bluuebunny/crossref_metadata_2025 huggingface dataset:
Babesia microti Infection Inhibits Melanoma Growth by Activating Macrophages in Mice
Authors: Shu Xiang , Nie Zheng , Luo Wanxin , Zheng Yaxin , Han Zhen , Zhang Hongyan , Xia Yingjun , Deng Han , Li Fangjie , Wang Sen , Zhao Junlong , He Lan
Published: June 2022

Babesia microti is an obligate intraerythrocytic protozoan transmitted by an Ixodes tick. Infections caused by protozoa, including Plasmodium yoelii and Toxoplasma gondii, are shown to inhibit tumor development by activating immune responses. Th1 immune response and macrophages not only are essential key factors in Babesia infection control but also play an important role in regulating tumor development. In this study, we investigated the effects of B. microti infection on melanoma in tumor-bearing mice. The results showed that B. microti infection could inhibit the growth of melanoma, significantly enlarge the spleen size (p ≤ 0.0001), and increase the survival period (over 7 days) of tumor-bearing mice. Mouse spleen immune cell analysis revealed that B. microti-infected tumor-bearing mice could increase the number of macrophages and CD4+ T cells, as well as the proportion of CD4+ T cells and M1 macrophages in the tumor. Immunohistochemical assays showed that B. microti infection could inhibit tumor angiogenesis (p ≤ 0.0032). Meanwhile, both B. microti-infected erythrocytes and culture supernatant were observed to significantly (p ≤ 0.0021) induce the mRNA expression of iNOS, IL-6, and TNF-α in macrophages. Moreover, B. microti culture supernatant could also repolarize IL-4-induced M2 macrophages to the M1 type. Overall, B. microti exerted antitumor effects by stimulating the immune system of tumor-bearing mice and inducing the polarization of immunosuppressive M2 macrophages to pro-inflammatory M1 macrophages.
The Impact of COVID-19 Pandemic on Seafood Safety and Human Health
Authors: Rathod Nikheel Bhojraj , Elabed Nariman , Özogul Fatih , Regenstein Joe M. , Galanakis Charis M. , Aljaloud Sulaiman Omar , Ibrahim Salam A.
Published: June 2022

The coronavirus disease (COVID-19) pandemic caused several negative impacts on global human health and the world’s economy. Food and seafood safety and security were among the principal challenges and causes of concern for the food industry and consumers during the spread of this global pandemic. This article focused on the effects of COVID-19 pandemic on potential safety issues with seafood products and their processing methods. Moreover, the potential impacts of coronavirus transmission through seafood on human health were evaluated. The role of authenticity, traceability, and antimicrobials from natural sources to preserve seafood and the possible interaction of functional foods on the human immune system are also discussed. Although seafood is not considered a principal vector of SARS-CoV-2 transmission, the possible infections through contaminated surfaces of such food products cannot be neglected. The positive effects of seafood consumption on possible immunity built up, and COVID-19 are also summarized.
Serum Pregenomic RNA Combined With Hepatitis B Core-Related Antigen Helps Predict the Risk of Virological Relapse After Discontinuation of Nucleos(t)ide Analogs in Patients With Chronic Hepatitis B
Authors: Wang Fa-Da , Zhou Jing , Li Lan-Qing , Wang Meng-Lan , Tao Ya-Cao , Wang Yong-Hong , Zhang Dong-Mei , Chen En-Qiang
Published: June 2022

Background and Aim

Cessation of nucleos(t)ide analogs (NAs) therapy in patients with chronic hepatitis B (CHB) is uncommon. Although criteria for discontinuation appear in some guidelines, the indicators for assessing discontinuation of NAs are limited, whether NAs can be safely ceased remains a difficult clinical issue. Our study aimed to investigate the role of serum pregenomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) at the end of treatment (EOT) in guiding the safe discontinuation of NAs in CHB patients.

Methods

This is a retrospective study, clinical data of all CHB patients who discontinued NAs treatment at West China Hospital between June 2020 and January 2021 were collected, including EOT pgRNA, HBcrAg, hepatitis B surface antigen (HBsAg), etc. All patients should meet the Asian-Pacific guideline for discontinuation. Observing virological relapse (VR) rates during 1 year of NAs discontinuation and analyzing the relationship between EOT pgRNA, HBcrAg, and VR.

Results

A total of 64 patients were enrolled in this study and 33 (51.5%) patients experienced VR in 1 year. EOT pgRNA positivity (OR = 14.59, p = 0.026) and EOT higher HBcrAg levels (OR = 14.14, p = 0.001) were independent risk factors for VR. The area under the receiver-operating characteristic (AUROC) value of EOT HBcrAg for VR was 0.817 (p < 0.001), optimal cut-off value was 3.3 log10 U/mL. Patients with EOT pgRNA positivity and EOT HBcrAg >3.3 log10 U/mL were more likely to experience VR after discontinuation of NAs (88.9 vs. 45.5%, p = 0.027).

