bluuebunny/crossref_metadata_2025 huggingface dataset:
High GTSE1 expression promotes cell proliferation, metastasis and cisplatin resistance in ccRCC and is associated with immune infiltrates and poor prognosis
Authors: Lei Pu , Zhang Mengzhao , Li Yan , Wang Ziming
Published: March 2023

Background: Clear cell renal cell carcinoma is the most common and fatal form of kidney cancer, accounting for 80% of new cases. Although it has been reported that GTSE1 is highly expressed in a variety of tumors and associated with malignant progression and poor clinical prognosis, its clinical significance, correlations with immune cell infiltration and biological function in ccRCC are still poorly understood.

Methods: The gene expression, clinicopathological features, and clinical significance of GTSE1 were analyzed using multiple databases, including TCGA, GEO, TIMER, and UALCAN Kaplan–Meier survival analysis, gene set enrichment analysis gene ontology enrichment Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed. Tumor-infiltrating immune cells and immunomodulators were extracted and analyzed using TCGA-KIRC profiles. Protein‒protein interactions were built using the STRING website. The protein level of GTSE1 in ccRCC patients was detected by immunohistochemistry using a ccRCC tissue chip. Finally, MTT assays, colony-formation assays, cell flow cytometry analyses, EdU-staining assays, wound-healing assays, and transwell migration and invasion assays were conducted to assess the biological function of GTSE1 in vitro.

Results: GTSE1 was overexpressed in ccRCC tissues and cells, and GTSE1 overexpression was associated with adverse clinical-pathological factors and poor clinical prognosis. Meanwhile, the functional enrichment analysis indicated that GTSE1 and its coexpressed genes were mainly related to the cell cycle, DNA replication, and immunoreaction, such as T-cell activation and innate immune response, through multiple signaling pathways, including the P53 signaling pathway and T-cell receptor signaling pathway. Furthermore, we observed a significant relationship between GTSE1 expression and the levels of infiltrating immune cells in ccRCC. Biological functional studies demonstrated that GTSE1 could promote the malignant progression of ccRCC by promoting cell proliferation, cell cycle transition, migration, and invasion capacity and decreasing the sensitivity of ccRCC cells to cisplatin.

Conclusion: Our results indicate that GTSE1, serving as a potential oncogene, can promote malignant progression and cisplatin resistance in ccRCC. Additionally, high GTSE1 expression contributes to an increased level of immune cell infiltration and is associated with a worse prognosis, providing a potential target for tumor therapy in ccRCC.
Effect of monovalency on anti-contactin-1 IgG4
Authors: Taieb Guillaume , Jentzer Alexandre , Vegezzi Elisa , Lleixà Cinta , Illa Isabel , Querol Luis , Devaux Jérôme J.
Published: March 2023

Introduction

Autoimmune nodopathies (AN) have been diagnosed in a subset of patients fulfilling criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who display no or poor response to intravenous immunoglobulins. Biomarkers of AN are autoantibodies, mainly IgG4, directed against the ternary paranodal complex composed by neurofascin-155, contactin-1 (CNTN1), and Contactin-associated-protein-1 (CASPR1) or against the nodal isoforms of neurofascin. IgG4 can undergo a Fab-arm exchange (FAE) which results in functionally monovalent antibody. This phenomenon differentially affects the pathogenicity of IgG4 depending on the target of autoantibodies. Here, we have evaluated this issue by examining the impact of valency on anti-CNTN1 IgG4 which induces paranodal destruction through a function blocking activity.

Methods

Sera were obtained from 20 patients with AN associated with anti-CNTN1 antibodies. The proportion of monospecific/bispecific anti-CNTN1 antibodies was estimated in each patient by ELISA by examining the ability of serum antibodies to cross-link untagged CNTN1 with biotinylated CNTN1. To determine the impact of monovalency, anti-CNTN1 IgG4 were enzymatically digested into monovalent Fab and tested in vitro on cell aggregation assay. Also, intraneural injections were performed to determine whether monovalent Fab and native IgG4 may penetrate paranode, and antibody infiltration was monitored 1- and 3-days post injection.

Results and discussion

We found that the percentage of monospecific antibodies were lower than 5% in 14 out of 20 patients (70%), suggesting that IgG4 have undergone extensive FAE in situ. The levels of monospecific antibodies correlated with the titers of anti-CNTN1 antibodies. However, no correlation was found with clinical severity, and patients with low or high percentage of monospecific antibodies similarly showed a severe phenotype. Native anti-CNTN1 IgG4 were shown to inhibit the interaction between cells expressing CNTN1/CASPR1 and cells expressing neurofascin-155 using an in vitro aggregation assay. Similarly, monovalent Fab significantly inhibited the interaction between CNTN1/CASPR1 and neurofascin-155. Intraneural injections of Fab and native anti-CNTN1 IgG4 indicated that both mono- and bivalent anti-CNTN1 IgG4 potently penetrated the paranodal regions and completely invaded this region by day 3. Altogether, these data indicate anti-CNTN1 IgG4 are mostly bispecific in patients, and that functionally monovalent anti-CNTN1 antibodies have the pathogenic potency to alter paranode.
Porphyromonas gingivalis regulates atherosclerosis through an immune pathway
Authors: Ruan Qijun , Guan Peng , Qi Weijuan , Li Jiatong , Xi Mengying , Xiao Limin , Zhong Sulan , Ma Dandan , Ni Jia
Published: March 2023

