bluuebunny/crossref_metadata_2025 huggingface dataset:
Obstructive Sleep Apnea Increases the Risk of Perioperative Myocardial Infarction Following Off-Pump Coronary Artery Bypass Grafting
Authors: Fan Kangjun , Gao Mingxin , Yu Wenyuan , Liu Hongli , Chen Liang , Ding Xiaohang , Yu Yang
Published: July 2021

Background and Aims: The impact of obstructive sleep apnea (OSA) on perioperative myocardial infarction (PMI) following coronary artery bypass grafting (CABG) remains unclear. Off-pump CABG (OPCABG) has become a common practice for CABG in China. The present study investigated mainly the correlation between OSA and PMI following OPCABG.

Methods: In this prospective observational single-center study, consecutive eligible patients listed for elective OPCABG underwent cardiorespiratory polygraphy before surgery between January 2019 and June 2020. OSA was defined as an apnea-hypopnea index (AHI) ≥15 events/h. The primary end point was perioperative myocardial infarction (PMI) following OPCABG (type 5 MI).

Results: Patients with OSA accounted for 42.2% (62/147) of the cohort. Twenty-four patients (16.3%) met the protocol criteria for PMI: 17 (27.4%) in the OSA group and 7 (8.2%) in the non-OSA group (P = 0.002). Multivariate logistic regression analysis revealed that AHI (OR = 1.115, 95% CI 1.066 to 1.166, P < 0.001), high-sensitivity c-reactive protein (hs-CRP) (OR = 1.080, 95% CI 1.025 to 1.138, P = 0.004), and SYNTAX score (OR = 1.098, 95% CI 1.056 to 1.141, P < 0.001) were associated with PMI incidence. Furthermore, ROC analysis revealed that the AHI (AUC = 0.766, 95% CI 0.689 to 0.832, P < 0.001) and SYNTAX score (AUC = 0.789, 95% CI 0.715 to 0.852, P < 0.001) had predictive value for PMI. In addition, multiple linear regression analysis showed that the AHI was an independent influencing factor of hs-CRP (B = 0.176, 95% CI 0.090 to 0.263, P < 0.001) and the SYNTAX score (B = 0.553, 95% CI 0.397 to 0.709, P < 0.001).

Conclusions: OSA was independently associated with a higher incidence of PMI following OPCABG, and the formation of severe coronary atherosclerotic lesions aggravated by an enhanced inflammatory response might be the potential mechanism. The efficacy of CPAP treatment for improving prognosis after CABG remains to be further investigated.
Two and Three-Dimensional Echocardiography in Primary Mitral Regurgitation: Practical Hints to Optimize the Surgical Planning
Authors: Pastore Maria Concetta , Mandoli Giulia Elena , Sannino Anna , Dokollari Aleksander , Bisleri Gianluigi , D'Ascenzi Flavio , Cavigli Luna , Pasquini Annalisa , Lisi Matteo , Ghionzoli Nicolò , Santoro Ciro , Miglioranza Marcelo Haertel , Focardi Marta , Patti Giuseppe , Valente Serafina , Mondillo Sergio , Cameli Matteo
Published: July 2021

Primary mitral regurgitation (MR) is the second most common valvular disease, characterized by a high burden in terms of quality of life, morbidity, and mortality. Surgical treatment is considered the best therapeutic strategy for patients with severe MR, especially if they are symptomatic. However, pre-operative echocardiographic evaluation is an essential step not only for surgical candidate selection but also to avoid post-operative complications. Therefore, a strong collaboration between cardiologists and cardiac surgeons is fundamental in this setting. A meticulous pre-operative echocardiographic exam, both with transthoracic or transesophageal echocardiography, followed by a precise report containing anatomical information and parameters should always be performed to optimize surgical planning. Moreover, intraoperative transesophageal evaluation is often required by cardiac surgeons as it may offer additive important information with different hemodynamic conditions. Three-dimensional echocardiography has recently gained higher consideration and availability for the evaluation of MR, providing more insights into mitral valve geometry and MR mechanism. This review paper aims to realize a practical overview on the main use of basic and advanced echocardiography in MR surgical planning and to provide a precise checklist with reference parameters to follow when performing pre-operative echocardiographic exam, in order to aid cardiologists to provide a complete echocardiographic evaluation for MR operation planning from clinical and surgical point-of-view.
Effect of Isolated Fracture on the Carbonate Acidizing Process
Authors: Jia Cunqi , Huang Tao , Yao Jun , Xing Hongchuan , Zhang Haiyang
Published: July 2021

Carbonate reservoirs are one of the most important fossil fuel sources, and the acidizing stimulation is a practical technique for improving the recovery of carbonate reservoirs. In this study, the improved two-scale continuum model, including the representative elementary volume (REV) scale model and the upscaling model, is used to study the acidizing process with an isolated fracture. Based on this model, a comprehensive discussion is presented to study the effect of the physical parameters of the isolated fracture on the acidizing results and dissolution images, including the isolated fracture geometry, location, and morphology. Results show that the isolated fracture system is still the target system for the acidizing stimulation. The isolated fracture provides a limited contribution to the core porosity. The permeability of the core sample with fracture can be obviously increased only when the fracture penetrates through the whole sample. The existence of the isolated fracture reduces the consumption of acid solution to achieve a breakthrough. The acidizing curve is sensitive to the change of the length, aperture, and position of the isolated fracture. The acidizing curve difference corresponding to different rotation angles has not changed significantly for clockwise rotation and anticlockwise rotation groups.
Association Between Aggressive Clinicopathologic Features of Papillary Thyroid Carcinoma and Body Mass Index: A Systematic Review and Meta-Analysis
Authors: Economides Aliki , Giannakou Konstantinos , Mamais Ioannis , Economides Panayiotis A. , Papageorgis Panagiotis
Published: July 2021

