bluuebunny/crossref_metadata_2025_split huggingface dataset:
BRCAness digitalMLPA profiling predicts benefit of intensified platinum-based chemotherapy in triple-negative and luminal-type breast cancer
Authors: Lips Esther H. , Benard-Slagter Anne , Opdam Mark , Scheerman Caroline E. , Wesseling Jelle , Hogervorst Frans B. L. , Linn Sabine C. , Savola Suvi , Nederlof Petra M. 
Published: July 2020

Abstract
Background
We previously showed that BRCA-like profiles can be used to preselect individuals with the highest risk of carrying BRCA mutations but could also indicate which patients would benefit from double-strand break inducing chemotherapy. A simple, robust, and reliable assay for clinical use that utilizes limited amounts of formalin-fixed, paraffin-embedded tumor tissue to assess BRCAness status in both ER-positive and ER-negative breast cancer (BC) is currently lacking.

Methods
A digital multiplex ligation-dependent probe amplification (digitalMLPA) assay was designed to detect copy number alterations required for the classification of BRCA1-like and BRCA2-like BC. The BRCA1-like classifier was trained on 71 tumors, enriched for triple-negative BC; the BRCA2-like classifier was trained on 55 tumors, enriched for luminal-type BC. A shrunken centroid-based classifier was developed and applied on an independent validation cohort. A total of 114 cases of a randomized controlled trial were analyzed, and the association of the classifier result with intensified platinum-based chemotherapy response was assessed.

Results
The digitalMLPA BRCA1-like classifier correctly classified 91% of the BRCA1-like samples and 82% of the BRCA2-like samples. Patients with a BRCA-like tumor derived significant benefit of high-dose chemotherapy (adjusted hazard ratio (HR) 0.12, 95% CI 0.04–0.44) which was not observed in non-BRCA-like patients (HR 0.9, 95% CI 0.37–2.18) (p = 0.01). Analysis stratified for ER status showed borderline significance.

Conclusions
The digitalMLPA is a reliable method to detect a BRCA1- and BRCA2-like pattern on clinical samples and predicts platinum-based chemotherapy benefit in both triple-negative and luminal-type BC.
Conducting clinical trials in sub-Saharan Africa: challenges and lessons learned from the Malawi Cryptosporidium study
Authors: Toto Neema , Douglas Elaine , Gmeiner Markus , Barrett Lynn K. , Lindblad Robert , Makhaza Lumbani , Nedi Wilfred , Phulusa Jacob , Quinnan Gerald V. , Sawyer Leigh A. , Thole Herbert , Van Voorhis Wesley C. , Iroh Tam Pui-Ying 
Published: July 2020

Abstract
Background
An effective drug to treat cryptosporidial diarrhea in HIV-infected individuals is a global health priority. Promising drugs need to be evaluated in endemic areas which may be challenged by both lack of resources and experience to conduct International Committee of Harmonisation-Good Clinical Practice (ICH-GCP)-compliant clinical trials.

Methods
We present the challenges and lessons learned in implementing a phase 2A, randomized, double-blind, placebo-controlled trial of clofazimine, in treatment of cryptosporidiosis among HIV-infected adults at a single site in Malawi.

Results
Primary challenges are grouped under study initiation, study population, study implementation, and cultural issues. The lessons learned primarily deal with regulatory system and operational barriers, and recommendations can be applied to other human experimental trials in low- and middle-income countries, specifically in sub-Saharan Africa.

Conclusion
This study demonstrated that initiating and implementing human experimental trials in sub-Saharan Africa can be challenging. However, solutions exist and successful execution requires careful planning, ongoing evaluation, responsiveness to new developments, and oversight of all trial operations.
Accuracy of time to treatment estimates in the CRASH-3 clinical trial: impact on the trial results
Authors: Mansukhani Raoul , Frimley Lauren , Shakur-Still Haleema , Sharples Linda , Roberts Ian 
Published: July 2020

Abstract
Background
Early treatment with tranexamic acid may reduce deaths after traumatic brain injury (TBI). In mild and moderate TBI, there is a time to treatment interaction, with early treatment being most beneficial. Time to treatment was recorded by clinicians and is subject to error. Using monitoring data from the CRASH-3 trial, we examine the impact of errors in time to treatment on estimated treatment effects.