Atherosclerosis (AS) is a chronic inflammatory disease, involving a pathological process of endothelial dysfunction, lipid deposition, plaque rupture, and arterial occlusion, and is one of the leading causes of death in the world population. The progression of AS is closely associated with several inflammatory diseases, among which periodontitis has been shown to increase the risk of AS. Porphyromonas gingivalis (P. gingivalis), presenting in large numbers in subgingival plaque biofilms, is the “dominant flora” in periodontitis, and its multiple virulence factors are important in stimulating host immunity. Therefore, it is significant to elucidate the potential mechanism and association between P. gingivalis and AS to prevent and treat AS. By summarizing the existing studies, we found that P. gingivalis promotes the progression of AS through multiple immune pathways. P. gingivalis can escape host immune clearance and, in various forms, circulate with blood and lymph and colonize arterial vessel walls, directly inducing local inflammation in blood vessels. It also induces the production of systemic inflammatory mediators and autoimmune antibodies, disrupts the serum lipid profile, and thus promotes the progression of AS. In this paper, we summarize the recent evidence (including clinical studies and animal studies) on the correlation between P. gingivalis and AS, and describe the specific immune mechanisms by which P. gingivalis promotes AS progression from three aspects (immune escape, blood circulation, and lymphatic circulation), providing new insights into the prevention and treatment of AS by suppressing periodontal pathogenic bacteria.
First in man study: Bcl-Xl_42-CAF®09b vaccines in patients with locally advanced prostate cancer
Authors: Mørk Sofie Kirial , Kongsted Per , Westergaard Marie Christine Wulff , Albieri Benedetta , Granhøj Joachim Stoltenborg , Donia Marco , Martinenaite Evelina , Holmström Morten Orebo , Madsen Kasper , Kverneland Anders H. , Kjeldsen Julie Westerlin , Holmstroem Rikke Boedker , Lorentzen Cathrine Lund , Nørgaard Nis , Andreasen Lars Vibe , Wood Grith Krøyer , Christensen Dennis , Klausen Michael Schantz , Hadrup Sine Reker , thor Straten Per , Andersen Mads Hald , Svane Inge Marie
Published: March 2023

Background

The B-cell lymphoma-extra-large (Bcl-XL) protein plays an important role in cancer cells’ resistance to apoptosis. Pre-clinical studies have shown that vaccination with Bcl-XL-derived peptides can induce tumor-specific T cell responses that may lead to the elimination of cancer cells. Furthermore, pre-clinical studies of the novel adjuvant CAF®09b have shown that intraperitoneal (IP) injections of this adjuvant can improve the activation of the immune system. In this study, patients with hormone-sensitive prostate cancer (PC) received a vaccine consisting of Bcl-XL-peptide with CAF®09b as an adjuvant. The primary aim was to evaluate the tolerability and safety of IP and intramuscular (IM) administration, determine the optimal route of administration, and characterize vaccine immunogenicity.

Patients and methods

Twenty patients were included. A total of six vaccinations were scheduled: in Group A (IM to IP injections), ten patients received three vaccines IM biweekly; after a three-week pause, patients then received three vaccines IP biweekly. In Group B (IP to IM injections), ten patients received IP vaccines first, followed by IM under a similar vaccination schedule. Safety was assessed by logging and evaluating adverse events (AE) according to Common Terminology Criteria for Adverse Events (CTCAE v. 4.0). Vaccines-induced immune responses were analyzed by Enzyme-Linked Immunospot and flow cytometry.

Results

No serious AEs were reported. Although an increase in T cell response against the Bcl-XL-peptide was found in all patients, a larger proportion of patients in group B demonstrated earlier and stronger immune responses to the vaccine compared to patients in group A. Further, we demonstrated vaccine-induced immunity towards patient-specific CD4, and CD8 T cell epitopes embedded in Bcl-XL-peptide and an increase in CD4 and CD8 T cell activation markers CD107a and CD137 following vaccination. At a median follow-up of 21 months, no patients had experienced clinically significant disease progression.

Conclusion

The Bcl-XL-peptide-CAF®09b vaccination was feasible and safe in patients with l hormone-sensitive PC. In addition, the vaccine was immunogenic and able to elicit CD4 and CD8 T cell responses with initial IP administration eliciting early and high levels of vaccine-specific responses in a higher number og patients.

Clinical trial registration

https://clinicaltrials.gov, identifier NCT03412786.
Cytosolic DNA sensors and glial responses to endogenous DNA
Authors: Suptela Alexander J. , Marriott Ian
Published: March 2023

Genomic instability is a key driving force for the development and progression of many neurodegenerative diseases and central nervous system (CNS) cancers. The initiation of DNA damage responses is a critical step in maintaining genomic integrity and preventing such diseases. However, the absence of these responses or their inability to repair genomic or mitochondrial DNA damage resulting from insults, including ionizing radiation or oxidative stress, can lead to an accumulation of self-DNA in the cytoplasm. Resident CNS cells, such as astrocytes and microglia, are known to produce critical immune mediators following CNS infection due to the recognition of pathogen and damage-associated molecular patterns by specialized pattern recognition receptors (PRRs). Recently, multiple intracellular PRRs, including cyclic GMP-AMP synthase, interferon gamma-inducible 16, absent in melanoma 2, and Z-DNA binding protein, have been identified as cytosolic DNA sensors and to play critical roles in glial immune responses to infectious agents. Intriguingly, these nucleic acid sensors have recently been shown to recognize endogenous DNA and trigger immune responses in peripheral cell types. In the present review, we discuss the available evidence that cytosolic DNA sensors are expressed by resident CNS cells and can mediate their responses to the presence of self-DNA. Furthermore, we discuss the potential for glial DNA sensor-mediated responses to provide protection against tumorigenesis versus the initiation of potentially detrimental neuroinflammation that could initiate or foster the development of neurodegenerative disorders. Determining the mechanisms that underlie the detection of cytosolic DNA by glia and the relative role of each pathway in the context of specific CNS disorders and their stages may prove pivotal in our understanding of the pathogenesis of such conditions and might be leveraged to develop new treatment modalities.
Recombinant viral hemorrhagic septicemia virus with rearranged genomes as vaccine vectors to protect against lethal betanodavirus infection
Authors: Souto Sandra , Mérour Emilie , Le Coupanec Alain , Lamoureux Annie , Bernard Julie , Brémont Michel , Millet Jean K. , Biacchesi Stéphane
Published: March 2023