Background

The association between adiposity and papillary thyroid carcinoma (PTC) has been reported in several studies, but its association with aggressive clinicopathologic features is not well-recognized. Our aim is to systematically review the literature to identify whether adiposity, expressed through Body Mass Index (BMI), is related to aggressive clinicopathologic features such as tumor-node-metastasis (TNM) stage, extrathyroidal extension (ETE), lymph node (LN) metastasis and multifocality in patients with PTC.

Methods

A systematic search for articles was performed using the PubMed, EBSCO, and Cochrane Library for all articles published in English until December 2020. Specific keywords such as “papillary thyroid carcinoma”, “Body Mass Index”, “clinicopathologic features” were used in the search strategy. Two independent reviewers screened all retrieved articles based on predefined inclusion and exclusion criteria. Meta-analysis was performed in the studies that reported crude and adjusted odds ratios (OR). The methodological quality was assessed using the Newcastle-Ottawa Scale.

Results

A total of 11 retrospective cohort studies involving 26,196 participants included. Our findings showed that elevated BMI was significantly associated with ETE in both overweight (OR 1.26, 95% CI: 1.09-1.44) and obesity group (OR 1.45, 95% CI:1.26-1.64). Elevated BMI was also significantly associated with multifocality in overweight patients (OR 1.17, 95% CI:1.10-1.24) and obese patients (OR 1.45, 95% CI:1.29-1.62). Also, obesity was significantly associated with increased tumor size (OR 1.77, 95% CI:1.52-2.03) and with LN metastasis (OR 1.28, 95% CI: 1.12-1.44), whereas being overweight was significantly associated with advanced TNM stage (OR 1.55, 95% CI:1.27-1.83)

Conclusion

Our results provide strong evidence for the association between higher BMI and ETE, multifocality, and tumor size. Further studies with a larger number of participants are required to elucidate further the association of increased BMI with advanced TNM stage and LN metastasis.
Deforestation Simplifies Understory Bird Seed-Dispersal Networks in Human-Modified Landscapes
Authors: Menezes Pinto Ícaro , Emer Carine , Cazetta Eliana , Morante-Filho José Carlos
Published: July 2021

Global biodiversity is threatened by land-use changes through human activities. This is mainly due to the conversion of continuous forests into forest fragments surrounded by anthropogenic matrices. In general, sensitive species are lost while species adapted to disturbances succeed in altered environments. However, whether the interactions performed by the persisting species are also modified, and how it scales up to the network level throughout the landscape are virtually unknown in most tropical hotspots of biodiversity. Here we evaluated how landscape predictors (forest cover, total core area, edge density, inter-patch isolation) and local characteristics (fruit availability, vegetation complexity) affected understory birds seed-dispersal networks in 19 forest fragments along the hyperdiverse but highly depauperate northeast distribution of the Brazilian Atlantic Forest. Also, our sampled sites were distributed in two regions with contrasting land cover changes. We used mist nets to obtain samples of understory bird food contents to identify the plant species consumed and dispersed by them. We estimated network complexity on the basis of the number of interactions, links per species, interaction evenness, and modularity. Our findings showed that the number of interactions increased with the amount of forest cover, and it was significantly lower in the more deforested region. None of the other evaluated parameters were affected by any other landscape or local predictors. We also observed a lack of significant network structure compared to null models, which we attribute to a pervasive impoverishment of bird and plant communities in these highly modified landscapes. Our results demonstrate the importance of forest cover not only to maintain species diversity but also their respective mutualistic relationships, which are the bases for ecosystem functionality, forest regeneration and the provision of ecological services.
Viewing Cancer Through the Lens of Corruption: Using Behavioral Ecology to Understand Cancer
Authors: Bukkuri Anuraag , Adler Frederick R.
Published: July 2021

All biological systems depend on signals for coordination: signals which pass information among agents that run the gamut from cells to organisms. However, their very importance makes signals vulnerable to subversion. How can a receiver know whether a signal is honest or deceptive? In other words, are signals necessarily a reliable indicator of agent quality or need? By drawing parallels to ecological phenomena ranging from begging by nestlings to social insects, we investigate the role of signal degradation in cancer. We thus think of cancer as a form of corruption, in which cells command huge resource investment through relatively cheap signals, just as relatively small bribes can leverage large profits. We discuss various mechanisms which prevent deceptive signaling in the natural world and within tissues. We show how cancers evolve ways to escape these controls and relate these back to evasion mechanisms in ecology. We next introduce two related concepts, co-option and collusion, and show how they play critical roles in ecology and cancer. Drawing on public policy, we propose new approaches to view treatment based on taxation, changing the incentive structure, and the recognition of corrupted signaling networks.
Mechanisms and Clinical Trials of Hepatocellular Carcinoma Immunotherapy
Authors: Huang Shao-Li , Wang Yu-Ming , Wang Quan-Yue , Feng Guang-Gui , Wu Fu-Qing , Yang Liu-Ming , Zhang Xi-He , Xin Hong-Wu
Published: July 2021

