bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Different Timing of Multivessel Intervention During Index-Hospitalization for Patients With Acute Myocardial Infarction
Authors: Liu En-Shao , Hung Cheng Chung , Chiang Cheng-Hung , Chang Chia-His , Cheng Chin-Chang , Kuo Feng-You , Mar Guang-Yuan , Huang Wei-Chun
Published: June 2021

Background: Many patients presenting with acute myocardial infarction (AMI) were found to have a multivessel disease. Uncertainty still exists in the optimal revascularization strategy in AMI patients. The purpose of this study was to assess the outcome of immediate multivessel revascularization compared with staged multivessel percutaneous coronary intervention (PCI) in patients with AMI.

Method: This was a nationwide cohort study of 186,112 patients first diagnosed with AMI, 78,699 of whom received PCI for revascularization. Patients who received repetitive PCI during the index hospitalization were referred to as staged multivessel PCI. Immediate multivessel PCI was defined as patients with two-vessel PCI or three-vessel PCI during the index procedure. Cox proportional hazards regression models were performed to evaluate the different indicators of mortality risks in AMI.

Result: Immediate multivessel PCI was associated with a worse long-term outcome than staged multivessel PCI during the index admission (log-rank P < 0.001). There was a higher incidence of stroke in patients with multivessel PCI during hospitalization. In Cox analysis, immediate multivessel PCI was an independent risk factor for mortality compared to those with staged multivessel PCI, regardless of the type of myocardial infarction.

Conclusion: This study demonstrated that performing immediate multivessel PCI for AMI may lead to worse long-term survival than staged multivessel PCI. Our findings emphasized the importance of PCI timing for non-infarct-related artery stenosis and provided information to supplement current evidence.
Diagnostic Informatics—The Role of Digital Health in Diagnostic Stewardship and the Achievement of Excellence, Safety, and Value
Authors: Georgiou Andrew , Li Julie , Hardie Rae-Anne , Wabe Nasir , Horvath Andrea R. , Post Jeffrey J. , Eigenstetter Alex , Lindeman Robert , Lam Que , Badrick Tony , Pearce Christopher
Published: June 2021

Diagnostic investigations (pathology laboratory and medical imaging) aim to: increase certainty of the presence or absence of disease by supporting the process of differential diagnosis; support clinical management; and monitor a patient's trajectory (e. g., disease progression or response to treatment). Digital health can be defined as the collection, storage, retrieval, transmission, and utilization of data, information, and knowledge to support healthcare. Digital health has become an essential component of the diagnostic process, helping to facilitate the accuracy and timeliness of information transfer and enhance the effectiveness of decision-making processes. Digital health is also important to diagnostic stewardship, which involves coordinated guidance and interventions to ensure the appropriate utilization of diagnostic tests for therapeutic decision-making. Diagnostic stewardship and informatics are thus important in efforts to establish shared decision-making. This is because they contribute to the establishment of shared information platforms (enabling patients to read, comment on, and share in decisions about their care) based on timely and meaningful communication. This paper will outline key diagnostic informatics and stewardship initiatives across three interrelated fields: (1) diagnostic error and the establishment of outcomes-based diagnostic research; (2) the safety and effectiveness of test result management and follow-up; and (3) digitally enhanced decision support systems.
Using Virtual Reality to Assess Reading Fluency in Children
Authors: Mirault Jonathan , Albrand Jean-Patrice , Lassault Julie , Grainger Jonathan , Ziegler Johannes C.
Published: June 2021

Here we provide a proof-of-concept for the use of virtual reality (VR) goggles to assess reading behavior in beginning readers. Children performed a VR version of a lexical decision task that allowed us to record eye-movements. External validity was assessed by comparing the VR measures (lexical decision RT and accuracy, gaze durations and refixation probabilities) to a gold standard reading fluency test—the One-Minute Reading test. We found that the VR measures correlated strongly with the classic fluency measure. We argue that VR-based techniques provide a valid and child-friendly way to study reading behavior in a school environment. Importantly, they enable not only the collection of a richer dataset than standard behavioral assessments but also the possibility to tightly control the environment.
Immune Checkpoint Inhibitors-Related Thyroid Dysfunction: Epidemiology, Clinical Presentation, Possible Pathogenesis, and Management
Authors: Zhan Ling , Feng Hong-fang , Liu Han-qing , Guo Lian-tao , Chen Chuang , Yao Xiao-li , Sun Sheng-rong
Published: June 2021

Immune checkpoint inhibitors (ICIs) are a group of drugs employed in the treatment of various types of malignant tumors and improve the therapeutic effect. ICIs blocks negative co-stimulatory molecules, such as programmed cell death gene-1 (PD-1) and its ligand (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), reactivating the recognition and killing effect of the immune system on tumors. However, the reactivation of the immune system can also lead to the death of normal organs, tissues, and cells, eventually leading to immune-related adverse events (IRAEs). IRAEs involve various organs and tissues and also cause thyroid dysfunction. This article reviews the epidemiology, clinical manifestations, possible pathogenesis, and management of ICIs-related thyroid dysfunction.
Multiphysics Investigation on Coolant Thermohydraulic Conditions and Fuel Rod Behavior During a Loss-of-Coolant Accident
Authors: Yu Meng , Qian Libo , Zhou Wenzhong
Published: June 2021

