bluuebunny/crossref_metadata_2025 huggingface dataset:
Protective action of natural and induced immunization against the occurrence of delta or alpha variants of SARS-CoV-2 infection: a test-negative case-control study
Authors: Corrao Giovanni , Franchi Matteo , Rea Federico , Cereda Danilo , Barone Antonio , Borriello Catia Rosanna , Della Valle Petra Giulia , Ercolanoni Michele , Fortino Ida , Jara Jose , Leoni Olivia , Mazziotta Francesco , Pierini Elisabetta , Preziosi Giuseppe , Tirani Marcello , Galli Massimo , Bertolaso Guido , Pavesi Giovanni , Bortolan Francesco
Published: February 2022

Background

The evolution of SARS-CoV-2 has led to the emergence of several new variants, and few data are available on the impact of vaccination on SARS-CoV-2 variants. We aimed to assess the association between natural (previous infection) and induced (partial or complete vaccination) exposure to SARS-CoV-2 and the onset of new infection supported by the delta variant, and of comparing it with that supported by alpha.

Methods

We performed a test-negative case-control study, by linking population-based registries of confirmed diagnoses of infection with SARS-CoV-2, vaccinations against Covid-19 and healthcare utilization databases of the Italian Lombardy Region. Four hundred ninety-six persons who between 27 December 2020 and 16 July 2021 had an infection by the delta variant were 1:1 matched with citizens affected by alphavariant and 1:10 matched with persons who had a negative molecular test, according to gender, age and date of molecular ascertainment. We used a conditional logistic regression for estimating relative risk reduction of either variants associated with natural and/or induced immunization and corresponding 95% confidence interval (CI).

Results

Previous infection was associated with 91% (95% CI 85% to 95%) reduced relative risk of reinfection, without evidence of significant differences between delta and alpha cases (p=0.547). Significant lower vaccinal protection against delta than alpha variant infection was observed with reduced relative risk associated with partial vaccination respectively of 29% (7% to 45%), and 62% (48% to 71%) (p=0.001), and with complete vaccination respectively of 75% (66% to 82%) and 90% (85% to 94%) (p=0.003).

Conclusions

Lower protection towards infections caused by the delta variant with respect to alpha variant was noticed, even after the completion of the vaccination cycle. This finding would support efforts to maximize both vaccine uptake with two doses and fulfilment with individual protection measures, especially as the delta variant is rampant worldwide presently.
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

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

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

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

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

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

Globally, 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

Atherosclerosis 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

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

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

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

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.
Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives
Authors: Barbieri Federica , Bosio Alessia Graziana , Pattarozzi Alessandra , Tonelli Michele , Bajetto Adriana , Verduci Ivan , Cianci Francesca , Cannavale Gaetano , Palloni Luca M. G. , Francesconi Valeria , Thellung Stefano , Fiaschi Pietro , Mazzetti Samanta , Schenone Silvia , Balboni Beatrice , Girotto Stefania , Malatesta Paolo , Daga Antonio , Zona Gianluigi , Mazzanti Michele , Florio Tullio
Published: February 2022

Background

Chloride intracellular channel-1 (CLIC1) activity controls glioblastoma proliferation. Metformin exerts antitumor effects in glioblastoma stem cells (GSCs) inhibiting CLIC1 activity, but its low potency hampers its translation in clinical settings.

Methods

We synthesized a small library of novel biguanide-based compounds that were tested as antiproliferative agents for GSCs derived from human glioblastomas, in vitro using 2D and 3D cultures and in vivo in the zebrafish model. Compounds were compared to metformin for both potency and efficacy in the inhibition of GSC proliferation in vitro (MTT, Trypan blue exclusion assays, and EdU labeling) and in vivo (zebrafish model), migration (Boyden chamber assay), invasiveness (Matrigel invasion assay), self-renewal (spherogenesis assay), and CLIC1 activity (electrophysiology recordings), as well as for the absence of off-target toxicity (effects on normal stem cells and toxicity for zebrafish and chick embryos).