Hepatocellular carcinoma (HCC), one of the most common and lethal tumors worldwide, is usually not diagnosed until the disease is advanced, which results in ineffective intervention and unfavorable prognosis. Small molecule targeted drugs of HCC, such as sorafenib, provided only about 2.8 months of survival benefit, partially due to cancer stem cell resistance. There is an urgent need for the development of new treatment strategies for HCC. Tumor immunotherapies, including immune check point inhibitors, chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAb), have shown significant potential. It is known that the expression level of glypican-3 (GPC3) was significantly increased in HCC compared with normal liver tissues. A bispecific antibody (GPC3-S-Fabs) was reported to recruit NK cells to target GPC3 positive cancer cells. Besides, bispecific T-cell Engagers (BiTE), including GPC3/CD3, an aptamer TLS11a/CD3 and EpCAM/CD3, were recently reported to efficiently eliminate HCC cells. It is known that immune checkpoint proteins programmed death-1 (PD-1) binding by programmed cell death-ligand 1 (PD-L1) activates immune checkpoints of T cells. Anti-PD-1 antibody was reported to suppress HCC progression. Furthermore, GPC3-based HCC immunotherapy has been shown to be a curative approach to prolong the survival time of patients with HCC in clinically trials. Besides, the vascular endothelial growth factor (VEGF) inhibitor may inhibit the migration, invasion and angiogenesis of HCC. Here we review the cutting-edge progresses on mechanisms and clinical trials of HCC immunotherapy, which may have significant implication in our understanding of HCC and its immunotherapy.
On Assessing Trustworthy AI in Healthcare. Machine Learning as a Supportive Tool to Recognize Cardiac Arrest in Emergency Calls
Authors: Zicari Roberto V. , Brusseau James , Blomberg Stig Nikolaj , Christensen Helle Collatz , Coffee Megan , Ganapini Marianna B. , Gerke Sara , Gilbert Thomas Krendl , Hickman Eleanore , Hildt Elisabeth , Holm Sune , Kühne Ulrich , Madai Vince I. , Osika Walter , Spezzatti Andy , Schnebel Eberhard , Tithi Jesmin Jahan , Vetter Dennis , Westerlund Magnus , Wurth Renee , Amann Julia , Antun Vegard , Beretta Valentina , Bruneault Frédérick , Campano Erik , Düdder Boris , Gallucci Alessio , Goffi Emmanuel , Haase Christoffer Bjerre , Hagendorff Thilo , Kringen Pedro , Möslein Florian , Ottenheimer Davi , Ozols Matiss , Palazzani Laura , Petrin Martin , Tafur Karin , Tørresen Jim , Volland Holger , Kararigas Georgios
Published: July 2021

Artificial Intelligence (AI) has the potential to greatly improve the delivery of healthcare and other services that advance population health and wellbeing. However, the use of AI in healthcare also brings potential risks that may cause unintended harm. To guide future developments in AI, the High-Level Expert Group on AI set up by the European Commission (EC), recently published ethics guidelines for what it terms “trustworthy” AI. These guidelines are aimed at a variety of stakeholders, especially guiding practitioners toward more ethical and more robust applications of AI. In line with efforts of the EC, AI ethics scholarship focuses increasingly on converting abstract principles into actionable recommendations. However, the interpretation, relevance, and implementation of trustworthy AI depend on the domain and the context in which the AI system is used. The main contribution of this paper is to demonstrate how to use the general AI HLEG trustworthy AI guidelines in practice in the healthcare domain. To this end, we present a best practice of assessing the use of machine learning as a supportive tool to recognize cardiac arrest in emergency calls. The AI system under assessment is currently in use in the city of Copenhagen in Denmark. The assessment is accomplished by an independent team composed of philosophers, policy makers, social scientists, technical, legal, and medical experts. By leveraging an interdisciplinary team, we aim to expose the complex trade-offs and the necessity for such thorough human review when tackling socio-technical applications of AI in healthcare. For the assessment, we use a process to assess trustworthy AI, called 1Z-Inspection® to identify specific challenges and potential ethical trade-offs when we consider AI in practice.
TIRAP in the Mechanism of Inflammation
Authors: Rajpoot Sajjan , Wary Kishore K. , Ibbott Rachel , Liu Dongfang , Saqib Uzma , Thurston Teresa L. M. , Baig Mirza S.
Published: July 2021

The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP’s role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.
Efficacy, Safety and Tolerability of a New 10% Intravenous Immunoglobulin for the Treatment of Primary Immunodeficiencies
Authors: Perez Elena E. , Hébert Jacques , Ellis Anne K. , Alpan Oral , Lumry William R. , Shapiro Ralph , Suez Daniel , Mandujano J. Fernando , Wasserman Richard L.
Published: July 2021

