bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness and Safety of DOACs vs. VKAs in AF Patients With Cancer: Evidence From Randomized Clinical Trials and Observational Studies
Authors: Liu Fuwei , Xu Zixuan , Luo Jun , Yu Peng , Ma Jianyong , Yuan Ping , Zhu Wengen
Published: November 2021

Background: The use of direct oral anticoagulants (DOACs) is recommended as the preferred treatment drug in patients with nonvalvular atrial fibrillation (AF). However, the effectiveness and safety of DOACs compared with vitamin K antagonists (VKAs) in patients with cancer and AF are still controversial. Therefore, we performed a meta-analysis regarding the effectiveness and safety of DOACs vs. VKAs in AF patients with cancer.

Methods: A search of the Pubmed and EMBASE databases until August 2021 was performed. Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model with an inverse variance method.

Results: Thirteen studies were deemed to meet the criteria. For the effectiveness outcomes, the use of DOACs compared with VKAs use was significantly associated with decreased risks of stroke or systemic embolism (RR = 0.66, 95% CI: 0.54–0.80) and venous thromboembolism (RR = 0.40, 95% CI: 0.26–0.61), but not ischemic stroke (RR = 0.79, 95% CI: 0.56–1.11), myocardial infarction (RR = 0.78, 95% CI: 0.56–1.11), cardiovascular death (RR = 0.76, 95% CI: 0.53–1.09), and all-cause death (RR = 0.82, 95% CI: 0.43–1.56). For the safety outcomes, compared with VKAs use, the use of DOACs was associated with reduced risks of intracranial bleeding (RR = 0.60, 95% CI: 0.50–0.71) and gastrointestinal bleeding (RR = 0.87, 95% CI: 0.80–0.95). There were no significant differences in major bleeding (RR = 0.87, 95% CI: 0.74–1.04), major or nonmajor clinically relevant bleeding (RR = 0.87, 95% CI: 0.74–1.01), and any bleeding (RR = 0.88, 95% CI: 0.76–1.03).

Conclusion: Compared with VKAs, DOACs appeared to have significant reductions in stroke or systemic embolism, venous thromboembolism, intracranial bleeding, and gastrointestinal bleeding, but comparable risks of ischemic stroke, myocardial infarction, cardiovascular death, all-cause death, major bleeding, major or nonmajor clinically relevant bleeding, and any bleeding in patients with AF and cancer.
Transcatheter Aortic Valve Implantation in Sievers Type 0 vs. Type 1 Bicuspid Aortic Valve Morphology: Systematic Review and Meta-Analysis
Authors: Du Yu , Wang Zhijian , Liu Wei , Guo Yonghe , Han Wei , Shen Hua , Jia Shuo , Yu Yi , Han Kangning , Shi Dongmei , Zhao Yingxin , Zhou Yujie
Published: November 2021

Background:Transcatheter aortic valve implantation (TAVI) has achieved satisfactory outcomes in the selected patients with bicuspid aortic valve (BAV), predominately type 1 BAV (~90%). However, there are few reports about the safety and efficacy of TAVI in type 0 BAV. Therefore, in the current study, we aimed to compare procedural and 30-day outcomes after TAVI between type 0 and type 1 BAV.

Methods:Studies comparing the outcomes of TAVI in Sievers type 0 vs. type 1 BAV were retrieved from PubMed, EMBASE, Cochrane Library, and Web of Science from inception to May 2021. The data were extracted regarding the study characteristics and outcomes. The odds ratios (ORs) with 95% CIs were pooled for procedural and 30-day outcomes.

Results:Six observational studies were included with determined type 0 BAV in 226 patients and type 1 BAV in 902 patients. The patients with type 0 BAV were slightly younger, had larger supra-annular structure, and more frequently implanted self-expanding prosthesis compared with type 1 BAV. In the pooled analyses, the patients with type 0 BAV had a similar incidence of procedural death (OR = 2.6, 95% CI 0.7–10.3), device success (OR = 0.6; 95% CI 0.3–1.3), and ≥ mild (OR = 0.8; 95% CI 0.4–1.6) or moderate (OR = 0.9, 95% CI 0.4–1.8) paravalvular leak, whereas significantly higher mean aortic gradient (mean difference = 1.4 mmHg, 95% CI 0.03–2.7) and increased coronary compromise risk (OR = 7.2; 95% CI 1.5–34.9), compared with type 1 BAV. Meanwhile, the incidence of death (OR = 1.2; 95% CI 0.5–3.1), stroke (OR = 0.5; 95% CI 0.1–2.4), and new pacemaker (OR = 0.6; 95% CI 0.2–2.2) at 30 days were not significantly different between the BAV morphologies (p> 0.05). The treatment effect heterogeneity across the studies for the above outcomes were low.

