bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Applications of Liquid Biopsy in Gastric Cancer
Authors: Chivu-Economescu Mihaela , Necula Laura , Matei Lilia , Dragu Denisa , Bleotu Coralia , Diaconu Carmen C.
Published: September 2021

Liquid biopsy represents an exciting new area in the field of cancer diagnosis and management, offering a less invasive and more convenient approach to obtain a time-point image of the tumor burden and its genomic profile. Samples collected from several body fluids, mostly blood, can be used to gain access to circulating tumor cells and DNA, non-coding RNAs, microRNAs, and exosomes, at any moment, offering a dynamic picture of the tumor. For patients with GC, the use of blood-based biopsies may be particularly beneficial since tissue biopsies are difficult to obtain and cause real distress to the patient. With advantages such as repeatability and minimal invasion, it is no wonder that the field of liquid biopsy has received tremendous attention. However, the abundance of studies, involving a wide range of assays with different principles, prevented for the moment the reproducibility of the results and therefore the translation into the clinic of liquid biopsy. In this review, we present the latest technical development and data on circulating biomarkers available through liquid biopsy in gastric cancer with an emphasis on their clinical utility in areas such as cancer screening, prognostic stratification, and therapeutic management.
Viruses and Their Interactions With Bacteria and Archaea of Hypersaline Great Salt Lake
Authors: Bhattarai Bishav , Bhattacharjee Ananda S. , Coutinho Felipe H. , Goel Ramesh K.
Published: September 2021

Viruses play vital biogeochemical and ecological roles by (a) expressing auxiliary metabolic genes during infection, (b) enhancing the lateral transfer of host genes, and (c) inducing host mortality. Even in harsh and extreme environments, viruses are major players in carbon and nutrient recycling from organic matter. However, there is much that we do not yet understand about viruses and the processes mediated by them in the extreme environments such as hypersaline habitats. The Great Salt Lake (GSL) in Utah, United States is a hypersaline ecosystem where the biogeochemical role of viruses is poorly understood. This study elucidates the diversity of viruses and describes virus–host interactions in GSL sediments along a salinity gradient. The GSL sediment virosphere consisted of Haloviruses (32.07 ± 19.33%) and members of families Siphoviridae (39.12 ± 19.8%), Myoviridae (13.7 ± 6.6%), and Podoviridae (5.43 ± 0.64%). Our results demonstrate that salinity alongside the concentration of organic carbon and inorganic nutrients (nitrogen and phosphorus) governs the viral, bacteria, and archaeal diversity in this habitat. Computational host predictions for the GSL viruses revealed a wide host range with a dominance of viruses that infect Proteobacteria, Actinobacteria, and Firmicutes. Identification of auxiliary metabolic genes for photosynthesis (psbA), carbon fixation (rbcL, cbbL), formaldehyde assimilation (SHMT), and nitric oxide reduction (NorQ) shed light on the roles played by GSL viruses in biogeochemical cycles of global relevance.
Analysis of Microbial Diversity and Dynamics During Bacon Storage Inoculated With Potential Spoilage Bacteria by High-Throughput Sequencing
Authors: Li Xinfu , Xiong Qiang , Zhou Hui , Xu Baocai , Sun Yun
Published: September 2021

Staphylococcus xylosus, Leuconostoc mesenteroides, Carnobacterium maltaromaticum, Leuconostoc gelidum, and Serratia liquefaciens were investigated for their roles in in the spoilage of sterilized smoked bacon. These five strains, individually and in combination, were applied as starters on sliced bacon at 4–5 log10 CFU/g using a hand-operated spraying bottle and stored for 45 days at 0–4°C. Dynamics, diversity, and succession of microbial community during storage of samples were studied by high-throughput sequencing (HTS) of the V3–V4 region of the 16S rRNA gene. A total of 367 bacterial genera belonging to 21 phyla were identified. Bacterial counts in all the inoculated specimens increased significantly within the first 15 days while the microbiota developed into more similar communities with increasing storage time. At the end of the storage time, the highest abundance of Serratia (96.46%) was found in samples inoculated with S. liquefaciens. Similarly, for samples inoculated with C. maltaromaticum and L. mesenteroides, a sharp increase in Carnobacterium and Leuconostoc abundance was observed as they reached a maximum relative abundance of 97.95 and 81.6%, respectively. Hence, these species were not only the predominant ones but could also have been the more competitive ones, potentially inhibiting the growth of other microorganisms. By analyzing the bacterial load of meat products using the SSO model, the relationships between the microbial communities involved in spoilage can be understood to assist further research.
Cross-Sectional Study on the Gut Microbiome of Parkinson’s Disease Patients in Central China
Authors: Mao Liangwei , Zhang Yu , Tian Jing , Sang Ming , Zhang Guimin , Zhou Yuling , Wang Puqing
Published: September 2021