We report here the results of a phase 3 study to assess the efficacy, safety, and tolerability of GC5107, a new 10% liquid intravenous immunoglobulin (IVIG) in preventing serious bacterial infections in patients with primary immunodeficiency (ClinicalTrials.gov: NCT02783482). Over a 12-month study period, 49 patients aged 3 to 70 years with a confirmed diagnosis of primary immunodeficiency received GC5107 at doses ranging from 319 to 881 mg/kg body weight every 21 or 28 days, according to their previous IVIG maintenance therapy. A total of 667 infusions of GC5107 were administered comprising a total of 45.86 patient-years of treatment. A single acute serious bacterial infection occurred during the study, resulting in an incidence of 0.02 events per patient-year (upper 99% one-sided confidence interval limit: 0.21), meeting the prespecified primary efficacy endpoint. The mean incidence of infections other than acute serious bacterial infections was 2.9 infections per patient-year. Efficacy was also demonstrated by the low mean annualized rate of hospitalizations due to infection (0.1 day) and the mean annualized duration of hospitalizations (0.1 day). The mean rate of intravenous and oral antibiotic use was 0.1 day and 13.2 days, respectively. There was a mean of 7.1 days of missed work, school, or daycare days. The proportion of infusions with temporally associated adverse events (TAAEs) occurring during or within 72 hours after GC5107 infusion was 0.24 (upper 95% one-sided confidence interval limit: 0.31), meeting the pre-specified primary safety endpoint. Overall, 149 of 667 infusions (22%) were associated with TAAEs. The most common TAAE was headache, reported by 49% of patients. More than 98% (731/743) of all adverse events that occurred throughout the 12-month study period were mild or moderate. More than 98% of infusions were completed without discontinuation, interruption or rate reduction. There were no treatment-emergent serious adverse events related to GC5107 or study discontinuations due to an adverse event. Overall, pharmacokinetic parameters for GC5107 were within the range of those reported in studies of other marketed IVIG products. Results of the present study demonstrate that GC5107 is an effective, safe and well-tolerated treatment for patients with primary immunodeficiency.
The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations
Authors: Zhao Chenchen , Zhang Yi , Zheng Hong
Published: July 2021

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. This beneficial effect is derived mainly from graft-versus-leukemia (GVL) effects mediated by alloreactive T cells. However, these alloreactive T cells can also induce graft-versus-host disease (GVHD), a life-threatening complication after allo-HSCT. Significant progress has been made in the dissociation of GVL effects from GVHD by modulating alloreactive T cell immunity. However, many factors may influence alloreactive T cell responses in the host undergoing allo-HSCT, including the interaction of alloreactive T cells with both donor and recipient hematopoietic cells and host non-hematopoietic tissues, cytokines, chemokines and inflammatory mediators. Interferons (IFNs), including type I IFNs and IFN-γ, primarily produced by monocytes, dendritic cells and T cells, play essential roles in regulating alloreactive T cell differentiation and function. Many studies have shown pleiotropic effects of IFNs on allogeneic T cell responses during GVH reaction. Epigenetic mechanisms, such as DNA methylation and histone modifications, are important to regulate IFNs’ production and function during GVHD. In this review, we discuss recent findings from preclinical models and clinical studies that characterize T cell responses regulated by IFNs and epigenetic mechanisms, and further discuss pharmacological approaches that modulate epigenetic effects in the setting of allo-HSCT.
Restoration of Abundance and Dynamics of Coastal Fish and Lobster Within Northern Marine Protected Areas Across Two Decades
Authors: Moland Even , Fernández-Chacón Albert , Sørdalen Tonje Knutsen , Villegas-Ríos David , Thorbjørnsen Susanna Huneide , Halvorsen Kim Tallaksen , Huserbråten Mats , Olsen Esben Moland , Nillos Kleiven Portia Joy , Kleiven Alf Ring , Knutsen Halvor , Espeland Sigurd Heiberg , Freitas Carla , Knutsen Jan Atle
Published: July 2021

This article reviews a suite of studies conducted in a network of coastal Marine Protected Areas (MPAs) in Skagerrak, Southeast Norway. In 2006, Norway’s first lobster reserves were implemented, with the aim of protecting European lobster (Homarus gammarus) through a ban on fixed gear. A before–after control-impact paired series (BACIPS) monitoring program was initiated to evaluate effects of protection on depleted lobster populations. Experimental trapping and capture-recapture techniques were combined to track demography of populations, also including movement of individuals within and beyond MPAs and adjacent control areas. Further, population genetics and parentage studies were applied, allowing for estimation of gene flow, and novel work on sexual selection in lobsters. Additional studies have evaluated MPA effects on coastal cod (Gadus morhua), and on commercially harvested labrids (Ctenolabrus rupestrisandSymphodus melops) and anadromous brown trout (Salmo trutta). Together, these studies reported effects of protection pertaining to increased population density, survival, body size and phenotypic diversity, changes in emigration and interaction with surrounding fisheries, and alteration of selection pressure on morphological- and behavioral traits. Designation of MPAs in close collaboration with fishers and managers, long-term monitoring, inclusion of citizen science and evolving research protocols—also including fisheries data—have revealed novel effects of protection and harvesting on marine populations, thus providing substantial contributions to conservation science. Moreover, knowledge of MPA effects on coastal species has impacted harvest regulations showing the utility of MPAs as empirically documented management tools in Norway.
Dry Eye and Phacoemulsification Cataract Surgery: A Systematic Review and Meta-Analysis
Authors: Lu Qiang , Lu Yi , Zhu Xiangjia
Published: July 2021

Purpose: To evaluate whether dry eye deteriorates after phacoemulsification cataract surgery, and to explore the influential factors.