Methods
The CRASH-3 trial was a randomised trial of the effect of tranexamic acid on death and vascular occlusive events in 12,737 TBI patients. This analysis includes the 8107 patients with a Glasgow coma scale score of 9 to 15 since previous analyses showed that these patients benefit most from early treatment. Clinician-recorded time to treatment was checked against ambulance and hospital records for 1368/12,737 (11%) patients. Patients who died were preferentially selected for monitoring and we monitored 36% of head injury deaths. We describe measurement errors using Bland-Altman graphs. We model the effect of tranexamic acid on head injury death using logistic regression with a time-treatment interaction term. We use regression calibration, multiple imputation and Bayesian analysis to estimate the impact of time to treatment errors.

Results
Clinicians rounded times to the nearest half or full hour in 66% of cases. Monitored times were also rounded and were identical to clinician times in 63% of patients. Times were underestimated by an average of 9 min (95% CI − 85, 66). There was more variability between clinician-recorded and monitored times in low- and middle-income countries than in high-income countries. The treatment effect estimate at 1 h was greater for monitored times OR = 0.61 (95% CI 0.47, 0.81) than for clinician-recorded times OR = 0.63 (95% CI 0.48, 0.83). All three adjustment methods gave similar time to treatment interactions. For Bayesian methods, the treatment effect at 1 h was OR = 0.58 (95% CI 0.43, 0.78). Using monitored times increased the time-treatment interaction term from 1.15 (95% CI 1.03, 1.27) to 1.16 (95% CI 1.05, 1.28).

Conclusions
Accurate estimation of time from injury to treatment is challenging, particularly in low resource settings. Adjustment for known errors in time to treatment had minimal impact on the trial results.

Trial registration
ClinicalTrials.gov NCT01402882. Registered on 25 July 2011
Synthesis, density functional theory study and in vitro antimicrobial evaluation of new benzimidazole Mannich bases
Authors: Marinescu Maria , Cinteză Ludmila Otilia , Marton George Iuliu , Chifiriuc Mariana-Carmen , Popa Marcela , Stănculescu Ioana , Zălaru Christina-Marie , Stavarache Cristina-Elena 
Published: July 2020

AbstractThe tri-component synthesis of novel chiral benzimidazole Mannich bases, by reaction between benzimidazole, aqueous 30% formaldehyde and an amine, the biological evaluation and DFT studies of the new compounds are reported here. The 1H-NMR, 13C-NMR, FTIR spectra and elemental analysis confirm the structures of the new compounds. All synthesized compounds were screened by qualitative and quantitative methods for their in vitro antibacterial activity against 4 bacterial strains. DFT studies were accomplished using GAMESS 2012 software and HOMO–LUMO analysis allowed the calculation of electronic and structural parameters of the chiral Mannich bases. The geometry of 1-methylpiperazine, the cumulated Mullikan atomic charges of the two heteroatoms and of the methyl, and the value of the global electrophilicity index (ω = 0.0527) of the M-1 molecule is correlated with its good antimicrobial activity. It was found that the presence of saturated heterocycles from the amine molecule, 1-methyl piperazine and morpholine, respectively, contributes to an increased biological activity, compared to aromatic amino analogs, diphenylamino-, 4-nitroamino- and 4-aminobenzoic acid. The planarity of the molecules, specific bond lengths and localization of HOMO–LUMO orbitals is responsible for the best biological activities of the compounds.
Eimeria tenella Eimeria-specific protein that interacts with apical membrane antigen 1 (EtAMA1) is involved in host cell invasion
Authors: Li Cong , Zhao Qiping , Zhu Shunhai , Wang Qingjie , Wang Haixia , Yu Shuilan , Yu Yu , Liang Shashan , Zhao Huanzhi , Huang Bing , Dong Hui , Han Hongyu 
Published: July 2020

Abstract
Background
Avian coccidiosis is a widespread, economically significant disease of poultry, caused by several Eimeria species. These parasites have complex and diverse life-cycles that require invasion of their host cells. This is mediated by various proteins secreted from apical secretory organelles. Apical membrane antigen 1 (AMA1), which is released from micronemes and is conserved across all apicomplexans, plays a central role in the host cell invasion. In a previous study, some putative EtAMA1-interacting proteins of E. tenella were screened. In this study, we characterized one putative EtAMA1-interacting protein, E. tenella Eimeria -specific protein (EtEsp).

Methods
Bimolecular fluorescence complementation (BiFC) and glutathione S-transferase (GST) fusion protein pull-down (GST pull-down) were used to confirm the interaction between EtAMA1 and EtEsp in vivo and in vitro. The expression of EtEsp was analyzed in different developmental stages of E. tenella with quantitative PCR and western blotting. The secretion of EtEsp protein was tested with staurosporine when sporozoites were incubated in complete medium at 41 °C. The localization of EtEsp was analyzed with an immunofluorescence assay (IFA). An in vitro invasion inhibition assay was conducted to assess the ability of antibodies against EtEsp to inhibit cell invasion by E. tenella sporozoites.