Gastrointestinal dysfunction plays an important role in the occurrence and development of Parkinson’s disease (PD). This study investigates the composition of the gut microbiome using shotgun metagenomic sequencing in PD patients in central China. Fecal samples from 39 PD patients (PD group) and the corresponding 39 healthy spouses of the patients (SP) were collected for shotgun metagenomics sequencing. Results showed a significantly altered microbial composition in the PD patients.Bilophila wadsworthiaenrichment was found in the gut microbiome of PD patients, which has not been reported in previous studies. The random forest (RF) model, which identifies differences in microbiomes, reliably discriminated patients with PD from controls; the area under the receiver operating characteristic curve was 0.803. Further analysis of the microbiome and clinical symptoms showed thatKlebsiellaandParasutterellawere positively correlated with the duration and severity of PD, whereas hydrogen-generatingPrevotellawas negatively correlated with disease severity. The Cluster of Orthologous Groups of protein database, the KEGG Orthology database, and the carbohydrate-active enzymes of gene-category analysis showed that branched-chain amino acid–related proteins were significantly increased, and GH43 was significantly reduced in the PD group. Functional analysis of the metagenome confirmed differences in microbiome metabolism in the PD group related to short-chain fatty acid precursor metabolism.
Structural and Kinetic Insights Into the Molecular Basis of Salt Tolerance of the Short-Chain Glucose-6-Phosphate Dehydrogenase From Haloferax volcanii
Authors: Fuentes-Ugarte Nicolás , Herrera Sixto M. , Maturana Pablo , Castro-Fernandez Victor , Guixé Victoria
Published: September 2021

Halophilic enzymes need high salt concentrations for activity and stability and are considered a promising source for biotechnological applications. The model study for haloadaptation has been proteins from the Halobacteria class of Archaea, where common structural characteristics have been found. However, the effect of salt on enzyme function and conformational dynamics has been much less explored. Here we report the structural and kinetic characteristics of glucose-6-phosphate dehydrogenase from Haloferax volcanii (HvG6PDH) belonging to the short-chain dehydrogenases/reductases (SDR) superfamily. The enzyme was expressed in Escherichia coli and successfully solubilized and refolded from inclusion bodies. The enzyme is active in the presence of several salts, though the maximum activity is achieved in the presence of KCl, mainly by an increment in the kcat value, that correlates with a diminution of its flexibility according to molecular dynamics simulations. The high KM for glucose-6-phosphate and its promiscuous activity for glucose restrict the use of HvG6PDH as an auxiliary enzyme for the determination of halophilic glucokinase activity. Phylogenetic analysis indicates that SDR-G6PDH enzymes are exclusively present in Halobacteria, with HvG6PDH being the only enzyme characterized. Homology modeling and molecular dynamics simulations of HvG6PDH identified a conserved NLTX2H motif involved in glucose-6-phosphate interaction at high salt concentrations, whose residues could be crucial for substrate specificity. Structural differences in its conformational dynamics, potentially related to the haloadaptation strategy, were also determined.
Complete Genome Sequence of Weissella confusa LM1 and Comparative Genomic Analysis
Authors: Yuan Shenglei , Wang Yundan , Zhao Fangqing , Kang Le
Published: September 2021

The genus Weissella is attracting an increasing amount of attention because of its multiple functions and probiotic potential. In particular, the species Weissella confusa is known to have great potential in industrial applications and exhibits numerous biological functions. However, the knowledge on this bacterium in insects is not investigated. Here, we isolated and identified W. confusa as the dominant lactic acid bacteria in the gut of the migratory locust. We named this strain W. confusa LM1, which is the first genome of an insect-derived W. confusa strain with one complete chromosome and one complete plasmid. Among all W. confusa strains, W. confusa LM1 had the largest genome. Its genome was the closest to that of W. confusa 1001271B_151109_G12, a strain from human feces. Our results provided accurate evolutionary relationships of known Weissella species and W. confusa strains. Based on genomic analysis, the pan-genome of W. confusa is in an open state. Most strains of W. confusa had the unique genes, indicating that these strains can adapt to different ecological niches and organisms. However, the variation of strain-specific genes did represent significant correlations with their hosts and ecological niches. These strains were predicted to have low potential to produce secondary metabolites. Furthermore, no antibiotic resistance genes were identified. At the same time, virulence factors associated with toxin production and secretion system were not found, indicating that W. confusa strains were not sufficient to perform virulence. Our study facilitated the discovery of the functions of W. confusa LM1 in locust biology and their potential application to locust management.
Molecular Dissection of Pro-Fibrotic IL11 Signaling in Cardiac and Pulmonary Fibroblasts
Authors: Widjaja Anissa A. , Viswanathan Sivakumar , Jinrui Dong , Singh Brijesh K. , Tan Jessie , Wei Ting Joyce Goh , Lamb David , Shekeran Shamini G. , George Benjamin L. , Schafer Sebastian , Carling David , Adami Eleonora , Cook Stuart A.
Published: September 2021

In fibroblasts, TGFβ1 stimulates IL11 upregulation that leads to an autocrine loop of IL11-dependent pro-fibrotic protein translation. The signaling pathways downstream of IL11, which acts via IL6ST, are contentious with both STAT3 and ERK implicated. Here we dissect IL11 signaling in fibroblasts and study IL11-dependent protein synthesis pathways in the context of approved anti-fibrotic drug mechanisms of action. We show that IL11-induced ERK activation drives fibrogenesis and while STAT3 phosphorylation (pSTAT3) is also seen, this appears unrelated to fibroblast activation. Ironically, recombinant human IL11, which has been used extensively in mouse experiments to infer STAT3 activity downstream of IL11, increases pSTAT3 in Il11ra1 null mouse fibroblasts. Unexpectedly, inhibition of STAT3 was found to induce severe proteotoxic ER stress, generalized fibroblast dysfunction and cell death. In contrast, inhibition of ERK prevented fibroblast activation in the absence of ER stress. IL11 stimulated an axis of ERK/mTOR/P70RSK protein translation and its selectivity for Collagen 1 synthesis was ascribed to an EPRS-regulated, ribosome stalling mechanism. Surprisingly, the anti-fibrotic drug nintedanib caused dose-dependent ER stress and lesser pSTAT3 expression. Pirfenidone had no effect on ER stress whereas anti-IL11 specifically inhibited the ERK/mTOR axis while reducing ER stress. These studies define the translation-specific signaling pathways downstream of IL11, intersect immune and metabolic signaling and reveal unappreciated effects of nintedanib.
Development of α-Synuclein Real-Time Quaking-Induced Conversion as a Diagnostic Method for α-Synucleinopathies
Authors: Nakagaki Takehiro , Nishida Noriyuki , Satoh Katsuya
Published: September 2021

Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy are characterized by aggregation of abnormal α-synuclein (α-syn) and collectively referred to as α-synucleinopathy. Because these diseases have different prognoses and treatments, it is desirable to diagnose them early and accurately. However, it is difficult to accurately diagnose these diseases by clinical symptoms because symptoms such as muscle rigidity, postural dysreflexia, and dementia sometimes overlap among these diseases. The process of conformational conversion and aggregation of α-syn has been thought similar to that of abnormal prion proteins that cause prion diseases. In recent years,in vitroconversion methods, such as real-time quaking-induced conversion (RT-QuIC), have been developed. This method has succeeded in amplifying and detecting trace amounts of abnormal prion proteins in tissues and central spinal fluid of patients by inducing conversion of recombinant prion proteinsviashaking. Additionally, it has been used for antemortem diagnosis of prion diseases. Recently, aggregated α-syn has also been amplified and detected in patients by applying this method and many clinical studies have examined diagnosis using tissues or cerebral spinal fluid from patients. In this review, we discuss the utility and problems of α-syn RT-QuIC for antemortem diagnosis of α-synucleinopathies.
Individual Scores for Associative Learning in a Differential Appetitive Olfactory Paradigm Using Binary Logistic Regression Analysis
Authors: Borstel Kim J. , Stevenson Paul A.
Published: September 2021

Numerous invertebrates have contributed to our understanding of the biology of learning and memory. In most cases, learning performance is documented for groups of individuals, and nearly always based on a single, typically binary, behavioural metric for a conditioned response. This is unfortunate for several reasons. Foremost, it has become increasingly apparent that invertebrates exhibit inter-individual differences in many aspects of their behaviour, and also that the conditioned response probability for an animal group does not adequately represent the behaviour of individuals in classical conditioning. Furthermore, a binary response character cannot yield a graded score for each individual. We also hypothesise that due to the complexity of a conditioned response, a single metric need not reveal an individual's full learning potential. In this paper, we report individual learning scores for freely moving adult male crickets (Gryllus bimaculatus) based on a multi-factorial analysis of a conditioned response. First, in an absolute conditioning paradigm, we video-tracked the odour responses of animals that, in previous training, received either odour plus reward (sugar water), reward alone, or odour alone to identify behavioural predictors of a conditioned response. Measures of these predictors were then analysed using binary regression analysis to construct a variety of mathematical models that give a probability for each individual that it exhibited a conditioned response (Presp). Using standard procedures to compare model accuracy, we identified the strongest model which could reliably discriminate between the different odour responses. Finally, in a differential appetitive olfactory paradigm, we employed the model after training to calculate the Presp of animals to a conditioned, and to an unconditioned odour, and from the difference a learning index for each animal. Comparing the results from our multi-factor model with a single metric analysis (head bobbing in response to a conditioned odour), revealed advantageous aspects of the model. A broad distribution of model-learning scores, with modes at low and high values, support the notion of a high degree of variation in learning capacity, which we discuss.
Bone Marrow Mesenchymal Stem Cell-Derived Exosome-Educated Macrophages Promote Functional Healing After Spinal Cord Injury
Authors: Li Chengjun , Qin Tian , Zhao Jinyun , He Rundong , Wen Haicheng , Duan Chunyue , Lu Hongbin , Cao Yong , Hu Jianzhong
Published: September 2021

The spinal cord injury is a site of severe central nervous system (CNS) trauma and disease without an effective treatment strategy. Neurovascular injuries occur spontaneously following spinal cord injury (SCI), leading to irreversible loss of motor and sensory function. Bone marrow mesenchymal stem cell (BMSC)–derived exosome-educated macrophages (EEM) have great characteristics as therapeutic candidates for SCI treatment. It remains unknown whether EEM could promote functional healing after SCI. The effect of EEM on neurovascular regeneration after SCI needs to be further explored. We generated M2-like macrophages using exosomes isolated from BMSCs, which were known as EEM, and directly used these EEM for SCI treatment. We aimed to investigate the effects of EEM using a spinal cord contusive injury mouse modelin vivocombined with anin vitrocell functional assay and compared the results to those of a normal spinal cord without any biological intervention, or PBS treatment or macrophage alone (MQ). Neurological function measurements and histochemical tests were performed to evaluate the effect of EEM on angiogenesis and axon regrowth. In the current study, we found that treatment with EEM effectively promoted the angiogenic activity of HUVECs and axonal growth in cortical neurons. Furthermore, exogenous administration of EEM directly into the injured spinal cord could promote neurological functional healing by modulating angiogenesis and axon growth. EEM treatment could provide a novel strategy to promote healing after SCI and various other neurovascular injury disorders.
End-of-Life Care Decision-Making in Stroke
Authors: Gao Lucy , Zhao Charlie W. , Hwang David Y.
Published: September 2021

