of the input parameters, with the result being many fault-model realizations. Here two methods are examined for ranking and selecting the fault-model realizations for further analysis: (i) calculating the flow-indicator fault properties (effective cross-fault transmissibility and effective cross-fault permeability) from the static model; and (ii) employing a simplified flow-based connectivity calculation, returning dynamic measures of model connectivity. The aims are to outline the methodology and workflow used, evaluate the impact of the different input parameters on the results, and examine the results of the static and dynamic approaches to understand how the ranking and selection of models compares between the two.
Our results are dependent on the structural model. In a strongly compartmentalized model based on the Gullfaks Field, North Sea, fluid-flow-indicator fault properties are weakly correlated with measures of dynamic behaviour. In particular, models with low fault transmissibility show a much greater range of dynamic behaviour, and are less predictable, than models with high fault transmissibility. In a weakly compartmentalized model with strongly channelized fluvial facies based on the Whitley Bay area in NE England, there was a strong correlation between flow-indicator fault properties and measures of dynamic behaviour. We ascribe these results to the greater complexity of flow paths expected when a highly compartmentalized model contains faults that are likely to be baffles to cross-fault flow.

Thematic collection:
This article is part of the Fault and top seals collection available at:
https://www.lyellcollection.org/cc/fault-and-top-seals-2019
Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle–based Chemotherapy in Pten-deleted Mouse Models of Sarcoma
Authors: Dodd Rebecca D. , Scherer Amanda , Huang Wesley , McGivney Gavin R. , Gutierrez Wade R. , Laverty Emily A. , Ashcraft Kathleen A. , Stephens Victoria R. , Yousefpour Parisa , Saha Soumen , Knepper-Adrian Vickie , Floyd Warren , Chen Mark , Ma Yan , Mastria Eric M. , Cardona Diana M. , Eward William C. , Chilkoti Ashutosh , Kirsch David G. 
Published: July 2020

Abstract

Purpose:
Nanoparticle-encapsulated drug formulations can improve responses to conventional chemotherapy by increasing drug retention within the tumor and by promoting a more effective antitumor immune response than free drug. New drug delivery modalities are needed in sarcomas because they are often chemoresistant cancers, but the rarity of sarcomas and the complexity of diverse subtypes makes it challenging to investigate novel drug formulations.

Experimental Design:
New drug formulations can be tested in animal models of sarcomas where the therapeutic response of different formulations can be compared using mice with identical tumor-initiating mutations. Here, using Cre/loxP and CRISPR/Cas9 techniques, we generated two distinct mouse models of Pten-deleted soft-tissue sarcoma: malignant peripheral nerve sheath tumor (MPNST) and undifferentiated pleomorphic sarcoma (UPS). We used these models to test the efficacy of chimeric polypeptide doxorubicin (CP-Dox), a nanoscale micelle formulation, in comparison with free doxorubicin.

Results:
The CP-Dox formulation was superior to free doxorubicin in MPNST models. However, in UPS tumors, CP-Dox did not improve survival in comparison with free doxorubicin. While CP-Dox treatment resulted in elevated intratumoral doxorubicin concentrations in MPNSTs, this increase was absent in UPS tumors. In addition, elevation of CD8+ T cells was observed exclusively in CP-Dox–treated MPNSTs, although these cells were not required for full efficacy of the CP nanoparticle–based chemotherapy.

Conclusions:
These results have important implications for treating sarcomas with nanoparticle-encapsulated chemotherapy by highlighting the tumor subtype–dependent nature of therapeutic response.
Low-Dose Hsp90 Inhibitor Selectively Radiosensitizes HNSCC and Pancreatic Xenografts
Authors: Mehta Ranjit K. , Pal Sanjima , Kondapi Koushik , Sitto Merna , Dewar Cuyler , Devasia Theresa , Schipper Matthew J. , Thomas Dafydd G. , Basrur Venkatesha , Pai Manjunath P. , Morishima Yoshihiro , Osawa Yoichi , Pratt William B. , Lawrence Theodore S. , Nyati Mukesh K. 
Published: July 2020

