bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of two empirical prolonged infusion dosing regimens for meropenem in patients with septic shock: A pilot two-center study
Authors: Eisert Albrecht , Lanckohr Christian , Frey Janina , Frey Otto , Wicha Sebastian G. , Horn Dagmar , Ellger Bjoern , Schuerholz Tobias , Marx Gernot , Simon Tim Philipp 
Published: August 2020

Abstract
Background : Sepsis is a severe disease with complex pathophysiology and high mortality. Meropenem is frequently used in sepsis to treat the underlying infection. Studies have shown that standard doses of meropenem are frequently inadequate due to high pharmacokinetic and pharmacodynamic variability. Therapeutic drug monitoring (TDM) of meropenem is not widely available, and increased empiric dosing recommendations are needed. Methods : We compared two empiric dosing schemes of meropenem using extended infusion (120 minutes) in 32 patients with sepsis in the ICUs at two different hospitals. One regimen was 3x 2 g meropenem/ 24 h for two days, followed by 3x 1 g meropenem/ 24 h; the other regimen was 4x 1 g meropenem/ 24 h. Serum meropenem concentrations were measured for the first 72 h of therapy, and pharmacokinetic modelling was performed to define the percentage of time the dosing interval was above various target minimal inhibitory concentrations (MICs) for each regimen (%fT >MIC ). Results : Both regimens led to a sufficiently high %fT >MIC for pathogens with target MICs below 4 mg/L. When higher MICs were targeted, the %fT >MIC of 4x 1 g meropenem decreased faster than that of 3x 2 g meropenem. At high MICs of 32 mg/L, both dosing regimens failed to provide drug concentrations deemed appropriate for clinical improvement. Conclusions : The results of this pilot study can guide clinicians in their choice of an empirical dosing scheme when prescribing meropenem in the absence of TDM. If pathogens with low MICs (<4 mg/L) are targeted, both dosing regimens are adequate, whereas more resistant clones require higher doses. The control of β-lactam therapy by therapeutic drug monitoring is desirable.
Degradation and sorption of the herbicides 2,4-D and quizalofop-P-ethyl and their metabolites in soils from railway tracks
Authors: Buerge Ignaz J , Pavlova Pavlina , Hanke Irene , Bächli Astrid , Poiger Thomas 
Published: August 2020

Abstract
Background: Broad spectrum of activity and low risk of groundwater contamination are important arguments for the application of the herbicide glyphosate on railway tracks. Nevertheless, certain weeds are insufficiently controlled or develop resistance, and there is also an ongoing controversial discussion about possible carcinogenicity of glyphosate. Alternatives are thus strongly desired. 2,4-D and quizalofop-P-ethyl (QE) are two selective herbicides with a complementary spectrum of activity. When used in agriculture, the compounds and their metabolites pose low risk to groundwater. Uses on railway tracks are, however, more critical since degradation likely is slower and mobility higher than in agricultural soils. In this study, we investigated degradation and sorption of the two active substances as well as five metabolites in three soils collected from railway tracks and in a crushed sand, used for construction works.Results: In these railway materials, the compounds were indeed degraded slower than in agricultural soils (mean half-lives differed by a factor of 2-26) and mobility was higher (mean sorption coefficients differed by a factor of 3-19). Half-lives and sorption coefficients were also estimated by extrapolation of data from agricultural soils, considering the organic carbon content of railway soils and agricultural soils. Estimated values were more conservative than measured values, i.e., for herbicides, for which no measured parameters are available for railway soils, estimated values may be a viable alternative for a first tier groundwater assessment.Conclusions: Based on our experimental data, possible leaching to groundwater is predicted to be highest for 2,4-D and quizalofop-acid, the primary metabolite of QE, moderate for 2,4-dichlorophenol, the primary metabolite of 2,4-D, but low for QE. Secondary and tertiary metabolites were formed in only low quantities. For an advanced groundwater risk assessment, leaching studies, e.g., with lysimeters, would be a reasonable next step.
A New grading system based on T2-weighted axial MRI for Cervical Canal stenosis
Authors: Wang Shaoyi , Zhao Yunpeng , Wei Jianlu , Pan Xin , Nie Lin , Shi Jie , Cheng Lei 
Published: August 2020