Results
The interaction between EtAMA1 and EtEsp was confirmed with BiFC and by GST pull-down. Our results show that EtEsp is differentially expressed during distinct phases of the parasite life-cycle. IFA showed that the EtEsp protein is mainly distributed on the parasite surface, and that the expression of this protein increases during the development of the parasite in the host cells. Using staurosporine, we showed that EtEsp is a secreted protein, but not from micronemes. In inhibition tests, a polyclonal anti-rEtEsp antibody attenuated the capacity of E. tenella to invade host cells.

Conclusion
In this study, we show that EtEsp interacts with EtAMA1 and that the protein is secreted protein, but not from micronemes. The protein participates in sporozoite invasion of host cells and is maybe involved in the growth of the parasite. These data have implications for the use of EtAMA1 or EtAMA1-interacting proteins as targets in intervention strategies against avian coccidiosis.
Neospora caninum infection induces an isolate virulence-dependent pro-inflammatory gene expression profile in bovine monocyte-derived macrophages
Authors: García-Sánchez Marta , Jiménez-Pelayo Laura , Horcajo Pilar , Collantes-Fernández Esther , Ortega-Mora Luis Miguel , Regidor-Cerrillo Javier 
Published: July 2020

AbstractBackgroundNeospora caninumis an obligate intracellular parasite, and its ability to survive inside host immune cells may be a key mechanism for the establishment of infection in cattle.In vitrostudies carried out by our group have shown thatN. caninumis able to replicate in bovine macrophages (MØs), alter their microbicidal mechanisms and exploit their motility. Furthermore, host-cell control seems to be isolate virulence-dependent.MethodsTo investigate the molecular basis underlying the innate responses in MØs againstN. caninumand the mechanisms of parasite manipulation of the host cell environment, the transcriptome profile of bovine monocyte-derived MØs infected with high-virulence (Nc-Spain7) or low-virulence (Nc-Spain1H)N. caninumisolates was studied.ResultsFunctional enrichment revealed upregulation of genes involved in chemokine signalling, inflammation, cell survival, and inhibition of genes related with metabolism and phagolysosome formation. MØs activation was characterized by the induction of a predominantly M1 phenotype with expression ofTLR2,TLR3andTLR9and activation of the NF-ƙB signalling pathway. Heat-killedN. caninumtachyzoites failed to activate NF-ƙB, and to inhibit lysosomal activity and apoptosis, which indicates active modulation by the parasite. The FoxO signalling pathway, Th1-Th2 differentiation, glycosaminoglycan degradation and apoptosis were pathways enriched only for low virulent Nc-Spain1H infection. In addition, Nc-Spain1H infection upregulated theIL12AandIL8pro-inflammatory cytokines, whereasIL23was downregulated by high virulent Nc-Spain7.ConclusionsThis study revealed mechanisms implicated in the recognition ofN. caninumby bovine MØs and in the development of the subsequent immune response. NF-ƙB seems to be the main signalling pathway implicated in the pro-inflammatory bovine MØs response against this pathogen. Apoptosis and phagolysosome maturation are processes repressed byN. caninuminfection, which may guarantee its intracellular survival. The results also indicate that Nc-Spain7 may be able to partially circumvent the pro-inflammatory response whereas Nc-Spain1H induces a protective response to infection, which may explain the more efficient transmission of the high-virulence Nc-Spain7 isolate observedin vivo.
Assessing the effect of interventions for axial spondyloarthritis according to the endorsed ASAS/OMERACT core outcome set: a meta-research study of trials included in Cochrane reviews
Authors: Andreasen Rikke A. , Kristensen Lars E. , Baraliakos Xenofon , Strand Vibeke , Mease Philip J. , de Wit Maarten , Ellingsen Torkell , Hansen Inger Marie J. , Kirkham Jamie , Wells George A. , Tugwell Peter , Maxwell Lara , Boers Maarten , Egstrup Kenneth , Christensen Robin 
Published: July 2020