This article simulates the multiphysics coolant thermohydraulic conditions and fuel performance of a pressurized water reactor (PWR) during a loss-of-coolant accident (LOCA). In the coolant channel of a PWR, the coolant undergoes a series of different boiling regimes along the axial direction. At the inlet of the coolant channel, heat exchange between the cladding wall and coolant is based on single-phase forced convection. As the coolant flow distance increases, the boiling regime gradually converts to nucleate boiling. When a LOCA occurs, on the one hand, the coolant flux and coolant pressure decrease sharply; on the other hand, the heat flux at the cladding wall decreases relatively slowly. They both contribute to a swift increase in coolant temperature. As a consequence, a boiling crisis may occur as critical heat flux (CHF) decreases. In this article, the void fraction along the length of coolant channel in a reactor and mechanical performance of Zr cladding enwrapping UO2 fuel are investigated by establishing a fully coupled multiphysics model based on the CAMPUS code. Physical models of coolant boiling regimes are implemented into the CAMPUS code by adopting different heat transfer models and void fraction models. Physical properties of the coolant are implemented into the CAMPUS code using curve-fitting results. All physical models and parameters related to solid heat transfer are implemented into the CAMPUS code with a 2D axisymmetric geometry. The modeling results help enhance our understanding of void fraction along the length of the coolant channel and mechanical performance of Zr cladding enwrapping UO2 fuel under different coolant pressure and mass flux conditions during a LOCA.
Study on Emission Reduction Strategies of Dual-Channel Supply Chain Considering Green Finance
Authors: Che Cheng , Chen Yi , Zhang Xiaoguang , Zhao Liangyan , Guo Peng , Ye Jingwen
Published: June 2021

As a weapon for economic development, green finance plays an important supporting and promoting role in the economic recovery and transformation of enterprises in the post-epidemic era. By constructing a dual-channel supply chain model, this paper considers two situations in which manufacturers participate in carbon trading and green finance loans, and uses Stackelberg game to study the impact of different situations on participants’ profits and emission reduction decisions. The results show that: under the carbon trading mechanism, the carbon emission reduction level of the manufacturer is inversely proportional to the relevant price, and the demand and profit of the two channels increase with the increase in emission reduction; when carbon trading and green financial loans are carried out at the same time, participants have lower profits, but with the increase in emission reductions, it is still a growing trend.
Thermal Sensitivity of Heat Sensor TRPA1 Correlates With Temperatures Inducing Heat Avoidance Behavior in Terrestrial Ectotherms
Authors: Akashi Hiroshi
Published: June 2021

Temperature is an essential environmental factor that controls an organism’s performances. As ectothermic animals largely rely on external heat sources for adjusting their body temperature, thermal perception is a primary process of behavioral thermoregulation. Transient receptor potential ankyrin 1 (TRPA1) is a heat sensitive ion channel in most non-mammalian species, and its heat activation has been suggested to induce heat avoidance behaviors in ectothermic animals. However, associations between TRPA1 and ecologically relevant temperatures have not been investigated, and the analyses including diverse taxa will provide robust support for understanding the associations. Here, I conducted extensive literature review, and assembled published data on thermal threshold of TRPA1 and three physiological parameters: the experimental voluntary maximum (EVM), which is body temperatures when heat avoidance behaviors are induced; the critical thermal maximum (CTmax), which is a point in temperature beyond which an organism becomes incapacitated; and average body temperature (Tmean) recorded in the field. Then, I examined the relationships between thermal threshold of TRPA1 and each of the three physiological parameters. As phylogenetically closely related species tend to show similar trait values among species, I conducted the regression analyses by accounting for phylogenetic distances among species. This study supports previous research by affirming that thermal threshold of TRPA1 is substantially correlated with body temperature that the animals escaped from the heat source, represented here as EVM. Nevertheless, thermal threshold of TRPA1 showed a statistically insignificant correlation with CTmax and Tmean. The results suggest that although thermal threshold of TRPA1 is evolutionarily labile, its associations with EVM is highly conserved among diverse terrestrial ectotherms. Therefore, thermal threshold of TRPA1 could be a useful parameter to evaluate species vulnerability to thermal stress particularly in the recent climate warming scenario.
Anatomy of the Nasal and Auditory Regions of the Fossil Lagomorph Palaeolagus haydeni: Systematic and Evolutionary Implications
Authors: Ruf Irina , Meng Jin , Fostowicz-Frelik Łucja
Published: June 2021