Conclusion

According to current guidelines, a higher VR rate occurs after cessation of NAs. EOT pgRNA positivity and higher HBcrAg level carries a higher risk of VR. Combining these novel markers can better help us assess whether patients can safely cease NAs treatment.
Immunogenicity of Mycobacterial Extracellular Vesicles Isolated From Host-Related Conditions Informs About Tuberculosis Disease Status
Authors: Schirmer Sebastian , Rauh Lucas , Alebouyeh Sogol , Delgado-Velandia Mario , Salgueiro Vivian C. , Lerma Laura , Serrano-Mestre José L. , Azkargorta Mikel , Elortza Félix , Lavín José L. , García Maria Jesus , Tórtola Fernández María Teresa , Gola Susanne , Prados-Rosales Rafael
Published: June 2022

Tuberculosis (TB) still represents a major global health problem affecting over 10 million people worldwide. The gold-standard procedures for TB diagnosis are culture and nucleic acid amplification techniques. In this context, both lipoarabinomannan (LAM) urine test and rapid molecular tests have been major game changers. However, the low sensitivity of the former and the cost and the prohibitive infrastructure requirements to scale-up in endemic regions of the latter, make the improvement of the TB diagnostic landscape a priority. Most forms of life produce extracellular vesicles (EVs), including bacteria despite differences in bacterial cell envelope architecture. We demonstrated that Mycobacterium tuberculosis (Mtb), the causative agent of TB, produces EVs in vitro and in vivo as part of a sophisticated mechanism to manipulate host cellular physiology and to evade the host immune system. In a previous serology study, we showed that the recognition of several mycobacterial extracellular vesicles (MEV) associated proteins could have diagnostic properties. In this study, we pursued to expand the capabilities of MEVs in the context of TB diagnostics by analyzing the composition of MEVs isolated from Mtb cultures submitted to iron starvation and, testing their immunogenicity against a new cohort of serum samples derived from TB+ patients, latent TB-infected (LTBI) patients and healthy donors. We found that despite the stringent condition imposed by iron starvation, Mtb reduces the number of MEV associated proteins relative to iron sufficient conditions. In addition, TB serology revealed three new MEV antigens with specific biomarker capacity. These results suggest the feasibility of developing a point-of-care (POC) device based on selected MEV-associated proteins.
Temporal Alignment of Longitudinal Microbiome Data
Authors: Armoni Ran , Borenstein Elhanan
Published: June 2022

A major challenge in working with longitudinal data when studying some temporal process is the fact that differences in pace and dynamics might overshadow similarities between processes. In the case of longitudinal microbiome data, this may hinder efforts to characterize common temporal trends across individuals or to harness temporal information to better understand the link between the microbiome and the host. One possible solution to this challenge lies in the field of “temporal alignment” – an approach for optimally aligning longitudinal samples obtained from processes that may vary in pace. In this work we investigate the use of alignment-based analysis in the microbiome domain, focusing on microbiome data from infants in their first years of life. Our analyses center around two main use-cases: First, using the overall alignment score as a measure of the similarity between microbiome developmental trajectories, and showing that this measure can capture biological differences between individuals. Second, using the specific matching obtained between pairs of samples in the alignment to highlight changes in pace and temporal dynamics, showing that it can be utilized to predict the age of infants based on their microbiome and to uncover developmental delays. Combined, our findings serve as a proof-of-concept for the use of temporal alignment as an important and beneficial tool in future longitudinal microbiome studies.
Sodium Benzoate Delays the Development of Drosophila melanogaster Larvae and Alters Commensal Microbiota in Adult Flies
Authors: Dong Yuling , Ding Zhongfeng , Song Linxia , Zhang Desheng , Xie Changjian , Zhang Shujing , Feng Ling , Liu Hongliang , Pang Qiuxiang
Published: June 2022

Sodium benzoate (SB), the sodium salt of benzoic acid, is widely used as a preservative in foods and drinks. The toxicity of SB to the human body attracted people’s attention due to the excessive use of preservatives and the increased consumption of processed and fast foods in modern society. The SB can inhibit the growth of bacteria, fungi, and yeast. However, less is known of the effect of SB on host commensal microbial community compositions and their functions. In this study, we investigated the effect of SB on the growth and development of Drosophila melanogaster larvae and whether SB affects the commensal microbial compositions and functions. We also attempted to clarify the interaction between SB, commensal microbiota and host development by detecting the response of commensal microbiota after the intervention. The results show that SB significantly retarded the development of D. melanogaster larvae, shortened the life span, and changed the commensal microbial community. In addition, SB changed the transcription level of endocrine coding genes such as ERR and DmJHAMT. These results indicate that the slow down in D. melanogaster larvae developmental timing and shortened life span of adult flies caused by SB intake may result from the changes in endocrine hormone levels and commensal microbiota. This study provided experimental data that indicate SB could affect host growth and development of D. melanogaster through altering endocrine hormone levels and commensal microbial composition.
Antibiotic-Induced Changes in Pigment Accumulation, Photosystem II, and Membrane Permeability in a Model Cyanobacterium
Authors: Yalcin Yavuz S. , Aydin Busra N. , Sayadujjhara Mst , Sitther Viji
Published: June 2022

Fremyella diplosiphon is a well-studied a model cyanobacterium for photosynthesis due to its efficient light absorption potential and pigment accumulation. In the present study, the impact of ampicillin, tetracycline, kanamycin, and cefotaxime on pigment fluorescence and photosynthetic capacity in Fremyella diplosiphon strains B481-WT and B481-SD was investigated. Our results indicated that both strains exposed to kanamycin from 0.2 to 3.2 mg/L and tetracycline from 0.8 to 12.8 mg/L enhanced growth and pigment accumulation. Additionally, B481-SD treated with 0.2–51.2 mg/L ampicillin resulted in a significant enhancement of pigment fluorescence. A detrimental effect on growth and pigmentation in both the strains exposed to 6.4–102.5 mg/L kanamycin and 0.8–102.5 mg/L cefotaxime was observed. Detection of reactive oxygen species revealed highest levels of oxidative stress at 51.2 and 102.5 mg/L kanamycin for B481-SD and 102.5 mg/L for B481-WT. Membrane permeability detected by lactate dehydrogenase assay indicated maximal activity at 0.8 mg/L ampicillin, kanamycin, and tetracycline treatments on day 6. Abundant vacuolation, pyrophosphate, and cyanophycin granule formation were observed in treated cells as a response to antibiotic stress. These findings on the hormetic effect of antibiotics on F. diplosiphon indicate that optimal antibiotic concentrations induce cellular growth while high concentrations severely impact cellular functionality. Future studies will be aimed to enhance cellular lipid productivity at optimal antibiotic concentrations to disintegrate the cell wall, thus paving the way for clean bioenergy applications.
DNA Damage Response Gene-Based Subtypes Associated With Clinical Outcomes in Early-Stage Lung Adenocarcinoma
Authors: Zhao Yang , Qing Bei , Xu Chunwei , Zhao Jing , Liao Yuchen , Cui Peng , Wang Guoqiang , Cai Shangli , Song Yong , Cao Liming , Duan Jianchun
Published: June 2022

