bluuebunny/crossref_metadata_2025_split huggingface dataset:
YTHDC1 is downregulated by the YY1/HDAC2 complex and controls the sensitivity of ccRCC to sunitinib by targeting the ANXA1-MAPK pathway
Authors: Li Wei , Ye Kun , Li Xurui , Liu Xinlin , Peng Mou , Chen Fang , Xiong Wei , Wang Yinhuai , Zhu Liang 
Published: August 2022

Abstract
Background
Tyrosine kinase inhibitors (TKIs) such as sunitinib are multitarget antiangiogenic agents in clear cell renal cell carcinoma (ccRCC). They are widely used in the treatment of advanced/metastatic renal cancer. However, resistance to TKIs is common in the clinic, particularly after long-term treatment. YTHDC1 is the main nuclear reader protein that binds with m6A to regulate the splicing, export and stability of mRNA. However, the specific role and corresponding mechanism of YTHDC1 in renal cancer cells are still unclear.

Methods
The Cancer Genome Atlas (TCGA) dataset was used to study the expression of YTHDC1 in ccRCC. Cell counting kit-8 (CCK-8), wound healing, Transwell and xenograft assays were applied to explore the biological function of YTHDC1 in ccRCC. Western blot, quantitative real time PCR (RT‒qPCR), RNA immunoprecipitation PCR (RIP-qPCR), methylated RIP-qPCR (MeRIP-qPCR) and RNA sequencing (RNA-seq) analyses were applied to study the YY1/HDAC2/YTHDC1/ANXA1 axis in renal cancer cells. The CCK-8 assay and xenograft assay were used to study the role of YTHDC1 in determining the sensitivity of ccRCC to sunitinib.

Results
Our results demonstrated that YTHDC1 is downregulated in ccRCC tissues compared with normal tissues. Low expression of YTHDC1 is associated with a poor prognosis in patients with ccRCC. Subsequently, we showed that YTHDC1 inhibits the progression of renal cancer cells via downregulation of the ANXA1/MAPK pathways. Moreover, we also showed that the YTHDC1/ANXA1 axis modulates the sensitivity of tyrosine kinase inhibitors. We then revealed that HDAC2 inhibitors resensitize ccRCC to tyrosine kinase inhibitors through the YY1/HDAC2 complex. We have identified a novel YY1/HDAC2/YTHDC1/ANXA1 axis modulating the progression and chemosensitivity of ccRCC.

Conclusion
We identified a novel YY1/HDAC2/YTHDC1/ANXA1 axis modulating the progression and chemosensitivity of ccRCC.
HORNBILL: a phase I/IIa trial examining the safety, tolerability and early response of BI 764524 in patients with diabetic retinopathy and diabetic macular ischaemia—rationale, study design and protocol
Authors: Chong Victor , Nguyen Quan Dong , Sepah Yasir , Giani Andrea , Pearce Elizabeth 
Published: August 2022

Abstract
Background
Diabetic macular ischaemia (DMI) is a complication of diabetic retinopathy that leads to irreversible vision loss. DMI is characterised by reduced retinal vessel density and enlargement of the foveal avascular zone (FAZ). Despite its clinical burden, there is no formal consensus on the definition of DMI, and no approved treatment. Semaphorin 3A (Sema3A) is an axonal guidance molecule that blocks revascularisation of the ischaemic retina. Sema3A modulation is therefore a promising mechanism of action for the treatment of ischaemic eye diseases. BI 764524 is an intravitreal anti-Sema3A ischaemia modulator agent.

Methods
HORNBILL (NCT04424290) is a phase I/IIa trial comprising a non-randomised, open-label, single rising dose (SRD) part and a randomised, masked, sham-controlled multiple dose (MD) part to investigate the safety, tolerability and early biological response of ischaemia modulator BI 764524 in adults (≥18 years) with DMI. DMI will be defined using optical coherence tomography angiography (OCTA) as either any degree of disruption in the retinal vascularity (SRD) or a FAZ of ≥0.5 mm2 (MD). Subjects in the SRD part will receive 0.5, 1.0 or 2.5 mg of BI 764524; the maximum tolerated dose will then be used in the MD part. A minimum of 12 subjects will be enrolled into the SRD part; planned enrollment is 30 for the MD part. The primary endpoint of the SRD part is the number of subjects with dose-limiting adverse events (AEs) until day 8. The primary endpoint of the MD part is the number of subjects with drug-related AEs from baseline to end of study, and secondary endpoints include change from baseline in the size of the FAZ, best-corrected visual acuity and central retinal thickness.