AbstractThe Assessment of SpondyloArthritis international Society (ASAS) has defined core sets for (i) symptom-modifying anti-rheumatic drugs (SM-ARD), (ii) clinical record keeping, and (iii) disease-controlling anti-rheumatic therapy (DC-ART). These include the following domains for all three core sets: “physical function,” “pain,” “spinal mobility,” “spinal stiffness,” and “patient’s global assessment” (PGA). The core set for clinical record keeping further includes the domains “peripheral joints/entheses” and “acute phase reactants,” and the core set for DC-ART further includes the domains “fatigue” and “spine radiographs/hip radiographs.” The Outcome Measures in Rheumatology (OMERACT) endorsed the core sets in 1998.Using empirical evidence from axSpA trials, we investigated the efficacy (i.e., net benefit) according to the ASAS/OMERACT core outcome set for axSpA across all interventions tested in trials included in subsequent Cochrane reviews. For all continuous scales, we combined data using the standardized mean difference (SMD) to meta-analyze outcomes involving the same domains. Also, through meta-regression analysis, we examined the effect of the separate SMD measures (independent variables) on the primary endpoint (log [OR], dependent variable) across all trials.Based on 11 eligible Cochrane reviews, from these, 85 articles were screened; we included 43 trials with 63 randomized comparisons. Mean (SD) number of ASAS/OMERACT core outcome domains measured for SM-ARD/physical therapy trials was 4.2 (1.7). Six trials assessed all proposed domains. Mean (SD) for number of core outcome domains for DC-ART trials was 5.8 (1.7). No trials assessed all nine domains. Eight trials (16%) were judged to have inadequate (i.e., high risk of) selective outcome reporting bias. The most responsible core domains for achieving success in meeting the primary objective per trial were pain, OR (95% CI) 5.19 (2.28, 11.77), and PGA, OR (95% CI) 1.87 (1.14, 3.07). In conclusion, selective outcome reporting (and “missing data”) should be reduced by encouraging the use of the endorsed ASAS/OMERACT outcome domains in clinical trials. Overall outcome reporting was good for SM-ARD/physical therapy trials and poor for DC-ART trials. Our findings suggest that both PGA and pain provide a valuable holistic construct for the assessment of improvement beyond more objective measures of spinal inflammation.
Does periodontitis affect the treatment response of biologics in the treatment of rheumatoid arthritis?
Authors: Tachibana Masahiro , Yonemoto Yukio , Okamura Koichi , Suto Takahito , Sakane Hideo , Kaneko Tetsuya , Dam Trang Thuy , Okura Chisa , Tajika Tsuyoshi , Tsushima Yoshito , Chikuda Hirotaka 
Published: July 2020

Abstract
Background
Rheumatoid arthritis (RA) and periodontitis (PD) have been suggested to share many clinical and pathological features. However, few reports have investigated the relationship between the degree of PD and the treatment response to RA.
This study aimed to examine the relationship between the extent of PD and the treatment response to biologics in RA patients using FDG-PET/CT.

Methods
Sixty RA patients (male, n = 14; female, n = 46; average age, 58.3 years) treated with biologic agents were included in this study. FDG-PET/CT was performed at baseline and 6 months after the initiation of biological therapy. The maximum standardized uptake value (SUVmax) was used as a representative value for the assessment of the FDG uptake in periodontal tissue and joints including the bilateral shoulders, elbows, wrists, hip, knees, and ankle joints. The Disease Activity Score (DAS) 28-CRP and the following clinical parameters were assessed: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-cyclic citrullinated peptide antibody (ACPA), rheumatoid factor (RF), and matrix metalloproteinase 3 (MMP-3). The relationship between the treatment response of RA and the baseline SUVmax of the periodontal tissue was evaluated.

Results
The baseline periodontal SUVmax was related to patient age (r = 0.302, p = 0.009) and the ACPA level (r = 0.265, p = 0.025). The DAS28-CRP, CRP, ESR, MMP-3, and joint SUVmax values were significantly decreased after 6 months of biological therapy. However, the mean periodontal SUVmax, ACPA, and RF showed no significant changes after treatment. There was a significantly negative correlation between the baseline periodontal SUVmax and the treatment response of DAS28-CRP (r = − 0.369, p = 0.004).

Conclusion
There was a negative correlation between the extent of PD at baseline and the treatment response of RA patients who received biological therapy. The evaluation of the periodontal condition is considered to be an essential part for the management of RA.
Linking the westernised oropharyngeal microbiome to the immune response in Chinese immigrants
Authors: Guo Jing , Zhang Xiaoping , Saiganesh Aarti , Peacock Christopher , Chen Shu , Dykes Gary A. , Hales Belinda J. , Le Souëf Peter N. , Zhang Guicheng 
Published: July 2020

Abstract
Background
Human microbiota plays a fundamental role in modulating the immune response. Western environment and lifestyle are envisaged to alter the human microbiota with a new microbiome profile established in Chinese immigrants, which fails to prime the immune system. Here, we investigated how differences in composition of oropharyngeal microbiome may contribute to patterns of interaction between the microbiome and immune system in Chinese immigrants living in Australia.