The outbreaks of viral hemorrhagic septicemia (VHS) and viral encephalopathy and retinopathy (VER) caused by the enveloped novirhabdovirus VHSV, and the non-enveloped betanodavirus nervous necrosis virus (NNV), respectively, represent two of the main viral infectious threats for aquaculture worldwide. Non-segmented negative-strand RNA viruses such as VHSV are subject to a transcription gradient dictated by the order of the genes in their genomes. With the goal of developing a bivalent vaccine against VHSV and NNV infection, the genome of VHSV has been engineered to modify the gene order and to introduce an expression cassette encoding the major protective antigen domain of NNV capsid protein. The NNV Linker-P specific domain was duplicated and fused to the signal peptide (SP) and the transmembrane domain (TM) derived from novirhabdovirus glycoprotein to obtain expression of antigen at the surface of infected cells and its incorporation into viral particles. By reverse genetics, eight recombinant VHSVs (rVHSV), termed NxGyCz according to the respective positions of the genes encoding the nucleoprotein (N) and glycoprotein (G) as well as the expression cassette (C) along the genome, have been successfully recovered. All rVHSVs have been fully characterized in vitro for NNV epitope expression in fish cells and incorporation into VHSV virions. Safety, immunogenicity and protective efficacy of rVHSVs has been tested in vivo in trout (Oncorhynchus mykiss) and sole (Solea senegalensis). Following bath immersion administration of the various rVHSVs to juvenile trout, some of the rVHSVs were attenuated and protective against a lethal VHSV challenge. Results indicate that rVHSV N2G1C4 is safe and protective against VHSV challenge in trout. In parallel, juvenile sole were injected with rVHSVs and challenged with NNV. The rVHSV N2G1C4 is also safe, immunogenic and efficiently protects sole against a lethal NNV challenge, thus presenting a promising starting point for the development of a bivalent live attenuated vaccine candidate for the protection of these two commercially valuable fish species against two major diseases in aquaculture.
Can we actually monitor the spatial distribution of small pelagic fish based on Sentinel-3 data? An example from the North Aegean Sea (Eastern Mediterranean Sea)
Authors: Spondylidis Spyros , Giannoulaki Marianna , Machias Athanassios , Batzakas Ioannis , Topouzelis Konstantinos
Published: March 2023

Fish population spatial distribution data provide essential information for fleet monitoring and fishery spatial planning. Modern high resolution ocean color remote sensing sensors with daily temporal coverage can enable consistent monitoring of highly productive areas, giving insight in seasonal and yearly variations. Here is presented the methodology to monitor small pelagic fish spatial distribution by means of 500m resolution satellite data in a geographically and oceanographically complex area. Specifically, anchovy (Engraulis encrasicolus) and sardine (Sardina pilchardus) acoustic biomass data are modeled against environmental proxies obtained from the Sentinel-3 satellite mission. Three modeling techniques (Logistic Regression, Generalized Additive Models, Random Forest) were applied and validated against the in-situ measurements. The accuracy of anchovy presence detection peaked at 76% and for sardine at 78%. Additionally, the spatial distribution of the models’ output highlighted known fishing grounds. For anchovy, biomass modeling highlighted the importance of bathymetry, SST, and the distance from thermal fronts, whereas for sardine, bathymetry, CHL and chlorophyll fronts. The models are applied to a sample dataset to showcase a potential outcome of the proposed methodology and its spatial characteristics. Finally, the results are discussed and compared to other habitat studies and findings in the area.
Analysis of free and forced convections in the flow of radiative viscous fluid with oxytactic microorganisms
Authors: Bilal S. , Ullah Asad , Shah Imtiaz Ali , Asjad Muhammad Imran , Almusawa Musawa Yahya , Eldin Sayed M.
Published: March 2023