Discussion
DMI is a poorly defined condition with no treatment options. HORNBILL is the first clinical trial to assess a treatment for DMI and to use OCTA as a means to define and examine DMI. The OCTA data generated in this trial could form the basis of formal diagnostic criteria for DMI. Furthermore, the novel mechanism of action (Sema3A modulation) explored in this trial has the potential to revolutionise the treatment landscape for patients with DMI.

Trial registration
ClinicalTrials.govNCT04424290; EudraCT 2019-004432-28. Registered on 9 June 2020
Comparison of explanatory and pragmatic design choices in a cluster-randomized hypertension trial: effects on enrollment, participant characteristics, and adherence
Authors: Margolis Karen L. , Crain A. Lauren , Green Beverly B. , O’Connor Patrick J. , Solberg Leif I. , Beran MarySue , Bergdall Anna R. , Pawloski Pamala A. , Ziegenfuss Jeanette Y. , JaKa Meghan M. , Appana Deepika , Sharma Rashmi , Kodet Amy J. , Trower Nicole K. , Rehrauer Daniel J. , McKinney Zeke , Norton Christine K. , Haugen Patricia , Anderson Jeffrey P. , Crabtree Benjamin F. , Norman Sarah K. , Sperl-Hillen JoAnn M. 
Published: August 2022

Abstract
Background
Explanatory trials are designed to assess intervention efficacy under ideal conditions, while pragmatic trials are designed to assess whether research-proven interventions are effective in “real-world” settings without substantial research support.

Methods
We compared two trials (Hyperlink 1 and 3) that tested a pharmacist-led telehealth intervention in adults with uncontrolled hypertension. We applied PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) scores to describe differences in the way these studies were designed and enrolled study-eligible participants, and the effect of these differences on participant characteristics and adherence to study interventions.

Results
PRECIS-2 scores demonstrated that Hyperlink 1 was more explanatory and Hyperlink 3 more pragmatic. Recruitment for Hyperlink 1 was conducted by study staff, and 2.9% of potentially eligible patients enrolled. Enrollees were older, and more likely to be male and White than non-enrollees. Study staff scheduled the initial pharmacist visit and adherence to attending this visit was 98%. Conversely for Hyperlink 3, recruitment was conducted by clinic staff at routine encounters and 81% of eligible patients enrolled. Enrollees were younger, and less likely to be male and White than non-enrollees. Study staff did not assist with scheduling the initial pharmacist visit and adherence to attending this visit was only 27%. Compared to Hyperlink 1, patients in Hyperlink 3 were more likely to be female, and Asian or Black, had lower socioeconomic indicators, and were more likely to have comorbidities. Owing to a lower BP for eligibility in Hyperlink 1 (>140/90 mm Hg) than in Hyperlink 3 (>150/95 mm Hg), mean baseline BP was 148/85 mm Hg in Hyperlink 1 and 158/92 mm Hg in Hyperlink 3.

Conclusion
The pragmatic design features of Hyperlink 3 substantially increased enrollment of study-eligible patients and of those traditionally under-represented in clinical trials (women, minorities, and patients with less education and lower income), and demonstrated that identification and enrollment of a high proportion of study-eligible subjects could be done by usual primary care clinic staff. However, the trade-off was much lower adherence to the telehealth intervention than in Hyperlink 1, which is likely to reflect uptake under real-word conditions and substantially dilute intervention effect on BP.