Stroke is one of the leading causes of death and long-term disability in the United States. Though advances in interventions have improved patient survival after stroke, prognostication of long-term functional outcomes remains challenging, thereby complicating discussions of treatment goals. Stroke patients who require intensive care unit care often do not have the capacity themselves to participate in decision making processes, a fact that further complicates potential end-of-life care discussions after the immediate post-stroke period. Establishing clear, consistent communication with surrogates through shared decision-making represents best practice, as these surrogates face decisions regarding artificial nutrition, tracheostomy, code status changes, and withdrawal or withholding of life-sustaining therapies. Throughout decision-making, clinicians must be aware of a myriad of factors affecting both provider recommendations and surrogate concerns, such as cognitive biases. While decision aids have the potential to better frame these conversations within intensive care units, aids specific to goals-of-care decisions for stroke patients are currently lacking. This mini review highlights the difficulties in decision-making for critically ill ischemic stroke and intracerebral hemorrhage patients, beginning with limitations in current validated clinical scales and clinician subjectivity in prognostication. We outline processes for identifying patient preferences when possible and make recommendations for collaborating closely with surrogate decision-makers on end-of-life care decisions.
Abdominal Acupuncture as an Adjunctive Therapy for the Recovery of Motor Function After Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Zhan Jie , Xiong Buhui , Zhang Peiming , Wang Yiqiao , Tang Yuyuan , Zhan Lechang , Lu Liming
Published: September 2021

Background:Bo's abdominal acupuncture (BAA) is a novel therapy in alternative and complementary medicine and has been frequently used for stroke recovery in recent decades. However, no systematic evidence has been performed to confirm the effect and safety of BAA as an adjunctive therapy for post-stroke motor dysfunction (PSMD).

Objectives:This review aimed to assess the efficacy and safety of BAA as an adjunctive therapy for improving allover motor function, upper limb motor function, lower limb motor function, and activities of daily living (ADL) in patients with PSMD.

Methods:Seven databases were searched from inception to December 2020: Embase, PubMed, Cochrane Library, Chinese Biological Medicine Database, Chinese Scientific Journal Database, WAN FANG, and the China National Knowledge Infrastructure. All randomized controlled trials (RCTs) involving BAA plus another therapy vs. the same other therapy alone were identified. The methodological quality of the included trials was assessed according to the Cochrane risk of bias criteria. If more than half of the domains in a study are at low risk of bias, the overall quality of the study is low risk. We conducted a meta-analysis for primary outcomes using a random effects model and performed a narrative summary for the secondary outcome. We also conducted subgroup analysis for primary outcomes based on different add-on treatments to BAA. Random effects and fixed effects models were used to test the robustness of the pooled data. We also tested the robustness of the meta-analysis using specific methodological variables that could affect primary outcome measures.

Results:Twenty-onetrials with 1,473 patients were included in this systematic review. The overall quality of the 14 included trials (66.7%) was low risk. Meta-analyses indicated that the effect of the BAA group was better than that of the non-EA group on the Fugl-Meyer Assessment Scale (FMA) (weight mean difference (WMD) 9.53, 95% confidence interval (CI) 7.23 to 11.83,P< 0.00001), FMA for upper extremities (WMD 11.08, 95% CI 5.83 to 16.32,P< 0.0001), FMA for lower extremities (WMD 5.57, 95% CI 2.61 to 8.54,P= 0.0002), and modified Barthel Index (standardized mean difference (SMD) 1.02, 95% CI 0.65 to 1.39,P< 0.00001). Two trials (9.5%) reported BAA-related adverse events, and the most common adverse event was local subcutaneous ecchymosis.

Conclusions:BAA as an adjunctive therapy may have clinical benefits for improving allover motor function, upper limb motor function, lower limb motor function, and ADL in patients with PSMD. BAA-related adverse events were rare, tolerable, and recoverable. However, our review findings should be interpreted with caution because of the methodological weaknesses in the included trials. High-quality trials are needed to assess the adjunctive role of BAA in patients with PSMD.
Inattention and Uncertainty in the Predictive Brain
Authors: Kujala Tuomo , Lappi Otto
Published: September 2021

Negative effects of inattention on task performance can be seen in many contexts of society and human behavior, such as traffic, work, and sports. In traffic, inattention is one of the most frequently cited causal factors in accidents. In order to identify inattention and mitigate its negative effects, there is a need for quantifying attentional demands of dynamic tasks, with a credible basis in cognitive modeling and neuroscience. Recent developments in cognitive science have led to theories of cognition suggesting that brains are an advanced prediction engine. The function of this prediction engine is to support perception and action by continuously matching incoming sensory input with top-down predictions of the input, generated by hierarchical models of the statistical regularities and causal relationships in the world. Based on the capacity of this predictive processing framework to explain various mental phenomena and neural data, we suggest it also provides a plausible theoretical and neural basis for modeling attentional demand and attentional capacity “in the wild” in terms of uncertainty and prediction error. We outline a predictive processing approach to the study of attentional demand and inattention in driving, based on neurologically-inspired theories of uncertainty processing and experimental research combining brain imaging, visual occlusion and computational modeling. A proper understanding of uncertainty processing would enable comparison of driver's uncertainty to a normative level of appropriate uncertainty, and thereby improve definition and detection of inattentive driving. This is the necessary first step toward applications such as attention monitoring systems for conventional and semi-automated driving.
Off-Label Use of Thrombopoietin Receptor Agonists: Case Series and Review of the Literature
Authors: Capecchi Marco , Serpenti Fabio , Giannotta Juri , Pettine Loredana , Reda Gianluigi , Martinelli Ida , Artoni Andrea , Barcellini Wilma , Fattizzo Bruno
Published: September 2021