The prime intend behind the current effort is to explicate flow attributes of magnetically influenced Newtonian fluids toward a stretchable sheet under the novel physical impact of oxytactic microorganisms in a comparative manner for free and forced convections. In addition, modified Fourier and Fick’s laws are implemented to examine the change in temperature and concentration distributions in a more realistic manner by accounting thermal and mass relaxation parameters in the flow. The obtained PDEs are reduced into the non-linear ODEs by employing similarity variables. Due to the complexity of parametrically based differential equations, a numerical scheme based on a finite-difference approach is implemented via the MATLAB built-in routine known as BVP4C. Flow-controlling parameter effects on associated distributions are evaluated through graphs and tables. Subsequently, the influence of flow-controlling parameters on associated distributions is revealed through pictures in a comparative manner for different convection regimes. Additionally, the quantities such as heat and mass fluxes along with the density of motile microorganisms are also illustrated. From the thorough analysis of the current investigation, it is inferred that velocity distribution enhances for free and forced convections, whereas the temperature of the fluid diminishes against the mentioned convective regimes. It is manifested that the Nusselt number is more in the situation of free convection instead of the forced convection situation. The magnitude of the skin friction factor is more in case of free convection as compared to the forced convection regime. It is also reported that by uplifting the magnitudes of concentration and thermal relaxation parameters, depreciation in associated heat and mass transfer rate arises. In addition, it is also reported that with the increment in the magnetic field, buoyancy ratio, bioconvection parameters, and Rayleigh number skin friction accelerate, while the behavior is quite opposite in case of stretching the ratio parameter.
Molecular phylogeny and morphology reveal four new species of Thelephora (Thelephorales, Basidiomycota) from subtropical China, closely related to T. ganbajun
Authors: Yang Shi-Rong , Wei Yu-Lian , Yuan Hai-Sheng
Published: March 2023

The genus of Thelephora is a group of cosmopolitan ectomycorrhizal fungi with basidiocarps of morphological diversity that has an extremely scarce species reported from the forest ecosystem in China. In this study, phylogenetic analyses of Thelephora species from subtropical China were carried out based on multiple loci including the internal transcribed spacer (ITS) regions, the large subunit of nuclear ribosomal RNA gene (nLSU), and the small subunit of mitochondrial rRNA gene (mtSSU). Maximum likelihood and Bayesian analyses were used to construct the phylogenetic tree. The phylogenetic positions of four new species, Th. aquila, Th. glaucoflora, Th. nebula, and Th. pseudoganbajun, were revealed based on morphological and molecular evidence. Molecular analyses demonstrated that the four new species were closely related to Th. ganbajun and formed a clade with robust support in the phylogenetic tree. Regarding morphology, they share some common morphological characteristics, including flabelliform to imbricate pilei, generative hyphae more or less covered by crystals, and subglobose to irregularly lobed basidiospores (5–8 × 4–7 μm) with tuberculate ornamentation. These new species are described and illustrated and are compared to similar morphological or phylogenetically related species. A key to the new and allied species from China is provided.
Contribution of clinical information to the predictive performance of plasma β-amyloid levels for amyloid positron emission tomography positivity
Authors: Chun Min Young , Jang Hyemin , Kim Hee Jin , Kim Jun Pyo , Gallacher John , Allué José Antonio , Sarasa Leticia , Castillo Sergio , Pascual-Lucas María , Na Duk L. , Seo Sang Won ,   on behalf of DPUK
Published: March 2023

Background

Early detection of β-amyloid (Aβ) accumulation, a major biomarker for Alzheimer’s disease (AD), has become important. As fluid biomarkers, the accuracy of cerebrospinal fluid (CSF) Aβ for predicting Aβ deposition on positron emission tomography (PET) has been extensively studied, and the development of plasma Aβ is beginning to receive increased attention recently. In the present study, we aimed to determine whether APOE genotypes, age, and cognitive status increase the predictive performance of plasma Aβ and CSF Aβ levels for Aβ PET positivity.

Methods

We recruited 488 participants who underwent both plasma Aβ and Aβ PET studies (Cohort 1) and 217 participants who underwent both cerebrospinal fluid (CSF) Aβ and Aβ PET studies (Cohort 2). Plasma and CSF samples were analyzed using ABtest-MS, an antibody-free liquid chromatography-differential mobility spectrometry-triple quadrupole mass spectrometry method and INNOTEST enzyme-linked immunosorbent assay kits, respectively. To evaluate the predictive performance of plasma Aβ and CSF Aβ, respectively, logistic regression and receiver operating characteristic analyses were performed.

Results

When predicting Aβ PET status, both plasma Aβ42/40 ratio and CSF Aβ42 showed high accuracy (plasma Aβ area under the curve (AUC) 0.814; CSF Aβ AUC 0.848). In the plasma Aβ models, the AUC values were higher than plasma Aβ alone model, when the models were combined with either cognitive stage (p < 0.001) or APOE genotype (p = 0.011). On the other hand, there was no difference between the CSF Aβ models, when these variables were added.

Conclusion

Plasma Aβ might be a useful predictor of Aβ deposition on PET status as much as CSF Aβ, particularly when considered with clinical information such as APOE genotype and cognitive stage.
Arc ubiquitination regulates endoplasmic reticulum-mediated Ca2+ release and CaMKII signaling
Authors: Ghane Mohammad A. , Wei Wei , Yakout Dina W. , Allen Zachary D. , Miller Cassandra L. , Dong Bin , Yang Jenny J. , Fang Ning , Mabb Angela M.
Published: March 2023