Results

We identified Q48 and Q54 as two novel CLIC1 blockers, characterized by higher antiproliferative potency than metformin in vitro, in both GSC 2D cultures and 3D spheroids. Q48 and Q54 also impaired GSC self-renewal, migration and invasion, and displayed low systemic in vivo toxicity. Q54 reduced in vivo proliferation of GSCs xenotransplanted in zebrafish hindbrain. Target specificity was confirmed by recombinant CLIC1 binding experiments using microscale thermophoresis approach. Finally, we characterized GSCs from GBMs spontaneously expressing low CLIC1 protein, demonstrating their ability to grow in vivo and to retain stem-like phenotype and functional features in vitro. In these GSCs, Q48 and Q54 displayed reduced potency and efficacy as antiproliferative agents as compared to high CLIC1-expressing tumors. However, in 3D cultures, metformin and Q48 (but not Q54) inhibited proliferation, which was dependent on the inhibition dihydrofolate reductase activity.

Conclusions

These data highlight that, while CLIC1 is dispensable for the development of a subset of glioblastomas, it acts as a booster of proliferation in the majority of these tumors and its functional expression is required for biguanide antitumor class-effects. In particular, the biguanide-based derivatives Q48 and Q54, represent the leads to develop novel compounds endowed with better pharmacological profiles than metformin, to act as CLIC1-blockers for the treatment of CLIC1-expressing glioblastomas, in a precision medicine approach.
Tracheostomy timing and clinical outcomes in ventilated COVID-19 patients: a systematic review and meta-analysis
Authors: Ji Yun , Fang Yumin , Cheng Baoli , Li Libin , Fang Xiangming
Published: February 2022

Background

The association of tracheostomy timing and clinical outcomes in ventilated COVID-19 patients remains controversial. We performed a meta-analysis to evaluate the impact of early tracheostomy compared to late tracheostomy on COVID-19 patients’ outcomes.

Methods

We searched Medline, Embase, Cochrane, and Scopus database, along with medRxiv, bioRxiv, and Research Square, from December 1, 2019, to August 24, 2021. Early tracheostomy was defined as a tracheostomy conducted 14 days or less after initiation of invasive mechanical ventilation (IMV). Late tracheostomy was any time thereafter. Duration of IMV, duration of ICU stay, and overall mortality were the primary outcomes of the meta-analysis. Pooled odds ratios (OR) or the mean differences (MD) with 95%CIs were calculated using a random-effects model.

Results

Fourteen studies with a cumulative 2371 tracheostomized COVID-19 patients were included in this review. Early tracheostomy was associated with significant reductions in duration of IMV (2098 patients; MD − 9.08 days, 95% CI − 10.91 to − 7.26 days,p < 0.01) and duration of ICU stay (1224 patients; MD − 9.41 days, 95% CI − 12.36 to − 6.46 days,p < 0.01). Mortality was reported for 2343 patients and was comparable between groups (OR 1.09, 95% CI 0.79–1.51,p = 0.59).

Conclusions

The results of this meta-analysis suggest that, compared with late tracheostomy, early tracheostomy in COVID-19 patients was associated with shorter duration of IMV and ICU stay without modifying the mortality rate. These findings may have important implications to improve ICU availability during the COVID-19 pandemic.

Trial registrationThe protocol was registered at INPLASY (INPLASY202180088).
Analysis of a delay-induced mathematical model of cancer
Authors: Das Anusmita , Dehingia Kaushik , Sarmah Hemanta Kumar , Hosseini Kamyar , Sadri Khadijeh , Salahshour Soheil
Published: February 2022

In this paper, the dynamical behavior of a mathematical model of cancer including tumor cells, immune cells, and normal cells is investigated when a delay term is induced. Though the model was originally proposed by De Pillis et al. (Math. Comput. Model. 37:1221–1244, 2003), to make the model more realistic, we have added a delay term into the model, and it has incorporated novelty in our present work. The stability of existing equilibrium points in the delay-induced system is studied in detail. Global stability conditions of the tumor-free equilibrium point have been found. It is shown that due to this delay effect, the coexisting equilibrium point may lose its stability through a Hopf bifurcation. The implicit function theorem is applied to characterize a complex function in a neighborhood of delay terms. Additionally, the presence of Hopf bifurcation is demonstrated when the transversality conditions are satisfied. The length of delay for which the solutions preserve the stability of the limit cycle is estimated. Finally, through a series of numerical simulations, the theoretical results are formally examined.
Interaction of potential and effective entrepreneurial capabilities in adolescents: modeling youth entrepreneurship structure using structural equation modeling
Authors: Campo-Ternera Lilia , Amar-Sepúlveda Paola , Olivero-Vega Enohemit
Published: February 2022