Trial registration
The Hyperlink 1 study (NCT00781365) and the Hyperlink 3 study (NCT02996565) are registered at ClinicalTrials.gov.
Design, synthesis, anticancer evaluation and docking studies of novel 2-(1-isonicotinoyl-3-phenyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-one derivatives as Aurora-A kinase inhibitors
Authors: Beniwal Meenu , Jain Neelam , Jain Sandeep , Aggarwal Navidha 
Published: August 2022

AbstractIntroductionAurora-A kinase is associated with the Aurora kinase family which has been considered a striking anticancer target for the treatment of human cancers.ObjectiveTo design, synthesize, anticancer evaluation, and docking studies of novel 2-(1-isonicotinoyl-3-phenyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-one derivatives as Aurora-A Kinase inhibitors.MethodA total of 21 Pyrazole derivativesP (1–21)were synthesized by using the Vilsmeier Haack reagent which was characterized by FT-IR,1H NMR,13C NMR, and Mass spectroscopy. The synthesized derivatives were evaluated for their potential in vitro anticancer activity by MTT assay and Aurora-A kinase inhibition assay.ResultsThe cytotoxicity assay (MTT assay) showed that compoundP-6exhibited potent cytotoxicity (IC50 = 0.37–0.44 μM) against two cancer (HCT 116 and MCF-7) cell lines, which were comparable to the standard compound, VX-680. CompoundP-6also showed inhibition of Aurora-A kinase with an IC50value of 0.11 ± 0.03 µM. A Docking study was done to compoundP-6andP-20into the active site of Aurora A kinase, in order to get the probable binding model for further study.ConclusionA series of 21 novel pyrazole derivativesP(1–21)were designed, synthesized, in vitro anticancer evaluation, and docking studies for Aurora A kinase inhibition. The results established thatP-6is a prospective aspirant for the development of anticancer agents targeting Aurora-A kinase.
A statistical calibration tool for methods used to sample outdoor-biting mosquitoes
Authors: Ngowo Halfan S. , Limwagu Alex J. , Ferguson Heather M. , Matthiopoulos Jason , Okumu Fredros O. , Nelli Luca 
Published: August 2022

Abstract
Background
Improved methods for sampling outdoor-biting mosquitoes are urgently needed to improve surveillance of vector-borne diseases. Such tools could potentially replace the human landing catch (HLC), which, despite being the most direct option for measuring human exposures, raises significant ethical and logistical concerns. Several alternatives are under development, but detailed evaluation still requires common frameworks for calibration relative to HLC. The aim of this study was to develop and validate a statistical framework for predicting human-biting rates from different exposure-free alternatives.

Methods
We obtained mosquito abundance data (Anopheles arabiensis, Anopheles funestus and Culex spp.) from a year-long Tanzanian study comparing six outdoor traps [Suna Trap (SUN), BG Sentinel (BGS), M-Trap (MTR), M-Trap + CDC (MTRC), Ifakara Tent Trap-C (ITT-C) and Mosquito Magnet-X Trap (MMX)] and HLC. Generalised linear models were developed within a Bayesian framework to investigate associations between the traps and HLC, taking intra- and inter-specific density dependence into account. The best model was used to create a calibration tool for predicting HLC-equivalents.

Results
For An. arabiensis, SUN catches had the strongest correlation with HLC (R2 = 19.4), followed by BGS (R2 = 17.2) and MTRC (R2 = 13.1) catches. The least correlated catch was MMX (R2 = 2.5). For An. funestus, BGS had the strongest correlation with the HLC (R2 = 53.4), followed by MTRC (R2 = 37.4) and MTR (R2 = 37.4). For Culex mosquitoes, the traps most highly correlated with the HLC were MTR (R2 = 45.4) and MTRC (R2 = 44.2). Density dependence, both between and within species, influenced the performance of only BGS traps. An interactive Shiny App calibration tool was developed for this and similar applications.

Conclusion
We successfully developed a calibration tool to assess the performance of different traps for assessing outdoor-biting risk, and established a valuable framework for estimating human exposures based on the trap catches. The performance of candidate traps varied between mosquito taxa; thus, there was no single optimum. Although all the traps tested underestimated the HLC-derived exposures, it was possible to mathematically define their representativeness of the true biting risk, with or without density dependence. The results of this study emphasise the need to aim for a consistent and representative sampling approach, as opposed to simply seeking traps that catch the most mosquitoes.

Graphical Abstract
A systematic method for comparing multimorbidity in national surveys
Authors: Roomaney Rifqah Abeeda , van Wyk Brian , Pillay-van Wyk Victoria 
Published: August 2022

Abstract
Objective
Due to gaps in the literature, we developed a systematic method to assess multimorbidity using national surveys. The objectives of this study were thus to identify methods used to define and measure multimorbidity, to create a pre-defined list of disease conditions, to identify potential national surveys to include, to select disease conditions for each survey, and to analyse and compare the survey findings.