Synaptic plasticity relies on rapid, yet spatially precise signaling to alter synaptic strength. Arc is a brain enriched protein that is rapidly expressed during learning-related behaviors and is essential for regulating metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD). We previously showed that disrupting the ubiquitination capacity of Arc enhances mGluR-LTD; however, the consequences of Arc ubiquitination on other mGluR-mediated signaling events is poorly characterized. Here we find that pharmacological activation of Group I mGluRs with S-3,5-dihydroxyphenylglycine (DHPG) increases Ca2+ release from the endoplasmic reticulum (ER). Disrupting Arc ubiquitination on key amino acid residues enhances DHPG-induced ER-mediated Ca2+ release. These alterations were observed in all neuronal subregions except secondary branchpoints. Deficits in Arc ubiquitination altered Arc self-assembly and enhanced its interaction with calcium/calmodulin-dependent protein kinase IIb (CaMKIIb) and constitutively active forms of CaMKII in HEK293 cells. Colocalization of Arc and CaMKII was altered in cultured hippocampal neurons, with the notable exception of secondary branchpoints. Finally, disruptions in Arc ubiquitination were found to increase Arc interaction with the integral ER protein Calnexin. These results suggest a previously unknown role for Arc ubiquitination in the fine tuning of ER-mediated Ca2+ signaling that may support mGluR-LTD, which in turn, may regulate CaMKII and its interactions with Arc.
The adenosine hypothesis of schizophrenia into its third decade: From neurochemical imbalance to early life etiological risks
Authors: Singer Philipp , Yee Benjamin K.
Published: March 2023

The adenosine hypothesis of schizophrenia was conceptualized about two decades ago in an attempt to integrate two prominent theories of neurochemical imbalance that attribute the pathogenesis of schizophrenia to hyperfunction of the mesocorticolimbic dopamine neurotransmission and hypofunction of cortical glutamate neurotransmission. Given its unique position as an endogenous modulator of both dopamine and glutamate signaling in the brain, adenosine was postulated as a potential new drug target to achieve multiple antipsychotic actions. This new strategy may offer hope for improving treatment, especially in alleviating negative symptoms and cognitive deficits of schizophrenia that do not respond to current medications. To date, however, the adenosine hypothesis has yet led to any significant therapeutic breakthroughs. Here, we address two possible reasons for the impasse. First, neither the presence of adenosine functional deficiency in people with schizophrenia nor its causal relationship to symptom production has been satisfactorily examined. Second, the lack of novel adenosine-based drugs also impedes progress. This review updates the latest preclinical and clinical data pertinent to the construct validity of the adenosine hypothesis and explores novel molecular processes whereby dysregulation of adenosine signaling could be linked to the etiology of schizophrenia. It is intended to stimulate and revitalize research into the adenosine hypothesis towards the development of a new and improved generation of antipsychotic drugs that has eluded us for decades.
Unified ICH quantification and prognosis prediction in NCCT images using a multi-task interpretable network
Authors: Gong Kai , Dai Qian , Wang Jiacheng , Zheng Yingbin , Shi Tao , Yu Jiaxing , Chen Jiangwang , Huang Shaohui , Wang Zhanxiang
Published: March 2023

With the recent development of deep learning, the regression, classification, and segmentation tasks of Computer-Aided Diagnosis (CAD) using Non-Contrast head Computed Tomography (NCCT) for spontaneous IntraCerebral Hematoma (ICH) have become popular in the field of emergency medicine. However, a few challenges such as time-consuming of ICH volume manual evaluation, excessive cost demanding patient-level predictions, and the requirement for high performance in both accuracy and interpretability remain. This paper proposes a multi-task framework consisting of upstream and downstream components to overcome these challenges. In the upstream, a weight-shared module is trained as a robust feature extractor that captures global features by performing multi-tasks (regression and classification). In the downstream, two heads are used for two different tasks (regression and classification). The final experimental results show that the multi-task framework has better performance than single-task framework. And it also reflects its good interpretability in the heatmap generated by Gradient-weighted Class Activation Mapping (Grad-CAM), which is a widely used model interpretation method, and will be presented in subsequent sections.
Systematic identification of potential key microRNAs and circRNAs in the dorsal root ganglia of mice with sciatic nerve injury
Authors: Yu Youfen , Xu Xueru , Lin Chun , Liu Rongguo
Published: March 2023

Background

Neuropathic pain (NeP) is a pathological condition arising from a lesion or disease affecting the somatosensory system. Accumulating evidence has shown that circular RNAs (circRNAs) exert critical functions in neurodegenerative diseases by sponging microRNAs (miRNAs). However, the functions and regulatory mechanisms of circRNAs as competitive endogenous RNAs (ceRNAs) in NeP remain to be determined.

Methods

The sequencing dataset GSE96051 was obtained from the public Gene Expression Omnibus (GEO) database. First, we conducted a comparison of gene expression profiles in the L3/L4 dorsal root ganglion (DRG) of sciatic nerve transection (SNT) mice (n = 5) and uninjured mice (Control) (n = 4) to define the differentially expressed genes (DEGs). Then, critical hub genes were screened by exploring protein–protein interaction (PPI) networks with Cytoscape software, and the miRNAs bound to them were predicted and selected and then validated by qRT-PCR. Furthermore, key circRNAs were predicted and filtered, and the network of circRNA-miRNA-mRNA in NeP was constructed.

Results

A total of 421 DEGs were identified, including 332 upregulated genes and 89 downregulated genes. Ten hub genes, including IL6, Jun, Cd44, Timp1, and Csf1, were identified. Two miRNAs, mmu-miR-181a-5p and mmu-miR-223-3p, were preliminarily verified as key regulators of NeP development. In addition, circARHGAP5 and circLPHN3 were identified as key circRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that these differentially expressed mRNAs and targeting miRNAs were involved in signal transduction, positive regulation of receptor-mediated endocytosis and regulation of neuronal synaptic plasticity. These findings have useful implications for the exploration of new mechanisms and therapeutic targets for NeP.