Palaeolagus, a late Eocene to early Miocene North American lagomorph genus, represented by numerous and well-preserved specimens, has been long considered a basal leporid, although it is currently understood as a stem lagomorph. Based on micro-computed tomography (μCT) data and 3D reconstructions, here we present the first description of intracranial structures of the nasal and auditory regions of a complete skull of Palaeolagus haydeni from the early Oligocene of Nebraska. Although Palaeolagus haydeni shows a puzzling mixture of extant leporid and ochotonid characters, it helps to polarize and re-evaluate already known lagomorph intracranial characters based on outgroup comparison with Rodentia and Scandentia. Common derived features of Palaeolagus haydeni and extant Lagomorpha are the dendritic maxilloturbinal and the excavated nasoturbinal that contacts the lamina semicircularis. Generally, Palaeolagus haydeni and Leporidae have several characters in common, some of which are certainly plesiomorphic (e.g., thin wall of bulla tympani and flat conic cochlea). Palaeolagus haydeni resembles Leporidae in having an interturbinal between the two frontoturbinals, and three ethmoturbinals plus one interturbinal between ethmoturbinal I and II. Now, this should also be regarded as a plesiomorphic grundplan pattern for Leporidae whereas ochotonids are derived from the lagomorph grundplan as concerns the number of frontoturbinals. Concerning the middle ear, Palaeolagus haydeni significantly contributes to the polarization of the anterior anchoring of the malleus in extant lagomorphs. Palaeolagus haydeni resembles the pattern observed in early ontogenetic stages of Ochotonidae, i.e., the attachment of the malleus to the ectotympanic via a short processus anterior. The patterns in adult ochotonids and leporids now can be regarded as two different and apomorphic character states. Autapomorphic characters of Palaeolagus haydeni are the reduced frontoturbinal 2 and the additional anterolaterally oriented process of the lamina semicircularis. Interestingly, among the investigated intracranial structures the loss of the secondary crus commune is the only apomorphic grundplan character of crown Lagomorpha.
The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity
Authors: Wu Zhengguo , Li Shang , Zhu Xiao
Published: June 2021

Cancer immunotherapy is a kind of therapy that can control and eliminate tumors by restarting and maintaining the tumor-immune cycle and restoring the body’s normal anti-tumor immune response. Although immunotherapy has great potential, it is currently only applicable to patients with certain types of tumors, such as melanoma, lung cancer, and cancer with high mutation load and microsatellite instability, and even in these types of tumors, immunotherapy is not effective for all patients. In order to enhance the effectiveness of tumor immunotherapy, this article reviews the research progress of tumor microenvironment immunotherapy, and studies the mechanism of stimulating and mobilizing immune system to enhance anti-tumor immunity. In this review, we focused on immunotherapy against tumor microenvironment (TME) and discussed the important research progress. TME is the environment for the survival and development of tumor cells, which is composed of cell components and non-cell components; immunotherapy for TME by stimulating or mobilizing the immune system of the body, enhancing the anti-tumor immunity. The checkpoint inhibitors can effectively block the inhibitory immunoregulation, indirectly strengthen the anti-tumor immune response and improve the effect of immunotherapy. We also found the checkpoint inhibitors have brought great changes to the treatment model of advanced tumors, but the clinical treatment results show great individual differences. Based on the close attention to the future development trend of immunotherapy, this study summarized the latest progress of immunotherapy and pointed out a new direction. To study the mechanism of stimulating and mobilizing the immune system to enhance anti-tumor immunity can provide new opportunities for cancer treatment, expand the clinical application scope and effective population of cancer immunotherapy, and improve the survival rate of cancer patients.
Emerging Roles of MHC Class I Region-Encoded E3 Ubiquitin Ligases in Innate Immunity
Authors: Jia Xiuzhi , Zhao Chunyuan , Zhao Wei
Published: June 2021

The major histocompatibility complex (MHC) class I (MHC-I) region contains a multitude of genes relevant to immune response. Multiple E3 ubiquitin ligase genes, including tripartite motif 10 (TRIM10), TRIM15, TRIM26, TRIM27, TRIM31, TRIM38, TRIM39, TRIM40, and RING finger protein 39 (RNF39), are organized in a tight cluster, and an additional two TRIM genes (namely TRIM38 and TRIM27) telomeric of the cluster within the MHC-I region. The E3 ubiquitin ligases encoded by these genes possess important roles in controlling the intensity of innate immune responses. In this review, we discuss the E3 ubiquitin ligases encoded within the MHC-I region, highlight their regulatory roles in innate immunity, and outline their potential functions in infection, inflammatory and autoimmune diseases.
Harnessing Mechanisms of Immune Tolerance to Improve Outcomes in Solid Organ Transplantation: A Review
Authors: Slepicka Priscila Ferreira , Yazdanifar Mahboubeh , Bertaina Alice
Published: June 2021

Survival after solid organ transplantation (SOT) is limited by chronic rejection as well as the need for lifelong immunosuppression and its associated toxicities. Several preclinical and clinical studies have tested methods designed to induce transplantation tolerance without lifelong immune suppression. The limited success of these strategies has led to the development of clinical protocols that combine SOT with other approaches, such as allogeneic hematopoietic stem cell transplantation (HSCT). HSCT prior to SOT facilitates engraftment of donor cells that can drive immune tolerance. Recent innovations in graft manipulation strategies and post-HSCT immune therapy provide further advances in promoting tolerance and improving clinical outcomes. In this review, we discuss conventional and unconventional immunological mechanisms underlying the development of immune tolerance in SOT recipients and how they can inform clinical advances. Specifically, we review the most recent mechanistic studies elucidating which immune regulatory cells dampen cytotoxic immune reactivity while fostering a tolerogenic environment. We further discuss how this understanding of regulatory cells can shape graft engineering and other therapeutic strategies to improve long-term outcomes for patients receiving HSCT and SOT.
Assessing South Africa’s Potential to Address Climate Change Impacts and Adaptation in the Fisheries Sector
Authors: Ortega-Cisneros Kelly , Cochrane Kevern L. , Rivers Nina , Sauer Warwick H. H.
Published: June 2021