Abstract
Background: Cervical Canal Stenosis (CCS) is a common cervical disease that occurs during and after middle age. There are a variety of grading systems and Measurement methods based on X-ray, Computed Tomography(CT) for cervical canal stenosis. Although many authors measured and classified cervical canal stenosis on the basis of T2-weighted sagittal MRI after the appearance of magnetic resonance, the research on Cervical Canal Stenosis remains to be improved. To explore a more detailed grading system on MRI for cervical canal stenosis and could be used to the clinical diagnosis and treatment.Methods: We retrospectively studied 200 patients with cervical spinal stenosis. Cervical canal stenosis was classified according to the T2-weighted axial MRI with the most serious compression into the following grades: grade 0,normal; grade 1, mild canal stenosis with obliteration of anterior or posterior of cerebrospinal fluid (CSF) space ; grade 2, moderate canal stenosis with obliteration of both sides of the CSF space but no significant changes in spinal morphology; Grade 3, severe canal stenosis with spinal cord deformity, 3A the oppression ratio of cervical spinal cord is under 50%, 3B the angle of the protrusion less than 90°; Grade 4, serious canal stenosis with spinal cord deformity and the oppression ratio of cervical spinal cord is exceeding 50%, 4A the non-ossification protrusion, 4B the ossific protrusion. We collected the relevant clinical and imaging data of the patients and analyzed the relationship between them and our new grading system. Patients were followed up one year later.Results: Our new grading system was easy to learn and communication. The the ICC reliabilities between six readers was between 0.817-0.865. And the Effective sagittal spinal canal was significantly different along with our grades at each disc level. In terms of clinical data, our grading system is correlated with the patient's preoperative mJOA score and had impact on the choice of surgical strategy. Conclusions: We suggest our new grading system can provided as a reliable assessment that can guide clinical treatment for Cervical Canal Stenosis.
An Annotation-free Whole-slide Training Approach to Pathological Classification of Lung Cancer Types by Deep Neural Network
Authors: Chen Chi-Long , Chen Chi-Chung , Yu Wei-Hsiang , Chen Szu-Hua , Chang Yu-Chan , Hsu Tai-I , Hsiao Michael , Yeh Chao-Yuan , Chen Cheng-Yu 
Published: August 2020

Abstract
Deep learning for digital pathology is hindered by the extremely high spatial resolution of whole slide images (WSIs). Most studies adopt patch-based methods which, however, require well annotated data for training. These are typically done by laboriously free-hand contouring on the WSI by experts. To both alleviate annotation burdens of experts and enjoy benefits from scaling up amounts of data, we develop a whole-slide training method for entire WSIs to classify types of lung cancers using slide-level diagnoses. Our method leverages unified memory to offload the excessive amount of memory consumption to host memory to train a classifier by entire hundreds-of-million-pixels slides. Experiments were conducted on the lung cancer dataset which contains 9,662 digital slides with various main types. The results showed that the proposed method can achieve an AUC of 0.950 and 0.924 for adenocarcinoma and squamous cell carcinoma on a separate testing set respectively. Furthermore, critical regions highlighted by the class activation map (CAM) technique of our model reveals a high correspondence to cancerous areas annotated by pathologists.
Flightless I Homolog Reverses Neo-Endocrine Therapy Resistance through YBX1/PD-L1 Axis Mediated-Immune Evasion in Prostate Cancer
Authors: Ruan Hailong , Bao Lin , Tao Zhen , Chen Ke 
Published: August 2020

