bluuebunny/crossref_metadata_2025_split huggingface dataset:
The signature of pharmaceutical sensitivity based on ctDNA mutation in eleven cancers
Authors: Zhang Shumei , Su Mu , Sun Zhongyi , Lu Haibo , Zhang Yan 
Published: February 2020

Gene mutations are closely related to cancers and drug sensitivity. Noninvasive liquid biopsy was used to detect mutations of ctDNA in plasma, which is regarded as an indicator of chemotherapy reaction. In this study, we performed exon sequencing of 416 cancer-related genes for cancer primary tissue and plasma samples of 20 patients in 11 cancers. The comprehensive mutation landscape was obtained by bioinformatics tools. In all samples, a total of 0–135 genes involved somatic mutations, and 5–209 genes involved copy number variation. APC, KRAS, and TP53 were detected as frequently mutated genes. Nineteen genes with high-frequency copy-number amplification and 59 with frequent copy-number deletions were identified. By quantitatively assessing the degree of agreement, we found that liquid biopsy is reliable instead of tissues. Besides, 31 mutation prognostic markers in 7 cancers were screened by integrating the consistent mutations and enlarging samples in TCGA. Moreover, from drug-mutation network, 25 drugs connected with 9 mutations (B-Mut-9) were obtained which can be served as drug biomarkers in blood. This was proved by further integrating the mutation information of patients in TCGA into drug-mutation network. In summary, the variation in ctDNA can be used as the biomarkers for cancer prognosis and drug efficacy prediction.Impact statementGene mutations are closely related to cancers and drug sensitivity and noninvasive liquid biopsy was used to detect mutations of ctDNA in plasma. In this study, we performed exon sequencing of 416 cancer-related genes for cancer primary tissue and plasma samples of 20 patients in 11 cancers and obtained the comprehensive mutation landscape. We found that liquid biopsy is reliable in place of tissue biopsy. And 31 potential unique mutation prognostic markers were screened in 7 cancer types. Moreover, the drug-mutation network (DMN) was constructed and 9 gene mutations (B-Mut-9) were confirmed that can be served as drug biomarkers in blood. Our study showed that the variation in ctDNA can be used as the biomarkers for cancer prognosis and drug efficacy prediction. This can provide a reference for clinical noninvasive testing.
Scorpion alleviates bone cancer pain through inhibition of bone destruction and glia activation
Authors: Yu Jiachuan , Luo Yuanyuan , Jin Huidan , Lv Jiaxin , Zhou Tingting , Yabasin Iddrisu Baba , Wen Qingping 
Published: February 2020

Background Bone cancer pain is common in patients with advanced cancers as tumor metastasizes to bone. The inefficient clinical treatment severely reduces quality of life of bone cancer pain patients. During the pain status, activated spinal astrocytes and microglia release various inflammatory cytokines, resulting in spinal inflammation and the development of neuron sensitization. Scorpion is the dry body of Buthus martensii Karsch and is often used for various pain management in clinical practice. However, its function on bone cancer pain is unclear. Methods We investigated the effects of intragastric administration of scorpion on bone cancer pain induced by left tibial cavity injection of Walker 256 cells. Nociceptive behavior was measured using the von Frey filaments test and the spontaneous ambulatory pain score. The bone destruction was assessed by tibial radiographs. Expression of spinal cord astrocyte marker glial fibrillary acidic protein and microglial marker Iba1 was monitored by Western blot assay and immunofluorescence. Tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β was detected by real-time polymerase chain reaction. The proliferation of Walker 256 cells was evaluated by CCK8 assay. Results Intragastric administration of scorpion reduced bone cancer pain behavior and relieved bone destruction, accompanied by decreased expression of spinal glial fibrillary acidic protein and Iba1 protein level and TNF-α, IL-6, and IL-1β mRNA level. Besides, scorpion inhibited proliferation of Walker 256 cells in a dose- and time-dependent manner. Conclusion Our results demonstrate that scorpion produces an analgesic effect in a rat model of bone cancer pain via inhibiting bone destruction and activation of spinal cord astrocytes and microglia.
Point-of-Care Early Infant Diagnosis Improves Adherence to the Testing Algorithm in Kenya
Authors: Odhiambo Collins Otieno , Githuka George , Bowen Nancy , Kingwara Leonard , Onsase Jared , Ochuka Bernard , Waweru Michael , Masaba Rose , Matu Lucy , Mwangi Eliud , Cohn Jennifer 
Published: February 2020