Since their license in 2008, studies on thrombopoietin receptor agonists (TPO-RAs) are proceeding at a fast pace. Their favorable efficacy and safety profile makes them good candidates for the management of thrombocytopenia in different settings, even beyond their current indications. In the last 10 years, we faced patients with refractory thrombocytopenia that required treatment with off-label TPO-RA, despite the paucity of data in the literature and the possible risks, particularly that of thrombosis. We hereby report our 10-year real-life single-center experience of TPO-RA used off-label. Fourteen patients were divided into three groups according to the etiology of thrombocytopenia: myelodysplastic syndromes, post-transplantation, and lymphoproliferative diseases. Clinical features and results are reported within each group. Overall, TPO-RA proved effective in all these conditions achieving responses also in heavily pretreated patients. The overall response rate (ORR) was 100% in patients with thrombocytopenia after transplantation and in those with lymphoproliferative diseases and 75% in patients with myelodysplastic syndromes. The median duration of therapy was 285 days (range 93–1,513 days). Four patients (29%) discontinued treatment because of lack of response (n=2) or a sustained response (n=2). No grade 3–4 adverse events occurred, particularly no thrombosis. In our real-life experience, TPO-RAs were effective and safe and proved of value in the challenging management of patients with refractory thrombocytopenia associated with different conditions.
LncRNA SLCO4A1-AS1 Accelerates Growth and Metastasis of Gastric Cancer via Regulation of the miR-149/XIAP Axis
Authors: Fang Yantian , Sun Bo , Gao Jianpeng , Huang Yakai , Wang Chenchen
Published: September 2021

Objective

Recently, long noncoding RNA SLCO4A1 antisense RNA 1 (SLCO4A1-AS1) has been shown to act as an oncogene in several cancer types; however, its role in gastric cancer (GC) and its underlying molecular mechanisms are yet to be elucidated.

Methods

Using the ENCORI database, we identified SLCO4A1-AS1, miR-149-5p (miR-149), and the X-linked inhibitor of apoptosis (XIAP) whose expressions were obviously changed in GC samples, and analyzed the correlation between their expressions in GC samples. Moreover, we explored the expression of SLCO4A1-AS1, miR-149, and XIAP in clinical samples and GC cell lines using RT-qPCR and western blotting assay; the correlation between them was analyzed using RNA immunoprecipitation and dual-luciferase reporter. CCK-8, colony formation, and Transwell assays were conducted to determine the effects of SLCO4A1-AS1, miR-149, and XIAP expression on cell proliferation, migration, and invasion, respectively. A nude mouse xenograft model was used to explore their function in xenograft growth.

Results

SLCO4A1-AS1 was significantly upregulated in the GC samples and cell lines, and a high level of SLCO4A1-AS1 was associated with an advanced tumor stage and shortened patient survival. Mechanistically, SLCO4A1-AS1 post-transcriptionally regulated XIAP by functioning as competing endogenous RNA in GC to sponge miR-149. Further functional assays revealed that the overexpression of miR-149 and knockdown of XIAP considerably inhibited GC cell viability and its migratory and invasive characteristics in vitro. SLCO4A1-AS1 knockdown also determined the function of GC cells but was diminished by the miR-149 inhibitor in vitro. Finally, we demonstrated that the deletion of SLCO4A1-AS1 suppressed tumor growth and metastasis in vivo.

Conclusions

Altogether, these findings suggest that SLCO4A1-AS1 functions as a crucial oncogenic lncRNA in GC and it can facilitate GC tumor growth and metastasis by interacting with miR-149 and enhancing XIAP expression. Therefore, SLCO4A1-AS1 is a potential novel therapeutic target in GC treatment.
Resistance to Hypomethylating Agents in Myelodysplastic Syndrome and Acute Myeloid Leukemia From Clinical Data and Molecular Mechanism
Authors: Zhao Guangjie , Wang Qian , Li Shuang , Wang Xiaoqin
Published: September 2021

The nucleoside analogs decitabine (5-AZA-dC) and azacitidine (5-AZA) have been developed as targeted therapies to reverse DNA methylation in different cancer types, and they significantly improve the survival of patients who are not suitable for traditional intensive chemotherapies or other treatment regimens. However, approximately 50% of patients have a response to hypomethylating agents (HMAs), and many patients have no response originally or in the process of treatment. Even though new combination regimens have been tested to overcome the resistance to 5-AZA-dC or 5-AZA, only a small proportion of patients benefited from these strategies, and the outcome was very poor. However, the mechanisms of the resistance remain unknown. Some studies only partially described management after failure and the mechanisms of resistance. Herein, we will review the clinical and molecular signatures of the HMA response, alternative treatment after failure, and the causes of resistance in hematological malignancies.
TNFα Signaling Is Increased in Progressing Oral Potentially Malignant Disorders and Regulates Malignant Transformation in an Oral Carcinogenesis Model
Authors: Chadwick Jeffrey W. , Macdonald Rachel , Ali Aiman A. , Glogauer Michael , Magalhaes Marco A.
Published: September 2021