Abstract
Background: Tumor cells can evade immune surveillance and immune killing effects during neo-endocrine therapy resistance, but the mechanisms that induce this phenomenon are still unclear. Flightless I homolog (FLII) functions as a coregulator of transcription factors in malignancies. Here, we aim to identify the functions and mechanisms of FLII-mediated neo-endocrine therapy resistance and immune evasion in prostate cancer (PCa).Methods: Bioinformatics analysis and PCa tissue microarray were used to assess the correlation between FLII and the immune checkpoint PD-L1. Immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP) were used to investigate the regulation of PD-L1 expression by FLII. Enzyme-linked immunosorbent assay (ELISA) was used to study the effect of FLII on cytokine secretion. The number of effector T cells and immunosuppressive lymphocytes was detected by flow cytometry (FCM).Results: FLII was negatively correlated with the expression of PD-L1 in PCa. Mechanistic studies demonstrated that FLII physically interacted with YBX1 to inhibit the nuclear localization of YBX1 and thereby suppressed the transcriptional expression of PD-L1 in enzalutamide-resistant tumors. Restoration of FLII expression reversed neo-endocrine therapy resistance by activating the T cell response in the tumor microenvironment mediated by partial inhibition of the YBX1/PD-L1 pathway. The reversal of neo-endocrine therapy resistance and immune evasion was mediated by the proliferation of effector CD8+ T cells and inhibition of the infiltration of regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment.Conclusions: FLII inhibits tumor progression in part through repressing YBX1/PD-L1-mediated immune evasion. Combination therapy with FLII and neo-endocrine therapy may improve the benefits in prostate cancer patients and avoid immune evasion.
Healthy Mitochondria: The Brake of Cell Proliferation of Malignant Melanoma
Authors: Yu Zhenyao , Zhao Zizhen , Fu Chen , Zhou Wei , Wang Junchen , Fu Ailing 
Published: August 2020

Abstract
Background: Melanoma has become the leading cause of death from skin disease, and male patients show higher mortality rate than female. Mitochondrial transplantation therapy is an active area of current research but the anti-melanoma activity and specific mechanism involved in the therapy remain to be fully characterized.Methods: In the study, we intravenously administrated mitochondria extracted from male and female mouse livers respectively to the mice bearing malignantly subcutaneous and metastatic melanoma, and identified the signal mechanism responsible for the mitochondrial treatment through transcriptomic analysis. Meanwhile, the efficiency of female mitochondria and male mitochondria was compared in the cultured melanoma cells and transplanted melanoma in mice. Results: The results suggested that the mitochondria significantly inhibited the tumor growth, and the transcriptomic analysis suggested that general chromosome silencing and local opening of UPRmt effect region were strongly associated with the mitochondria against melanoma., which represented cell cycle arrest, autophagy, and cell apoptosis in the mitochondrial therapy on the metastasis melanoma. Moreover, the anti-tumor activity of mitochondria from female animals was more efficient in comparison to the males, and the female mitochondria could probably induce more persuasive mitochondria-nuclear communication than the mitochondria from male mice.Conclusions: The study not only reveals the anti-tumor mechanism of the mitochondria but also provides a novel insight into the effect of mitochondria in different genders.
Intravenous Iron Therapy Replenishes Iron Stores without Enhancing Tumour Responses in Anaemic Patients with Colorectal Cancer: Comparison with Oral Iron Supplementation.
Authors: Al-Hassi Hafid O , Ng Oliver , Evstatiev Rayko , Mangalika Manel , Worton Natalie , Jambrich Manuela , Khare Vineeta , Phipps Oliver , Keeler Barrie , Gasche Christoph , Acheson Austin G , Brookes Matthew J. 
Published: August 2020

Abstract
Background: Oral iron promotes intestinal tumourigenesis in animal models. In humans, expression of iron transport proteins are altered in colorectal cancer. This study examines whether the route of iron therapy alters iron transport and tumour growth. Methods: Colorectal adenocarcinoma patients with pre-operative iron deficiency anaemia received oral ferrous sulphate (n=15), or intravenous ferric carboxymaltose (n=15). Paired (normal and tumour tissues) samples were compared for expression of iron loading, iron transporters, proliferation, apoptosis, Wnt signalling pathway and microsatellite instability using immunohistochemistry and RT-PCR. Results: Iron loading was increased in tumour and distributed to the stroma in intravenous treatment and to the epithelium in oral treatment. The protein and mRNA expression of iron transporters were increased in tumours compared to normal tissues but there were no significant differences between the treatment groups. However, intravenous iron treatment reduced ferritin mRNA levels in tumours (p<0.001) and successfully replenished body iron stores without increasing tumour growth, DNA damage markers, proliferation or apoptosis compared with oral iron treatment. Conclusion: Iron distribution to non-epithelial cells in intravenous iron treatment suggests that iron is less bioavailable to tumour cells. Therefore, intravenous iron supplementation could be a safer option in the treatment of colorectal cancer patients with iron deficiency anaemia due to the differential compartmentalisation of iron within the intestinal mucosa and its efficiency in replenishing body iron levels without increasing the risk of tumour growth.Trial registration: The study was registered with the Medicines and Healthcare Regulatory Agency, clinical trials.gov (NCT01927328) and EudraCT (2013-000209-22).
GSK3β Inhibition Synergizes with PARP Inhibitors through the Induction of Homologous Recombination Deficiency in Colorectal Cancer
Authors: Zhang Ning , Tian Yu-Nan , Zhou Li-Na , Li Meng-Zhu , Song Shan-Shan , Huan Xia-Juan , Bao Xu-Bing , Zhang Ao , Miao Ze-Hong , He Jin-Xue 
Published: August 2020