Methods: Studies published before February 2020 indexed on PubMed and the Cochrane Central Register of Controlled Trials were retrieved. A meta-analysis, including meta-regression, a sensitivity analysis, and a subgroup analysis, were performed.

Results: Twenty studies with 2,247 eyes were included in the meta-analysis, dry eye-related parameters were investigated preoperatively and 1 month postoperatively. Patients with pre-existing meibomian gland dysfunction (MGD) had worsened subjective symptoms of dry eye (1.31, 95% confidence interval (CI) [0.66, 1.95], P < 0.0001), a reduced tear break-up time (BUT) (−2.27, 95% CI [−2.66, −1.88], P < 0.0001), and a worse corneal fluorescein staining (CFS) score (0.75, 95% CI [0.5, 1.0], P < 0.0001) after phacoemulsification cataract surgery, whereas in the general population, the subjective symptoms score and CFS remained unchanged and BUT decreased slightly after surgery. Patients without diabetes showed significantly reduced total tear secretion after phacoemulsification cataract surgery (−1.25, 95% CI [−1.62, −0.88], P < 0.0001).

Conclusion: Dry eye generally remained unchanged 1 month after phacoemulsification cataract surgery. Notably, worsened symptoms and signs of dry eye were observed more frequently in patients with pre-existing MGD. Patients without diabetes were more susceptible to reduced tearing postoperatively.

Clinical Trial Registration: Identifier: PERSPERO (2020: CRD42020203316).
The “Slow Horse Racing Effect” on Lung Function in Adult Life in Chronic Obstructive Pulmonary Disease Associated to Biomass Exposure
Authors: Ramírez-Venegas Alejandra , Montiel-Lopez Francisco , Falfan-Valencia Ramces , Pérez-Rubio Gloria , Sansores Raúl H
Published: July 2021

Although different trajectories in lung function decline have been identified in patients with COPD associated to tobacco exposure (TE-COPD), genetic, environmental, and infectious factors affecting lung function throughout life have not been fully elucidated in patients with COPD associated to biomass (BE-COPD). In this review, we present current epidemiological findings and notable advances in the natural history of lung decline in BE-COPD, as well as conditions modeling the FEV1trajectory, such as health insults, during the first years of childhood. Evidence shows that women exposed to biomass smoke reach adult life with a lower FEV1than expected. However, in contrast to the “horse racing effect” predicting an excessive lung-function decline in forthcoming years, as observed in smokers, this decline is slower in non-smokers, and no rapid decliners are observed. Accordingly, BE-COPD might be considered another phenotype of COPD based on assessments of lung function decline. Likewise, other functional and clinical aspects described in this review suggest that this condition might be similar to TE-COPD. More research is needed to fully characterize this subgroup of variants of COPD.
Binding of Plasminogen to Streptococcus suis Protein Endopeptidase O Facilitates Evasion of Innate Immunity in Streptococcus suis
Authors: Zhou Yang , Yan Kang , Sun Chengfeng , Liu Feng , Peng Wei , Chen Huanchun , Yuan Fangyan , Bei Weicheng , Li Jinquan
Published: July 2021

The Gram-positive bacterial speciesStreptococcus suisis an important porcine and human pathogen that causes severe life-threatening diseases associated with high mortality rates. However, the mechanisms by whichS. suisevades host innate immunity remain elusive, so identifying novel virulence factors involved in immune evasion is crucial to gain control over this threatening pathogen. Our previous work has shown thatS. suisprotein endopeptidase O (SsPepO) is a novel fibronectin-binding protein. Here, we identified that recombinant SsPepO binds human plasminogen in a dose-dependent manner. Moreover, the binding of SsPepO and plasminogen, upon the activation of urokinase-type plasminogen activator, generated plasmin, which could cleave complement C3b, thus playing an important role in complement control. Additionally, aSspepO-deficient mutant showed impaired adherence to plasminogen as well as impaired adherence to and invasion of rat brain microvascular endothelial cells compared with the wildtype strain. We further found that theSspepO-deficient mutant was efficiently killed by human serum and blood. We also confirmed that theSspepO-deficient mutant had a lower mortality rate than the wildtype strain in a mouse model. In conclusion, these results indicate that SsPepO is a novel plasminogen-binding protein that contributes toS. suisimmune evasion.
A Single Point Mutation Controls the Rate of Interconversion Between the g+ and g− Rotamers of the Histidine 189 χ2 Angle That Activates Bacterial Enzyme I for Catalysis
Authors: Purslow Jeffrey A. , Thimmesch Jolene N. , Sivo Valeria , Nguyen Trang T. , Khatiwada Balabhadra , Dotas Rochelle R. , Venditti Vincenzo
Published: July 2021