Oral carcinogenesis represents a multi-stage process which encompasses several genetic and molecular changes that promote the progression of oral potentially malignant disorders (OPMDs) to oral squamous cell carcinomas (OSCCs). A better understanding of critical pathways governing the progression of OMPDs to OSCCs is critical to improve oncologic outcomes in the future. Previous studies have identified an important role of tumor necrosis factor α (TNFα) and TNF receptor 1 (TNFR1) in the invasiveness of oral cancer cell lines. Here, we investigate the expression of TNFα and TNFR1 in human OPMDs that progress to OSCC compared to non-progressing OPMDs utilizing fluorescent immunohistochemistry (FIHC) to show increased TNFα/TNFR1 expression in progressing OPMDs. In order to interrogate the TNFα/TNFR1 signaling pathway, we utilized a 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis to demonstrate that TNFα/TNFR1 expression is upregulated in 4-NQO-induced OSCCs. TNFα neutralization decreased serum cytokines, inhibited the development of invasive lesions and reduced tumor-associated neutrophils in vivo. Combined, this data supports the role of TNFα in oral malignant transformation, suggesting that critical immunoregulatory events occur downstream of TNFR1 leading to malignant transformation. Our results advance the understanding of the mechanisms governing OSCC invasion and may serve as a basis for alternative diagnostic and therapeutic approaches to OPMDs and OSCC management.
Smoking, DNA Methylation, and Breast Cancer: A Mendelian Randomization Study
Authors: Tang Haibo , Yang Desong , Han Chaofei , Mu Ping
Published: September 2021

Background

Smoking was strongly associated with breast cancer in previous studies. Whether smoking promotes breast cancer through DNA methylation remains unknown.

Methods

Two-sample Mendelian randomization (MR) analyses were conducted to assess the causal effect of smoking-related DNA methylation on breast cancer risk. We used 436 smoking-related CpG sites extracted from 846 middle-aged women in the ARIES project as exposure data. We collected summary data of breast cancer from one of the largest meta-analyses, including 69,501 cases for ER+ breast cancer and 21,468 cases for ER− breast cancer. A total of 485 single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for smoking-related DNA methylation. We further performed an MR Steiger test to estimate the likely direction of causal estimate between DNA methylation and breast cancer. We also conducted colocalization analysis to evaluate whether smoking-related CpG sites shared a common genetic causal SNP with breast cancer in a given region.

Results

We established four significant associations after multiple testing correction: the CpG sites of cg2583948 [OR = 0.94, 95% CI (0.91–0.97)], cg0760265 [OR = 1.07, 95% CI (1.03–1.11)], cg0420946 [OR = 0.95, 95% CI (0.93–0.98)], and cg2037583 [OR =1.09, 95% CI (1.04–1.15)] were associated with the risk of ER+ breast cancer. All the four smoking-related CpG sites had a larger variance than that in ER+ breast cancer (all p < 1.83 × 10−11) in the MR Steiger test. Further colocalization analysis showed that there was strong evidence (based on PPH4 > 0.8) supporting a common genetic causal SNP between the CpG site of cg2583948 [with IMP3 expression (PPH4 = 0.958)] and ER+ breast cancer. There were no causal associations between smoking-related DNA methylation and ER− breast cancer.

Conclusions

These findings highlight potential targets for the prevention of ER+ breast cancer. Tissue-specific epigenetic data are required to confirm these results.
A Tumor-Infiltration CD8+ T Cell-Based Gene Signature for Facilitating the Prognosis and Estimation of Immunization Responses in HPV+ Head and Neck Squamous Cell Cancer
Authors: Wu Yingning , Meng Lingzhang , Cai Kai , Zhao Jingjie , He Siyuan , Shen Jiajia , Wei Qiuju , Wang Zechen , Sooranna Suren , Li Hengguo , Song Jian
Published: September 2021

Background

CD8+ T cells, which play a vital role in response to adaptive immunity, are closely related to the immunization responses to kill tumor cells. Understanding the effects exerted by tumor-infiltrated CD8+ T cells in HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) patients is critical for predicting their prognosis as well as their responses towards immunization-related therapy.

Materials and Methods

HNSCC single cell transcriptome was used to screen for differentially expressed genes (DEGs) based on CD8+ T cells. A gene signature associated with CD8+ T cells was built and verified with the cancer genome atlas dataset with a view to predicting the prognosis of HNSCC patients. Risk scores were calculated for HNSCC cases and categorized into either high- or low-risk cohorts. The prognosis-correlated data of the risk scores were analyzed by using Kaplan-Meier survival curves and multi-variate Cox regression plots. In addition, the possibility of using the genetic profiles to predict responses toward immunization-related therapy was explored.

Results

From the DEGs screened from the sequencing of single-cell RNA, a gene signature of 4 genes (ACAP1, ANKRD28, C12orf75, and M6PR) were identified. It was seen that these genes could predict overall survival in HPV+ HNSCC patients. In addition, high- and low-risk HPV+ HNSCC patients showed marked differences in their CD8+ T-cell infiltration due to immunization when clinical characteristics were taken into consideration. This correlated with their immunization therapy responses.