The marine fisheries sector is one of the most important income sectors in South Africa and plays an important role in food security for small-scale and subsistence fishers. Climate-driven impacts have resulted in distribution shifts and declines in abundance of important fisheries targets, with negative consequences to the users dependent on these resources. The sustainability of the sector depends on its readiness to adapt to climate change. The inclusion of climate change impacts and adaptation in fisheries management documents in South Africa is essential to ensure adequate climate adaptation responses are implemented at the short- and long-term. This study aims to 1) determine if the relevant fisheries national management documents address climate change and adaptation, 2) determine if the relevant national climate change documents address climate change and adaptation in the fisheries sector and 3) evaluate the extent to which fisheries management documents address climate change and adaptation. A content analysis of fisheries management and climate change documents was carried out to determine if they incorporated information on climate change impacts and adaptation and marine fisheries respectively. Fisheries management documents were then screened against nine pre-determined criteria (or themes) based on climate change adaptation to determine the level of inclusion of best practice for climate change adaptation. Results indicate that climate change impacts and adaptation are rarely incorporated in the main fisheries management documents, except for the Climate Change Adaptation and Mitigation Plan for the agriculture, fisheries and forestry sectors. However, this document is still waiting to be adopted. The only direct reference identified in all the fisheries documents that supports climate change adaptation was ‘conservation and sustainable management of biodiversity’. With regards to indirect references to climate change adaptation, ‘equity,’ ‘participatory management,’ and ‘capacity building’ were most frequently incorporated in fisheries management documents. There is a need to explicitly incorporate information on climate change impacts and adaptation in South African fisheries management documents and increase the human and financial capacity at national institutions to ensure that the fisheries sector can adequately adapt to climate change.
Exploring Impacts of River Discharge on Forage Fish and Predators Using Ecopath With Ecosim
Authors: Sinnickson Dylan , Chagaris David , Allen Micheal
Published: June 2021

The ecology of estuaries is shaped significantly by the extent of freshwater discharge which regulates abiotic processes and influences overall biological productivity. The Suwannee River Estuary of Florida’s Big Bend Coastline has historically been a productive and diverse estuarine ecosystem supported by significant freshwater inputs from the Suwannee River. In recent years, significant changes in land use and climatic conditions have resulted in lower discharges from the Suwannee. Our objectives were to explore the impact of freshwater inputs from the Suwannee River on the estuarine forage fish and sportfish communities downstream. We built a trophic-dynamic food web model in Ecopath with Ecosim to simulate different levels of discharge and evaluate how changes in discharge (drought and floods) would influence the trophic structure of the food web. Using the fitted model, we applied a series of different short-term and long-term flow projections under different climatic scenarios to evaluate impacts on fish functional groups and sportfish biomass. Simulations suggested that ecological production was more influenced by drought conditions than flood conditions. In our short-term scenarios, the drought simulations produced biomass changes that were approximately twice as substantial as the flood scenarios. When making comparisons to other published EwE models, we generally observed smaller changes in biomass production. Although this model focused on the influence of bottom-up effects, we observed strong top-down control of snook (Centropomus undecimalis) on the system. Several functional groups were particularly sensitive to changes in snook abundance which included spotted seatrout (Cynoscion nebulosus), sand seatrout (C. arenarius), and other members of the familySciaenidae. Because snook have recently colonized the estuary, likely as a result of warmer winter temperatures, this finding has implications for climate change and natural resource management.
Effectiveness of Pre-procedural Mouth Rinses in Reducing Aerosol Contamination During Periodontal Prophylaxis: A Systematic Review
Authors: Mohd-Said Shahida , Mohd-Dom Tuti Ningseh , Suhaimi Nawal , Rani Haslina , McGrath Colman
Published: June 2021

Background:Aerosol-producing dental procedures are of concern in the spread of infections, especially during the COVID-19 pandemic. Periodontal prophylaxis is the most common aerosol-producing procedure conducted in dental practice globally. During COVID-19, many national and international organizations advocated the use of pre-procedural mouth rinsing to prevent the spread of infections from aerosol-generating procedures in the dental setting; however, many questioned the scientific basis for such recommendations.

Objective:This systematic review aimed to evaluate the effectiveness of pre-procedural rinsing when preforming periodontal prophylaxis in reducing aerosol contamination in the dental setting.

Methods:A comprehensive standardized search strategy was employed, informed by a defined PICO question across four electronic databases. The review of the literature was conducted using the PRISMA framework. Agreement between assessors was determined throughout. Synthesis of study characteristics and key outcomes were conducted. Cochrane's risk-of-bias tool for randomized trials (RoB 2) was employed to assess the quality/bias among studies.

Results:The initial search yielded 731 citations across the four databases; 95 potentially effective studies were identified, with 56 effective studies found. Thirty randomized control trial studies were identified, 21 with a focus on effectiveness of pre-procedural mouth rinsing, involving 984 participants (aged 18–70). Agreement between assessors was high (Kappa >0.80). Various pre-procedural mouth rinses were tested, most frequently chlorhexidine (CHX) in 18 studies. The concentrations, volume, and prescribed duration of rinsing varied among studies, hampering meta-analyses. Nonetheless, all studies identified significant reductions in bacterial contamination, as measured by colony forming units (cfu). The effectiveness of CHX over other agents was evident with more than half of the studies (7/15) reporting over a 70% reduction in bacterial contamination (cfu). There were concerns over the risk of bias in most studies (76.2%); 19.0% had a high risk of bias and 4.8% were of low risk of bias.

