bluuebunny/crossref_metadata_2025_split huggingface dataset:
The synergistic anticancer effect of the bromodomain inhibitor OTX015 and histone deacetylase 6 inhibitor WT-161 in osteosarcoma
Authors: Yu Bo , Liu Lang , Cai Feng , Peng Yuanxiang , Tang Xiaofeng , Zeng Duo , Li Teng , Zhang Feifei , Liang Yiping , Yuan Xuhui , Li Jiayu , Dai Zhengzai , Liao Qi , Lv Xiao-Bin 
Published: February 2022

Abstract
Background
Osteosarcoma (OS) is a tumour with a high malignancy level and a poor prognosis. First-line chemotherapy for OS has not been improved for many decades. Bromodomain and extraterminal domain (BET) and histone deacetylases (HDACs) regulate histone acetylation in tandem, and BET and HDACs have emerged as potential cancer therapeutic targets.

Methods
Cell proliferation, migration, invasion, colony formation, and sphere-forming assays were performed with the two inhibitors alone or in combination to evaluate their suppressive effect on the malignant properties of OS cells. Apoptosis and the cell cycle profile were measured by flow cytometry. The synergistic inhibitory effect of OTX015/WT-161 on tumours was also examined in a nude mouse xenograft model.

Results
The combined therapy of OTX015/WT-161 synergistically inhibited growth, migration, and invasion and induced apoptosis, resulting in G1/S arrest of OS cells. Additionally, OTX015/WT-161 inhibited the self-renewal ability of OS stem cells (OSCs) in a synergistic manner. Further mechanistic exploration revealed that the synergistic downregulation of β-catenin by OTX015-mediated suppression of FZD2 and WT-161-mediated upregulation of PTEN may be critical for the synergistic effect. Finally, the results of an in vivo assay showed that tumour xenografts were significantly decreased after treatment with the OTX015/WT-161 combination compared with OTX015 or WT-161 alone.

Conclusions
Our findings in this study demonstrated that OTX015 and WT-161 had synergistic anticancer efficacy against OS, and their combination might be a promising therapeutic strategy for OS.
A role for the NPM1/PTPN14/YAP axis in mediating hypoxia-induced chemoresistance to sorafenib in hepatocellular carcinoma
Authors: Zhang Dengke , Wu Fazong , Song Jingjing , Meng Miaomiao , Fan Xiaoxi , Lu Chenying , Weng Qiaoyou , Fang Shiji , Zheng Liyun , Tang Bufu , Yang Yang , Tu Jianfei , Xu Min , Zhao Zhongwei , Ji Jiansong 
Published: February 2022

Abstract
Background
Tumor microenvironments are characterized by resistance to chemotherapeutic agents and radiotherapy. Hypoxia plays an important role in the development of tumor resistance, as well as the generation of metastatic potential. YAP also participates in the regulation of hypoxia-mediated chemoresistance, and is negatively regulated by protein tyrosine phosphatase non-receptor type 14 (PTPN14).

Methods
The PTPN14 expression in hepatocellular carcinoma (HCC) tissues were evaluated by qRT-PCR, western blot and tissue microarrays. The effect of PTPN14 on HCC progression was investigated in vitro and in vivo.

Results
Here, we report that PTPN14 expression was downregulated in HCC tissues and cell lines. Silencing PTPN14 significantly enhanced proliferation, migration, invasion of HepG2 cells in vitro and tumor growth and metastasis in vivo, whereas overexpression of PTPN14 significantly inhibited these abilities in SK-Hep1 cells. We also found that hypoxia-induced nuclear translocation and accumulation of PTPN14 led to resistance to sorafenib in HCC cells. Further mechanistic studies suggested that NPM1 regulates PTPN14 localization, and that NPM1 regulates YAP by retaining PTPN14 in the nucleus under hypoxic conditions.

Conclusions
These data suggest that a therapeutic strategy against chemoresistant HCC may involve disruption of NPM1-mediated regulation of YAP by retaining PTPN14 in the nucleus under hypoxic conditions.
Effect of three years’ seasonal malaria chemoprevention on molecular markers of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine and amodiaquine in Ouelessebougou, Mali
Authors: Mahamar Almahamoudou , Sumner Kelsey M. , Levitt Brandt , Freedman Betsy , Traore Aliou , Barry Amadou , Issiaka Djibrilla , Dembele Adama B. , Kanoute Moussa B. , Attaher Oumar , Diarra Boubacar N. , Sagara Issaka , Djimde Abdoulaye , Duffy Patrick E. , Fried Michal , Taylor Steve M. , Dicko Alassane 
Published: February 2022

Abstract
Background
In 2012, seasonal malaria chemoprevention (SMC) was recommended as policy for malaria control by the World Health Organization (WHO) in areas of highly seasonal malaria transmission across the Sahel sub-region in Africa along with monitoring of drug resistance. We assessed the long-term impact of SMC on Plasmodium falciparum resistance to sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) over a 3-year period of SMC implementation in the health district of Ouelessebougou, Mali.