Introduction: We determine the level of adherence to the revised Kenya early infant diagnosis (EID) algorithm during implementation of a point-of-care (POC) EID project. Methods: Data before (August 2016 to July 2017) and after (August 2017 to July 2018) introduction of POC EID were collected retrospectively from the national EID database and registers for 33 health facilities. We assessed the number of HIV-infected infants who underwent confirmatory testing and received baseline viral load test and proportion of infants with an initial negative result who had a subsequent test. Results and Discussion: Significantly higher number of infants accessed confirmatory testing (94.2% versus 38.6%; P < .0001) with POC EID. Baseline viral load test and follow-up testing at 6 months, although higher with POC EID, were not significantly different from the pre-POC EID intervention period. Conclusion: The POC EID implementation has the potential to increase proportion of infants who receive confirmatory testing, thus reducing the risk of false-positive results.
A validated novel continuous prognostic index to deliver stratified medicine in pediatric acute lymphoblastic leukemia
Authors: Enshaei Amir , O’Connor David , Bartram Jack , Hancock Jeremy , Harrison Christine J. , Hough Rachael , Samarasinghe Sujith , den Boer Monique L. , Boer Judith M. , de Groot-Kruseman Hester A. , Marquart Hanne V. , Noren-Nystrom Ulrika , Schmiegelow Kjeld , Schwab Claire , Horstmann Martin A. , Escherich Gabriele , Heyman Mats , Pieters Rob , Vora Ajay , Moppett John , Moorman Anthony V. 
Published: February 2020

Abstract
Risk stratification is essential for the delivery of optimal treatment in childhood acute lymphoblastic leukemia. However, current risk stratification algorithms dichotomize variables and apply risk factors independently, which may incorrectly assume identical associations across biologically heterogeneous subsets and reduce statistical power. Accordingly, we developed and validated a prognostic index (PIUKALL) that integrates multiple risk factors and uses continuous data. We created discovery (n = 2405) and validation (n = 2313) cohorts using data from 4 recent trials (UKALL2003, COALL-03, DCOG-ALL10, and NOPHO-ALL2008). Using the discovery cohort, multivariate Cox regression modeling defined a minimal model including white cell count at diagnosis, pretreatment cytogenetics, and end-of-induction minimal residual disease. Using this model, we defined PIUKALL as a continuous variable that assigns personalized risk scores. PIUKALL correlated with risk of relapse and was validated in an independent cohort. Using PIUKALL to risk stratify patients improved the concordance index for all end points compared with traditional algorithms. We used PIUKALL to define 4 clinically relevant risk groups that had differential relapse rates at 5 years and were similar between the 2 cohorts (discovery: low, 3% [95% confidence interval (CI), 2%-4%]; standard, 8% [95% CI, 6%-10%]; intermediate, 17% [95% CI, 14%-21%]; and high, 48% [95% CI, 36%-60%; validation: low, 4% [95% CI, 3%-6%]; standard, 9% [95% CI, 6%-12%]; intermediate, 17% [95% CI, 14%-21%]; and high, 35% [95% CI, 24%-48%]). Analysis of the area under the curve confirmed the PIUKALL groups were significantly better at predicting outcome than algorithms employed in each trial. PIUKALL provides an accurate method for predicting outcome and more flexible method for defining risk groups in future studies.
Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma
Authors: De Smedt Renate , Morscio Julie , Reunes Lindy , Roels Juliette , Bardelli Valentina , Lintermans Beatrice , Van Loocke Wouter , Almeida Afonso , Cheung Laurence C. , Kotecha Rishi S. , Mansour Marc R. , Uyttebroeck Anne , Vandenberghe Peter , La Starza Roberta , Mecucci Cristina , Lammens Tim , Van Roy Nadine , De Moerloose Barbara , Barata João T. , Taghon Tom , Goossens Steven , Van Vlierberghe Pieter 
Published: February 2020