Enzyme I (EI) of the bacterial phosphotransferase system (PTS) is a master regulator of bacterial metabolism and a promising target for development of a new class of broad-spectrum antibiotics. The catalytic activity of EI is mediated by several intradomain, interdomain, and intersubunit conformational equilibria. Therefore, in addition to its relevance as a drug target, EI is also a good model for investigating the dynamics/function relationship in multidomain, oligomeric proteins. Here, we use solution NMR and protein design to investigate how the conformational dynamics occurring within the N-terminal domain (EIN) affect the activity of EI. We show that the rotameric g+-to-g− transition of the active site residue His189 χ2 angle is decoupled from the state A-to-state B transition that describes a ∼90° rigid-body rearrangement of the EIN subdomains upon transition of the full-length enzyme to its catalytically competent closed form. In addition, we engineered EIN constructs with modulated conformational dynamics by hybridizing EIN from mesophilic and thermophilic species, and used these chimeras to assess the effect of increased or decreased active site flexibility on the enzymatic activity of EI. Our results indicate that the rate of the autophosphorylation reaction catalyzed by EI is independent from the kinetics of the g+-to-g− rotameric transition that exposes the phosphorylation site on EIN to the incoming phosphoryl group. In addition, our work provides an example of how engineering of hybrid mesophilic/thermophilic chimeras can assist investigations of the dynamics/function relationship in proteins, therefore opening new possibilities in biophysics.
Hearing Loss and Dementia: A Meta-Analysis of Prospective Cohort Studies
Authors: Liang Zheng , Li Ao , Xu Yuanyuan , Qian Xiaoyun , Gao Xia
Published: July 2021

Background: Consensus is lacking with regard to whether hearing loss is an independent risk factor for dementia. We therefore conducted a meta-analysis to clarify the relationship of hearing loss and dementia.

Methods: Prospective cohort studies investigating the association between hearing loss and the incidence of dementia in a community-derived population were included by searching electronic databases that included PubMed, Embase, and Cochrane's Library. A random-effects model was adopted to combine the results.

Results: Fourteen cohorts including 726,900 participants were analyzed. It was shown that hearing loss was independently associated with dementia [adjusted hazard ratio (HR): 1.59, 95% confidence interval (CI): 1.37 to 1.86, p < 0.001; I2 = 86%]. Sensitivity analysis sequentially excluding any of the individual studies included showed similar results. Subgroup analysis according to the diagnostic methods for hearing loss, validation strategy for dementia, follow-up duration, and adjustment of apolipoprotein E genotype also showed consistent results (p-values for subgroup differences all > 0.05). Meta-analysis with five studies showed that hearing loss was also connected to higher risk of Alzheimer's disease (adjusted HR: 2.24, 95% CI: 1.32 to 3.79, p = 0.003; I2 = 2%).

Conclusions: Hearing loss may increase the risk of dementia in the adult population. Whether effective treatment for hearing loss could reduce the incidence of dementia should be explored in the future.
Second-Order Conditioning in Humans
Authors: Lee Jessica C.
Published: July 2021

In contrast to the large body of work demonstrating second-order conditioning (SOC) in non-human animals, the evidence for SOC in humans is scant. In this review, I examine the existing literature and suggest theoretical and procedural explanations for why SOC has been so elusive in humans. In particular, I discuss potential interactions with conditioned inhibition, whether SOC is rational, and propose critical parameters needed to obtain the effect. I conclude that SOC is a real but difficult phenomenon to obtain in humans, and suggest directions for future research.
Transient Global Amnesia (TGA): Influence of Acute Hypertension in Patients Not Adapted to Chronic Hypertension
Authors: Rogalewski Andreas , Beyer Anne , Friedrich Anja , Plümer Jorge , Zuhorn Frédéric , Greeve Isabell , Klingebiel Randolf , Woermann Friedrich G. , Bien Christian G. , Schäbitz Wolf-Rüdiger
Published: July 2021

Objective: Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear etiology for a period of <24 h. Several studies showed differences in vascular risk factors between TGA compared to transient ischemic attack (TIA) or healthy controls with varying results. This retrospective and cross-sectional study compares the cardiovascular risk profile of TGA patients with that of acute stroke patients.

Methods: Cardiovascular risk profile and MR imaging of 277 TGA patients was retrospectively analyzed and compared to 216 acute ischemic stroke patients (26% TIA).

Results: TGA patients were significantly younger and predominantly female compared to stroke patients. A total of 90.6% of TGA patients underwent MRI, and 53% of those showed hippocampal diffusion-weighted imaging (DWI) lesions. Scores for cerebral microangiopathy were lower in TGA patients compared to stroke patients. After statistical correction for age, TGA patients had higher systolic and diastolic blood pressure, higher cholesterol levels, lower HbA1c, as well as blood glucose levels, and lower CHA2DS2-VASc scores. Stroke patients initially displayed higher CRP levels than TIA and TGA patients. TGA patients without DWI lesions were older and showed higher CHA2DS2-VASc scores compared to TGA patients with DWI lesions.