Methods
In 8 randomly selected sub-districts of Ouelessebougou, Mali, children aged 0–5 years were randomly selected during cross-sectional surveys at baseline (August 2014) and 1, 2 and 3 years post-SMC, at the beginning and end of the malaria transmission season. Blood smears and blood spots on filter paper were obtained and frequencies of mutation in P. falciparum genes related to resistance to SP and AQ (Pfdhfr, Pfdhps, Pfmdr1, and Pfcrt) were assessed by PCR amplification on individual samples and PCR amplification followed by deep sequencing on pooled (by site and year) samples.

Results
At each survey, approximately 50–100 individual samples were analysed by PCR amplification and a total of 1,164 samples were analysed by deep sequencing with an average read depth of 18,018–36,918 after pooling by site and year. Most molecular markers of resistance did not increase in frequency over the period of study (2014–2016). After 3 years of SMC, the frequencies of Pfdhps 540E, Pfdhps 437G and Pfcrt K76T remained similar compared to baseline (4.0 vs 1.4%, p = 0.41; 74.5 vs 64.6%, p = 0.22; 71.3 vs 67.4%, p = 0.69). Nearly all samples tested carried Pfdhfr 59R, and this proportion remained similar 3 years after SMC implementation (98.8 vs 100%, p = 1). The frequency of Pfmdr1 N86Y increased significantly over time from 5.6% at baseline to 18.6% after 3 years of SMC (p = 0.016). Results of pooled analysis using deep sequencing were consistent with those by individual analysis with standard PCR, but also indicated for the first time the presence of mutations at the Pfdhps A581G allele at a frequency of 11.7% after 2 years of SMC, as well as the Pfdhps I431V allele at frequencies of 1.6–9.3% following 1 and 2 years of SMC, respectively.

Conclusion
Two and 3 years of SMC implementation were associated with increased frequency of the Pfmdr1 N86Y mutation but not Pfdhps 540E, Pfdhps 437G and Pfcrt K76T. The first-time detection of the Pfdhps haplotype bearing the I431V and A581G mutations in Mali, even at low frequency, warrants further long-term surveillance.
Adverse Effects of fine particulate matter on human kidney functioning: a systematic review
Authors: Rasking Leen , Vanbrabant Kenneth , Bové Hannelore , Plusquin Michelle , De Vusser Katrien , Roels Harry A. , Nawrot Tim S. 
Published: February 2022

Abstract
Background
Ambient fine particulate matter (PM < 2.5 μm, PM2.5) is gaining increasing attention as an environmental risk factor for health. The kidneys are considered a particularly vulnerable target to the toxic effects that PM2.5 exerts. Alteration of kidney function may lead to a disrupted homeostasis, affecting disparate tissues in the body. This review intends to summarize all relevant knowledge published between January 2000 and December 2021 on the effects of ambient PM2.5 and the adverse effects on kidney function in adults (≥ 18 years).

Results and Discussion
Studies published in peer-reviewed journals, written in English, regarding the effects of PM2.5 on kidney function and the development and/or exacerbation of kidney disease(s) were included. Of the 587 nonduplicate studies evaluated, 40 were included, comprising of studies on healthy or diagnosed with pre-existing disease (sub)populations. Most of the studies were cohort studies (n = 27), followed by 10 cross-sectional, 1 ecological and 2 time-series studies. One longitudinal study was considered intermediate risk of bias, the other included studies were considered low risk of bias. A large portion of the studies (n = 36) showed that PM2.5 exposure worsened kidney outcome(s) investigated; however, some studies show contradictory results. Measurement of the estimated glomerular filtration rate, for instance, was found to be positively associated (n = 8) as well as negatively associated (n = 4) with PM2.5.

Limitations and Conclusion
The main limitations of the included studies include residual confounding (e.g., smoking) and lack of individual exposure levels. The majority of included studies focused on specific subpopulations, which may limit generalizability. Evidence of the detrimental effects that ambient PM2.5 may exert on kidney function is emerging. However, further investigations are required to determine how and to what extent air pollution, specifically PM2.5, exerts adverse effects on the kidney and alters its function.