DNA damage response (DDR) pathways play a crucial role in lung cancer. In this retrospective analysis, we aimed to develop a prognostic model and molecular subtype based on the expression profiles of DDR-related genes in early-stage lung adenocarcinoma (LUAD). A total of 1,785 lung adenocarcinoma samples from one RNA-seq dataset of The Cancer Genome Atlas (TCGA) and six microarray datasets of Gene Expression Omnibus (GEO) were included in the analysis. In the TCGA dataset, a DNA damage response gene (DRG)–based signature consisting of 16 genes was constructed to predict the clinical outcomes of LUAD patients. Patients in the low-DRG score group had better outcomes and lower genomic instability. Then, the same 16 genes were used to develop DRG-based molecular subtypes in the TCGA dataset to stratify early-stage LUAD into two subtypes (DRG1 and DRG2) which had significant differences in clinical outcomes. The Kappa test showed good consistency between molecular subtype and DRG (K = 0.61, p < 0.001). The DRG subtypes were significantly associated with prognosis in the six GEO datasets (pooled estimates of hazard ratio, OS: 0.48 (0.41–0.57), p < 0.01; DFS: 0.50 (0.41–0.62), p < 0.01). Furthermore, patients in the DRG2 group benefited more from adjuvant therapy than standard-of-care, which was not observed in the DRG1 group. In summary, we constructed a DRG-based molecular subtype that had the potential to predict the prognosis of early-stage LUAD and guide the selection of adjuvant therapy for early-stage LUAD patients.
The Future of Seed Amplification Assays and Clinical Trials
Authors: Coysh Thomas , Mead Simon
Published: June 2022

Prion-like seeded misfolding of host proteins is the leading hypothesised cause of neurodegenerative diseases. The exploitation of the mechanism in the protein misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC) assays have transformed prion disease research and diagnosis and have steadily become more widely used for research into other neurodegenerative disorders. Clinical trials in adult neurodegenerative diseases have been expensive, slow, and disappointing in terms of clinical benefits. There are various possible factors contributing to the failure to identify disease-modifying treatments for adult neurodegenerative diseases, some of which include: limited accuracy of antemortem clinical diagnosis resulting in the inclusion of patients with the “incorrect” pathology for the therapeutic; the role of co-pathologies in neurodegeneration rendering treatments targeting one pathology alone ineffective; treatment of the primary neurodegenerative process too late, after irreversible secondary processes of neurodegeneration have become established or neuronal loss is already extensive; and preclinical models used to develop treatments not accurately representing human disease. The use of seed amplification assays in clinical trials offers an opportunity to tackle these problems by sensitively detecting in vivo the proteopathic seeds thought to be central to the biology of neurodegenerative diseases, enabling improved diagnostic accuracy of the main pathology and co-pathologies, and very early intervention, particularly in patients at risk of monogenic forms of neurodegeneration. The possibility of quantifying proteopathic seed load, and its reduction by treatments, is an attractive pharmacodynamic biomarker in the preclinical and early clinical stages of drug development. Here we review some potential applications of seed amplification assays in clinical trials.
Atonal Music as a Model for Investigating Exploratory Behavior
Authors: Mencke Iris , Omigie Diana , Quiroga-Martinez David Ricardo , Brattico Elvira
Published: June 2022

Atonal music is often characterized by low predictability stemming from the absence of tonal or metrical hierarchies. In contrast, Western tonal music exhibits intrinsic predictability due to its hierarchical structure and therefore, offers a directly accessible predictive model to the listener. In consequence, a specific challenge of atonal music is that listeners must generate a variety of new predictive models. Listeners must not only refrain from applying available tonal models to the heard music, but they must also search for statistical regularities and build new rules that may be related to musical properties other than pitch, such as timbre or dynamics. In this article, we propose that the generation of such new predictive models and the aesthetic experience of atonal music are characterized by internal states related to exploration. This is a behavior well characterized in behavioral neuroscience as fulfilling an innate drive to reduce uncertainty but which has received little attention in empirical music research. We support our proposal with emerging evidence that the hedonic value is associated with the recognition of patterns in low-predictability sound sequences and that atonal music elicits distinct behavioral responses in listeners. We end by outlining new research avenues that might both deepen our understanding of the aesthetic experience of atonal music in particular, and reveal core qualities of the aesthetic experience in general.
Electroencephalograph-Based Emotion Recognition Using Brain Connectivity Feature and Domain Adaptive Residual Convolution Model
Authors: Chen Jingxia , Min Chongdan , Wang Changhao , Tang Zhezhe , Liu Yang , Hu Xiuwen
Published: June 2022