Conclusions:The patients with type 0 BAV appear to have similar short-term outcomes after TAVI compared with type 1 BAV. Whereas, TAVI for type 0 BAV aortic stenosis might lead to an elevated coronary obstruction risk and suboptimal aortic valvular hemodynamics.
Non-Conventional Clinical Uses of TSH Receptor Antibodies: The Case of Chronic Autoimmune Thyroiditis
Authors: Napolitano Giorgio , Bucci Ines , Di Dalmazi Giulia , Giuliani Cesidio
Published: November 2021

Anti TSH receptor antibodies (TSHrAb) are a family of antibodies with different activity, some of them stimulating thyroid function (TSAb), others with blocking properties (TBAb), it is a common finding that antibodies with different function might coexist in the same patient and can modulate the function of the thyroid. However, most of the labs routinely detect all antibodies binding to the TSH receptor (TRAb, i.e. TSH-receptor antibodies detected by binding assay without definition of functional property). Classical use of TSHr-Ab assay is in Graves’ disease where they are tested for diagnostic and prognostic issues; however, they can be used in specific settings of chronic autoimmune thyroiditis (CAT) as well. Aim of the present paper is to highlight these conditions where detection of TSHr-Ab can be of clinical relevance. Prevalence of TSHrAb is different in in the 2 main form of CAT, i.e. classical Hashimoto’s thyroiditis and in atrophic thyroiditis, where TBAb play a major role. Simultaneous presence of both TSAb and TBAb in the serum of the same patient might have clinical implication and cause the shift from hyperthyroidism to hypothyroidism and vice versa. Evaluation of TRAb is recommended in case of patients with Thyroid Associated Orbitopathy not associated with hyperthyroidism. At present, however, the most relevant recommendation for the use of TRAb assay is in patients with CAT secondary to a known agent; in particular, after treatment with alemtuzumab for multiple sclerosis. In conclusion, the routine use of anti-TSH receptor antibodies (either TRAb or TSAb/TBAb) assay cannot be suggested at the present for diagnosis/follow up of patients affected by CAT; there are, however, several conditions where their detection can be clinically relevant.
Symbiosis in Digital Evolution: Past, Present, and Future
Authors: Vostinar Anya E. , Skocelas Katherine G. , Lalejini Alexander , Zaman Luis
Published: November 2021

Symbiosis, the living together of unlike organisms as symbionts, is ubiquitous in the natural world. Symbioses occur within and across all scales of life, from microbial to macro-faunal systems. Further, the interactions between symbionts are multimodal in both strength and type, can span from parasitic to mutualistic within one partnership, and persist over generations. Studying the ecological and evolutionary dynamics of symbiosis in natural or laboratory systems poses a wide range of challenges, including the long time scales at which symbioses evolvede novo, the limited capacity to experimentally control symbiotic interactions, the weak resolution at which we can quantify interactions, and the idiosyncrasies of current model systems. These issues are especially challenging when seeking to understand the ecological effects and evolutionary pressures on and of a symbiosis, such as how a symbiosis may shift between parasitic and mutualistic modes and how that shift impacts the dynamics of the partner population. In digital evolution, populations of computational organisms compete, mutate, and evolve in a virtual environment. Digital evolution features perfect data tracking and allows for experimental manipulations that are impractical or impossible in natural systems. Furthermore, modern computational power allows experimenters to observe thousands of generations of evolution in minutes (as opposed to several months or years), which greatly expands the range of possible studies. As such, digital evolution is poised to become a keystone technique in our methodological repertoire for studying the ecological and evolutionary dynamics of symbioses. Here, we review how digital evolution has been used to study symbiosis, and we propose a series of open questions that digital evolution is well-positioned to answer.
Ten Reasons Why People With Down Syndrome are Protected From the Development of Most Solid Tumors -A Review
Authors: Osuna-Marco Marta Pilar , López-Barahona Mónica , López-Ibor Blanca , Tejera Águeda Mercedes
Published: November 2021

People with Down syndrome have unique characteristics as a result of the presence of an extra chromosome 21. Regarding cancer, they present a unique pattern of tumors, which has not been fully explained to date. Globally, people with Down syndrome have a similar lifetime risk of developing cancer compared to the general population. However, they have a very increased risk of developing certain tumors (e.g., acute leukemia, germ cell tumors, testicular tumors and retinoblastoma) and, on the contrary, there are some other tumors which appear only exceptionally in this syndrome (e.g., breast cancer, prostate cancer, medulloblastoma, neuroblastoma and Wilms tumor). Various hypotheses have been developed to explain this situation. The genetic imbalance secondary to the presence of an extra chromosome 21 has molecular consequences at several levels, not only in chromosome 21 but also throughout the genome. In this review, we discuss the different proposed mechanisms that protect individuals with trisomy 21 from developing solid tumors: genetic dosage effect, tumor suppressor genes overexpression, disturbed metabolism, impaired neurogenesis and angiogenesis, increased apoptosis, immune system dysregulation, epigenetic aberrations and the effect of different microRNAs, among others. More research into the molecular pathways involved in this unique pattern of malignancies is still needed.
Immunotherapy With Recombinant Alt a 1 Suppresses Allergic Asthma and Influences T Follicular Cells and Regulatory B Cells in Mice
Authors: Liu Juan , Yin Jia
Published: November 2021

Background

Alternaria is a major source of asthma-inducing allergens. Allergen-specific immunotherapy improves the progression of allergic asthma. The current treatment is based on crude Alternaria extracts. Alt a 1 is the predominant allergen in Alternaria. However, the treatment efficacy of recombinant Alt a 1 (rAlt a 1) in an asthmatic animal model and its influence on Tfh and Breg cells are unknown.

Objective

To explore the therapeutic treatment effects of rAlt a 1 on the progress of an asthmatic mouse model and its effect on Tfh and Breg cells.

Methods

We synthesized and purified rAlt a 1. Alternaria-sensitized and challenged mice received subcutaneous immunotherapy (SCIT) with four different rAlt a 1 dosages (5, 50, 100, and 150 µg) or PBS only. Finally, lung and airway inflammation, mouse mast cell protease 1 (MMCP-1), serum immunoglobulin responses, Tfh and Breg cell levels, and the correlation between asthmatic features (inflammation grades and IL-4 and IL-10 levels) and these two cell types were measured after Alternaria rechallenge.