AbstractPurpose:Treatment approaches using Hsp90 inhibitors at their maximum tolerated doses (MTDs) have not produced selective tumor toxicity. Inhibition of Hsp90 activity causes degradation of client proteins including those involved in recognizing and repairing DNA lesions. We hypothesized that if DNA repair proteins were degraded by concentrations of an Hsp90 inhibitor below those required to cause nonspecific cytotoxicity, significant tumor-selective radiosensitization might be achieved.Experimental Design:Tandem mass tagged-mass spectrometry was performed to determine the effect of a subcytotoxic concentration of the Hsp90 inhibitor, AT13387 (onalespib), on global protein abundance. The effect of AT13387 on in vitro radiosensitization was assessed using a clonogenic assay. Pharmacokinetics profiling was performed in mice bearing xenografts. Finally, the effect of low-dose AT13387 on the radiosensitization of three tumor models was assessed.Results:A subcytotoxic concentration of AT13387 reduced levels of DNA repair proteins, without affecting the majority of Hsp90 clients. The pharmacokinetics study using one-third of the MTD showed 40-fold higher levels of AT13387 in tumors compared with plasma. This low dose enhanced Hsp70 expression in peripheral blood mononuclear cells (PBMCs), which is a biomarker of Hsp90 inhibition. Low dose monotherapy was ineffective, but when combined with radiotherapy, produced significant tumor growth inhibition.Conclusions:This study shows that a significant therapeutic ratio can be achieved by a low dose of Hsp90 inhibitor in combination with radiotherapy. Hsp90 inhibition, even at a low dose, can be monitored by measuring Hsp70 expression in PBMCs in human studies.
The Oldowan in the Egyptian Nile Valley
Authors: Bakry Aboualhassan , Saied Ahmed , Ibrahim Doaa 
Published: July 2020

Abstract
Although there is no good “Oldowan” record in the Egyptian Nile Valley, the presence of the “Pebble Tools Tradition” is confirmed by surface finds, scattered in the valley and the deserts, recorded through both early and recent excavations, and confirmed by three important stratified sites at Western Thebes, Nag el Amra and Abassieh. Evidence for the existence of the Oldowan complex in Egypt was found, although there was no water corridor connecting the East African highlands to the Mediterranean, as the Proto-Nile had its sources within Egypt itself at the time of the Plio-Pleistocene boundary. The western coast of the Red Sea also should be considered a possible corridor for early Pleistocene hominins. There is still much more research to be done, especially in the Eastern Egyptian Desert and Sinai, to obtain a clearer picture of the scenario that happened during the Plio-Pleistocene episode of hominin dispersal out of Africa.
Testing the Trade Wind Charging Mechanism and Its Influence on ENSO Variability
Authors: Chakravorty Soumi , Perez Renellys C. , Anderson Bruce T. , Giese Benjamin S. , Larson Sarah M. , Pivotti Valentina 
Published: July 2020

AbstractDuring the positive phase of the North Pacific Oscillation, westerly wind anomalies over the subtropical North Pacific substantially increase subsurface heat content along the equator by “trade wind charging” (TWC). TWC provides a direct pathway between extratropical atmospheric circulation and El Niño–Southern Oscillation (ENSO) initiation. Previous model studies of this mechanism lacked the ocean–atmospheric coupling needed for ENSO growth, so it is crucial to examine whether TWC-induced heat content anomalies develop into ENSO events in a coupled model. Here, coupled model experiments, forced with TWC favorable (+TWC) or unfavorable (−TWC) wind stress, are used to examine the ENSO response to TWC. The forcing is imposed on the ocean component of the model through the first winter and then the model evolves in a fully coupled configuration through the following winter. The +TWC (−TWC) forcing consistently charges (discharges) the equatorial Pacific in spring and generates positive (negative) subsurface temperature anomalies. These subsurface temperature anomalies advect eastward and upward along the equatorial thermocline and emerge as like-signed sea surface temperature (SST) anomalies in the eastern Pacific, creating favorable conditions upon which coupled air–sea feedback can act. During the fully coupled stage, warm SST anomalies in +TWC forced simulations are amplified by coupled feedbacks and lead to El Niño events. However, while −TWC forcing results in cool SST anomalies, pre-existing warm SST anomalies in the far eastern equatorial Pacific persist and induce local westerly wind anomalies that prevent consistent development of La Niña conditions. While the TWC mechanism provides adequate equatorial heat content to fuel ENSO development, other factors also play a role in determining whether an ENSO event develops.
Mega Fibula Free Flap for Reconstruction of an Extensive Mandibulofacial Defect
Authors: Lin Chen , Tamaki Akina , Ozer Enver 
Published: July 2020

Objective: Extensive mandibulofacial defects can be challenging to reconstruct. We present the case of a complex mandibulofacial defect reconstructed with a mega, chimeric fibula free flap. Methods: Ablation of the oral cavity tumor resulted in a large defect involving mandible, floor of mouth, and tongue. Skin of the chin and neck as well as the lower lip were also resected. A fibula free flap was harvested with the skin paddle involving most of the lateral compartment. Results: The fibula free flap was split into proximal (80 cm2) and distal (120 cm2) skin paddle islands, which were supplied by separate perforators off the peroneal artery. The intraoral soft tissue defect was reconstructed with the proximal skin paddle while the skin was recreated with the distal skin paddle. A Karapandzic flap was used to reconstruct the lower lip. Conclusions: The traditional fibula free flap skin paddle often does not provide sufficient soft tissue coverage for large mandibulofacial defects. Some surgeons opt to harvest a second free flap. We describe our technique for using the mega fibula free flap – one of the largest reported in the literature – as a single mode of reconstruction.
Psychology Students’ Understanding of Ethics and Application of Ethical Principles
Authors: Duncan Mary Katherine , Geist Kendall 
Published: July 2020