In electroencephalograph (EEG) emotion recognition research, obtaining high-level emotional features with more discriminative information has become the key to improving the classification performance. This study proposes a new end-to-end emotion recognition method based on brain connectivity (BC) features and domain adaptive residual convolutional network (short for BC-DA-RCNN), which could effectively extract the spatial connectivity information related to the emotional state of the human brain and introduce domain adaptation to achieve accurate emotion recognition within and across the subject’s EEG signals. The BC information is represented by the global brain network connectivity matrix. The DA-RCNN is used to extract high-level emotional features between different dimensions of EEG signals, reduce the domain offset between different subjects, and strengthen the common features between different subjects. The experimental results on the large public DEAP data set show that the accuracy of the subject-dependent and subject-independent binary emotion classification in valence reaches 95.15 and 88.28%, respectively, which outperforms all the benchmark methods. The proposed method is proven to have lower complexity, better generalization ability, and domain robustness that help to lay a solid foundation for the development of high-performance affective brain-computer interface applications.
Dysbiosis in Children With Neurological Impairment and Long-Term Enteral Nutrition
Authors: Panelli Simona , Calcaterra Valeria , Verduci Elvira , Comandatore Francesco , Pelizzo Gloria , Borghi Elisa , Bandi Claudio , Zuccotti Gianvincenzo
Published: June 2022

Severe neurological impairment (NI) is often accompanied by the need for artificial nutritional support, normally provided enterally (enteral nutrition [EN]) to ensure growth, counteract morbidity and mortality, and improve quality of life. On the other hand, long-term EN (LTEN) may contribute to the establishment, or exacerbation, of gastrointestinal disorders that may lead to malnutrition, which in turn is associated with alterations in gut microbiota (GM) composition and functional capacities. To the best of our knowledge, we investigated, for the first time in this study, the consequences of LTEN in a pediatric population in this pathological context. Using amplicon sequencing, we compared the fecal microbiota of a pediatric population suffering from severe NI and under LTEN to that of sex- and age-matched controls. The two groups presented evident differences in GM composition and a consistent differential clustering. In general, the taxonomic picture in NI children under LTEN seemed to mirror a profound dysbiotic condition, in which anti-inflammatory taxa appear severely depleted (among others, the Clostridiales families of Lachnospiraceae and Ruminococcaceae, and, within the latter, Faecalibacterium spp. and Gemmiger spp.), while known pathobionts (Gammaproteobacteria and Klebsiella) or emerging pathogens (e.g., Synergistales, Cloacibacillus, and Fusobacterium) were significantly enriched. Our data suggest that LTEN has a significant impact on the GM taxonomic composition in NI children. Even if other factors are probably at work, such as the bidirectional interaction between gastrointestinal impairment/immaturity and the central nervous system (CNS), the assumption of drugs, and physical inactivity, these data define possible routes and targets to try to alleviate this dysbiosis, with a view to better management of these patients and an improvement in their quality of life.
A Clinical-Radiomics Nomogram Based on Magnetic Resonance Imaging for Predicting Progression-Free Survival After Induction Chemotherapy in Nasopharyngeal Carcinoma
Authors: Liu Lu , Pei Wei , Liao Hai , Wang Qiang , Gu Donglian , Liu Lijuan , Su Danke , Jin Guanqiao
Published: June 2022

Purpose

This paper aimed to establish and verify a radiomics model based on magnetic resonance imaging (MRI) for predicting the progression-free survival of nasopharyngeal carcinoma (NPC) after induction chemotherapy (IC).

Materials and Methods

This cohort consists of 288 patients with clinical pathologically confirmed NPC, which was collected from January 2015 to December 2018. All NPC patients were randomly divided into two cohorts: training (n=202) and validation (n=86). Radiomics features from the MRI images of NPC patients were extracted and selected before IC. The patients were classified into high- and low-risk groups according to the median of Radscores. The significant imaging features and clinical variables in the univariate analysis were constructed for progression-free survival (PFS) using the multivariate Cox regression model. A survival analysis was performed using Kaplan–Meier with log-rank test and then each model’s stratification ability was evaluated.

Results

Epstein–Barr virus (EBV) DNA before treatment was an independent predictor for PFS (p < 0.05). Based on the pyradiomic platform, we extracted 1,316 texture parameters in total. Finally, 16 texture features were used to build the model. The clinical radiomics-based model had good prediction capability for PFS, with a C-index of 0.827. The survival curve revealed that the PFS of the high-risk group was poorer than that of the low-risk group.

Conclusion

This research presents a nomogram that merges the radiomics signature and the clinical feature of the plasma EBV DNA load, which may improve the ability of preoperative prediction of progression-free survival and facilitate individualization of treatment in NPC patients before IC.
The Evaluation of Zoomed Echo-Planar Diffusion-Weighted Magnetic Resonance Imaging With Two-dimensional Spatial-Selective Radiofrequency Excitation Pulses in Patients With Hilar Cholangiocarcinoma
Authors: Liu Jingjing , Huang Mengyue , Ren Yanan , Xu Man , Li Yinhua , Cheng Jingliang , Zhu Jinxia
Published: June 2022

Background

We aimed to investigate the feasibility and application of using the zoomed diffusion-weighted echo-planar imaging (z-EPI DWI) sequences for hilar cholangiocarcinoma assessment compared with conventional single-shot EPI diffusion-weighted imaging (c-EPI DWI).

Methods

Both c-EPI DWI and z-EPI DWI were preoperatively performed in 16 patients with histopathologically-confirmed hilar cholangiocarcinoma. A two-dimensional spatial-selective radiofrequency (RF) pulse was applied to the z-EPI DWI using an echo-planar transmit trajectory. Anatomic structural visualization, lesion conspicuity, artifact presence and overall image quality were evaluated and compared between the two sequence images. The ratio of differences regarding hilar cholangiocarcinoma lesion sizes measured on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) were compared from both EPI techniques. The DW images for tumor involvement of the bile duct were reviewed based on histopathological examination of the surgical intraoperative evaluation. ADC measurements of DWIs in the hilar cholangiocarcinoma lesions were conducted.