This article emphasizes entrepreneurial skills in adolescents, in order to determine the relationship between entrepreneurial skills (dependent variable) and the key factors for their development: personal, social, and educational (independent variables). It has an empirical‒analytical design which is explanatory in nature. After the design, validation, and application of the evaluation instrument, the estimation was carried out using Structural Equation Modeling (SEM). The results show great impact of potential entrepreneurial capacity on effective entrepreneurial capacity, determined by the direct effect of personal traits and life skills, the family as a moderating element, as well as the mediating role of entrepreneurship training processes. The complex nature of entrepreneurship is highlighted, which is influenced by multiple factors as possible boosters for the success of entrepreneurial initiatives.
Anti-inflammatory components isolated from Atractylodes macrocephala in LPS-induced RAW264.7 macrophages and BV2 microglial cells
Authors: Jin Hong-Guang , Kim Kwan-Woo , Li Jing , Lee Dae Young , Yoon Dahye , Jeong Jin Tae , Kim Geum-Soog , Oh Hyuncheol , An Ren-Bo , Kim Youn-Chul
Published: February 2022

The phytochemical investigation on the methanol extract of the rhizomes of Atractylodes macrocephala resulted in the discovery of one new compound 9α-hydroxyatractylenolide (1) and 21 known compounds including atractylone (2), 3β-acetoxyatractylon (3), atractylenolide I (4), atractylenolide II (5), 8-epiasterolid (6), atractylenolide III (7), atractylenolide VII (8), 8-epiatractylenolide III (9), eudesm-4(15)-ene-7α,11-diol (10), linoleic acid (11), myristic acid (12), 3-O-caffeoyl-1-methyquinic acid (13), (2E,8E,10E)-tetradecatriene-4,6-diyne-1,14-diol (14), 14-aceroxy-12-senecioyloxytetradeca-2E,8Z,10E-trien-4,6-diyn-1-ol (15), isoscopoletin (16), caffeic acid (17), protocatechic acid (18), 3-O-caffeoylquinic acid (19), 4-O-caffeoylquinic acid (20), 1,5-di-O-caffeoylquinic acid (21), and nicotinic acid (22). Their structures were identified using nuclear magnetic resonance (NMR) and mass spectroscopy, and by comparison with previously published data. Compounds 4, 5, 6, 8, and 10–22 significantly inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages, and compounds 4, 5, 6, 16, and 17 showed those responses in BV2 microglial cells. Especially, compound 6 showed the second-best effect, and inhibited the LPS-induced production of prostaglandin E2 (PGE2), the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and the production of cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in both cells. These inhibitory effects were mediated by the inactivation of nuclear factor kappa B (NF-κB) signaling pathway.
The inflammatory pathology of dysferlinopathy is distinct from calpainopathy, Becker muscular dystrophy, and inflammatory myopathies
Authors: Becker Nicole , Moore Steven A. , Jones Karra A.
Published: February 2022

The descriptions of muscle pathology in dysferlinopathy patients have classically included an inflammatory infiltrate that can mimic inflammatory myopathies. Based on over 20 years of institutional experience in evaluating dystrophic and inflammatory myopathy muscle biopsies at the University of Iowa, we hypothesized the inflammatory histopathology of dysferlinopathy is more similar to limb-girdle pattern muscular dystrophies such as calpainopathy and Becker muscular dystrophy, and distinct from true inflammatory myopathies. Muscle biopsies from 32 dysferlinopathy, 30 calpainopathy, 30 Becker muscular dystrophy, and 30 inflammatory myopathies (15 each of dermatomyositis and inclusion body myositis) were analyzed through digital quantitation of CD3, CD4, CD8, CD20, and PU.1 immunostaining. The expression of MHC class I and deposition of complement C5b-9 was also evaluated. Dysferlinopathy, calpainopathy, and Becker muscular dystrophy muscle biopsies had similar numbers of inflammatory cell infiltrates and significantly fewer CD3+ T-lymphocytes than dermatomyositis (p = 0.05) and inclusion body myositis (p < 0.0001) biopsies. There was no statistically significant difference in the number of PU.1+ macrophages identified in any diagnostic group. MHC class I expression was significantly lower in the limb-girdle pattern muscular dystrophies compared to the inflammatory myopathies (p < 0.0001). In contrast, complement C5b-9 deposition was similar among dysferlinopathy, dermatomyositis, and inclusion body myositis biopsies but significantly greater than calpainopathy and Becker muscular dystrophy biopsies (p = 0.05). Compared to calpainopathy, Becker muscular dystrophy, and inflammatory myopathies, the unique profile of minimal inflammatory cell infiltrates, absent to focal MHC class I, and diffuse myofiber complement C5b-9 deposition is the pathologic signature of dysferlinopathy muscle biopsies.
Cluster analysis of personality traits in psychiatric patients with borderline personality disorder
Authors: Oladottir Kristin , Wolf-Arehult Martina , Ramklint Mia , Isaksson Martina
Published: February 2022