Results

High purity and allergenic potency of rAlt a 1 protein were obtained. Following treatment with four different rAlt a 1 dosages, both lung and airway inflammation ameliorated, including lung pathology, serum MMCP-1 levels, inflammatory cell numbers, and cytokine levels in bronchoalveolar lavage fluid (BALF). Additionally, rAlt a 1-SCIT increased the expression of Alternaria-sIgG1, rAlt a 1-sIgG1, rAlt a 1-sIgG2a, and rAlt a 1-sIgG2b in serum. Moreover, the number and percentage of CXCR5+PD-1+Tfh cells were increased in the PC control, while they decreased in the rAlt a 1-SCIT groups. Meanwhile, the absolute numbers and proportions of Breg cells were evaluated after administration of rAlt a 1. A positive correlation was observed between CXCR5+PD-1+Tfh cells and inflammation grades (r = 0.50, p = 0.01), as well as a slightly strong positive relationship with IL-4 (r = 0.55, p = 0.005) and IL-10 (r = 0.58, p = 0.003) levels; Breg cells showed an opposite correlation with the grades of inflammation (r = -0.68, p = 0.0003), along with a negative correlation to IL-4 (r = -0.61, p = 0.001) and IL-10 (r = -0.53, p = 0.008) levels.

Conclusions

We verified that treatment with rAlt a 1 can alleviate asthma progression and further have a regulatory effect on Tfh and Breg cells in an Alternaria-induced asthmatic mouse model.
Tissue Specific Transcriptome Changes Upon Influenza A Virus Replication in the Duck
Authors: Campbell Lee K. , Fleming-Canepa Ximena , Webster Robert G. , Magor Katharine E.
Published: November 2021

Ducks are the natural host and reservoir of influenza A virus (IAV), and as such are permissive to viral replication while being unharmed by most strains. It is not known which mechanisms of viral control are globally regulated during infection, and which are specific to tissues during infection. Here we compare transcript expression from tissues from Pekin ducks infected with a recombinant H5N1 strain A/Vietnam 1203/04 (VN1203) or an H5N2 strain A/British Columbia 500/05 using RNA-sequencing analysis and aligning reads to the NCBI assembly ZJU1.0 of the domestic duck (Anas platyrhynchos) genome. Highly pathogenic VN1203 replicated in lungs and showed systemic dissemination, while BC500, like most low pathogenic strains, replicated in the intestines. VN1203 infection induced robust differential expression of genes all three days post infection, while BC500 induced the greatest number of differentially expressed genes on day 2 post infection. While there were many genes globally upregulated in response to either VN1203 or BC500, tissue specific gene expression differences were observed. Lungs of ducks infected with VN1203 and intestines of birds infected with BC500, tissues important in influenza replication, showed highest upregulation of pattern recognition receptors and interferon stimulated genes early in the response. These tissues also appear to have specific downregulation of inflammatory components, with downregulation of distinct sets of proinflammatory cytokines in lung, and downregulation of key components of leukocyte recruitment and complement pathways in intestine. Our results suggest that global and tissue specific regulation patterns help the duck control viral replication as well as limit some inflammatory responses in tissues involved in replication to avoid damage.
Biomass Mapping for an Improved Understanding of the Contribution of Cold-Water Coral Carbonate Mounds to C and N Cycling
Authors: De Clippele Laurence Helene , van der Kaaden Anna-Selma , Maier Sandra Rosa , de Froe Evert , Roberts J. Murray
Published: November 2021

This study used a novel approach combining biological, environmental, and ecosystem function data of the Logachev cold-water coral carbonate mound province to predictively map coral framework (bio)mass. A more accurate representation and quantification of cold-water coral reef ecosystem functions such as Carbon and Nitrogen stock and turnover were given by accounting for the spatial heterogeneity. Our results indicate that 45% is covered by dead and only 3% by live coral framework. The remaining 51%, is covered by fine sediments. It is estimated that 75,034–93,534 tons (T) of live coral framework is present in the area, of which ∼10% (7,747–9,316 T) consists of Cinorg and ∼1% (411–1,061 T) of Corg. A much larger amount of 3,485,828–4,357,435 T (60:1 dead:live ratio) dead coral framework contained ∼11% (418,299–522,892 T) Cinorg and <1% (0–16 T) Corg. The nutrient turnover by dead coral framework is the largest, contributing 45–51% (2,596–3,626 T) C year–1 and 30–62% (290–1,989 T) N year–1 to the total turnover in the area. Live coral framework turns over 1,656–2,828 T C year–1 and 53–286 T N year–1. Sediments contribute between 1,216–1,512 T C year–1 and 629–919 T N year–1 to the area’s benthic organic matter mineralization. However, this amount is likely higher as sediments baffled by coral framework might play a much more critical role in reefs CN cycling than previously assumed. Our calculations showed that the area overturns 1–3.4 times the C compared to a soft-sediment area at a similar depth. With only 5–9% of the primary productivity reaching the corals via natural deposition, this study indicated that the supply of food largely depends on local hydrodynamical food supply mechanisms and the reefs ability to retain and recycle nutrients. Climate-induced changes in primary production, local hydrodynamical food supply and the dissolution of particle-baffling coral framework could have severe implications for the survival and functioning of cold-water coral reefs.
Sickle Cell Disease: Thoughts for India From the Jamaican Cohort Study
Authors: Serjeant Graham R.
Published: November 2021