Results

The hepatic hilar region was better delineated by visualization of anatomical structures, lesion conspicuity and overall image quality using the z-EPI DWI and these analyses were compared with the c-EPI DWI method (all p<0.05). Better lesion delineation of bile duct walls and lumens was noted in four patients with z-EPI DWI compared with those of c-EPI DWI. No significant differences were noted between the two image datasets for artifacts (p=0.876). The ratio of differences regarding hilar cholangiocarcinoma lesion sizes was significantly lower (p= 0.018) on T2WI and DWI, as determined by the z-EPI DWI than that determined by the c-EPI method. The use of z-EPI DWI resulted in the accurate diagnosis of the Bismuth-Corlette classification of 15 tumors (15/16, 93.75%), whereas the use of c-EPI DWI resulted in correct diagnosis of 12 tumors (12/16, 75.00%). There were no significant differences between c-EPI DWI and z-EPI DWI in the ADC values of hilar cholangiocarcinoma lesions (p= 0.48).

Conclusion

z-EPI DWI resulted in remarkable image quality improvements for hilar cholangiocarcinoma. The ability to detect and delineate lesions using z-EPI DWI was superior to that of c-EPI DWI.
Global Proteomics Analysis of Bone Marrow: Establishing Talin-1 and Centrosomal Protein of 55 kDa as Potential Molecular Signatures for Myelodysplastic Syndromes
Authors: Moura Arlindo A. , Bezerra Maria Julia B. , Martins Aline M. A. , Borges Daniela P. , Oliveira Roberta T. G. , Oliveira Raphaela M. , Farias Kaio M. , Viana Arabela G. , Carvalho Guilherme G. C. , Paier Carlos R. K. , Sousa Marcelo V. , Fontes Wagner , Ricart Carlos A. O. , Moraes Maria Elisabete A. , Magalhães Silvia M. M. , Furtado Cristiana L. M. , Moraes-Filho Manoel O. , Pessoa Claudia , Pinheiro Ronald F.
Published: June 2022

Myelodysplastic syndrome (MDS) is a hematological disorder characterized by abnormal stem cell differentiation and a high risk of acute myeloid leukemia transformation. Treatment options for MDS are still limited, making the identification of molecular signatures for MDS progression a vital task. Thus, we evaluated the proteome of bone marrow plasma from patients (n = 28) diagnosed with MDS with ring sideroblasts (MDS-RS) and MDS with blasts in the bone marrow (MDS-EB) using label-free mass spectrometry. This strategy allowed the identification of 1,194 proteins in the bone marrow plasma samples. Polyubiquitin-C (UBC), moesin (MSN), and Talin-1 (TLN1) showed the highest abundances in MDS-EB, and centrosomal protein of 55 kDa (CEP55) showed the highest relative abundance in the bone marrow plasma of MDS-RS patients. In a follow-up, in the second phase of the study, expressions of UBC, MSN, TLN1, and CEP55 genes were evaluated in bone marrow mononuclear cells from 45 patients by using qPCR. This second cohort included only seven patients from the first study. CEP55, MSN, and UBC expressions were similar in mononuclear cells from MDS-RS and MDS-EB individuals. However, TLN1 gene expression was greater in mononuclear cells from MDS-RS (p = 0.049) as compared to MDS-EB patients. Irrespective of the MDS subtype, CEP55 expression was higher (p = 0.045) in MDS patients with abnormal karyotypes, while MSN, UBC, and TALIN1 transcripts were similar in MDS with normal vs. abnormal karyotypes. In conclusion, proteomic and gene expression approaches brought evidence of altered TLN1 and CEP55 expressions in cellular and non-cellular bone marrow compartments of patients with low-risk (MDS-RS) and high-risk (MDS-EB) MDSs and with normal vs. abnormal karyotypes. As MDS is characterized by disrupted apoptosis and chromosomal alterations, leading to mitotic slippage, TLN1 and CEP55 represent potential markers for MDS prognosis and/or targeted therapy.
Glaucocalyxin A Inhibits the Malignancies of Gastric Cancer Cells by Downregulating MDM2 and RNF6 via MiR-3658 and the SMG1-UPF mRNA Decay Pathway
Authors: Liu Yanqi , Chen Ping , Qi Daqing , Chen Linhui
Published: June 2022

Gastric cancer (GC) ranks as the most common gastrointestinal cancer and is among the leading causes of cancer death worldwide. Glaucocalyxin A (GLA), an entkauranoid diterpene isolated from Rab-dosia japonica var., possesses various bioactivities. To date, the data on the effect of GLA on GC are still minimal, and the molecular mechanisms remain largely unknown. Herein, we found that GLA could significantly inhibit the proliferation, cell adhesion, and invasion of HGT-1, SNU-1, SNU-6, and NCI-N87 GC cells in a dose-dependent manner. GLA enhanced the apoptosis of the GC cells as evidenced by the increased caspase-3 activity and the elevated levels of cleaved caspase-3 and cleaved PARP in GC cells in the presence of GLA. We then showed that the downregulation of Murine Double Minute Clone 2 (MDM2) and Ring Finger Protein 6 (RNF6) by GLA was implicated in the GLA-induced inhibition of the GC cells. Furthermore, MDM2 and RNF6 were identified as the targets of miR-3658 that was downregulated in the GC cells and upregulated by GLA. Moreover, it was shown that miR-3658 was hypermethylated in the GC cells, and GLA could rescue the expression of miR-3658 via demethylation by abrogating EZH2-mediated epigenetic silencing. In addition to the miR-3658-MDM2/RNF6 regulatory axis, activation of the SMG1-UPF mRNA decay pathway contributed to the downregulation of MDM2 and RNF6 by GLA in the GC cells. The inhibitory effect of GLA on gastric cancer and the expression of MDM2 and RNF6 was also validated in in vivo study. Our findings suggest that has the therapeutic potential for GC by downregulating oncogenes via posttranscriptional regulation.
Case Report: Giant Cell Tumor of Tendon Sheath After Breast Augmentation
Authors: Zhang Yu , Fan Yingying , Zhang Hongying , Bu Hong , Chen Min , Yang Jieliang , Zhang Zhang
Published: June 2022