Background: The American Psychological Association (APA) has called on undergraduate psychology programs to embed training in ethics throughout their curricula. Although guidelines and resources exist, research on students’ understanding of and ability to apply the discipline’s ethical principles is limited. Objective: The purpose of this study was to learn more about psychology students’ perceptions of their undergraduate training in ethics, understanding of what it means to behave ethically, and competence at applying ethical principles. Method: Forty-four psychology students rated their undergraduate coursework and fieldwork training in ethics, described what it means to be ethical, and proposed a department honor code. Responses were independently coded using a rubric based on APA’s five ethical principles. Results: Participants reported that their undergraduate training gave them an adequate understanding of ethics. The majority included at least three ethical principles in their descriptions of ethical behavior but fewer than three principles in their proposed honor codes. Upper-level students rated their fieldwork training in ethics significantly higher than lower-level students. Participants with higher ratings of fieldwork training in ethics included significantly more ethical principles in their honor codes. Conclusion: Findings support APA’s call to embed training on ethics throughout the undergraduate curriculum.
Effects of water-based exercise on functioning and quality of life in people with Parkinson’s disease: a systematic review and meta-analysis
Authors: Gomes Neto Mansueto , Pontes Sarah Souza , Almeida Lorena de Oliveira , da Silva Cássio Magalhães , da Conceição Sena Cristiano , Saquetto Micheli Bernardone 
Published: July 2020

Aim: To investigate the effects of the water-based exercise on balance, mobility, mobility and functional independence, functional performance, fear of falling and quality of life in people with Parkinson’s disease. Methods: We searched pubmed/MEDLINE, Cochrane Central Register of Controlled Trials, PEDro data base and SciELO to June 2020 for randomised controlled trials that investigated the effects of water-based exercise in people with Parkinson’s disease. Two comparisons were made: water-based exercise versus usual care and water-based exercise versus land-exercise. The main outcomes were Balance, Confidence, Mobility, Unified Parkinson’s Disease Rating Scale and quality of life. Mean differences (MD) with 95% confidence interval (CI) were calculated, and heterogeneity was assessed using the I2 test. Results: Fifteen randomised controlled trials were found (435 people). Compared to usual care, water-based exercise resulted in improvement in balance MD (9.1, 95% CI: 6.5, 11.8, N = 45). Water-based exercise resulted in improvement in balance MD (3.1, 95% CI: 1.2, 5.0, N = 179), mobility MD (−2.2, 95% CI: −3.3, −1.0, N = 197) and quality of life MD (−5.5, 95% CI: −11, −0.07, N = 98) compared to land-based exercise, but without significant difference in functional performance MD (0.01, 95% CI: −2.6 to 2.7, N = 69). Land-based exercise resulted in improvement in fear of falling MD (−3.5, 95% CI: −5.6, −1.3, N = 58) compared to water-based exercise. Conclusion: Water-based exercise was more efficient than land-based exercise and/or usual care in improving balance, mobility and quality of life in people with Parkinson’s disease.
How does PI-RADS v2.1 impact patient classification? A head-to-head comparison between PI-RADS v2.0 and v2.1
Authors: Linhares Moreira Ana Sofia , De Visschere Pieter , Van Praet Charles , Villeirs Geert 
Published: July 2020

Background PI-RADS classification has recently been updated, with the magnitude of changes implemented currently unknown. Purpose To quantify the categorization shifts between PI-RADS v2.0 and v2.1. Material and Methods Retrospective review of 535 consecutive diagnostic magnetic resonance imaging (MRI) studies performed over 18 months, assigning to each case a PI-RADS category in the peripheral zone (PZ), the transition zone (TZ), and the whole gland using both PI-RADS v2.0 and v2.1. Significance of changes in category assignments and of differences in the number of positive or negative MRIs were evaluated using the McNemar test. Results Comparing v2.0 to v2.1 for the whole gland, 11.2% of PI-RADS 2 categories shifted to PI-RADS 1 (6.9% in the PZ, 56.8% in the TZ), 16.1% of PI-RADS 3 categories shifted to PI-RADS 2 (15.0% in the PZ, 20.0% in the TZ), and 2.1% of PI-RADS 2 categories shifted to PI-RADS 3 (0.3% in the PZ, 1.9% in the TZ). The proportion of PI-RADS 1 significantly increased from 0.6% to 7.3%, PI-RADS 2 significantly decreased from 60.0% to 53.8%, and PI-RADS 3 non-significantly decreased from 11.6% to 11.0%. The total number of positive exams (PI-RADS 3–5) did not change significantly (39.4% versus 38.8%). Conclusion The most prominent change between v2.0 and v2.1 was observed in the TZ with the downgrading of typical benign prostatic hyperplasia nodules from category 2 into category 1. Overall, there were no significant changes in the number of positive and negative MRI results, with an expected low influence in clinical management.