The sickle cell gene in India represents a separate occurrence of the HbS mutation (the Asian haplotype), which has occurred against a genetic background characterised by high levels of fetal haemoglobin and widely varying frequencies of alpha thalassaemia. These features, which tend to inhibit sickling, change the expression of the disease, which, in India, may be further modified by poor nutrition, malaria and other infections, and limited public health resources. Sickle cell disease in Jamaica is predominantly of African origin (the Benin haplotype) and faces some similar challenges. This review assesses similarities and differences between disease expression in the two countries and seeks to explore lessons from Jamaica, which may be relevant to Indian health care. In particular, it addresses common causes of hospital admission as detailed from Indian clinical experience: anemia, bone pain crisis, and infections.
Global Distribution and Richness of Armillaria and Related Species Inferred From Public Databases and Amplicon Sequencing Datasets
Authors: Koch Rachel A. , Herr Joshua R.
Published: November 2021

Armillariais a globally distributed fungal genus most notably composed of economically important plant pathogens that are found predominantly in forest and agronomic systems. The genussensu latohas more recently received attention for its role in woody plant decomposition and in mycorrhizal symbiosis with specific plants. Previous phylogenetic analyses suggest that around 50 species are recognized globally. Despite this previous work, no studies have analyzed the global species richness and distribution of the genus using data derived from fungal community sequencing datasets or barcoding initiatives. To assess the global diversity and species richness ofArmillaria, we mined publicly available sequencing datasets derived from numerous primer regions for the ribosomal operon, as well as ITS sequences deposited on Genbank, and clustered them akin to metabarcoding studies. Our estimates reveal that species richness ranges from 50 to 60 species, depending on whether the ITS1 or ITS2 marker is used. Eastern Asia represents the biogeographic region with the highest species richness. We also assess the overlap of species across geographic regions and propose some hypotheses regarding the drivers of variability in species diversity and richness between different biogeographic regions.
Flooding Causes Dramatic Compositional Shifts and Depletion of Putative Beneficial Bacteria on the Spring Wheat Microbiota
Authors: Francioli Davide , Cid Geeisy , Kanukollu Saranya , Ulrich Andreas , Hajirezaei Mohammad-Reza , Kolb Steffen
Published: November 2021

Flooding affects both above- and below-ground ecosystem processes, and it represents a substantial threat for crop and cereal productivity under climate change. Plant-associated microbiota play a crucial role in plant growth and fitness, but we still have a limited understanding of the response of the crop-microbiota complex under extreme weather events, such as flooding. Soil microbes are highly sensitive to abiotic disturbance, and shifts in microbial community composition, structure and functions are expected when soil conditions are altered due to flooding events (e.g., anoxia, pH alteration, changes in nutrient concentration). Here, we established a pot experiment to determine the effects of flooding stress on the spring wheat-microbiota complex. Since plant phenology could be an important factor in the response to hydrological stress, flooding was induced only once and at different plant growth stages (PGSs), such as tillering, booting and flowering. After each flooding event, we measured in the control and flooded pots several edaphic and plant properties and characterized the bacterial community associated to the rhizosphere and roots of wheat plant using a metabarcoding approach. In our study, flooding caused a significant reduction in plant development and we observed dramatic shifts in bacterial community composition at each PGS in which the hydrological stress was induced. However, a more pronounced disruption in community assembly was always shown in younger plants. Generally, flooding caused a (i) significant increase of bacterial taxa with anaerobic respiratory capabilities, such as members of Firmicutes and Desulfobacterota, (ii) a significant reduction in Actinobacteria and Proteobacteria, (iii) depletion of several putative plant-beneficial taxa, and (iv) increases of the abundance of potential detrimental bacteria. These significant differences in community composition between flooded and control samples were correlated with changes in soil conditions and plant properties caused by the hydrological stress, with pH and total N as the soil, and S, Na, Mn, and Ca concentrations as the root properties most influencing microbial assemblage in the wheat mircobiota under flooding stress. Collectively, our findings demonstrated the role of flooding on restructuring the spring wheat microbiota, and highlighted the detrimental effect of this hydrological stress on plant fitness and performance.
Novel Therapeutic Targets in Liver Fibrosis
Authors: Zhang Jinhang , Liu Qinhui , He Jinhan , Li Yanping
Published: November 2021

Liver fibrosis is end-stage liver disease that can be rescued. If irritation continues due to viral infection, schistosomiasis and alcoholism, liver fibrosis can progress to liver cirrhosis and even cancer. The US Food and Drug Administration has not approved any drugs that act directly against liver fibrosis. The only treatments currently available are drugs that eliminate pathogenic factors, which show poor efficacy; and liver transplantation, which is expensive. This highlights the importance of clarifying the mechanism of liver fibrosis and searching for new treatments against it. This review summarizes how parenchymal, nonparenchymal cells, inflammatory cells and various processes (liver fibrosis, hepatic stellate cell activation, cell death and proliferation, deposition of extracellular matrix, cell metabolism, inflammation and epigenetics) contribute to liver fibrosis. We highlight discoveries of novel therapeutic targets, which may provide new insights into potential treatments for liver fibrosis.
A Pan-Cancer Landscape of HOX-Related lncRNAs and Their Association With Prognosis and Tumor Microenvironment
Authors: Shao Wei , Ding Qian , Guo Yugang , Xing Juan , Huo Zheng , Wang Zhan , Xu Qian , Guo Yue
Published: November 2021