Giant cell tumor of tendon sheath (GCTTS) is a benign tumor. It occurs predominantly in the hands, ankles, and knees. A 39-year-old female presented with GCTTS in the right breast after breast augmentation. There was a clear borderline between the tumor and breast tissue. In terms of morphological appearance, synovial metaplasia could be observed in part of the collagenous capsule. The tumor was moderately cellular and was composed of synovium-like monocytes. The main part of the tumor was blended with nested and scattered xanthomatous cells, lymphocytes, and osteoclast-like giant cells. Hemosiderin granules were distributed in the lesion. Immunohistochemical staining and fluorescence in situ hybridization (FISH) analyses were performed. CD68 staining was positive in osteoclast-like giant cells. In addition, neither significant USP6 translocation nor CSF1 translocation was detected by FISH. We hypothesized that the pathogenesis of this rare GCT-TS was based on synovial metaplasia and did not depend on the translocation of classical CSF1.
Contrast-Enhanced Computed Tomography–Based Radiogenomics Analysis for Predicting Prognosis in Gastric Cancer
Authors: Liu Han , Wang Yiyun , Liu Yingqiao , Lin Dingyi , Zhang Cangui , Zhao Yuyun , Chen Li , Li Yi , Yuan Jianyu , Chen Zhao , Yu Jiang , Kong Wentao , Chen Tao
Published: June 2022

Objective

The aim of this study is to identify prognostic imaging biomarkers and create a radiogenomics nomogram to predict overall survival (OS) in gastric cancer (GC).

Material

RNA sequencing data from 407 patients with GC and contrast-enhanced computed tomography (CECT) imaging data from 46 patients obtained from The Cancer Genome Atlas (TCGA) and The Cancer Imaging Archive (TCIA) were utilized to identify radiogenomics biomarkers. A total of 392 patients with CECT images from the Nanfang Hospital database were obtained to create and validate a radiogenomics nomogram based on the biomarkers.

Methods

The prognostic imaging features that correlated with the prognostic gene modules (selected by weighted gene coexpression network analysis) were identified as imaging biomarkers. A nomogram that integrated the radiomics score and clinicopathological factors was created and validated in the Nanfang Hospital database. Nomogram discrimination, calibration, and clinical usefulness were evaluated.

Results

Three prognostic imaging biomarkers were identified and had a strong correlation with four prognostic gene modules (P < 0.05, FDR < 0.05). The radiogenomics nomogram (AUC = 0.838) resulted in better performance of the survival prediction than that of the TNM staging system (AUC = 0.765, P = 0.011; Delong et al.). In addition, the radiogenomics nomogram exhibited good discrimination, calibration, and clinical usefulness in both the training and validation cohorts.

Conclusions

The novel prognostic radiogenomics nomogram that was constructed achieved excellent correlation with prognosis in both the training and validation cohort of Nanfang Hospital patients with GC. It is anticipated that this work may assist in clinical preferential treatment decisions and promote the process of precision theranostics in the future.
High Levels of DEAH-Box Helicases Relate to Poor Prognosis and Reduction of DHX9 Improves Radiosensitivity of Hepatocellular Carcinoma
Authors: Chen Xi , Lin Letao , Chen Guanyu , Yan Huzheng , Li Zhenyu , Xiao Meigui , He Xu , Zhang Fujun , Zhang Yanling
Published: June 2022

Background

Liver hepatocellular carcinoma (LIHC), one of the most common primary malignancies, exhibits high levels of molecular and clinical heterogeneity. Increasing evidence has confirmed the important roles of some RNA helicase families in tumor development, but the function of the DEAH-box RNA helicase family in LIHC therapeutic strategies has not yet been clarified.

Methods

The LIHC dataset was downloaded from The Cancer Genome Atlas (TCGA). Consensus clustering was applied to group the patients. Least absolute shrinkage and selection operator Cox regression and univariate and multivariate Cox regression were used to develop and validate a prognostic risk model. The Tumor Immune Estimation Resource and Tumor Immune Single Cell Hub databases were used to explore the role of DEAH-box RNA helicases in LIHC immunotherapy. In vitro experiments were performed to investigate the role of DHX9 in LIHC radiosensitivity.

Results

Twelve survival-related DEAH-box RNA helicases were identified. High helicase expression levels were associated with a poor prognosis and clinical features. A prognostic model comprising six DEAH-box RNA helicases (DHX8, DHX9, DHX34, DHX35, DHX38, and DHX57) was constructed. The risk score of this model was found to be an independent prognostic indicator, and LIHC patients with different prognosis were distinguished by the model in the training and test cohorts. DNA damage repair pathways were also enriched in patients with high-risk scores. The six DEAH-box RNA helicases in the risk model were substantially related to innate immune cell infiltration and immune inhibitors. In vitro experiments showed that DHX9 knockdown improved radiosensitivity by increasing DNA damage.