Conclusion:There is substantial evidence to support pre-procedural mouth rinsing, such as with chlorohexidine, to effectively reduce aerosol contamination when performing periodontal prophylaxis compared to mouth rinsing with water or not rinsing.
The Skin in Cowden Syndrome
Authors: Lim Agnes , Ngeow Joanne
Published: June 2021

Cowden syndrome (CS) is an autosomal dominant condition caused by mutations in the phosphatase and tensin homolog (PTEN) gene, and is characterized by multiple hamartomas and a predisposition to malignant tumors. Characteristic skin lesions include trichilemmomas, acral keratosis, mucocutaneous neuromas, oral papillomas, and penile macules, and are often the first clues to the underlying diagnosis. Here, we discuss the mucocutaneous manifestations of CS, differential diagnoses of genetic causes of each cutaneous finding, genetic analyses for patients with skin manifestations, management of patients with CS, and potential new targeted therapies for CS.
Poikiloderma With Neutropenia and Mastocytosis: A Case Report and a Review of Dermatological Signs
Authors: Piccolo Vincenzo , Russo Teresa , Di Pinto Daniela , Pota Elvira , Di Martino Martina , Piluso Giulio , Ronchi Andrea , Argenziano Giuseppe , Di Brizzi Eugenia Veronica , Santoro Claudia
Published: June 2021

Poikiloderma with neutropenia (PN) is a very rare genetic disorder mainly characterized by poikiloderma and congenital neutropenia, which explains the recurrence of respiratory infections and risk of developing bronchiectasis. Patients are also prone to develop hematological and skin cancers. Here, we present the case of a patient, the only child of apparently unrelated Serbian parents, affected by PN resulting from the homozygous mutation NM_024598.3:c.243G>A (p.Trp81Ter) of USB1; early onset of poikiloderma (1 year of age) was associated with cutaneous mastocytosis. We also provide a review of the literature on this uncommon condition with a focus on dermatological findings.
The Development of an ex vivo Flow System to Assess Acute Arterial Drug Retention of Cardiovascular Intravascular Devices
Authors: Cooper Kathryn , Cawthon Claire V. , Goel Emily , Atigh Marzieh , Christians Uwe , Yazdani Saami K.
Published: June 2021

Purpose: The goal of this study was to develop an ex vivo system capable of rapidly evaluating arterial drug levels in living, isolated porcine carotid arteries.

Methods: A vascular bioreactor system was developed that housed a native porcine carotid artery under physiological flow conditions. The ex vivo bioreactor system was designed to quantify the acute drug transfer of catheter-based drug delivery devices into explanted carotid arteries. To evaluate our ex vivo system, a paclitaxel-coated balloon and a perfusion catheter device delivering liquid paclitaxel were utilized. At 1-h post-drug delivery, arteries were removed, and paclitaxel drug levels measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Parallel experiments were performed in a pig model to validate ex vivo measurements.

Results: LC-MS/MS analysis demonstrated arterial paclitaxel levels of the drug-coated balloon-treated arteries to be 48.49 ± 24.09 ng/mg and the perfusion catheter-treated arteries to be 25.42 ± 9.74 ng/mg at 1 h in the ex vivo system. Similar results were measured in vivo, as arterial paclitaxel concentrations were measured at 59.23 ± 41.27 ng/mg for the drug-coated balloon-treated arteries and 23.43 ± 20.23 ng/mg for the perfusion catheter-treated arteries. Overall, no significant differences were observed between paclitaxel measurements of arteries treated ex vivo vs. in vivo.

Conclusion: This system represents the first validated ex vivo pulsatile system to determine pharmacokinetics in a native blood vessel. This work provides proof-of-concept of a quick, inexpensive, preclinical tool to study acute drug tissue concentration kinetics of drug-releasing interventional vascular devices.
Learning the Regulatory Code of Gene Expression
Authors: Zrimec Jan , Buric Filip , Kokina Mariia , Garcia Victor , Zelezniak Aleksej
Published: June 2021

Data-driven machine learning is the method of choice for predicting molecular phenotypes from nucleotide sequence, modeling gene expression events including protein-DNA binding, chromatin states as well as mRNA and protein levels. Deep neural networks automatically learn informative sequence representations and interpreting them enables us to improve our understanding of the regulatory code governing gene expression. Here, we review the latest developments that apply shallow or deep learning to quantify molecular phenotypes and decode thecis-regulatory grammar from prokaryotic and eukaryotic sequencing data. Our approach is to build from the ground up, first focusing on the initiating protein-DNA interactions, then specific coding and non-coding regions, and finally on advances that combine multiple parts of the gene and mRNA regulatory structures, achieving unprecedented performance. We thus provide a quantitative view of gene expression regulation from nucleotide sequence, concluding with an information-centric overview of the central dogma of molecular biology.
Coupling Complete Blood Count and Steroidomics to Track Low Doses Administration of Recombinant Growth Hormone: An Anti-Doping Perspective
Authors: Narduzzi Luca , Buisson Corinne , Morvan Marie-Line , Marchand Alexandre , Audran Michel , Le Bouc Yves , Varlet-Marie Emmanuelle , Ericsson Magnus , Le Bizec Bruno , Dervilly Gaud
Published: June 2021