Conclusion: This study revealed significant differences between TGA and stroke patients in regard to the cardiovascular risk profile. Our main findings show a strong association between acute hypertensive peaks and TGA in patients not adapted to chronic hypertension, indicating a vascular cause of the disease.
Effects of Transcranial Alternating Current Stimulation and Neurofeedback on Alpha (EEG) Dynamics: A Review
Authors: Orendáčová Mária , Kvašňák Eugen
Published: July 2021

Transcranial alternating current stimulation (tACS) and neurofeedback (NFB) are two different types of non-invasive neuromodulation techniques, which can modulate brain activity and improve brain functioning. In this review, we compared the current state of knowledge related to the mechanisms of tACS and NFB and their effects on electroencephalogram (EEG) activity (online period/stimulation period) and on aftereffects (offline period/post/stimulation period), including the duration of their persistence and potential behavioral benefits. Since alpha bandwidth has been broadly studied in NFB and in tACS research, the studies of NFB and tACS in modulating alpha bandwidth were selected for comparing the online and offline effects of these two neuromodulation techniques. The factors responsible for variability in the responsiveness of the modulated EEG activity by tACS and NFB were analyzed and compared too. Based on the current literature related to tACS and NFB, it can be concluded that tACS and NFB differ a lot in the mechanisms responsible for their effects on an online EEG activity but they possibly share the common universal mechanisms responsible for the induction of aftereffects in the targeted stimulated EEG band, namely Hebbian and homeostatic plasticity. Many studies of both neuromodulation techniques report the aftereffects connected to the behavioral benefits. The duration of persistence of aftereffects for NFB and tACS is comparable. In relation to the factors influencing responsiveness to tACS and NFB, significantly more types of factors were analyzed in the NFB studies compared to the tACS studies. Several common factors for both tACS and NFB have been already investigated. Based on these outcomes, we propose several new research directions regarding tACS and NFB.
Association of Red Meat and Poultry Consumption With the Risk of Metabolic Syndrome: A Meta-Analysis of Prospective Cohort Studies
Authors: Guo Hongbin , Ding Jun , Liang Jieyu , Zhang Yi
Published: July 2021

Objective: This study aims to investigate the association of red meat (processed and unprocessed) and poultry consumption with the risk of metabolic syndrome (MetS).

Methods: Prospective cohort studies on the association of red meat (processed and unprocessed) and poultry consumption with the risk of MetS were identified by comprehensive literature search in the PubMed, Web of Science, and Embase databases up to March 2021. The pooled relative risk (RR) of MetS with 95% CIs for the highest vs. lowest category of red meat or poultry consumption was extracted for meta-analysis.

Results: A total of nine prospective cohort studies were included in this study. Among them, eight studies were identified for red meat consumption. The overall multi-variable adjusted RR demonstrated that red meat consumption was associated with a higher risk of MetS (RR = 1.35, 95% CI: 1.13–1.62; P = 0.001). Moreover, four and three studies were specifically related to processed and unprocessed red meat consumption, respectively. Both processed (RR = 1.48, 95% CI: 1.11–1.97; P = 0.007) and unprocessed red meat (RR = 1.32, 95% CI: 1.14–1.54; P = 0.0003) consumption was associated with a higher risk of MetS. With regard to poultry consumption, three studies were included. The overall multi-variable adjusted RR suggested that poultry consumption was associated with lower risk of MetS (RR = 0.85, 95% CI: 0.75–0.97; P = 0.02).

Conclusions: The current evidence indicates that red meat (processed and unprocessed) consumption is associated with a higher risk of MetS, whereas, poultry consumption is associated with a lower risk of MetS. More well-designed randomized controlled trials are still needed to address the issues further.
Exploratory Analysis to Predict Optimal Tumor Burden for Starting Lenvatinib in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer
Authors: Suzuki Chiaki , Kiyota Naomi , Imamura Yoshinori , Goto Hideaki , Suto Hirotaka , Chayahara Naoko , Toyoda Masanori , Ito Yasuhiro , Miya Akihiro , Miyauchi Akira , Teshima Masanori , Otsuki Naoki , Nibu Ken-ichi , Minami Hironobu
Published: July 2021

Background

We previously reported that a high tumor burden is a prognostic factor based on an analysis of 26 patients with radioactive iodine-refractory differentiated thyroid cancer (RR-DTC) who were treated with lenvatinib. However, the optimal tumor burden for starting lenvatinib still remains to be defined. The aim of this retrospective study was to further explore in the same patient cohort the optimal timing for the start of lenvatinib by focusing on the pre- and post-treatment tumor burden.

Methods

The 26 patients were treated with lenvatinib from 2012 to 2017. We explored the optimal timing for the start of lenvatinib by comparing the characteristics of long-term responders who were defined as patients with progression-free survival ≥ 30 months and non-long-term responders.

Results

Long-term responders had a smaller post-treatment tumor burden at maximum shrinkage than non-long-term responders. Further, post-treatment tumor burden had a strong linear correlation with baseline tumor burden. We created an estimation formula for baseline tumor burden related to prognosis, using these regression lines. Patients with a sum of diameters of target lesions < 60 mm or maximum tumor diameter < 34 mm at baseline were estimated to have significantly better survival outcomes.

Conclusions

We found a strong linear correlation between pre- and post-treatment tumor burden. Our results suggested a cut-off value for baseline tumor burden for long-term prognosis among patients treated with lenvatinib.
Diagnostic Value of CircRNAs as Potential Biomarkers in Oral Squamous Cell Carcinoma: a Meta-Analysis
Authors: Wang Mingfei , Zhang Linfeng , Ren Wenhao , Li Shaoming , Zhi Keqian , Zheng Jingjing , Gao Ling
Published: July 2021

Introduction

Circular RNAs (CircRNAs), an emerging non-coding RNA, have been demonstrated to be involved in tumorigenesis, metastasis, and cancer progression, and could represent novel potential biomarkers for diagnosing oral squamous cell carcinoma (OSCC). However, no meta-analysis has investigated the diagnostic role of circRNAs in OSCC. Hence, to investigate whether circRNAs could serve as specific biomarkers for OSCC, the present systematic review and meta-analysis evaluated the diagnostic efficiency of circRNAs in patients with OSCC.