The highly conserved homology cassette family (HOX) as well as 18 referenced long non-coding antisense transcripts (HOXATs) play vital roles in the development of some cancers. Nevertheless, their expression patterns as well as their association with cancer prognosis and the tumor microenvironment (TME) in pan-cancers are still unclear. Here, based on public databases, the expression levels of HOXATs, their prognostic potentials, and correlation with tumor mutation burden (TMB), immune cell infiltration, immune subtype, immune response-related genes, and stemness scores corresponding to 33 tumor types were analyzed systematically using R language. The results of the analysis indicated that different cancer tissues show different HOXAT expression profiles. Further, HOXAT expression showed association with cancer prognosis and immune and stemness regulation. Gene set enrichment analysis also demonstrated that HOXATs participate in cancer- and immune-related pathways, and based on their expression levels, HOTAIRM1 and HOXB-AS1 showed potential involvement in oncogenesis as well as possible involvement in immune regulation across a variety of cancer types. Further investigation also confirmed a significantly higher expression of HOXB-AS1 in GBM than in lower grade glioma tissues. Importantly, in vitro cell function experiments indicated that HOXB-AS1 supports cancer stem cell and plays a fundamental role in glioma metastasis. In conclusion, our results provide valuable resources that can guide the investigation of the mechanisms related to the role of HOXATs in cancers as well as therapeutic analysis in this regard.
Microglia Polarization in Alzheimer’s Disease: Mechanisms and a Potential Therapeutic Target
Authors: Wang Qinqin , Yao Hongmei , Liu Wenyan , Ya Bailiu , Cheng Hongju , Xing Zhenkai , Wu Yili
Published: November 2021

Neuroinflammation regulated by microglia is one of the important factors involved in the pathogenesis of Alzheimer’s disease (AD). Activated microglia exhibited phenotypes termed as M1 and M2 phenotypes separately. M1 microglia contribute to the development of inflammation via upregulating pro-inflammatory cytokines, while M2 microglia exert anti-inflammation effects through enhancing the expression of anti-inflammation factors. Moreover, M1 and M2 microglia could be mutually transformed under various conditions. Both M1 and M2 microglia are implicated in AD. Amyloid-β (Aβ) and hyperphosphorylated tau are two major components of AD pathological hallmarks, neuritic plaques, and neurofibrillary tangles. Both Aβ and hyperphosphorylated tau were involved in microglial activation and subsequent inflammation, which further contribute to neuronal and synaptic loss in AD. In this review, we summarized the roles of M1 and M2 microglia in AD and underlying mechanisms, which will provide an insight into the role of microglia in the pathogenesis of AD and highlight the therapeutic potential of modulating microglia.
Sleep Disturbances in Rats With Genetic Pre-disposition to Spike-Wave Epilepsy (WAG/Rij)
Authors: Sitnikova Evgenia
Published: November 2021

Wistar Albino Glaxo Rijswijk (WAG/Rij) rats are widely used in basic and pre-clinical studies as a valid genetic model of absence epilepsy. Adult WAG/Rij rats exhibit generalized 8–10-Hz spike-wave discharges (SWDs) in the electroencephalogram. SWDs are known to result from thalamocortical circuit dysfunction, and this implies an intimate relationship between slow-wave EEG activity, sleep spindles, and SWDs. The present mini review summarizes relevant research on sleep-related disturbances associated with spike-wave epilepsy in WAG/Rij rats in the domain of slow-wave sleep EEG and microarousals. It also discusses enhancement of the intermediate stage of sleep. In general, sleep EEG studies provide important information about epileptogenic processes related to spike-wave epilepsy.
Nanoscopical Analysis Reveals an Orderly Arrangement of the Presynaptic Scaffold Protein Bassoon at the Golgi-Apparatus
Authors: Ghelani Tina , Montenegro-Venegas Carolina , Fejtova Anna , Dresbach Thomas
Published: November 2021

Bassoon is a core scaffold protein of the presynaptic active zone. In brain synapses, the C-terminus of Bassoon is oriented toward the plasma membrane and its N-terminus is oriented toward synaptic vesicles. At the Golgi-apparatus, Bassoon is thought to assemble active zone precursor structures, but whether it is arranged in an orderly fashion is unknown. Understanding the topology of this large scaffold protein is important for models of active zone biogenesis. Using stimulated emission depletion nanoscopy in cultured hippocampal neurons, we found that an N-terminal intramolecular tag of recombinant Bassoon, but not C-terminal tag, colocalized with markers of the trans-Golgi network (TGN). The N-terminus of Bassoon was located between 48 and 69 nm away from TGN38, while its C-terminus was located between 100 and 115 nm away from TGN38. Sequences within the first 95 amino acids of Bassoon were required for this arrangement. Our results indicate that, at the Golgi-apparatus, Bassoon is oriented with its N-terminus toward and its C-terminus away from the trans Golgi network membrane. Moreover, they suggest that Bassoon is an extended molecule at the trans Golgi network with the distance between amino acids 97 and 3,938, estimated to be between 46 and 52 nm. Our data are consistent with a model, in which the N-terminus of Bassoon binds to the membranes of the trans-Golgi network, while the C-terminus associates with active zone components, thus reflecting the topographic arrangement characteristic of synapses also at the Golgi-apparatus.
Understanding, Explanation, and Active Inference
Authors: Parr Thomas , Pezzulo Giovanni
Published: November 2021