Growth Hormone (GH) under its human recombinant homologue (rhGH), may be abused by athletes to take advantage of its well-known anabolic and lipolytic properties; hence it is prohibited in sports by the World Anti-Doping Agency. Due to the rapid turnover of rhGH, anti-doping screening tests have turned to monitor two endocrine biomarkers (IGF-I and P-III-NP), but unfortunately, they show population-wise variability, limiting the identification rate of rhGH users. Previous studies have evidenced the numerous effects of GH on human physiology, especially in hematopoiesis and steroidogenesis. In this work, aiming to discover novel physiological rhGH biomarkers, we analyzed the complete blood count and the steroidomics profile of healthy, physically active, young males treated either with EPO + rhGH or EPO + placebo. The time-trends of these two physiological routes have been analyzed through geometric trajectory analysis (GTA) and OPLS-DA. Individuals supplemented with micro-doses of rhGH exhibited different leukopoietic and steroidal profiles compared to the control population, suggesting a role of the rhGH in both pathways. In the article, hypotheses on the observed differences are discussed according to the most recent literature and compared to results in animal models. The use of leukopoietic and steroidal biomarkers together with endocrine biomarkers (IGF-1 and P-III-NP) allows to correctly classify over 98% of samples with no false positives, miss-classifying only one single sample (false negative) over a total of 56; a promising result, if compared to the current rhGH detection strategies.
Concurrent Modified Constant Modulus Algorithm and Decision Directed Scheme With Barzilai-Borwein Method
Authors: Xu Tongtong , Xiang Zheng , Yang Hua , Chen Yun , Luo Jun , Zhang Yutao
Published: June 2021

At present, in robot technology, remote control of robot is realized by wireless communication technology, and data anti-interference in wireless channel becomes a very important part. Any wireless communication system has an inherent multi-path propagation problem, which leads to the expansion of generated symbols on a time scale, resulting in symbol overlap and Inter-symbol Interference (ISI). ISI in the signal must be removed and the signal restores to its original state at the time of transmission or becomes as close to it as possible. Blind equalization is a popular equalization method for recovering transmitted symbols of superimposed noise without any pilot signal. In this work, we propose a concurrent modified constant modulus algorithm (MCMA) and the decision-directed scheme (DDS) with the Barzilai-Borwein (BB) method for the purpose of blind equalization of wireless communications systems (WCS). The BB method, which is two-step gradient method, has been widely employed to solve multidimensional unconstrained optimization problems. Considering the similarity of equalization process and optimization process, the proposed algorithm combines existing blind equalization algorithm and Barzilai-Borwein method, and concurrently operates a MCMA equalizer and a DD equalizer. After that, it modifies the DD equalizer's step size (SS) by the BB method. Theoretical investigation was involved and it demonstrated rapid convergence and improved equalization performance of the proposed algorithm compared with the original one. Additionally, the simulation results were consistent with the proposed technique.
Photoacoustic Neuroimaging - Perspectives on a Maturing Imaging Technique and its Applications in Neuroscience
Authors: Bodea Silviu-Vasile , Westmeyer Gil Gregor
Published: June 2021

A prominent goal of neuroscience is to improve our understanding of how brain structure and activity interact to produce perception, emotion, behavior, and cognition. The brain’s network activity is inherently organized in distinct spatiotemporal patterns that span scales from nanometer-sized synapses to meter-long nerve fibers and millisecond intervals between electrical signals to decades of memory storage. There is currently no single imaging method that alone can provide all the relevant information, but intelligent combinations of complementary techniques can be effective. Here, we thus present the latest advances in biomedical and biological engineering on photoacoustic neuroimaging in the context of complementary imaging techniques. A particular focus is placed on recent advances in whole-brain photoacoustic imaging in rodent models and its influential role in bridging the gap between fluorescence microscopy and more non-invasive techniques such as magnetic resonance imaging (MRI). We consider current strategies to address persistent challenges, particularly in developing molecular contrast agents, and conclude with an overview of potential future directions for photoacoustic neuroimaging to provide deeper insights into healthy and pathological brain processes.
Durable Response to the Combination of Atezolizumab With Platinum-Based Chemotherapy in an Untreated Non-Smoking Lung Adenocarcinoma Patient With BRAF V600E Mutation: A Case Report
Authors: Niu Xiaomin , Sun Yingjia , Planchard David , Chiu Luting , Bai Jian , Ai Xinghao , Lu Shun
Published: June 2021

Background

Immune checkpoint inhibitor (ICPi) has become a major treatment in advanced non-small cell lung cancer (NSCLC) and demonstrated a clinical benefit for NSCLC patients with high programmed death ligand-1 (PD-L1) expression without EGFR/ALK/ROS1 drivers; however, the benefit in BRAF V600E NSCLC is so far unknown. Here, we report a case of prolonged tumor response to the combination of immunotherapy with chemotherapy in a non-smoking BRAF V600E NSCLC patient.

Materials and Methods

We verify a co-expression of BRAF V600E mutation and PD-L1 high expression more than 50% on formalin-fixed paraffin-embedded tumor sample of a newly diagnosed lung adenocarcinoma patient by immunohistochemistry and BRAF V600E/EGFR/ALK/ROS1 Mutations Detection Kit. The tissue and liquid biopsies were further subjected to next-generation sequencing (NGS) for identification of mutations with progression on immunotherapy and BRAF inhibitor (BRAFi). The patient had provided written informed consent and authorized the publication of clinical case.