Registration
The systematic review protocol was submitted and published by the International Prospective Register of Systematic Reviews (PROSPERO; CRD42020175615).
circPTEN1, a circular RNA generated from PTEN, suppresses cancer progression through inhibition of TGF-β/Smad signaling
Authors: Zheng Lin , Liang Hui , Zhang Qiaoling , Shen Zichu , Sun Yixin , Zhao Xuyang , Gong Jingjing , Hou Zhiyuan , Jiang Kewei , Wang Quan , Jin Yan , Yin Yuxin 
Published: February 2022

Abstract
Background
PTEN is one of the most frequently mutated genes in human cancer. Although the roles of canonical PTEN protein and PTEN isoforms have been extensively explored, the current understanding of PTEN family members cannot fully illustrate the diversity of their roles in biological processes and tumor development. Notably, the function of noncoding RNAs arising from PTEN has been less elucidated.

Methods
We searched circBase and circInteractome to analyze the potential of PTEN for generating circRNAs. Then, Sanger sequencing, RNase R and Actinomycin D assays were used to verify the ring structure of circPTEN1. In situ hybridization and qRT-PCR were used to determine the level of circPTEN1 in peritumor and tumor tissues of colorectal cancer (CRC). Furthermore, functional experiments, including Transwell assay, 3D multicellular tumor spheroid invasion assay and metastasis models, were performed using circPTEN1 knockdown and overexpression cell lines in vitro and in vivo to investigate the effects of circPTEN1 on tumor metastasis in CRC. Mechanistically, luciferase reporter assay, fluorescence in situ hybridization, electrophoretic mobility shift assay, RNA immunoprecipitation, RNA pull-down and mass spectrometry were executed.

Results
We identified a circular RNA generated from the PTEN gene, designated circPTEN1, that is frequently downregulated in colorectal cancer, and decreased expression of circPTEN1 predicts poor survival. Low expression of circPTEN1 promotes metastasis in PDX models in vivo and accelerates cancer cell invasion in vitro, whereas overexpression of circPTEN1 reveals opposite roles. Mechanically, we found that circPTEN1 is capable of binding the MH2 domain of Smad4 to disrupt its physical interaction with Smad2/3, which reduces the formation and subsequent nucleus translocation of Smad complexes and consequently suppresses the expression of its downstream genes associated with epithelial-mesenchymal transition upon TGF-β stimulation. Furthermore, we found that eIF4A3 suppresses the cyclization of circPTEN1 by directly binding to the circPTEN1 flanking region.

Conclusions
Our study uncovered a novel PTEN gene-generated circRNA with a tumor suppression function, and further revealed the mechanism of circPTEN1 in CRC metastasis mediated by TGF-β. The identification of circPTEN1 provides a new direction for PTEN investigation, and elucidation of circPTEN1/TGF-β/Smad signaling may pave the way for the development of a potential therapeutic strategy for the suppression of cancer progression.
A novel small diameter nanotextile arterial graft is associated with surgical feasibility and safety and increased transmural endothelial ingrowth in pig
Authors: Joseph John , Domenico Bruno Vito , Sulaiman Nadiah , Ward Alexander , Johnson Thomas W. , Baby Helna Mary , Kerala Varma Praveen , Jose Rajesh , Nair Shantikumar V. , Menon Deepthy , George Sarah Jane , Ascione Raimondo 
Published: February 2022

AbstractGlobally, millions of patients are affected by myocardial infarction or lower limb gangrene/amputation due to atherosclerosis. Available surgical treatment based on vein and synthetic grafts provides sub-optimal benefits. We engineered a highly flexible and mechanically robust nanotextile-based vascular graft (NanoGraft) by interweaving nanofibrous threads of poly-L-lactic acid to address the unmet need. The NanoGrafts were rendered impervious with selective fibrin deposition in the micropores by pre-clotting. The pre-clotted NanoGrafts (4 mm diameter) and ePTFE were implanted in a porcine carotid artery replacement model. The fibrin-laden porous milieu facilitated rapid endothelization by the transmural angiogenesis in the NanoGraft. In-vivo patency of NanoGrafts was 100% at 2- and 4-weeks, with no changes over time in lumen size, flow velocities, and minimal foreign-body inflammatory reaction. However, the patency of ePTFE at 2-week was 66% and showed marked infiltration, neointimal thickening, and poor host tissue integration. The study demonstrates the in-vivo feasibility and safety of a thin-layered vascular prosthesis, viz., NanoGraft, and its potential superiority over the commercial ePTFE.
Graphical Abstract
Nanobiotechnology approaches for cardiovascular diseases: site-specific targeting of drugs and nanoparticles for atherothrombosis
Authors: Liu Haikun , Pietersz Geoffrey , Peter Karlheinz , Wang Xiaowei 
Published: February 2022