Abstract
Background: Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in limited objective response rate (≤ 60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Methods: The effects of PARPi combined with glycogen synthase kinase 3 (GSK3) inhibitors were investigated in vitro with respect to cell viability, cell cycle and apoptosis. The synergy was assessed by calculation of the combination index (CI). GSK3α null and GSK3β null cells were generated using CRISPR/Cas9 technique. The underlying mechanism was examined by western blotting, flow cytometry, qRT-PCR and fluorescence microscopy. This combination was also evaluated in the mouse xenograft model; tumor growth and tumor lysates were analyzed, and the immunohistochemistry assay was performed. All data are presented as mean ± SD. Comparison between two groups was performed with the Student’s t-test.Result: The data showed that ~25% of oncological drugs and kinase inhibitors that were evaluated displayed synergy with PARPi in HCT-15 cells. Among the tested agents, GSK3 inhibitors (GSK3i) exhibited the strongest synergistic effect with PARPi. Moreover, the synergistic antitumor effect of GSK3 and PARP inhibition was confirmed in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. Additionally, inhibition or genetic depletion of GSK3β was found to impair HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to simmiparib without toxicity.Conclusion: Our results provide a mechanistic understanding of combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.
Compositional Analysis Of The Bacterial Community In Colostrum Samples From Women With Gestational Diabetes Mellitus And Obesity
Authors: Gámez-Valdez July Stephany , García-Mazcorro José Francisco , Rincón Alan Heriberto Montoya , Reyes Dalia Liliana Rodríguez , Blanco Gelacio Jiménez , Rodriguez Melissa Tatiana Alanís , Vaca Rebeca Pérez-Cabeza de , García Mario René Alcorta , Brunck Marion Emilie Genevieve , Díaz Víctor Javier Lara , Licona-Cassani Cuauhtemoc 
Published: August 2020

Abstract
Background. Obesity and Gestational Diabetes Mellitus (GDM) are major concerns during pregnancy as they compromise both mother and newborn health. These pathophysiology leads to variations in gut and breastmilk microbiota, threatening the settlement of neonate’s gut microbiota and the stimulation of immune cells. While several studies have described compositional changes of breast milk, placenta and maternal and newborn intestinal microbiota, it is unknown how breastmilk microbiota is affected under maternal GDM. The molecular mechanisms in which microbial-unbalanced breastmilk affect development of infants is not well understood for the case of obesity and GDM. As a first step, we used 16S- amplicon sequencing to describe the taxonomical bias of breastmilk of 43 women with GDM and women with obesity. We sampled colostrum within the first 24 h taken after birth in order to identify and quantify the first microbial community potentially colonizing infants gut.Results. A total of 1,675 amplicon sequence variants (ASVs) were identified, being Proteobacteria and Firmicutes the dominant phyla. We found Pseudomonas, Gemellales and Enterobacter overrepresented in samples of women with obesity and GDM. We used observed ASV´s, Shannon index and Faith´s phylogenetic diversity scores as alpha diversity indicators and UniFrac and robust Aitchison distances beta diversity indicators. Both metrics show a distinct microbial composition for GDM (female sub-group) and Obesity (male subgroup) compared to controls. Finally, differentially abundance analysis showed that Rhodococcaceae was distinct for GDM and 7 families (Bdellovibrionaceae, Burkholderiaceae, Halomonadaceae, Pseudomonadaceae, Shewanallaceae, TM7-1 and Vibrionaceae) with an absolute effect size greater than 1, of which 5 had a q-value ≤ 0.05 were distinct for obesity groups.Conclusions. To our knowledge, this study represents the first approach to the breastmilk bacteria composition of mothers with GDM. Our work provides the foundation for the design of functional metagnomic studies aiming to understand molecular mechanisms of which breastmilk from individuals with GDM and obesity affect the physiology of the infants.
Distinct profiles of stimulus specific cortical activity for ignoring distraction during working memory encoding and maintenance, and associations with performance
Authors: Ashton Charlotte , Gouws André , Glennon Marcus , ZANTO THEODORE , Tipper Steve , McNab Fiona 
Published: August 2020