Results

We demonstrate the case of 62-year-old female non-smoker with high PD-L1 expression and BRAF V600E mutated NSCLC. The progression-free survival (PFS) of first-line combination of atezolizumab with platinum-based chemotherapy and sequential second-line treatment with BRAFi Vemurafenib are 20 and 5.5 months, respectively.

Conclusion

This case shows a durable response to ICPi in BRAF V600E non-smoking lung adenocarcinoma with PFS of 20 months under first-line atezolizumab plus chemotherapy treatment. The case supports the idea that the combination immunotherapy may be an attractive option for BRAF V600E mutated non-smoking NSCLC with high PD-L1 expression.
Real-World Data on Apatinib Efficacy - Results of a Retrospective Study in Metastatic Breast Cancer Patients Pretreated With Multiline Treatment
Authors: Liu Zhaoyun , Shan Jing , Yu Qian , Wang Xinzhao , Song Xiang , Wang Fukai , Li Chao , Yu Zhiyong , Yu Jinming
Published: June 2021

Objectives

The NCCN guidelines recommend that the addition of bevacizumab should be considered in metastatic breast cancers in some circumstances, but there are no recommendations for the similar antiangiogenic drug apatinib. The aim of this study was to evaluate the safety and efficacy of apatinib in metastatic breast cancer patients pretreated with multiline treatment in a real-world setting.

Materials and Methods

Metastatic breast cancer patients pretreated with multiline treatment who had apatinib treatment initiated from September 2015 to August 2019 at Shandong Cancer Hospital and Institute were included. The primary endpoints included PFS and OS, and the secondary endpoint was treatment-related toxicity.

Results

A total of 66 patients with metastatic breast cancer received apatinib treatment after failure of multiline chemotherapy in this study. The median PFS and OS of all 66 patients were 6.0 months and 10.0 months, respectively. The clinical beneficial rate was 40.9%. All patients tolerated treatment well, and no patients died of toxicity. The common toxicities of apatinib were hand and foot syndrome, secondary hypertension and fatigue events. The number of prior chemotherapy regimens was significantly associated with DFS and OS. Capecitabine may be a better choice for combination with a longer median OS of 19 months, while apatinib combined with other drugs was 9 months, and the apatinib monotherapy was 10 months.

Conclusion

Apatinib produced moderate efficacy in metastatic breast cancer patients pretreated with multiline treatment with no significant treatment-related adverse events. Apatinib might be a choice for women as a maintenance salvage therapy following multiline chemotherapy failure.
Acupuncture for Breast Cancer: A Systematic Review and Meta-Analysis of Patient-Reported Outcomes
Authors: Zhang Yuzhu , Sun Yang , Li Dongmei , Liu Xiaoyuan , Fang Chen , Yang Chunmin , Luo Tianyu , Lu Hai , Li Huachao , Zhang Hongyan , Liang Qianyi , Wu Jiahua , Huang Limei , Xu Rui , Ren Liping , Chen Qianjun
Published: June 2021

The present systematic review and meta-analysis was undertaken to evaluate the effects of acupuncture in women with breast cancer (BC), focusing on patient-reported outcomes (PROs).

Methods

A comprehensive literature search was carried out for randomized controlled trials (RCTs) reporting PROs in BC patients with treatment-related symptoms after undergoing acupuncture for at least four weeks. Literature screening, data extraction, and risk bias assessment were independently carried out by two researchers.

Results

Out of the 2, 524 identified studies, 29 studies representing 33 articles were included in this meta-analysis. At the end of treatment (EOT), the acupuncture patients’ quality of life (QoL) was measured by the QLQ-C30 QoL subscale, the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), the Functional Assessment of Cancer Therapy–General/Breast (FACT-G/B), and the Menopause-Specific Quality of Life Questionnaire (MENQOL), which depicted a significant improvement. The use of acupuncture in BC patients lead to a considerable reduction in the scores of all subscales of the Brief Pain Inventory-Short Form (BPI-SF) and Visual Analog Scale (VAS) measuring pain. Moreover, patients treated with acupuncture were more likely to experience improvements in hot flashes scores, fatigue, sleep disturbance, and anxiety compared to those in the control group, while the improvements in depression were comparable across both groups. Long-term follow-up results were similar to the EOT results.

Conclusions

Current evidence suggests that acupuncture might improve BC treatment-related symptoms measured with PROs including QoL, pain, fatigue, hot flashes, sleep disturbance and anxiety. However, a number of included studies report limited amounts of certain subgroup settings, thus more rigorous, well-designed and larger RCTs are needed to confirm our results.
Lactate Dehydrogenase-A (LDH-A) Preserves Cancer Stemness and Recruitment of Tumor-Associated Macrophages to Promote Breast Cancer Progression
Authors: Wang Shengnan , Ma Lingyu , Wang Ziyuan , He Huiwen , Chen Huilin , Duan Zhaojun , Li Yuyang , Si Qin , Chuang Tsung-Hsien , Chen Chong , Luo Yunping
Published: June 2021