While machine learning techniques have been transformative in solving a range of problems, an important challenge is to understand why they arrive at the decisions they output. Some have argued that this necessitates augmenting machine intelligence with understanding such that, when queried, a machine is able to explain its behaviour (i.e., explainable AI). In this article, we address the issue of machine understanding from the perspective of active inference. This paradigm enables decision making based upon a model of how data are generated. The generative model contains those variables required to explain sensory data, and its inversion may be seen as an attempt to explain the causes of these data. Here we are interested in explanations of one’s own actions. This implies a deep generative model that includes a model of the world, used to infer policies, and a higher-level model that attempts to predict which policies will be selected based upon a space of hypothetical (i.e., counterfactual) explanations—and which can subsequently be used to provide (retrospective) explanations about the policies pursued. We illustrate the construct validity of this notion of understanding in relation to human understanding by highlighting the similarities in computational architecture and the consequences of its dysfunction.
A Class of Protein-Coding RNAs Binds to Polycomb Repressive Complex 2 and Alters Histone Methylation
Authors: Liao Meijian , Sun Xiaolin , Gao Shoucui , Zhang Yaou
Published: November 2021

Polycomb repressive complex 2 (PRC2) is a multi-subunit protein complex mediating the methylation of lysine 27 on histone H3 and playing an important role in transcriptional repression during tumorigenesis and development. Previous studies revealed that both protein-coding and non-coding RNAs could bind to PRC2 complex. However, the functions of protein-coding RNAs that bind to PRC2 complex in tumor are still unknown. Through data mining and RNA immunoprecipitation (RIP) assay, our study found that there were a class of protein-coding RNAs bound to PRC2 complex and H3 with tri-methylation on lysine 27. The Bayesian gene regulatory network analysis pointed out that these RNAs regulated the expression of PRC2-regulated genes in cancer. In addition, gene set enrichment analysis (GSEA), gene ontology (GO) analysis, and weighted gene co-expression network analysis (WGCNA) also confirmed that these RNAs were associated with histone modification in cancer. We also confirmed that MYO1C, a PRC2-bound transcript, inhibited the modification level of H3K27me3. Further detailed study showed that TMEM117 regulated TSLP expression through EZH2-mediated H3K27me3 modification. Interestingly, the RNA recognition motif of PRC2 complex might help these RNAs bind to the PRC2 complex more easily. The same regulatory pattern was found in mice as well.
A Novel Combined Conjugate Therapeutic Cancer Vaccine, Recombinant EGF-CRM197, in Patients With Advanced Solid Tumors: A Phase I Clinical Study
Authors: Xiong An-Wen , Fang Jue-Min , Ren Sheng-Xiang , Li Wei , Wang Jing , Zhao Yu , Chen Guo-You , Xu Qing , Zhou Cai-Cun
Published: November 2021

Introduction

The therapeutic cancer vaccine recombinant Epidermal Growth Factor (EGF)-CRM197 is a novel combined conjugate EGF with CRM197 as a carrier protein. Immunization with the EGF-CRM197 vaccine can induce high levels of neutralizing anti-EGF antibodies that inhibit EGF/EGFR signaling and thereby suppress growth of tumors that rely on this signaling pathway. Herein, we characterize the humoral immune responses elicited by the recombinant EGF-CRM197 vaccine in patients with advanced solid tumors in a phase I clinical trial and assess the safety, tolerability, and immunogenicity of this vaccine (CTR20190473).

Methods

A total of 16 subjects were enrolled in this study. Under 6 + 3 design, patients in each dosing cohort were administrated subcutaneously at a dosage of 0.4 mg, 0.8 mg, and 1.6 mg, respectively. The patients received vaccinations for immune induction (once a week for 4 consecutive weeks) and booster vaccinations (once every 4 weeks). Safety evaluation was performed 1 week after the immune induction. Booster vaccination was given until the occurrence of disease progression, intolerance, withdrawal of informed consent by the patient, or negative result of anti-EGF test after two booster vaccinations.

Results

Vaccination with EGF-CRM197 is safe and well-tolerated in patients with advanced solid tumors. Adverse reactions at the injection site were the most common adverse events (AEs) in recipients. No severe adverse reactions post vaccination were observed in the present study. Vaccinated patients developed a robust neutralizing antibody response triggered by EGF-CRM197 that significantly reduced the levels of EGF in serum. For lung cancer patients who were super good antibody responders (sGAR) to EGF-CRM197, the median progress-free survival (PFS) was 4.83 months, significantly longer than that of the good antibody responder (GAR) patients with lung cancer whose median PFS was 2.10 months (P=0.0018). The median overall survival (OS) of GAR lung cancer patients was 10.67 months while the OS) for sGAR lung cancer patients was not reached until analysis was performed. The median follow-up of the sGAR lung cancer patients was 14.6 months.

Conclusion

Our study demonstrates that the recombinant EGF-CRM197 therapeutic cancer vaccine can induce a good immune response in patients with advanced solid tumors and is safe and well tolerated, which ensures further clinical development of the vaccine for extending the survival time of EGF-CRM197 sensitive patients with advanced solid tumors.

Clinical Trial Registration

http://www.chinadrugtrials.org.cn, identifier CTR20190473, EGF-CRM197.
Visualization of microRNA-21 Dynamics in Neuroblastoma Using Magnetic Resonance Imaging Based on a microRNA-21-Responsive Reporter Gene
Authors: Bao Guangcheng , Sun Jun , Zheng Helin , Hou Jingxin , Huang Jie , Wei Jie , Fu Yuanqiao , Qiu Jiawen , Zou Xuefeng , Xiang Bin , Cai Jinhua
Published: November 2021

Background

MicroRNAs (miRs) have been shown to be closely associated with the occurrence and development of tumors and to have potential as diagnostic and therapeutic targets. The detection of miRs by noninvasive imaging technology is crucial for deeply understanding their biological functions. Our aim was to develop a novel miR-21-responsive gene reporter system for magnetic resonance imaging (MRI) visualization of the miR-21 dynamics in neuroblastoma.