Materials and Methods

A thorough search of online databases (Pubmed, Web of Science, Embase, and the Cochrane Library) was conducted to collect relevant studies up to March 30th, 2021. All eligible studies were case-control studies. The quality of each study was evaluated by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. STATA (version 15.1) and Review Manager (version 5.4) were employed to conduct the meta-analysis, and the PRISMA statement was adopted in this study.

Results

A total of 16 studies were included in the meta-analysis, with five studies on upregulated circRNAs, and 11 on downregulated circRNAs. The enrolled studies that met our eligibility criteria all derived from China. The pooled sensitivity (SEN), specificity (SPE), diagnostic odds ratio (DOR), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and the area under receiver operating characteristics curve (AUC) with the 95% confidence intervals (95% CIs) were 0.74 (0.69–0.79), 0.79 (0.73–0.84), 10.74 (7.81–14.77), 3.50 (2.78–4.45), 0.33 (0.27–0.39) and 0.83 (0.79–0.86), respectively. The subgroup analysis demonstrated that serum, plasma, and saliva specimens had a better diagnostic performance than tissue samples, with a high value of sensitivity, specificity, DOR, and AUC values. The results also showed that the subgroups of upregulated circRNAs and a sample size of ≥100 manifested higher specificity, DOR, and AUC for cancer detection than downregulated circRNAs and a sample size of < 100.

Conclusions

A strong association was demonstrated between the dysregulated expression of circRNAs and the diagnosis of OSCC. Hence, circRNAs have the potential to function as promising biomarkers and therapeutic targets for OSCC.

Systematic Review Registration

PROSPERO, number CRD42021256857.
Wan-Nian-Qing, a Herbal Composite Prescription, Suppresses the Progression of Liver Cancer in Mice by Regulating Immune Response
Authors: Zhang Xinrui , Liu Xin , Zhang Yue , Yang Anhui , Zhang Yongfeng , Tong Zhijun , Wang Yingwu , Qiu Ye
Published: July 2021

The Wan-Nian-Qing prescription (WNQP), an herbal composite containing Ornithogalum caudatum, has been used in China for several years for cancer treatment. However, the mechanism of its pharmacological action against liver cancer is not clear. This study aimed to investigate the role of WNQP in inhibiting tumor growth in hepatocellular carcinoma model mice and determine its mechanism of action. We established HepG2- and SMMC-7721-xenografted tumor models in nude mice and BALB/c mice. The mice were administered WNQP for 2 weeks. The bodyweight of each mouse was monitored every day, and the tumor size was measured using vernier caliper before each round of WNQP administration. After the last dose, mice were sacrificed. The tumors were removed, lysed, and subjected to proteome profiling, enzyme-linked immunosorbent assay, and western blotting. The liver, spleen, and kidney were collected for histopathological examination. The effects of WNQP against liver cancer were first systematically confirmed in HepG2- and SMMC-7721-xenografted nude mice and BALB/c mice models. WNQP inhibited tumor growth, but failed to affect bodyweight and organ structures (liver and spleen), confirming that it was safe to use in mice. In BALB/c mice, WNQP regulated immune function, inferred from the modulation of immune-related cytokines such as interleukins, interferon, tumor necrosis factors, and chemokines. Further results confirmed that this regulation occurred via the regulatory effects of WNQP on Nrf2 signaling. WNQP can inhibit the growth of HepG2- and SMMC-7721-xenografted tumors in nude mice and BALB/c mice. This effect manifests at least partially through immunomodulation mediated apoptosis.
Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy
Authors: Tang Xuejia , Zuo Chenghai , Fang Pengchao , Liu Guojing , Qiu Yongyi , Huang Yi , Tang Rongrui
Published: July 2021

Glioblastoma (GBM) remains the most lethal and common primary brain tumor, even after treatment with multiple therapies, such as surgical resection, chemotherapy, and radiation. Although great advances in medical development and improvements in therapeutic methods of GBM have led to a certain extension of the median survival time of patients, prognosis remains poor. The primary cause of its dismal outcomes is the high rate of tumor recurrence, which is closely related to its resistance to standard therapies. During the last decade, glioblastoma stem cells (GSCs) have been successfully isolated from GBM, and it has been demonstrated that these cells are likely to play an indispensable role in the formation, maintenance, and recurrence of GBM tumors, indicating that GSCs are a crucial target for treatment. Herein, we summarize the current knowledge regarding GSCs, their related signaling pathways, resistance mechanisms, crosstalk linking mechanisms, and microenvironment or niche. Subsequently, we present a framework of targeted therapy for GSCs based on direct strategies, including blockade of the pathways necessary to overcome resistance or prevent their function, promotion of GSC differentiation, virotherapy, and indirect strategies, including targeting the perivascular, hypoxic, and immune niches of the GSCs. In summary, targeting GSCs provides a tremendous opportunity for revolutionary approaches to improve the prognosis and therapy of GBM, despite a variety of challenges.