Conclusion

These newly identified miRNAs and circRNAs in networks reveal potential diagnostic or therapeutic targets for NeP.
Facilitators and barriers associated with breastfeeding among mothers attending primary healthcare facilities in Mpumalanga, South Africa
Authors: Seabela Ethel Sekori , Modjadji Perpetua , Mokwena Kebogile Elizabeth
Published: March 2023

Introduction

Despite the health benefits of breastfeeding for both the mother and the child, early cessation of breastfeeding remains a public health problem in South Africa, attributed to contextual barriers and facilitators. Within the context of Mpumalanga province, which is characterized by low breastfeeding rates and high infant mortality rates in children under 5 years, we explored the facilitators and barriers to breastfeeding among mothers attending the three primary health facilities in Ermelo.

Methods

Using a semi-structured interview guide suggested by the socio-ecological model, three focus group discussions and 12 in-depth interviews were conducted among mothers selected using a purposive sampling. Transcripts from audiotaped and transcribed verbatim interviews were assessed through thematic analysis using NVivo version 10.

Results

Mothers were aged between 18 and 42 years and from poor sociodemographic backgrounds. At the individual level, mothers valued breastfeeding facilitated by their commitment, maintaining it, eating healthy foods, and having sufficient breast milk. However, returning to work, insufficient breast milk, misconceptions about breastfeeding, and interference with social life were the barriers for mothers to breastfeed continuously. At the interpersonal level, the family was identified as the main form of support to breastfeeding mothers; however, family interference was also identified as a barrier. At the community level, mothers shared some family beliefs and practices but were still split between societal and cultural norms and traditional beliefs as facilitators or barriers to breastfeeding. At the organizational level, most mothers valued the support provided by healthcare workers on childcare and techniques for breastfeeding at the health facilities. They did however articulate concerns on the miscommunication some healthcare workers offered regarding breastfeeding, which negatively influenced their infant feeding practices.

Discussion

Intervention efforts should focus on behaviour change to educate and equip mothers to overcome the barriers that are within their control. Such interventions should further focus on family-centered education and strengthening the proficiency of healthcare workers on advising breastfeeding mothers.
Analyzing the influence of withering degree on the dynamic changes in non-volatile metabolites and sensory quality of Longjing green tea by non-targeted metabolomics
Authors: Shan Xujiang , Yu Qinyan , Chen Le , Zhang Shan , Zhu Jiayi , Jiang Yongwen , Yuan Haibo , Zhou Qinghua , Li Ji , Wang Yujie , Deng Yuliang , Li Jia
Published: March 2023

Withering is an important processing stage in green tea, which contributes to the tea flavor quality. The aim of this work was to comprehensively investigate the changes of chemical features and flavor attributes in Longjing green teas produced with five different withering degrees (moisture content of 75.05, 72.53, 70.07, 68.00, and 64.78%, w.b.). Combined with human sensory evaluation, electronic tongue and chromatic differences analysis, an assessment of the relationship between the withering degree and the sensory quality of Longjing tea was obtained. By using a non-targeted metabolomics approach, 69 significantly differential metabolites were screened. As the withering degree increased, most free amino acids and catechin dimers were increased, largely attributed to the hydrolysis of proteins and catechin oxidative polymerization, respectively. The contents of organic acids as well as phenolic acids and derivatives were reduced. Interestingly, flavone C-glycosides decreased overall while flavonol O-glycosides increased. The correlation analysis revealed that metabolites such as theasinensin F, theasinensin B, theaflavin, theaflavin-3,3′-gallate, theaflavin-3′-gallate, malic acid, succinic acid, quinic acid, theanine glucoside and galloylglucose had a greater influence on the taste and color of tea infusion (|r| > 0.6, p < 0.05). Overall, an appropriate withering degree at a moisture content of around 70% is more favorable to enhance the Longjing tea quality. These results may enhance the understanding of green tea flavor chemistry associated with withering and provide a theoretical basis for green tea processing.
Cost-effectiveness of palbociclib plus fulvestrant as second-line therapy of women with HR+/HER2- advanced breast cancer - A Chinese healthcare system perspective
Authors: Zhu Wentao , Zheng Miaomiao , Xia Panpan , Hong Wanglong , Ma Guoqiang , Shen Aizong
Published: March 2023

Aim

To evaluate the cost-effectiveness of palbociclib plus fulvestrant in the second-line treatment of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer based on the latest published follow-up data from the perspective of the Chinese healthcare system.

Methods

In view of the PALOMA-3 trial, a Markov model was built for this purpose, which included three health states: progression-free survival (PFS), progressed disease (PD), and death. The cost and health utilities were mainly derived from the published literature. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to verify the robustness of the model.

Results

In the base case analysis, compared with the placebo plus fulvestrant arm, the palbociclib plus fulvestrant arm yielded an additional 0.65 quality-adjusted life years (QALYs) (2.56 QALYs vs. 1.90 QALYs) with an incremental cost of $36,139.94 ($55,482.06 vs. $19,342.12), resulting an incremental cost-effectiveness ratio (ICER) of $55,224.90/QALY, which was deeply higher than a willingness-to-pay (WTP) threshold of $34,138.28 per QALY in China. The results of one-way sensitivity analysis indicated that the utility of PFS, cost of palbociclib, and cost of neutropenia had a great influence on the ICER.

Conclusions

Palbociclib plus fulvestrant is unlikely to be cost-effective in comparison with placebo plus fulvestrant as second-line therapy of women with HR+/HER2- advanced breast cancer.
The 20 years transition of clinical characteristics and metabolic risk factors in primary liver cancer patients from China
Authors: Ding Yezhou , Feng Mingyang , Ma Di , Zhao Gangde , Wang Xiaolin , An Baoyan , Xu Yumin , Lou Shike , Lin Lanyi , Xie Qing , Liu Kehui , Bao Shisan , Wang Hui
Published: March 2023

Background

The clinical characteristics of primary liver cancer (PLC) patients are changing, maybe due to hepatitis viral vaccination and lifestyle changes, etc. The linkage between these changes and outcomes among these PLCs has not yet been fully elucidated.