AbstractAtherosclerosis and atherothrombosis, the major contributors to cardiovascular diseases (CVDs), represent the leading cause of death worldwide. Current pharmacological therapies have been associated with side effects or are insufficient at halting atherosclerotic progression effectively. Pioneering work harnessing the passive diffusion or endocytosis properties of nanoparticles and advanced biotechnologies in creating recombinant proteins for site-specific delivery have been utilized to overcome these limitations. Since CVDs are complex diseases, the most challenging aspect of developing site-specific therapies is the identification of an individual and unique antigenic epitope that is only expressed in lesions or diseased areas. This review focuses on the pathological mechanism of atherothrombosis and discusses the unique targets that are important during disease progression. We review recent advances in site-specific therapy using novel targeted drug-delivery and nanoparticle-carrier systems. Furthermore, we explore the limitations and future perspectives of site-specific therapy for CVDs.
Graphical Abstract
Continued alcohol consumption and hepatic encephalopathy determine quality of life and psychosocial burden of caregivers in patients with liver cirrhosis
Authors: Nagel Michael , Weidner Vanessa , Schulz Sina , Marquardt Jens U. , Galle Peter R. , Schattenberg Jörn M. , Nguyen-Tat Marc , Wörns Marcus-Alexander , Labenz Christian 
Published: February 2022

Abstract
Background
Patients with liver cirrhosis suffer from significantly reduced health-related quality of life and are often dependent on support from caregivers. In this context, caregivers often suffer from impaired quality of life (QoL) as well as psychosocial burden (PB). The aim of the present study was to identify factors influencing QoL and PB of caregivers in order to improve the social care of patients and caregivers.

Methods
In this cross-sectional study, 106 patients with liver cirrhosis and their caregivers were included. (Health-related) QoL was surveyed in patients (CLDQ) and caregivers (SF-36) and PB was determined by Zarit Burden Interview.

Results
Alcohol related liver cirrhosis (55%) was the predominant etiology of liver cirrhosis and the median MELD of the cohort was 14. QoL did not differ between patients with and without alcohol-related liver cirrhosis (p = 0.6). In multivariable analysis, continued alcohol consumption (p = 0.020), a history of hepatic encephalopathy (HE) (p = 0.010), poorer QoL of patients (p = 0.030) and poorer QoL of caregivers (p = 0.005) were associated with a higher PB of caregivers. Factors independently associated with poorer QoL of caregivers were continued alcohol consumption (p = 0.003) and a higher PB of caregivers (p = 0.030).

Conclusion
Caregivers of patients with liver cirrhosis suffer from impaired QoL and PB, especially in case of continued alcohol consumption or the occurrence of HE.
Assessment of the quality of the vital registration system for under-5 mortality in Yucatan, Mexico
Authors: Hernandez Bernardo , Rodriguez Angulo Elsa , Johnson Louisa M. , Palmisano Erin B. , Ojeda Ricardo , Ojeda Rafael , Gómez Carro Salvador , Chen Alan , Camarda Joseph , Johanns Casey , Flaxman Abraham 
Published: February 2022

Abstract
Introduction
Vital registration is an important element in health information systems which can inform policy and strengthen health systems. Mexico has a well-functioning vital registration system; however, there is still room for improvement, especially for deaths of children under 5. This study assesses the quality of the vital registration system in capturing deaths and evaluates the quality of cause of death certification in under-5 deaths in Yucatan, Mexico.

Methods
We collected information on under-5 deaths that occurred in 2015 and 2016 in Yucatan, Mexico. We calculated the Vital Statistics Performance Index (VSPI) to have a general assessment of the vital registration performance. We examined the agreement between vital registration records and medical records at the individual and population levels using the chance-corrected concordance (CCC) and cause-specific mortality fraction (CSMF) accuracy as quality metrics.