Background

Though the heterogeneous expression of symptoms of borderline personality disorder (BPD) is well-known, it is far from fully understood. Hybrid models combining dimensional and categorical ways of diagnosing BPD have been suggested to better handle this heterogeneity, but more research is needed. The aim of this study was to identify potential clusters in BPD, and evaluate if these clusters differed in diagnostic composition, severity, psychiatric symptoms, emotion regulation and control, or sociodemographic features.

Methods

Clusters were based on personality traits measured with the Swedish universities Scales of Personality (SSP) in 141 psychiatric patients diagnosed with BPD. Hierarchical cluster analysis was performed using Ward’s method. We used one-way analysis of variance to explore the different clusters’ properties. Effect sizes were calculated using partial eta squared.

Results

We found three distinct clusters: the lower psychopathology cluster (N = 67), the externalizing cluster (N = 28), and the internalizing cluster (N = 46). The clusters differed regarding trait composition, severity, and emotion regulation and control.

Conclusions

Our findings support hybrid models for diagnosing BPD by showing that clusters differed in terms of both severity (lower and higher psychopathology) and personality traits/style (internalizing and externalizing). Assessment of personality traits may be a feasible way to differentiate between clusters. In the future, this knowledge might be used to personalize treatment.
Enhanced l-ornithine production from glucose and sucrose via manipulation of the fructose metabolic pathway in Corynebacterium glutamicum
Authors: Nie Libin , Xu Kexin , Zhong Bin , Wu Xiaoyu , Ding Zhongtao , Chen Xuelan , Zhang Bin
Published: February 2022

l-Ornithine, an important non-essential amino acid, has considerable medicinal value in the treatment of complex liver diseases. Microbial fermentation strategies using robust engineered strains have remarkable potential for producing l-ornithine. We showed that glucose and sucrose co-utilization accumulate more l-ornithine in Corynebacterium glutamicum than glucose alone. Further manipulating the expression of intracellular fructose-1-phosphate kinase through the deletion of pfkB1resulted in the engineered strain C. glutamicum SO30 that produced 47.6 g/L of l-ornithine, which represents a 32.8% increase than the original strain C. glutamicum SO26 using glucose as substrate (35.88 g/L). Moreover, fed-batch cultivation of C. glutamicum SO30 in 5-L fermenters produced 78.0 g/L of l-ornithine, which was a 78.9% increase in yield compared with that produced by C. glutamicum SO26. These results showed that manipulating the fructose metabolic pathway increases l-ornithine accumulation and provides a reference for developing C. glutamicum to produce valuable metabolites.

Graphical Abstract
SimUniversity at a distance: a descriptive account of a team-based remote simulation competition for health professions students
Authors: Major Stella , Krage Ralf , Lazarovici Marc
Published: February 2022

Background

SimUniversity competition is an innovative Society in Europe for Simulation Applied to Medicine (SESAM) initiative which has existed since 2014, with the aim of creating opportunities for undergraduate healthcare students to take part in a formative educational experience on an international platform. The main educational focus is on promoting non-technical skills such as leadership, situation awareness, decision making, communication, and assertiveness, but also clinical reasoning within a team. In preparation for the 2021 virtual conference, the team designed a new methodology to meet the same mission, and yet be offered remotely.

Main text

In this article, we describe the way in which we transformed the SimUniversity competition activity from face to face to a remote simulation. We relied on Zoom as the main communication technology to enable the distance component and followed the key elements of pre-briefing, simulation, and debriefing with the students being onsite together in one location and the faculty and simulator technologists in distant locations. Thirty-eight medical and nursing students formed 8 teams from 7 different countries. Two participating teams were based in Germany and one in Italy, Belgium, the Netherlands, Romania, Portugal, and Syria. Each team consisted of between 4 and 5 members and was self-selected to consist of either medical students alone or medical and nursing students together. The SimUniversity faculty team was composed of 5 physician educators, one nurse educator, one paramedic simulation technologist, and one industry simulation technologist. The faculty members facilitated each simulation synchronously in Zoom, while being based in different geographical locations within Europe (Germany, Switzerland, and the Netherlands) and the Middle East (Qatar and Lebanon).