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) and T-cell acute lymphoblastic lymphoma (T-LBL) are aggressive hematological malignancies that are currently treated with high-dose chemotherapy. Over the last several years, the search toward novel and less-toxic therapeutic strategies for T-ALL/T-LBL patients has largely focused on the identification of cell-intrinsic properties of the tumor cell. However, non–cell-autonomous activation of specific oncogenic pathways might also offer opportunities that could be exploited at the therapeutic level. In line with this, we here show that endogenous interleukin 7 (IL7) can increase the expression of the oncogenic kinase proviral integration site for Moloney-murine leukemia 1 (PIM1) in CD127+ T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD127+ T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after short-term in vivo chemotherapy, display consistent upregulation of PIM1 as compared with bulk nontreated tumor cells. Notably, this effect was transient as increased PIM1 levels were not observed in reestablished disease after abrogation of the initial chemotherapy. Furthermore, we uncover that this phenomenon is, at least in part, mediated by the ability of glucocorticoids to cause transcriptional upregulation of IL7RA in T-ALL/T-LBL patient-derived xenograft (PDX) cells, ultimately resulting in non–cell-autonomous PIM1 upregulation by endogenous IL7. Finally, we confirm in vivo that chemotherapy in combination with a pan-PIM inhibitor can improve leukemia survival in a PDX model of CD127+ T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7-responsive CD127+ T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy.
Gut-brain Axis and migraine headache: a comprehensive review
Authors:   On behalf of the School of Advanced Studies of the European Headache Federation (EHF-SAS), Arzani Mahsa , Jahromi Soodeh Razeghi , Ghorbani Zeinab , Vahabizad Fahimeh , Martelletti Paolo , Ghaemi Amir , Sacco Simona , Togha Mansoureh 
Published: February 2020

AbstractThe terminology “gut-brain axis “points out a bidirectional relationship between the GI system and the central nervous system (CNS). To date, several researches have shown that migraine is associated with some gastrointestinal (GI) disorders such as Helicobacter pylori (HP) infection, irritable bowel syndrome (IBS), and celiac disease (CD). The present review article aims to discuss the direct and indirect evidence suggesting relationships between migraine and the gut-brain axis. However, the mechanisms explaining how the gut and the brain may interact in patients with migraine are not entirely clear. Studies suggest that this interaction seems to be influenced by multiple factors such as inflammatory mediators (IL-1β, IL-6, IL-8, and TNF-α), gut microbiota profile, neuropeptides and serotonin pathway, stress hormones and nutritional substances. Neuropeptides including CGRP, SP, VIP, NPY are thought to have antimicrobial impact on a variety of the gut bacterial strains and thus speculated to be involved in the bidirectional relationship between the gut and the brain. According to the current knowledge, migraine headache in patients harboring HP might be improved following the bacteria eradication. Migraineurs with long headache history and high headache frequency have a higher chance of being diagnosed with IBS. IBS and migraine share some similarities and can alter gut microflora composition and thereby may affect the gut-brain axis and inflammatory status. Migraine has been also associated with CD and the condition should be searched particularly in patients with migraine with occipital and parieto-occipital calcification at brain neuroimaging. In those patients, gluten-free diet can also be effective in reducing migraine frequency. It has also been proposed that migraine may be improved by dietary approaches with beneficial effects on gut microbiota and gut-brain axis including appropriate consumption of fiber per day, adhering to a low glycemic index diet, supplementation with vitamin D, omega-3 and probiotics as well as weight loss dietary plans for overweight and obese patients.
Genome-wide identification and analysis of B-BOX gene family in grapevine reveal its potential functions in berry development
Authors: Wei Hongru , Wang Peipei , Chen Jianqing , Li Changjun , Wang Yongzhang , Yuan Yongbing , Fang Jinggui , Leng Xiangpeng 
Published: February 2020

Abstract
Background
The B-BOX (BBX) proteins are the class of zinc-finger transcription factors and can regulate plant growth, development, and endure stress response. In plants, the BBX gene family has been identified in Arabidopsis, rice, and tomato. However, no systematic analysis of BBX genes has been undertaken in grapevine.