Results
We identified 966 records from the vital registry for all under-5 deaths, and 390 were linked to medical records of deaths occurring at public hospitals. The Yucatan vital registration system captured 94.8% of the expected under-5 deaths, with an overall VSPI score of 87.2%. Concordance between underlying cause of death listed in the vital registry and the cause determined by the medical record review varied substantially across causes, with a mean overall chance-corrected concordance across causes of 6.9% for neonates and 46.9% for children. Children had the highest concordance for digestive diseases, and neonates had the highest concordance for meningitis/sepsis. At the population level, the CSMF accuracy for identifying the underlying cause listed was 35.3% for neonates and 67.7% for children.

Conclusions
Although the vital registration system has overall good performance, there are still problems in information about causes of death for children under 5 that are related mostly to certification of the causes of death. The accuracy of information can vary substantially across age groups and causes, with causes reported for neonates being generally less reliable than those for older children. Results highlight the need to implement strategies to improve the certification of causes of death in this population.
Changes in intrathoracic pressure, not arterial pulsations, exert the greatest effect on tracer influx in the spinal cord
Authors: Liu Shinuo , Bilston Lynne E. , Flores Rodriguez Neftali , Wright Courtney , McMullan Simon , Lloyd Robert , Stoodley Marcus A. , Hemley Sarah J. 
Published: February 2022

Abstract
Background
Cerebrospinal fluid (CSF) circulation in the brain has garnered considerable attention in recent times. In contrast, there have been fewer studies focused on the spine, despite the expected importance of CSF circulation in disorders specific to the spine, including syringomyelia. The driving forces that regulate spinal CSF flow are not well defined and are likely to be different to the brain given the anatomical differences and proximity to the heart and lungs. The aims of this study were to determine the effects of heart rate, blood pressure and respiration on the distribution of CSF tracers in the spinal subarachnoid space, as well as into the spinal cord interstitium.

Methods
In Sprague Dawley rats, physiological parameters were manipulated such that the effects of spontaneous breathing (generating alternating positive and negative intrathoracic pressures), mechanical ventilation (positive intrathoracic pressure only), tachy/bradycardia, as well as hyper/hypotension were separately studied. To investigate spinal CSF hydrodynamics, in vivo near-infrared imaging of intracisternally infused indocyanine green was performed. CSF tracer transport was further characterised with in vivo two-photon intravital imaging. Tracer influx at a microscopic level was quantitatively characterised by ex vivo epifluorescence imaging of fluorescent ovalbumin.

Results
Compared to mechanically ventilated controls, spontaneous breathing animals had significantly greater movement of tracer in the subarachnoid space. There was also greater influx into the spinal cord interstitium. Hypertension and tachycardia had no significant effect on spinal subarachnoid spinal CSF tracer flux and exerted less effect than respiration on tracer influx into the spinal cord.

Conclusions
Intrathoracic pressure changes that occur over the respiratory cycle, particularly decreased intrathoracic pressures generated during inspiration, have a profound effect on tracer movement after injection into spinal CSF and increase cord parenchymal tracer influx. Arterial pulsations likely drive fluid transport from perivascular spaces into the surrounding interstitium, but their overall impact is less than that of the respiratory cycle on net tracer influx.
Contraceptive use in women with inherited metabolic disorders: a retrospective study and literature review
Authors: Gold Jessica I. , Gold Nina B. , DeLeon Diva D. , Ganetzky Rebecca 
Published: February 2022

Abstract
Background
Reproductive planning is an emerging concern for women with inherited metabolic disease (IMD). Anticipatory guidance on contraception is necessary to prevent unintended pregnancies in this population. Few resources exist to aid informed decision-making on contraceptive choice. A retrospective case–control study was performed to examine trends in reproductive planning for adolescent and adult women seen at the Children’s Hospital of Philadelphia (CHOP). Literature review on contraception and IMD was performed to assess global use.

Results
In a cohort of 221 reproductive-aged female IMD patients, 29.4% reported routine contraceptive use. Anticipatory guidance on contraception was provided by metabolic physicians to 36.8% of patients during the study period. Contraception discussion was more likely to occur in women older than 21 years, who lived independently and were followed by gynecology. Women who received contraception counseling from their metabolic physician were 40-fold more likely to use regular contraception. Use of combined hormonal contraceptives was most commonly reported, but contraception choice varied by age and IMD.

Conclusion
Metabolic physicians are ideally suited to provide guidance on contraception to women with IMD. Reproductive planning should be addressed routinely using shared decision-making. Contraceptives should be selected for their efficacy, effects on metabolism, and likelihood of patient adherence.