Conclusion

We conclude that assuming there is access to adequate internet connectivity and minimal technical setup, conducting a remote simulation with virtual debriefing is achievable in supporting team-based learning, particularly when learners and/or faculty members are in distant locations. While the authors do not recommend this method to be superior to a face-to-face experience, we propose this model to be an alternative method to consider when educators are faced with imposed restrictions such as what we faced during the COVID-19 pandemic. We discuss lessons learned and highlight other potential benefits that this method may provide, to consider even when the restrictions are lifted.
Missense mutation of a class B heat shock factor is responsible for the tomato bushy root-2 phenotype
Authors: Kevei Zoltan , Ferreira Silva Demetryus Silva , Casenave Cristina Maria Perez , Kurowski Tomasz , Mohareb Fady , Rickett Daniel , Stain Chris , Thompson Andrew J.
Published: February 2022

Thebushy root-2(brt-2) tomato mutant has twisting roots, and slower plant development. Here we used whole genome resequencing and genetic mapping to show thatbrt-2is caused by a serine to cysteine (S75C) substitution in the DNA binding domain (DBD) of a heat shock factor class B (HsfB) encoded bySolycHsfB4a. This gene is orthologous to the ArabidopsisSCHIZORIZAgene, also known asAtHsfB4. Thebrt-2phenotype is very similar toArabidopsislines in which the function ofAtHsfB4is altered: a proliferation of lateral root cap and root meristematic tissues, and a tendency for lateral root cap cells to easily separate. Thebrt-2S75C mutation is unusual because all other reported amino acid substitutions in the highly conserved DBD of eukaryotic heat shock factors are dominant negative mutations, butbrt-2is recessive. We further show through reciprocal grafting thatbrt-2exerts its effects predominantly through the root genotype even throughBRT-2is expressed at similar levels in both root and shoot meristems. SinceAtHsfB4is induced by root knot nematodes (RKN), and loss-of-function mutants of this gene are resistant to RKNs,BRT-2could be a target gene for RKN resistance, an important trait in tomato rootstock breeding.

Gene & accession numbers

SolycHsfB4a-Solyc04g078770.
Racial Disparities in Diabetes-Related Emergency Department Visits and Hospitalizations Among Cancer Survivors
Authors: Pinheiro Laura C. , Soroka Orysya , Kern Lisa M. , Leonard John P. , Safford Monika M.
Published: February 2022

PURPOSE:

Black and Hispanic individuals with diabetes receive less recommended diabetes care after cancer diagnosis than non-Hispanic Whites (NHW). We sought to determine whether racial/ethnic minorities with diabetes and cancer were at increased risk of diabetes-related emergency department (ED) visits and hospitalizations compared with NHW.

METHODS:

Using SEER cancer registry data linked to Medicare claims from 2006 to 2014, we included Medicare beneficiaries age 66+ years diagnosed with incident nonmetastatic breast, prostate, or colorectal cancer between 2007 and 2012 who had diabetes. Our primary outcome was any diabetes-related ED visit or hospitalization 366-731 days after cancer diagnosis. Using Fine-Gray subdistribution hazard models, we examined whether risk of ED visits or hospitalizations was higher for racial/ethnic minorities compared with NHW.

RESULTS:

We included 40,059 beneficiaries with mean age 75.5 years (standard deviation 6.3), 45.6% were women, and 28.9% were non-White. Overall, 825 (2.1%) had an ED visit and 3,324 (8.3%) had a hospitalization related to diabetes in the 366-731 days after cancer diagnosis. Compared with NHW, Black individuals were more likely to have ED visits (2.9% v 2.0%; P < .0001) and hospitalizations (11.7% v 7.8%; P < .0001). Adjusting for potential confounders, Black (adjusted hazard ratio, 1.22; 95% CI, 1.12 to 1.35) individuals had a higher risk of any ED visit or hospitalization compared with NHW.

CONCLUSION:

Black individuals with diabetes and cancer were at increased risk for diabetes-related ED visits and hospitalizations in the second year after cancer diagnosis compared with NHW even after accounting for confounders.