Methods

It was identified total of 1691 PLC cases diagnosed between 2000 ~ 2020. Cox proportional hazards models were utilized to determine the connections between the clinical presentations and their close risk factor(s) from PLC patients.

Results

The average age of PLC patients increased gradually from 52.74 ± 0.5 years in 2000 ~ 2004 to 58.63 ± 0.44 years in 2017 ~ 2020, accompanied by an increased proportion of females from 11.11% to 22.46%, and non-viral hepatitis-related PLC was raised from 1.5% to 22.35%. 840 (49.67%) PLC patients with alpha-fetoprotein (AFP) < 20ng/mL (AFP-negative). The mortality was 285 (16.85%) or 532 (31.46%) PLC patients with alanine transaminase (ALT) between 40 ~ 60 IU/L or ALT > 60 IU/L. The PLC patients with pre-diabetes/diabetes or dyslipidemia also increased from 4.29% or 11.1% in 2000 ~ 2004 to 22.34% or 46.83% in 2017 ~ 2020. The survival period of the PLC patients with normoglycemia or normolipidemic was 2.18 or 3.14 folds longer than those patients with pre-diabetes/diabetes or hyperlipidemia (P<0.05).

Conclusions

It was gradually increased that age, the proportion of females, non-viral hepatitis-related causes, AFP-negative, and abnormal glucose/lipids among PLC patients. Proper control of glucose/lipids or ALT may improve the prognosis of PLCs.
Concerns and priority outcomes for children with advanced cancer and their families in the Middle East: A cross-national qualitative study
Authors: Boufkhed Sabah , Yurduşen Sema , Alarjeh Ghadeer , Ahmed Fahad , Alrjoub Waleed , Guo Ping , Alajarmeh Sawsan , Şengelen Meltem , Cemaloğlu Mustafa , Aydın Burça , Alnassan Anwar , Al-Awady Shireen , Kutluk Tezer , Shamieh Omar , Harding Richard
Published: March 2023

Introduction

Palliative care access is limited in the Middle-East, with few specialist centers and forcibly displaced migrants facing additional struggles to access care. Little is known about the specificities of providing palliative care to children and young people (CYP) with cancer. They are rarely asked directly their concerns and needs, which limits the provision of quality patient-centered care. Our study aims to identify the concerns and needs of CYP with advanced cancer and their families, in Jordan and Turkey.

Method

A qualitative cross-national study in Jordan and Turkey with framework analysis was conducted two pediatric cancer centers in Jordan and Turkey. In each country, 25 CYP, 15 caregivers and 12 healthcare professionals participated (N=104). Most caregivers (70%) and healthcare professionals (75%) were women.

Results

We identified five areas of concern: (1) Physical pain and other symptoms (e.g. mobility, fatigue); (2) Psychological concerns and needs (e.g. anger, psychological changes); (3) Spirituality, uncertainty over the future and use of “Tawakkul” (e.g. use of religion as a coping mechanism); (4) Negative impact on social life (e.g. social isolation, loss of support); (5) Burden on caregiver and their families (e.g. financial issues, siblings left behind). Psychological concerns were a priority for both CYPs and caregivers (particularly for refugee and displaced families) but often overlooked during routine care. CYP were able to share their own concerns and care priorities.

Conclusions

Advanced cancer care must ensure assessment and management of concerns across the concerns identified. Developing child- and family-centered outcomes would ensure monitoring the quality of care. Spirituality had a more important role compared to similar investigation in other regions.
Optimization of postoperative surveillance protocols in upper tract urothelial cancer: A retrospective cohort study
Authors: Lindner Andrea Katharina , Pichler Martin , Maier Sarah , Ulmer Hanno , Gorreri Thomas , Luger Anna Katharina , Barth Dominik A. , Seeber Andreas , Kocher Florian , Pichler Renate
Published: March 2023

Upper tract urothelial carcinoma (UTUC) is an aggressive disease that is managed by radical or organ-sparing surgery. High recurrence rates require early detection and strict follow-up (FU) protocols. Recommendations are assigned to a low level of evidence. Our aim was to identify time-to-tumor recurrence, analyze the temporal relation to recommended FU regimens, and provide a critical proposal for further surveillance. This retrospective study included 54 patients receiving radical nephroureterectomy (RNU) in high-risk UTUC and 14 patients assigned to kidney-sparing surgery (KSS) with low-risk disease. FU surveillance protocols consisted of close intervals irrespective of the received type of surgery. In total, 68 patients were included with a median FU of 23 months. Mean overall survival (OS) was significantly shorter in RNU compared to KSS (P = .027). Recurrence in the bladder and/or upper urinary tract (UUT) was 57.1% in KSS and 38.9% after RNU (P = .241). Mean recurrence-free survival (RFS) was significantly shorter in RNU patients compared to KSS (22.4 vs. 47.9 months, P = .013), and 76.2% of the recurrences in the RNU group occurred in the first postoperative year. UUT recurrence was diagnosed after a median of 3.0 (RNU) and 25.0 (KSS) months. There was a frequent onset of metastases in the RNU group, with 85.7% in the first year compared to the KSS group with 50%. Multivariable regression analysis showed that the tumor stage was the parameter independently related to OS (P = .002), RFS (P = .008), and metastasis-free survival (MFS, P = .002). In conclusion, surveillance of UTUC should be adapted to real-time occurrence patterns. Strict imaging protocols are recommended in the first two years irrespective of the method of surgery. As recurrence is equally distributed over the years after KSS, cystoscopy should be offered regularly for five years and diagnostic URS for three years. After RNU, cystoscopies should be decreased to yearly intervals after year three. Contralateral UUT should also be examined after RNU.
Impact of lenvatinib-induced proteinuria and renal dysfunction in patients with thyroid cancer
Authors: Shibutani Yuma , Suzuki Shinya , Sagara Atsunobu , Enokida Tomohiro , Okano Susumu , Fujisawa Takao , Sato Fumiaki , Yumoto Tetsuro , Sano Motohiko , Kawasaki Toshikatsu , Tahara Makoto
Published: March 2023