Results
We used the count method to define multimorbidity. We created a pre-defined list of disease conditions by examining international literature and using local data on the burden of disease. We assessed national surveys, reporting on more than one disease condition in people 15 years and older, for inclusion. For each survey, the prevalence of multimorbidity was calculated, the disease patterns among the multimorbid population were assessed using a latent class analysis and logistic regression was used to identify sociodemographic and behavioural factors associated with multimorbidity. The prevalence of multimorbidity varied for each survey from 2.7 to 20.7%. We used a systematic and transparent method to interrogate multimorbidity in national surveys. While the prevalence in each survey differs, they collectively indicate that multimorbidity increases in older age groups and tends to be higher among women.
Enhanced CT-based radiomics predicts pathological complete response after neoadjuvant chemotherapy for advanced adenocarcinoma of the esophagogastric junction: a two-center study
Authors: Huang Wenpeng , Li Liming , Liu Siyun , Chen Yunjin , Liu Chenchen , Han Yijing , Wang Fang , Zhan Pengchao , Zhao Huiping , Li Jing , Gao Jianbo 
Published: August 2022

AbstractPurposeThis study aimed to develop and validate CT-based models to predict pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) for advanced adenocarcinoma of the esophagogastric junction (AEG).MethodsPre-NAC clinical and imaging data of AEG patients who underwent surgical resection after preoperative-NAC at two centers were retrospectively collected from November 2014 to September 2020. The dataset included training (n = 60) and external validation groups (n = 32). Three models, including CT-based radiomics, clinical and radiomics–clinical combined models, were established to differentiate pCR (tumor regression grade (TRG) = grade 0) and nonpCR (TRG = grade 1–3) patients. For the radiomics model, tumor-region-based radiomics features in the arterial and venous phases were extracted and selected. The naïve Bayes classifier was used to establish arterial- and venous-phase radiomics models. The selected candidate clinical factors were used to establish a clinical model, which was further incorporated into the radiomics–clinical combined model. ROC analysis, calibration and decision curves were used to assess the model performance.ResultsFor the radiomics model, the AUC values obtained using the venous data were higher than those obtained using the arterial data (training: 0.751 vs. 0.736; validation: 0.768 vs. 0.750). Borrmann typing, tumor thickness and degree of differentiation were utilized to establish the clinical model (AUC-training: 0.753; AUC-validation: 0.848). The combination of arterial- and venous-phase radiomics and clinical factors further improved the discriminatory performance of the model (AUC-training: 0.838; AUC-validation: 0.902). The decision curve reflects the higher net benefit of the combined model.ConclusionThe combination of CT imaging and clinical factors pre-NAC for advanced AEG could help stratify potential responsiveness to NAC.
Multirate DAE-simulation and its application in system simulation software for the development of electric vehicles
Authors: Kolmbauer Michael , Offner Günter , Pfau Ralf Uwe , Pöchtrager Bernhard 
Published: August 2022

AbstractThis work is devoted to the efficient simulation of large multi-physical networks stemming from automated modelling processes in system simulation software. The simulation of hybrid, battery and fuel cell electric vehicle applications requires the coupling of electrical, mechanical, fluid, and thermal networks. Each network is established by combining the connection structure of a graph with physical equations of elementary components and resulting in a DAE (differential algebraic equation). To speed up the simulation a non-iterative multirate time integration co-simulation method for the system of coupled DAEs is established. The power of the multirate method is shown via two representative examples of battery powered electric vehicle with a cooling system for the battery pack and a three phase inverter with a cooling system. This work is an extended version of (Kolmbauer et al. in Scientific Computing in Electrical Engineering (SCEE 2020), Springer, Cham, pp. 231–240, 2021).
The DHAV-1 protein VP1 interacts with PI3KC3 to induce autophagy through the PI3KC3 complex
Authors: Li Juan , Wang Mingshu , Zhou Shan , Cheng Anchun , Ou Xuming , Sun Di , Wu Ying , Yang Qiao , Gao Qun , Huang Juan , Tian Bin , Mao Sai , Zhang Shaqiu , Zhao Xinxin , Jia Renyong , Liu Mafeng , Zhu Dekang , Chen Shun , Liu Yunya , Yu Yanling , Zhang Ling , Pan Leichang 
Published: August 2022