Conclusions

Our work provides insights into explaining the restricted responses of current immunization checkpoint inhibiting substances in HPV+ HNSCC patients. A novel genetic signature to predict the prognosis and immunization-correlated therapeutic responses is presented. This will provide potential new therapeutic opportunities for HPV+ HNSCC patients.
Epidemiology, Clinical Features and Prognostic Factors of Pediatric SARS-CoV-2 Infection: Results From an Italian Multicenter Study
Authors: Garazzino Silvia , Lo Vecchio Andrea , Pierantoni Luca , Calò Carducci Francesca Ippolita , Marchetti Federico , Meini Antonella , Castagnola Elio , Vergine Gianluca , Donà Daniele , Bosis Samantha , Dodi Icilio , Venturini Elisabetta , Felici Enrico , Giacchero Roberta , Denina Marco , Pierri Luca , Nicolini Giangiacomo , Montagnani Carlotta , Krzysztofiak Andrzej , Bianchini Sonia , Marabotto Caterina , Tovo Pier-Angelo , Pruccoli Giulia , Lanari Marcello , Villani Alberto , Castelli Gattinara Guido ,   The Italian SITIP-SIP Pediatric Infection Study Group
Published: September 2021

Background: Many aspects of SARS-CoV-2 infection in children and adolescents remain unclear and optimal treatment is debated. The objective of our study was to investigate epidemiological, clinical and therapeutic characteristics of pediatric SARS-CoV-2 infection, focusing on risk factors for complicated and critical disease.

Methods: The present multicenter Italian study was promoted by the Italian Society of Pediatric Infectious Diseases, involving both pediatric hospitals and general pediatricians/family doctors. All subjects under 18 years of age with documented SARS-CoV-2 infection and referred to the coordinating center were enrolled from March 2020.

Results: As of 15 September 2020, 759 children were enrolled (median age 7.2 years, IQR 1.4; 12.4). Among the 688 symptomatic children, fever was the most common symptom (81.9%). Barely 47% of children were hospitalized for COVID-19. Age was inversely related to hospital admission (p < 0.01) and linearly to length of stay (p = 0.014). One hundred forty-nine children (19.6%) developed complications. Comorbidities were risk factors for complications (p < 0.001). Viral coinfections, underlying clinical conditions, age 5–9 years and lymphopenia were statistically related to ICU admission (p < 0.05).

Conclusions: Complications of COVID-19 in children are related to comorbidities and increase with age. Viral co-infections are additional risk factors for disease progression and multisystem inflammatory syndrome temporarily related to COVID-19 (MIS-C) for ICU admission.
Impact of Home Parenting Environment on Cognitive and Psychomotor Development in Children Under 5 Years Old: A Meta-Analysis
Authors: Yang Qing , Yang Jinlian , Zheng Liming , Song Wei , Yi Lilan
Published: September 2021

This study aims to evaluate the relationship between home parenting environment and the cognitive and psychomotor development in children under 5 years old by using meta-analysis. A systematic search of the Chinese and English databases including Pubmed, Embase, the Cochrane Library, CNKI, Weipu, Wanfang, and CBMdisc databases from January 1, 1990, to July 31, 2021, was performed. Articles concerning the relationship between home parenting environment and the cognitive and psychomotor development in children under 5 years old were included. Review Manager 5.4 was used for meta-analysis. Subgroup analysis in terms of age and region were performed. A total of 12 articles were included, including 11 in English and 1 in Chinese. Meta-analysis showed that there was significant relationship between home parenting environment and the cognitive and psychomotor development of children (r = 0.31; r = 0.21). Subgroup analysis showed that correlation between home parenting environment and the cognitive and psychomotor development of children was stronger in children over 18 months compared to those under 17 months [(r = 0.33, r = 0.21) vs. (r = 0.28, r = 0.17)]. The converted summary r value between home parenting environment and cognitive development in developing and developed countries was both 0.32. Conclusively, there is a positive correlation between the home parenting environment and the cognitive and psychomotor development of children under 5 years old. Improving the home parenting environment of children is beneficial to promote their early development.
Study of the Etiology of Acute Respiratory Infections in Children Under 5 Years at the Dr. Agostinho Neto Hospital, Praia, Santiago Island, Cabo Verde
Authors: Correia Wilson , Dorta-Guerra Roberto , Sanches Mitza , Almeida Semedo Carmen de Jesús Borges , Valladares Basilio , de Pina-Araújo Isabel Inês M. , Carmelo Emma
Published: September 2021

Background: Acute respiratory infections are one of the major causes of morbidity and mortality in children under 5 years in developing countries and are a challenge for the health system of these countries. In Cabo Verde, despite the lack of recent studies, data indicate that it affects thousands of children, being the fourth leading cause of infant mortality in 2013. The aim of this study was to identify and describe the etiological agents associated with acute respiratory tract infections in children under 5 years old, and their associated risk factors, such as clinical symptoms or socio-demographic characteristics.

Methods: Naso-pharyngeal samples were collected from children under 5 years attending at Dr. Agostinho Neto Hospital (Praia, Santiago Island, Cabo Verde) with suspected ARI at different time-points during 2019. Samples were analyzed using FilmArray® Respiratory Panel v. 2.0 Plus to identify etiological agents of ARI. A questionnaire with socio-demographic information was also collected for each participant. Data analyses were carried out using the IBM SPSS version 25 (IBM Corporation, Armonk, NY) and R 3.5.1 statistical software.