Background

Proteinuria is the most frequent adverse event of lenvatinib use. However, the association between lenvatinib-induced proteinuria and renal dysfunction remains unclear.

Methods

We retrospectively reviewed medical records of patients with thyroid cancer without proteinuria treated with lenvatinib as a first-line systemic therapy at the initiation of treatment to assess the association between lenvatinib-induced proteinuria and renal function and the risk factors for the development of ≥3+ proteinuria on a dipstick test. Proteinuria was assessed by the dipstick test throughout the treatment in all cases.

Results

Of the 76 patients, 39 developed ≤2+ proteinuria (low proteinuria group) and 37 developed ≥3+ proteinuria (high proteinuria group). There was no significant difference in estimated glomerular filtration rate (eGFR) between high and low proteinuria groups at each time point, but there was a trend toward a significant decrease in eGFR of -9.3 ml/min/1.73 m2 in all patients after 2 years of treatment. The percentage of change in eGFR (ΔeGFR) significantly decreased in the high proteinuria group compared to that in the low proteinuria group (ΔeGFR: -6.8% vs. -17.2%, p=0.04). However, there was no significant difference in development of severe renal dysfunction with eGFR <30 ml/min/1.73 m2 between the two groups. Moreover, no patients permanently discontinued treatment because of renal dysfunction in both groups. Furthermore, renal function after completion of lenvatinib was reversible.

Conclusions

There was no association between the degree of lenvatinib-induced proteinuria and renal function. Therefore, treatment should be continued with attention to renal function, regardless of the degree of proteinuria.
Case report: Gene mutations and clinical characteristics of four patients with osteopetrosis
Authors: Chen Yu , Zhou Lina , Guan Xianmin , Wen Xianhao , Yu Jie , Dou Ying
Published: March 2023

Osteopetrosis is characterized by increased bone density caused by decreased osteoclasts or dysfunction of their differentiation and absorption properties, usually caused by biallelic variants of the TCIRG1(OMIM:604592)and CLCN7(OMIM:602727) genes. Herein, the clinical, biochemical, and radiological manifestations of osteopetrosis in four Chinese children are described. Whole-exome sequencing identified compound heterozygous variants of the CLCN7 and TCIRG1 genes in these patients. In Patient 1, two novel variants were identified in CLCN7:c.880T > G(p.F294V) and c.686C > G(p.S229X). Patient 2 harbored previously reported a single gene variant c.643G > A(p.G215R) in CLCN7. Patient 3 had a novel variant c.569A > G(p.N190S) and a novel frameshift variant c.1113dupG(p.N372fs) in CLCN7. Patient 4 had a frameshift variant c.43delA(p.K15fs) and variant c.C1360T in TCIRG1, resulting in the formation of a premature termination codon (p.R454X), both of which were reported previously. Our results expand the spectrum of identified genetic variation in osteopetrosis and provide a deeper understanding of the relations between genotype and clinical characteristics of this disorder.
Risk prediction of bronchopulmonary dysplasia in preterm infants by the nomogram model
Authors: Gao Yang , Liu Dongyun , Guo Yingmeng , Cao Menghan
Published: March 2023

Backgrounds and Aims

Bronchopulmonary dysplasia (BPD) has serious immediate and long-term sequelae as well as morbidity and mortality. The objective of this study is to develop a predictive model of BPD for premature infants using clinical maternal and neonatal parameters.

Methods

This single-center retrospective study enrolled 237 cases of premature infants with gestational age less than 32 weeks. The research collected demographic, clinical and laboratory parameters. Univariate logistic regression analysis was carried out to screen the potential risk factors of BPD. Multivariate and LASSO logistic regression analysis was performed to further select variables for the establishment of nomogram models. The discrimination of the model was assessed by C-index. The Hosmer-Lemeshow test was used to assess the calibration of the model.

Results

Multivariate analysis identified maternal age, delivery option, neonatal weight and age, invasive ventilation, and hemoglobin as risk predictors. LASSO analysis selected delivery option, neonatal weight and age, invasive ventilation, hemoglobin and albumin as the risk predictors. Both multivariate (AUC = 0.9051; HL P = 0.6920; C-index = 0.910) and LASSO (AUC = 0.8935; HL P = 0.7796; C-index = 0.899) - based nomograms exhibited ideal discrimination and calibration as confirmed by validation dataset.

Conclusions

The probability of BPD in a premature infant could be effectively predicted by the nomogram model based on the clinical maternal and neonatal parameters. However, the model required external validation using larger samples from multiple medical centers.