AbstractDuck hepatitis A virus type 1 (DHAV-1) is one of the main pathogens responsible for death in ducklings. Autophagy is a catabolic process that maintains cellular homeostasis, and the PI3KC3 protein plays an important role in the initiation of autophagy. DHAV-1 infection induces autophagy in duck embryo fibroblasts (DEFs) but the molecular mechanism between it and autophagy has not been reported. First, we determined that DHAV-1 infection induces autophagy in DEFs and that autophagy induction is dependent on the integrity of viral proteins by infecting DEFs with UV-inactivated or heat-inactivated DHAV-1. Then, in experiments using the pharmacological autophagy inducer rapamycin and the autophagy inhibitor chloroquine, autophagy inhibition was shown to reduce intracellular and extracellular DHAV-1 genome copies and viral titres. These results suggest that autophagy activated by DHAV-1 infection in DEFs affects DHAV-1 proliferation and extracellular release. Next, we screened the autophagy-inducing effects of the DHAV-1 structural proteins VP0, VP3, and VP1 and found that all DHAV-1 structural proteins could induce autophagy in DEFs but not the full autophagic flux. Finally, we found that VP1 promotes protein expression of PI3KC3 and Beclin1 by western blot experiments and that VP1 interacts with PI3KC3 by co-immunoprecipitation experiments; moreover, 3-MA-induced knockdown of PI3KC3 inhibited VP1 protein-induced autophagy in DEFs. In conclusion, the DHAV-1 structural protein VP1 regulates the PI3KC3 complex by interacting with PI3KC3 to induce autophagy in DEFs.
Feasibility and preliminary efficacy of tantalum components in the management of acetabular reconstruction following periacetabular oncologic resection in primary malignancies
Authors: Zan Pengfei , Ma Xiaojun , Wang Hongsheng , Cai Zhengdong , Shen Jiakang , Sun Wei 
Published: August 2022

Abstract
Background
The aim of the study was to investigate the feasibility and preliminary efficacy of tantalum components utility in the reconstruction of acetabular defects following periacetabular oncologic resection of primary malignancies.

Methods
We prospectively collected a consecutive of 15 cases that were treated with tantalum components for acetabular reconstruction after periacetabular oncologic resection from January 2018 to December 2018. The cohort included 8 male and 7 female patients, with a mean age of 47.6 years (range, 33 to 67 years). Pathology types: chondrosarcoma (n = 9), malignant bone giant cell tumor (n = 3) and osteosarcoma (n = 3). Clinical outcomes, functional and radiographic results were recorded in detail for analysis.

Results
Patients received planned oncologic resection and tantalum components reconstruction without casualty; they were followed up with a mean of 39.7 months (35–45 months). The mean operation time was 4.0 h (3.0–6.0 h), and the mean blood loss was 1260 ml (800–2200 ml). Functional outcomes were assessed by MSTS-93 scale, with an average of 21.8 (12.0–26.0 scores), among which 3 cases were excellent, 11 were good and 1 was fair. The mean Harris Hip Score was 79.1scores (46.0–92.0 scores) at 1-year follow-up postoperatively. 3(3/15, 20.0%) cases experienced postoperative complications: 2 cases with hip dislocation received closed reduction under general anesthesia and were fixed with hip joint abduction braces for 6 weeks; one case had a superficial infection and received debridement with a delayed wound healing. Oncologic prognosis: one case relapsed at 8-month follow-up and received hemi-pelvic amputation; and another osteosarcoma patient experienced relapse with pulmonary metastasis and received further chemotherapy. No prosthetic loosening, displacement or fracture occurred during the follow-up period.

Conclusion
Preliminary results suggested that the use of tantalum components in the management of acetabular reconstruction following periacetabular oncologic resection provided reasonable improvement on functional outcomes and early stability of the prostheses. Porous tantalum components are conducive to bony ingrowth, which is a potential alternative to various existing reconstruction techniques to achieve better functional outcomes.