Results: A total of 129 naso-pharyngeal samples were included in the study. Seventeen different etiologic agents of respiratory infections were identified. HRV/EV was the most frequent agent detected, followed by FluA H3 and RSV. Coinfection with two or more pathogens was detected in up to 20% of positive samples. The results were analyzed in terms of age-group, sex, period of the year and other social and demographic factors.

Conclusion: Viruses are the main causative agents of ARI in children <5 years attending at the pediatrics service at the Dr. Agostinho Neto Hospital in Praia city, Santiago Island, Cabo Verde. Some factors are described in this study as statistically associated with the presence of an infectious agent, such as having one or more children sharing the bedroom with an adult and the presence of some clinical symptoms. The data addresses the need for studies on respiratory tract infections in Cabo Verde.
Neurodevelopmental Outcomes of Infants Younger Than 90 Days Old Following Enterovirus and Parechovirus Infections of the Central Nervous System
Authors: de Ceano-Vivas María , García M. Luz , Velázquez Ana , Martín del Valle Fernando , Menasalvas Ana , Cilla Amaia , Epalza Cristina , Romero M. Pilar , Cabrerizo María , Calvo Cristina
Published: September 2021

Enteroviruses (EVs) and human parechoviruses (HPeVs) are a major cause of central nervous system (CNS) infection in young infants. They have been implicated in neurodevelopmental delay, however limited data are available. The aim of this study is to describe the clinical outcome of young infants and to assess and compare the medium-term neurodevelopment following CNS infections caused by EV and HPeV. A multicentre observational ambispective study was conducted between May 2013 and March 2018. Children under 3 months of age with EV or HPeV CNS infection excluding encephalitis were included. Infants were contacted 1 year after the acute infection and their neurological development was evaluated using the Ages and Stages Questionnaire-3 (ASQ-3). If any area assessed was abnormal during the first round of tests, a second round was completed 6 to 12 months later. Forty-eight young infants with EV and HPeV CNS infection were identified: 33 (68.8%) were positive for EV and 15 (31.3%) for HPeV. At first assessment 14 out of 29 EV (48.3%) and 3 out of 15 HPeV (20%) positive cases presented some developmental concern in the ASQ-3 test. EV-positive infants showed mild and moderate alteration in all domains analyzed and HPeV-positive infants showed mild alterations only in gross and fine motor domains. Significant alterations in communication were observed in EV-positive but not in HPeV-positive infants (31 vs. 0%,p= 0.016). At second assessment 4 out of 13 EV-positive patients (30.8%) showed mild to moderate concerns in communication and gross motor function domains and 3 out of 13 (23.1%) showed significant concern in fine motor function. Although CNS infections without associated encephalitis are generally assumed to be benign our study shows that at a median age of 18 months almost half of the EV-infected infants (48.3%) and 20% of HPeV-positive infants presented some developmental concern in the ASQ-3 test. We recommend monitor the neurological development of infants during the first years of life after HPeV CNS infection and especially after EV CNS infection, even in mild cases, for an early intervention and stimulation of psychomotor development if necessary.
An Advanced Automated Patch Clamp Protocol Design to Investigate Drug—Ion Channel Binding Dynamics
Authors: Lukacs Peter , Pesti Krisztina , Földi Mátyás C. , Zboray Katalin , Toth Adam V. , Papp Gábor , Mike Arpad
Published: September 2021

Standard high throughput screening projects using automated patch-clamp instruments often fail to grasp essential details of the mechanism of action, such as binding/unbinding dynamics and modulation of gating. In this study, we aim to demonstrate that depth of analysis can be combined with acceptable throughput on such instruments. Using the microfluidics-based automated patch clamp, IonFlux Mercury, we developed a method for a rapid assessment of the mechanism of action of sodium channel inhibitors, including their state-dependent association and dissociation kinetics. The method is based on a complex voltage protocol, which is repeated at 1 Hz. Using this time resolution we could monitor the onset and offset of both channel block and modulation of gating upon drug perfusion and washout. Our results show that the onset and the offset of drug effects are complex processes, involving several steps, which may occur on different time scales. We could identify distinct sub-processes on the millisecond time scale, as well as on the second time scale. Automated analysis of the results allows collection of detailed information regarding the mechanism of action of individual compounds, which may help the assessment of therapeutic potential for hyperexcitability-related disorders, such as epilepsies, pain syndromes, neuromuscular disorders, or neurodegenerative diseases.
Normalized Shear Modulus and Damping Ratio of Soil–Rock Mixtures With Different Volumetric Block Proportions
Authors: Wang Shengnian , Gao Xinqun , Hui Honglei , Ma Wei , Shi Chong , Zhang Peng
Published: September 2021

The volume fraction of rock blocks plays a particularly significant role in static/dynamic shear behaviors of soil–rock mixtures (SRM). Large-scale cyclic triaxial tests for SRM with different volumetric block proportions (VBPs) were performed at different confining pressures to investigate the reduction of dynamic shear modulus (G) and the increase of damping ratio (λ). Results indicate that VBP has a significant effect on the dynamic behaviors of SRM. The higher VBP is more likely to result in a gentler reduction of G and a faster increase of λ. The variations of dynamic shear modulus ratio (G/G0) and normalized damping ratio (λnor) fall within relatively narrow bands but are very different with gravelly soils and sands due to VBP with particle size larger than 2 mm. The G/G0 and λnor can be characterized by empirical functions about normalized shear strain amplitude (γnor).