Results
In this study, 24 grapevine BBX (VvBBX) genes were identified by comprehensive bioinformatics analysis. Subsequently, the chromosomal localizations, gene structure, conserved domains, phylogenetic relationship, gene duplication, and cis-acting elements were analyzed. Phylogenetic analysis divided VvBBX genes into five subgroups. Numerous cis-acting elements related to plant development, hormone and/or stress responses were identified in the promoter of the VvBBX genes. The tissue-specific expressional dynamics of VvBBX genes demonstrated that VvBBXs might play important role in plant growth and development. The transcript analysis from transcriptome data and qRT-PCR inferred that 11 VvBBX genes were down-regulated in different fruit developmental stages, while three VvBBX genes were up-regulated. It is also speculated that VvBBX genes might be involved in multiple hormone signaling (ABA, ethylene, GA3, and CPPU) as transcriptional regulators to modulate berry development and ripening. VvBBX22 seems to be responsive to multiple hormone signaling, including ABA, ethylene GA3, and CPPU. Some VvBBX genes were strongly induced by Cu, salt, waterlogging, and drought stress treatment. Furthermore, the expression of VvBBX22 proposed its involvement in multiple functions, including leaf senescence, abiotic stress responses, fruit development, and hormone response.

Conclusions
Our results will provide the reference for functional studies of BBX gene family, and highlight its functions in grapevine berry development and ripening. The results will help us to better understand the complexity of the BBX gene family in abiotic stress tolerance and provide valuable information for future functional characterization of specific genes in grapevine.
Higher growth of the apple (Malus × domestica Borkh.) fruit cortex is supported by resource intensive metabolism during early development
Authors: Jing Shan , Malladi Anish 
Published: February 2020

AbstractBackgroundThe major fleshy tissues of the apple fruit are spatially separable into cortex and pith. These tissues display differential growth during development. Key features of such differential growth, and sink metabolic programs supporting it have not been investigated previously. We hypothesized that differential growth between these fruit tissues is supported by differential sink metabolic programs, particularly during early development. Growth, metabolite concentrations, and transcript abundance of metabolism-related genes were measured to determine characteristics of differential growth and their underlying metabolic programs.ResultsThe cortex displayed > 5-fold higher growth than the pith during early fruit development, indicating that differential growth was established during this period. Further, when resource availability was increased through sink-removal, cortex growth was preferentially enhanced. Greatest diversity in metabolic programs between these tissues was evident during early fruit development. Higher cortex growth during early development was facilitated by increased catabolism of imported carbon (C) resources, sorbitol and sucrose, and the nitrogen (N) resource, asparagine. It was also associated with enhanced primary C metabolism, and C storage as malate and quinate. The pith metabolic program during this period involved limited allocation of C and N to growth, but greater allocation to storage, and enhanced sucrose-sucrose cycling.ConclusionsTogether, these data indicate that the fruit cortex tissue displays a resource intensive metabolic program during early fruit development. This provides the C backbones, proteins, energy and osmolytes to support its higher growth.
A PTPN11 mutation in a woman with Noonan syndrome and protein-losing enteropathy
Authors: Wang Na , Shi Wen , Jiao Yang 
Published: February 2020

Abstract
Background
Noonan syndrome is an autosomal dominant, variably expressed multisystem disorder characterized by specific facial and cardiac defects, delayed growth, ectodermal abnormalities, and lymphatic dysplasias. Lymphedema and chylous pleural effusions are common in Noonan syndrome, but protein-losing enteropathy (PLE) has only rarely been described in the condition and little is known about its genetic associations.

Case presentation
We report the case of a 30-year-old Chinese woman who developed severe recurrent edema and hypoproteinemia. Gastroduodenoscopy showed a “snowflake” appearance of lymphangiectasia in the duodenum, and CT reconstruction of the small intestine showed segmental thickening of the intestinal wall with localized stenosis. Whole exome sequencing revealed that the patient harbored a pathogenic variant of PTPN11 (c.A922G p.N308D), which was unfortunately inherited by her 2.5-year-old daughter who had short stature and atrial septal defect but no hypoproteinemia.

Conclusions
This case of Noonan syndrome with PLE was associated with a PTPN11 mutation. A comprehensive review of PLE in Noonan syndrome revealed that PLE often presents late in this context but there is no clear genotype-phenotype correlation. Genetic evaluation with next-generation sequencing can be useful for securing the diagnosis and planning early intervention and management.
Faecal calprotectin is the biomarker that best distinguishes remission from different degrees of endoscopic activity in Crohn’s disease
Authors: e Penna Francisco Guilherme Cancela , Rosa Rodrigo Macedo , da Cunha Pedro Ferrari Sales , de Souza Stella Cristina Silva , de Abreu Ferrari Maria de Lourdes 
Published: February 2020

Abstract
Background
Effective control of the inflammatory process in Crohn’s disease (CD) is reflected in intestinal mucosal healing. The performances of faecal calprotectin (fcal), clinical and serologic parameters in the inflammatory activity evaluation and their correlation to the simple endoscopic score (SES-CD) are the goals of this study.