Conclusion

The DEAH-box RNA helicase signature can be used as a reliable prognostic biomarker for LIHC. In addition, DHX9 may be a definitive indicator and therapeutic target in radiotherapy and immunotherapy for LIHC.
Comprehensive Analysis of Role of Cyclin-Dependent Kinases Family Members in Colorectal Cancer
Authors: Guan Liping , Tang Yuanyuan , Li Guanghua , Qin Zhao , Li Shaoshan
Published: June 2022

Background

Cyclin-dependent kinases (CDKs) are cell cycle regulators, and abnormal activation can accelerate tumor cell proliferation. However, The relation between CDKs dysregulation to colorectal cancer incidence and progression have not been examined in detail. Methods:Differences in CDKs expression between colorectal cancer and normal tissues, associations between expression and clinical prognosis, incidence and frequencies of CDKs gene mutations, and the influences of CDKs on tumor infiltration by immune cells were examined by analyses of Oncomine, Gene Expression Profiling Interactive Analysis, Kaplan-Meier plotter, cBioPortal, GeneMANIA, and TIMER databases.

Results

Colorectal cancer tissues showed enhanced expression levels of CDKs 1/2/4/5/6/8/12/13/19 but reduced CDK3 expression. CDK7 was highly expressed in some colorectal cancer tissues but downregulated in others. Expression levels of CDK1/3/4/7/8/10/11b/13/18/19/20 were correlated with clinical stage, and CDK 5/10/12/16 expression levels predicted prognosis and survival. Differential CDKs expression correlated with cell cycle progression, amino acid polypeptide modifications, and activation of other protein kinases. Expression levels of all CDKs except CDK16 were correlated with infiltration of CD4+T, CD8+T, B and Tregs cells.

Conclusions

CDK 1 and 4 could be used as diagnostic biomarkers for CRC. CDK 5/10/12/16 can be utilized as prognostic biomarkers.
Time Free From Hospitalization in Children and Adolescents With Cystic Fibrosis: Findings From FEV1, Lung Clearance Index and Peak Work Rate
Authors: Gambazza Simone , Mariani Alessandra , Brivio Anna , Carta Federica , Blardone Chiara , Lisiero Saba , Russo Maria , Colombo Carla
Published: June 2022

Background

An exercise test combined with a multiple breath washout nitrogen test (MBWN2) may offer a comprehensive clinical evaluation of cystic fibrosis (CF) disease in children with normal spirometry. The purpose of the present study is to explore whether information derived from spirometry, MBWN2, and exercise tests can help the CF multidisciplinary team to characterize time free from hospitalization due to pulmonary exacerbation (PE) in a cohort of pediatric patients with CF.

Methods

This prospective observational study was carried out at the Lombardia Region Reference Center for Cystic Fibrosis in Milano, Italy. In 2015, we consecutively enrolled children and adolescents aged <18 years with spirometry, MBWN2, and Godfrey exercise test performed during an outpatient visit.

Results

Over a median follow-up time of 2.2 years (interquartile range [IQR], 2.01; 3.18), 28 patients aged between 13.0 and 17.4 years were included. When lung functions were outside the normal range, 50% of patients were hospitalized 4 months after the outpatient visit, and their response to exercise was abnormal (100%). Half of the individuals with normal forced expiratory volume in the first second (FEV1) and abnormal lung clearance index (LCI) experienced the first hospital admission 9 months after the clinic visit, and 84.2% presented an abnormal response to exercise. Conversely, 15.8% had abnormal exercise responses when lung functions were considered normal, with half of the adolescents hospitalized at 11 months.

Conclusion

Maintaining ventilation homogeneity, along with a normal ability to sustain intense work, may have a positive impact on the burden of CF disease, here conceived as time free from hospitalization due to PE.
Therapeutic Drug Monitoring of Ceftazidime-Avibactam Concentrations in Carbapenem-Resistant K. pneumoniae-Infected Patients With Different Kidney Statuses
Authors: Teng Xin-Qi , Qu Qiang , Luo Yue , Long Wen-Ming , Zhuang Hai-Hui , Xu Jiao-Hua , Wen Yu-Xin , Zhang Hui-Lin , Qu Jian
Published: June 2022

Aims: Carbapenem-resistant K. pneumoniae (CRKP) is the most common carbapenem-resistant Enterobacteriaceae with high mortality. Ceftazidime-avibactam (CAZ-AVI) has exhibited excellent in vitro activity in vivo against CRKP. However, the efficacy of CAZ-AVI in KPC-producing CRKP-infected patients with different kidney statuses varies, such as renal insufficiency, normal renal function, and augmented renal clearance (ARC). We explored the use of therapeutic drug monitoring (TDM) to evaluate the concentration and efficacy of CAZ-AVI in CRKP-infected patients with different kidney statuses.

Methods: Serum concentrations for CAZ and AVI were determined by the high-performance liquid chromatography method. Bacterial identification, routine susceptibility testing, renal function index, and others were performed in standard protocols in the hospital’s clinical laboratories.

Results: In the two patients with ARC, in case 1, CAZ-AVI 2.5g q6h was used with good efficacy, and the concentrations were up to the pharmacokinetics/pharmacodynamics targets. In Case 2, 2.5 g q8h was used with invalid effectiveness, and AVI Cmin was only 0.797 mg/l, which is lower than the PK/PD target. Case 3 was renal insufficiency using CAZ-AVI 1.25 q8h, and case 4 was normal renal function using 2.5 g q8h. Their concentrations were both up to the PK/PD targets.