Abstract
Our ability to hold information in mind for a short time (working memory) is separately predicted by our ability to ignore two types of distraction: distraction that occurs while we put information into working memory (encoding) and distraction that occurs while we maintain already encoded information within working memory. This suggests that ignoring these different types of distraction involves distinct mechanisms which separately limit performance. Here we used fMRI to measure category-sensitive cortical activity and probe these mechanisms. The results reveal speciﬁc neural mechanisms by which relevant information is remembered and irrelevant information is ignored, which contribute to intra-individual differences in WM performance.
Synthesis of monocarboxylic acids via direct CO2 conversion over Ni–Zn alloy catalysts
Authors: Sibi Malayil , Verma Deepak , Setiyadi Handi , Butolia Paresh , KHAN MUHAMMAD KASHIF , Kwak Sang Kyu , Chung Kyung Yoon , Park Jeaho , Han Daseul , Nam Kyung-Wan , Kim Jaehoon 
Published: August 2020

Abstract
The direct conversion of CO2 to methane, gasoline-to-diesel range fuels, methanol, and light olefins using renewable electricity sources is considered a promising approach for mitigating global warming. Nevertheless, the direct conversion of CO2 to high value-added chemicals, such as acetic and propanoic acids (AA and PA, respectively), has not been explored to date. Herein, we report a Ni–Zn alloy/Zn-rich NixZnyO catalyst that directly converted CO2 to AA and PA with an overall selectivity of 77.1% at a CO2 conversion of 13.4% at 325 °C. The surface restructuring of the ZnO and NiO phases during calcination and subsequent reduction led to the formation of a Ni–Zn alloy on the Zn-rich NixZnyO phase. Surface-adsorbed (*CHx)n species were formed via the reverse water-gas shift reaction and subsequent CO hydrogenation. Afterward, monocarboxylic acids were produced via the direct insertion of CO2 into the (*CHx)n species and subsequent hydrogenation. The synthesis of monocarboxylic acid was highly stable up to 216 h on-stream over the Ni–Zn alloy catalyst, and the catalyst maintained its phase structure and morphology during long-term CO2 hydrogenation. The high selectivity toward monocarboxylic acids and high stability of the Ni–Zn alloy demonstrated its excellent potential for the conversion of CO2 into value-added chemicals.
Simultaneous Determination of Fexofenadine Hydrochloride and Montelukast Sodium Using New Pencil Graphite Electrode in Their Pure, Synthetic Mixtures, and Combined Dosage Form
Authors: Nashed Dania , Noureldin Imad , Sakur Amir Alhaj 
Published: August 2020

Abstract
This paper introduces a new electrochemical approach for the concomitant determination of fexofenadine hydrochloride and montelukast sodium by constructing three new graphite electrodes coated with a polymeric membrane. The first electrode was constructed using ammonium molybdate reagent as an ion pair with fexofenadine cation for the determination of fexofenadine drug, the second electrode was constructed using cobalt nitrate as an ion pair with montelukast anion for the determination of montelukast drug, the third electrode was prepared by incorporating the two previously mention ion pairs in the same graphite sensor, which make this sensor sensitive to each fexofenadine and montelukast drug. The coating material was a polymeric film comprises of Poly Vinyl Chloride (PVC), Di-butyl phthalate as a plasticizer (DBP), ion pairs of drugs with previously mentioned reagents. The electrodes showed a Nernstian response with a mean calibration graph slopes of [58.97, 28.43, (59.048 , 28,643 )] mv.decade-1 for the three pencil electrodes respectively. The electrodes work effectively over pH range (2-4.5) for fexofenadine hydrochloride and (5-9.5) for montelukast sodium. The influence of the proposed interfering species was negligible. The effectiveness of the electrodes continued in a period of time (45-69) days. The suggested sensors demonstrated useful analytical features for the determination of both drugs in bulk powder, in laboratory prepared mixtures and their combined dosage form. We have validated the method in accordance with ICH protocol.