Methods
Patients with CD referred for ileocolonoscopy were prospectively included and distributed according to the degree of endoscopic inflammatory activity into remission, mild activity, and moderate to severe activity groups. The different degrees of endoscopic activity were correlated with the following indexes: Crohn’s disease activity index (CDAI), fCal, serum C-reactive protein (CRP), and haemogram. The control group comprised individuals without known intestinal disease who were referred for colorectal cancer screening.

Results
Eighty colonoscopies were performed in patients with CD and 21 in the control group. The control group had a lower median fCal (59.7 mcg/g) than patients with CD (683 mcg/g, p < 0.001). A moderate Spearman correlation occurred between SES-CD and CRP (r = 0.525), fCal (r = 0.450), and CDAI (r = 0.407), while a weak correlation was found with the platelet count (r = 0.257). Only fCal distinguished patients in remission from those with mild activity (236.6 mcg/g × 654.9 mcg/g, p = 0.014) or moderate to severe activity (236.6 mcg/g × 1128 mcg/g, p < 0.001). An fCal cut-off of 155 mcg/g was sensitive (96%) and accurate (78%) for the diagnosis of endoscopic activity.

Conclusions
fCal provides greater diagnostic accuracy than the other activity markers for endoscopic activity of patients with CD, moderate correlation to SES-CD, and a capacity to discriminate patients in remission from those with mild or moderate to severe activity.
Safety and effectiveness of acellular pertussis vaccination during pregnancy: a systematic review
Authors: Vygen-Bonnet Sabine , Hellenbrand Wiebke , Garbe Edeltraut , von Kries Rüdiger , Bogdan Christian , Heininger Ulrich , Röbl-Mathieu Marianne , Harder Thomas 
Published: February 2020

Abstract
Background
Infants < 3 months of age are at highest risk for developing severe complications after pertussis. The majority of pregnant women has low concentrations of pertussis-specific antibodies and thus newborns are insufficiently protected by maternally transferred antibodies. Acellular pertussis vaccination during pregnancy was recently implemented in various countries. Here, we assessed the evidence for safety and effectiveness of pertussis vaccination during pregnancy.

Methods
We searched Medline, Embase, and ClinicalTrials.gov from January 1st 2010 to January 10th 2019. We assessed risk of bias (ROB) using the Cochrane ROB tool and ROBINS-I. We evaluated the quality of evidence using the GRADE approach.

Results
We identified 1273 articles and included 22 studies (14 for safety; 8 for effectiveness), comprising 1.4 million pregnant women in safety studies and 855,546 mother-infant-pairs in effectiveness studies. No significant differences between vaccinated and unvaccinated women and their infants were observed for safety outcomes with the exception of fever and chorioamnionitis. Compared to no vaccination, three studies showed a significantly increased relative risk for the presence of the ICD-9 code for chorioamnionitis in electronic patient data after pertussis vaccination. However, no study reported an increased risk for clinical sequelae of chorioamnionitis after vaccination during pregnancy, such as preterm birth or neonatal intensive care unit admission. Vaccine effectiveness against pertussis in infants of immunized mothers ranged from 69 to 91% for pertussis prevention, from 91 to 94% for prevention of hospitalization and was 95% for prevention of death due to pertussis. Risk of bias was serious to critical for safety outcomes and moderate to serious for effectiveness outcomes. GRADE evidence quality was moderate to very low, depending on outcome.

Conclusion
Although an increased risk for a diagnosis of fever and chorioamnionitis was detected in pregnant women after pertussis vaccination, there was no association with a higher frequency of clinically relevant sequelae. Vaccine effectiveness for prevention of infant pertussis, hospitalization and death is high. Pertussis vaccination during pregnancy has an overall positive benefit-risk ratio. In view of the overall quality of available evidence ongoing surveillance of chorioamnionitis and its potential sequelae is recommended when pertussis vaccination in pregnancy is implemented.

Trial registration
PROSPERO CRD42018087814, CRD42018090357.