Conclusion: TDM results demonstrated that CAZ-AVI steady-state plasma concentration varies among patients with different kidney statuses, providing evidence for the utility of TDM of CAZ-AVI in individualized drug dose adjustment. ARC patients may need more CAZ-AVI daily doses than the standard dose.
Evidence-Based Management of Uterine Fibroids With Botanical Drugs-A Review
Authors: Arip Masita , Yap Vi Lien , Rajagopal Mogana , Selvaraja Malarvili , Dharmendra K , Chinnapan Sasikala
Published: June 2022

Uterine fibroids (UFs) are a common benign gynecological tumor that affect the majority of women over their lifetime. Several pharmacological agents are available to reduce the size of fibroids and ameliorate the symptoms of UF. However, these drugs are expensive and are usually associated with profound side effects. Thus, botanical drugs are gaining attention in this era due to their cost effectiveness with a comparable and more potent therapeutic efficacy while demonstrating lesser adverse effects. The objective of this review is to summarize the available information on the mechanism of various botanical drugs and polyherbal formulations with anti-uterine fibroid activity. A systematic search was performed on botanical drugs with anti-uterine fibroid activity using several search engines, which include PubMed, Google Scholar, and Science Direct. Based on the literatures identified, a total of five botanical drugs and three polyherbal formulations were included and discussed in this review, which yields useful information regarding the mechanism of different botanical drugs and polyherbal formulations in exerting anti-uterine fibroid activity for its potential use as an alternative treatment choice for uterine fibroids.
A Mechanistic Exploratory Study on the Therapeutic Efficacy of Astragaloside IV Against Diabetic Retinopathy Revealed by Network Pharmacology
Authors: Zhao Zhi-Hao , Xu Min , Fu Cong , Huang Ying , Wang Ting-Hua , Zuo Zhong-Fu , Liu Xue-Zheng
Published: June 2022

Purpose: Diabetic retinopathy (DR) is a serious complication of diabetes mellitus, which nearly happens to all the diabetic sufferers. This study aims to identify the preliminary molecular regulation involved in the therapeutic efficacy of astragaloside IV (AS- IV) for DR.

Methods: Diabetic rat models were established and treated with AS-IV. Optical coherence tomography (OCT) and Hematoxylin-eosin (HE) staining was employed to demonstrate the histopathological changes. The main targets of AS-IV were identified by searching from public databases of traditional Chinese medicine (GeneCards, PharmMapper and Swiss Target Prediction). Besides, disease targets of DR were also obtained by integrated data from GEO datasets and predicted from public databases. Protein-protein interaction (PPI) network was constructed by Cytoscape with overlapping genes and 10 core targets were selected, on which Gene Ontology (GO) along with Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted. The interaction between AS-IV and these crucial genes were analyzed using molecular docking. RT-qPCR and western blot were used to verify the expression variation of core targets.

Results: OCT imaging and HE staining demonstrated that AS-IV administration significantly increased retinal thickness in diabetic rats, obviously alleviating DR induced histopathological changes as well as elevated blood glucose levels. 107 common targets of AS-IV and DR were determined after intersection. PPI network analysis filtered 10 hub genes potentially targeted by AS-IV, including VEGFA, CASP3, HIF1α, STAT3, CTNNB1, SRC, AKT1, EGFR, IL1β and IL6. Enrichment analysis indicated that these genes were mainly enriched in biological processes like T cell activation, epithelial cell proliferation and protein kinase B signaling, and involved in oxidative stress, apoptosis and inflammation-related pathways. The molecular docking prediction suggested that AS-IV exhibited stable binding to these core targets. In addition, mRNA levels of core targets in diabetic rats were differentially expressed before and after AS-IV treatment. Western blot further revealed that AS-IV treatment elevated DR-depressed protein levels of PI3K and AKT.

Conclusion: Our study elucidated the effect of AS-IV in attenuating retinopathy induced by diabetes in rats and preliminarily unveiled the therapeutic efficacy of AS-IV in the treatment of DR might be attributed to activation of PI3K-AKT signaling pathway.
On-Line Solid Phase Extraction High Performance Liquid Chromatography Method Coupled With Tandem Mass Spectrometry for the Therapeutic Monitoring of Cannabidiol and 7-Hydroxy-cannabidiol in Human Serum and Saliva
Authors: Franco Valentina , Palmisani Michela , Marchiselli Roberto , Crema Francesca , Fattore Cinzia , De Giorgis Valentina , Varesio Costanza , Rota Paola , Dibari Vincenza Flora , Perucca Emilio
Published: June 2022

Cannabidiol is a novel antiseizure medication approved in Europe and the US for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome and tuberous sclerosis complex. We describe in this article a new and simple liquid chromatography-mass spectrometry method (LC-MS/MS) for the determination of cannabidiol and its active metabolite 7-hydroxy-cannabidiol in microvolumes of serum and saliva (50 μl), to be used as a tool for therapeutic drug monitoring (TDM) and pharmacokinetic studies. After on-line solid phase extraction cannabidiol, 7-hydroxy-cannabidiol and the internal standard cannabidiol-d3 are separated on a monolithic C18 column under gradient conditions. Calibration curves are linear within the validated concentration range (10–1,000 ng/ml for cannabidiol and 5–500 ng/ml for 7-hydroxy-cannabidiol). The method is accurate (intraday and interday accuracy within 94–112% for cannabidiol, 91–109% for 7-hydroxy-cannabidiol), precise (intraday and interday precision <11.6% for cannabidiol and <11.7% for 7- hydroxy-cannabidiol) and sensitive, with a LOQ of 2.5 ng/ml for cannabidiol and 5 ng/ml for 7-hydroxy-cannabidiol. The stability of the analytes was confirmed under different storage conditions. Extraction recoveries were in the range of 81–129% for cannabidiol and 100–113% for 7-hydroxy-cannabidiol. The applicability of the method to TDM was demonstrated by analysis of human serum and saliva samples obtained from patients with epilepsy treated with cannabidiol.