Methods

The reporter gene ferritin heavy chain (FTH1) was modified by the addition of 3 copies of the sequence completely complementary to miR-21 (3xC_miR-21) to its 3’-untranslated region (3’ UTR) and transduced into SK-N-SH cells to obtain SK-N-SH/FTH1-3xC_miR-21 cells. Then, the antagomiR-21 was delivered into cells by graphene oxide functionalized with polyethylene glycol and dendrimer. Before and after antagomiR-21 delivery, FTH1 expression, MRI contrast and intracellular iron uptake were assayed in vitro and in vivo.

Results

In the SK-N-SH/FTH1-3xC_miR-21 cells, FTH1 expression was in an “off” state due to the combination of intratumoral miR-21 with the 3’ UTR of the reporter gene. AntagomiR-21 delivered into the cells bound to miR-21 and thereby released it from the 3’ UTR of the reporter gene, thus “switching on” FTH1 expression in a dose-dependent manner. This phenomenon resulted in intracellular iron accumulation and allowed MRI detection in vitro and in vivo.

Conclusion

MRI based on the miR-21-responsive gene reporter may be a potential method for visualization of the endogenous miR-21 activity in neuroblastoma and its response to gene therapy.
Pan-Cancer Analysis of IGF-1 and IGF-1R as Potential Prognostic Biomarkers and Immunotherapy Targets
Authors: Zhang Yinqi , Gao Chengqi , Cao Fei , Wu Ying , Chen Shuanggang , Han Xue , Mo Jingqin , Qiu Zhiyu , Fan Weijun , Zhou Penghui , Shen Lujun
Published: November 2021

Aim

Insulin-like growth factor-1 receptor (IGF-1R) is one of the main members of the tyrosine protein kinase receptor family. This receptor binds insulin-like growth factor-1 (IGF-1) with a high affinity. IGF-1 is a member of a family of proteins involved in mediating growth and development. However, the correlations of IGF-1 and IGF-1R to prognosis and tumor-infiltrating lymphocytes in different cancers remain unclear.

Method

This research comprehensively analyzed the expression pattern of IGF-1 and IGF-1R and the influence of IGF-1 and IGF-1R on clinical significance in prognosis prediction among 33 types of malignancies using The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) databases. The correlation between IGF-1, IGF-1R, and cancer immunity was explored.

Results

IGF-1 and IGF-1R displayed inconsistent gene expression levels among diverse cancer cell lines. Typically, high expression level of IGF-1 and IGF-1R was detected in most malignant tumors. High expression of IGF-1 was closely bound up with the unfavorable overall survival (OS) for patients in BLCA, CHOL, and LAML upon Cox and Kaplan-Meier analyses. While high expression of IGF-1R was closely bound up with the unfavorable overall survival (OS) for patients in BLCA, LIHC, and LUAD. Furthermore, high expression level of IGF-1 and IGF-1R were closely connected with high degrees of tumor infiltrates, including CD4+ T cell, dendritic cells, and macrophages. In addition, we found that IGF-1 was commonly positively correlated with the expression of gene markers including LAIR1, ICOS, CD40LG, CTLA4, CD48, CD28, CD200R1, HAVCR2, and CD86. Whereas, IGF-1R was commonly positively correlated with the expression of gene markers including NRP1 and CD276. More importantly, IGF-1 and IGF-1R expression were correlated with tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methyltransferase (DNMT) of different types of cancers.

Conclusions

The impact of high IGF-1 and IGF-1R on prognosis and immune infiltrates differs across cancer types. Anti-IGF-1R therapy may inhibit tumor growth and contribute to immunotherapy in LIHC and KIRC.
Gastrointestinal Goblet Cell Adenocarcinomas Harbor Distinctive Clinicopathological, Immune, and Genomic Landscape
Authors: Lin Dong-Liang , Wang Li-Li , Zhao Peng , Ran Wen-Wen , Wang Wei , Zhang Long-Xiao , Han Ming , Bao Hua , Liu Kaihua , Wu Xue , Shao Yang , Xing Xiao-Ming
Published: November 2021

Goblet cell adenocarcinoma (GCA) is a rare amphicrine tumor and difficult to diagnose. GCA is traditionally found in the appendix, but extra-appendiceal GCA may be underestimated. Intestinal adenocarcinoma with signet ring cell component is also very rare, and some signet ring cell carcinomas are well cohesive, having some similar morphological features to GCAs. It is necessary to differentiate GCA from intestinal adenocarcinomas with cohesive signet ring cell component (IACSRCC). The goal of this study is to find occurrence of extra-appendiceal GCA and characterize the histological, immunohistochemical, transcriptional, and immune landscape of GCA. We collected 12 cases of GCAs and 10 IACSRCCs and reviewed the clinicopathologic characters of these cases. Immunohistochemical stains were performed with synaptophysin, chromogranin A, CD56, somatostatin receptor (SSTR) 2, and Ki-67. Whole transcriptome RNA-sequencing was performed, and data were used to analyze differential gene expression and predict immune cell infiltration levels in GCA and IACSRCC. RNA-sequencing data for colorectal adenocarcinoma were gathered from TCGA data portal. Of the 12 patients with GCA, there were 4 women and 8 men. There were three appendiceal cases and nine extra-appendiceal cases. GCAs were immunohistochemically different from IACSRCC. GCA also had different levels of B-cell and CD8+ T-cell infiltration compared to both colorectal adenocarcinoma and cohesive IACSRCCs. Differential gene expression analysis showed distinct gene expression patterns in GCA compared to colorectal adenocarcinoma, with a number of cancer-related differentially expressed genes, including upregulation of TMEM14A, GOLT1A, DSCC1, and HSD17B8, and downregulation of KCNQ1OT1 and MXRA5. GCA also had several differentially expressed genes compared to IACSRCCs, including upregulation of PRSS21, EPPIN, RPRM, TNFRSF12A, and BZRAP1, and downregulation of HIST1H2BE, TCN1, AC069363.1, RP11-538I12.2, and REG4. In summary, the number of extra-appendiceal GCA was underestimated in Chinese patients. GCA can be seen as a distinct morphological, immunohistochemical, transcriptomic, and immunological entity. The classic low-grade component of GCA and the immunoreactivity for neuroendocrine markers are the key points to diagnosing GCA.
Defective Toll-Like Receptors Driven B Cell Response in Hyper IgE Syndrome Patients With STAT3 Mutations
Authors: Gong Ruolan , Wu Jing , Jin Yingying , Chen Tongxin
Published: November 2021

Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare inherited primary immunodeficient disease (PIDs), which is caused by STAT3 gene mutations. Previous studies indicated a defective Toll-like receptor (TLR) 9-induced B cell response in AD-HIES patients, including proliferation, and IgG production. However, the other TLRs-mediated B cell responses in AD-HIES patients were not fully elucidated. In this study, we systematically studied the B cell response to TLRs signaling pathways in AD-HIES patients, including proliferation, activation, apoptosis, cytokine, and immunoglobulin production. Our results showed that the TLRs-induced B cell proliferation and activation was significantly impaired in AD-HIES patients. Besides, AD-HIES patients had defects in TLRs-induced B cell class switch, as well as IgG/IgM secretion and IL-10 production in B cells. Taken together, we first systematically reported the deficiency of TLRs driven B cell response in AD-HIES patients, which help to have a better understanding of the pathology of AD-HIES.
Dissection of the Functional Mechanism of Human Gut Bacterial Strain AD16 by Secondary Metabolites’ Identification, Network Pharmacology, and Experimental Validation
Authors: Wang Qin , Wang Yao , Wang Ya-Jing , Ma Nan , Zhou Yu-Jie , Zhuang He , Zhang Xing-Hua , Li Chang , Pei Yue-Hu , Liu Shu-Lin
Published: November 2021

Gut microbiota plays important roles in several metabolic processes, such as appetite and food intake and absorption of nutrients from the gut. It is also of great importance in the maintenance of the health of the host. However, much remains unknown about the functional mechanisms of human gut microbiota itself. Here, we report the identification of one anticancer gut bacterial strain AD16, which exhibited potent suppressive effects on a broad range of solid and blood malignancies. The secondary metabolites of the strain were isolated and characterized by a bioactivity-guided isolation strategy. Five new compounds, streptonaphthalenes A and B (1-2), pestaloficins F and G (3-4), and eudesmanetetraiol A (5), together with nine previously known compounds, were isolated from the effective fractions of AD16. Structures of the new compounds were established by 1D and 2D NMR and MS analysis, and the absolute configurations were determined by the CD method. The analysis of network pharmacology suggested that 3, 2, and 13 could be the key components for the anti-NSCLC activity of AD16. In addition to the PI3K–Akt signaling pathway, the proteoglycans in cancer pathway could be involved in the anti-NSCLC action of AD16.
G Protein–Coupled Estrogen Receptor 30 Reduces Transverse Aortic Constriction–Induced Myocardial Fibrosis in Aged Female Mice by Inhibiting the ERK1/2 -MMP-9 Signaling Pathway
Authors: Wang Xiaowu , Ma Jipeng , Zhang Shuaishuai , Li Zilin , Hong Ziwei , Jiang Liqing , Duan Weixun , Liu Jincheng
Published: November 2021

The incidence of cardiovascular diseases was significantly increased in postmenopausal women. The protection of estrogen in the cardiovascular system has been further reported for decades. Although menopausal hormone therapy has been used in many clinical trials, the debatable results indicate that the studies for elucidating the precise molecular mechanism are urgently required. G protein–coupled estrogen receptor 30 (GPR30) is a membrane receptor of estrogen and displays protective roles in diverse cardiovascular diseases. Previous studies have revealed that ERK1/2-mediated MMP-9 signaling was involved in ischemic heart diseases. However, the role of ERK1/2-mediated MMP-9 signaling in the protection of GPR30 against cardiac hypertrophy in aged female mice has not been investigated. Our present study demonstrated that GPR30 overexpression and its agonist G1 co-administration reduced transverse aortic constriction–induced myocardial fibrosis and preserved cardiac function in aged female mice. MMP-9 expression was markedly increased via ERK1/2 phosphorylation in transverse aortic constriction–injured myocardium of aged female mice. Further results showed that GPR30/G1 activation decreased MMP-9 expression via ERK1/2 inhibition, which further reduced TGF-β1 expression. Inhibition of the ERK1/2 signaling pathway by its inhibitor PD98059 suppressed the induction of the cardiomyocyte MMP-9 level caused by the GRP30 antagonist G15 and inhibited TGF-β1 expression in cardiac fibroblast in vitro. In summary, our results from in vivo and in vitro studies indicated that GPR30 activation inhibited myocardial fibrosis and preserved cardiac function via inhibiting ERK-mediated MMP-9 expression. Thus, the present study may provide the novel drug targets for prevention and treatment of cardiac pathological hypertrophy in postmenopausal women.