Increasing evidence reveals that breast cancer stem cells (BCSCs) subtypes with distinct properties are regulated by their abnormal metabolic changes; however, the specific molecular mechanism and its relationship with tumor microenvironment (TME) are not clear. In this study, we explored the mechanism of lactate dehydrogenase A (LDHA), a crucial glycolytic enzyme, in maintaining cancer stemness and BCSCs plasticity, and promoting the interaction of BCSCs with tumor associated macrophages (TAMs). Firstly, the expression of LDHA in breast cancer tissues was much higher than that in adjacent tissues and correlated with the clinical progression and prognosis of breast cancer patients based on The Cancer Genome Atlas (TCGA) data set. Moreover, the orthotopic tumor growth and pulmonary metastasis were remarkable inhibited in mice inoculated with 4T1-shLdha cells. Secondly, the properties of cancer stemness were significantly suppressed in MDA-MB-231-shLDHA or A549-shLDHA cancer cells, including the decrease of ALDH+ cells proportion, the repression of sphere formation and cellular migration, and the reduction of stemness genes (SOX2, OCT4, and NANOG) expression. However, the proportion of ALDH+ cells (epithelial-like BCSCs, E-BCSCs) was increased and the proportion of CD44+ CD24− cells (mesenchyme-like BCSCs, M-BCSCs) was decreased after LDHA silencing, suggesting a regulatory role of LDHA in E-BCSCs/M-BCSCs transformation in mouse breast cancer cells. Thirdly, the expression of epithelial marker E-cadherin, proved to interact with LDHA, was obviously increased in LDHA-silencing cancer cells. The recruitment of TAMs and the secretion of CCL2 were dramatically reduced after LDHA was knocked down in vitro and in vivo. Taken together, LDHA mediates a vicious cycle of mutual promotion between BCSCs plasticity and TAMs infiltration, which may provide an effective treatment strategy by targeting LDHA for breast cancer patients.
LRRC3B Polymorphisms Contributed to Breast Cancer Susceptibility in Chinese Han Population
Authors: Wang Yuxin
Published: June 2021

Purpose

LRRC3B gene, as a tumor suppressor gene was involved in the development and progress of breast cancer (BC). However, the effect of LRRC3B polymorphisms on BC has rarely been reported. In the study, we aimed to evaluate the relation between LRRC3B variants and BC risk.

Methods

Among 563 BC patients and 552 healthy controls, ten single-nucleotide polymorphisms (SNPs) in LRRC3B were genotyped by Agena MassARRAY. Odds ratios (ORs) and 95% confidence interval (CI) were calculated using logistic regression model.

Results

Our study demonstrated that rs1907168 polymorphism (heterozygous: OR = 0.71, p = 0.017) was related to the reduced risk of BC in the overall. In stratified analyses by age, rs1907168 was associated with the decreased (heterozygous: OR = 0.53, p = 0.002) while rs78205284 (homozygote: OR = 2.83, p = 0.034) increased BC susceptibility among the population at age ≤51 years. Rs6551122 (recessive: OR = 0.51, p = 0.028) and rs12635768 (homozygote, OR = 0.36, p = 0.023) polymorphisms were related to the smaller BC tumor size (<2 cm). In addition, rs112276562 (heterozygote OR = 0.56, p = 0.002), rs6551122 (heterozygote OR = 0.63, p = 0.016), and rs73150416 (heterozygote OR = 0.57, p = 0.005) variants contributed to the lower incidence of PR-positive BC. Moreover, rs6788033 was associated with a lower expression level of Ki-67 (log-additive: OR = 0.68, p = 0.024). Furthermore, we found an association of ‘GATT’ haplotype with an increased risk for BC. In addition, LRRC3B gene was down-regulated in BC tumor and had a poor prognosis in BC in in silico analysis.

Conclusion

Our study firstly found LRRC3B SNPs contributed to the risk of BC, suggesting LRRC3B variants might help to predict BC progression.
The Anti-Non-Small Cell Lung Cancer Cell Activity by a mTOR Kinase Inhibitor PQR620
Authors: Zha Jian-hua , Xia Ying-chen , Ye Chun-lin , Hu Zhi , Zhang Qin , Xiao Han , Yu Ben-tong , Xu Wei-hua , Xu Guo-qiu
Published: June 2021

In non-small-cell lung carcinoma (NSCLC), aberrant activation of mammalian target of rapamycin (mTOR) contributes to tumorigenesis and cancer progression. PQR620 is a novel and highly-potent mTOR kinase inhibitor. We here tested its potential activity in NSCLC cells. In primary human NSCLC cells and established cell lines (A549 and NCI-H1944), PQR620 inhibited cell growth, proliferation, and cell cycle progression, as well as cell migration and invasion, while inducing significant apoptosis activation. PQR620 disrupted assembles of mTOR complex 1 (mTOR-Raptor) and mTOR complex 2 (mTOR-Rictor-Sin1), and blocked Akt, S6K1, and S6 phosphorylations in NSCLC cells. Restoring Akt-mTOR activation by a constitutively-active Akt1 (S473D) only partially inhibited PQR620-induced cytotoxicity in NSCLC cells. PQR620 was yet cytotoxic in Akt1/2-silenced NSCLC cells, supporting the existence of Akt-mTOR-independent mechanisms. Indeed, PQR620 induced sphingosine kinase 1 (SphK1) inhibition, ceramide production and oxidative stress in primary NSCLC cells. In vivo studies demonstrated that daily oral administration of a single dose of PQR620 potently inhibited primary NSCLC xenograft growth in severe combined immune deficient mice. In PQR620-treated xenograft tissues, Akt-mTOR inactivation, apoptosis induction, SphK1 inhibition and oxidative stress were detected. In conclusion, PQR620 exerted potent anti-NSCLC cell activity via mTOR-dependent and -independent mechanisms.