Methods
We recruited 44 adult Chinese immigrants: newly-arrived (n = 22, living in Australia < 6 months) and long-term Chinese immigrants (n = 22, living in Australia > 5 years), with age and gender matched. Oropharyngeal swabs, serum and whole blood were collected. The 16 s ribosomal RNA gene from the swabs was sequenced on the Illumina MiSeq platform. Innate immune responses were determined by 23 Toll-like receptors (TLR) pathway cytokines, while adaptive immune responses were determined by IgG-associated response to specific microbial/viral pathogens.

Results
The relative abundance of the genus Leptotrichia was higher in long-term immigrants as compared to that in newly-arrived Chinese immigrants, while the genus Deinococcus was significantly lower in long-term Chinese immigrants. The genera uncultured Lachnospiraceae, Erysipelotrichaceae UCG-007, Veillonella, and Actinomycetales_ambiguous taxa were negatively correlated with cytokine IL-6 in long-term Chinese immigrants (rho range: − 0.46 ~ − 0.73). With respect to adaptive immunity, several microbial taxa were significantly associated with IgG1 responsiveness to microbial antigens in long-term immigrants, while a significant correlation with IgG1 responsiveness to viral antigens was detected in newly-arrived immigrants.

Conclusions
The composition of the oropharyngeal microbiome varies between newly-arrived and long-term Chinese immigrants. Specific microbial taxa are significantly associated with immunological parameters but with different association patterns between newly-arrived and long-term Chinese immigrants.
Double lingual frenulum: a case report
Authors: Filfilan Reham O. , Almazrooa Soulafa A. 
Published: July 2020

Abstract
Background
The lingual frenulum is a mucous membrane fold found underneath the tongue. It helps the tongue to perform its function. There are few anomalies that can affect the lingual frenulum, such as ankyloglossia and absence of the lingual frenulum. We report a case of two lingual frenula to educate practitioners about the presence of such an anomaly.

Case presentation
A 10-year-old healthy Saudi girl came to our dental clinic complaining of “malpositioned frontal teeth.” Upon intraoral examination, two lingual frenula were found connecting the tongue with the floor of the mouth. Intraoral examination revealed no other abnormalities.

Conclusion
Double lingual frenulum is an existing frenulum anomaly that did not affect normal function of our patient. A search of the literature revealed that this may well be the first reported case of such a condition.
miR-200a contributes to the migration of BMSCs induced by the secretions of E. faecalis via FOXJ1/NFκB/MMPs axis
Authors: Li Mingwei , Wei Lifan , Zhou Wei , He Zhiyan , Ran Shujun , Liang Jingping 
Published: July 2020

Abstract
Background
Upon migrating to the injured sites, bone marrow mesenchymal stem cells (BMSCs) play critical roles in the repair of bone lesion caused by chronic apical periodontitis. Emerging evidences have shown that Enterococcus faecalis is always associated with apical periodontitis, especially refractory apical periodontitis. But the mechanism underlying how Enterococcus faecalis affects the migration of BMSCs remains unclear.

Methods
The effects of Enterococcus faecalis supernatants on the migration of BMSCs were determined by transwell migration assays. miRNA sequencing was performed to detect the significantly differentially expressed miRNAs of BMSCs. Proteomics analysis was used to detect the protein expression alterations of BMSCs. Luciferase report assays were deployed to verify the targets of miRNA. Western blot analysis was performed to examine the expressions of matrix metalloproteinases-3, matrix metalloproteinases-9, Forkhead Box Protein J1 (FOXJ1), and nuclear factor kappa B (NFκB). The activations of NFκB were detected by luciferase assays with NFκBluc reporter.

Results
We found that Enterococcus faecalis supernatants could promote the migration of BMSCs. The upregulation of miR-200a-3p in this process contributed to BMSC migration through downregulating its target Forkhead Box Protein J1. Moreover, FOXJ1/ NFκB axis was found to regulate matrix metalloproteinases (MMPs) in this process.

Conclusions
These results above suggest that miR-200a contributes to the migration of BMSCs induced by the secretions of E. faecalis via FOXJ1/NFκB/MMPs axis.