Publications by authors named "Yuanyuan Lu"

227 Publications

The evolution of conglobation in Ceratocanthinae.

Commun Biol 2022 Aug 6;5(1):777. Epub 2022 Aug 6.

Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

Conglobation is an adaptive behaviour occurring independently in various animal groups. Here, we study the evolution of conglobation in Ceratocanthinae, a beetle group with the ability to roll three body segments into a tight ball. It is here implied that this ability evolved only once in the Mesozoic. Evidence is offered suggesting that the high defensive strength of Ceratocanthinae is due not only to the spherical body shape but also to the thickness and stronger mechanical properties of the dorsal cuticle. We further validate five adaptive characters including the allometrically thickened body wall and find that the specific adaptation of different body segments are likely separate evolutionary events. Finally, we propose an "attackers stress" hypothesis to explain the origin of conglobation behaviours. This work contributes to understanding how and why conglobation behaviour may have evolved in this group.
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http://dx.doi.org/10.1038/s42003-022-03685-2DOI Listing
August 2022

Genomic and Chemical Profiling of B9, a Unique Fungus Derived from Sponge.

J Fungi (Basel) 2022 Jun 29;8(7). Epub 2022 Jun 29.

School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.

This study presented the first insights into the genomic and chemical profiles of B9, a specific Penicillium strain derived from sponges of the South China Sea that demonstrated the closest morphological and phylogenetic affinity to . Via the Illumina MiSeq sequencing platform, the draft genome was sequenced, along with structural assembly and functional annotation. There were 34 biosynthetic gene clusters (BGCs) predicted against the antiSMASH database, but only 4 gene clusters could be allocated to known BGCs (≥50% identities). Meanwhile, the comparison between B9 and ATCC 10480 demonstrated clear distinctions in morphology, which might be ascribed to the unique environmental adaptability of marine endosymbionts. In addition, two novel pyridinones, penicidihydropyridone A (2) and penicidihydropyridone B (3), were isolated from cultures of B9, and structurally characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The absolute configurations were confirmed by comparison of experimental and calculated electronic circular dichroism (ECD) curves. In addition, structure-based molecular docking indicated that both neo-pyridinones might block the programmed cell death protein 1(PD-1) pathway by competitively binding a programmed cell death 1 ligand 1(PD-L1) dimer. This was verified by the significant inhibition rates of the PD-1/L1 interaction. These indicated that sp. B9 possessed a potential source of active secondary metabolites.
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http://dx.doi.org/10.3390/jof8070686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319512PMC
June 2022

Should we abandon annual physical examination? - A meta-analysis of annual physical examination and all-cause mortality in adults based on observational studies.

Prev Med 2022 08 3;161:107130. Epub 2022 Jul 3.

Study Design and Data Analysis Center, College of Public Health, University of South Florida, USA. Electronic address:

Several meta-analyses based on randomized clinical trials data have failed to find an association between the annual physical examination (APE) and reduced mortality; however, no comparable meta-analysis based on observational data exists. We conducted a meta-analysis of observational studies comparing APE versus non-APE in adults for all-cause mortality. English-language searches of four databases (PubMed, CINAHL, EMBASE, and Google Scholar) between the years 2000 to 2019 yielded seven observational studies that investigated APE versus non-APE in healthy adults in relation to all-cause mortality. Random effects models were used to calculate pooled hazard ratios and 95% confidence intervals (CI), and to incorporate variation between studies. During follow-up periods that ranged from two to 25 years, there were 35,055 deaths among 633,957 participants. APE was significantly associated with a 45% lower hazard of all-cause mortality, with pooled hazard ratio of 0.55 (95% CI 0.48 to 0.64, P < 0.01) for all participants. This meta-analysis of seven observational studies in the past 20 years provides evidence of an association between APE and a lower hazard of all-cause mortality, a finding that contrasts with findings based on meta-analyses of randomized clinical trials data. Nonetheless, at present the evidence available about the effectiveness or ineffectiveness of APE on all-cause mortality still needs further study.
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http://dx.doi.org/10.1016/j.ypmed.2022.107130DOI Listing
August 2022

A thioredoxin reductase 1 inhibitor pyrano [3,2-a] phenazine inhibits A549 cells proliferation and migration through the induction of reactive oxygen species production.

Mol Biol Rep 2022 Jul 2. Epub 2022 Jul 2.

Department of Marine Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.

Background: Thioredoxin reductase 1 (TrxR1) inhibitor, pyrano [3,2-a] phenazine, named CPUL-1, was synthesized with potential anticancer activity. The aim of the present work was to explore the potential anti-proliferative and anti-metastatic ability of CPUL-1 against A549 cancer cell lines in vitro.

Methods And Results: First, Cell Counting Kit-8 (CCK8) assay was used to assess cell proliferation. The A549 cell migration was evaluated by wound healing assay and transwell assay. Second, the epithelial-mesenchymal transition (EMT)-related proteins in A549 cells treated with CPUL-1 were analyzed by western blot methods. Then, TrxR1 enzyme activity assay and reactive oxygen species (ROS) assay were conducted to evaluate the effect of CPUL-1 on TrxR1 inhibition and ROS levels. Finally, western blotting was used to explore the mechanism of CPUL-1. The study results revealed that the ability of cell proliferation and migration was decreased under CPUL-1 treatment. CPUL-1 could distinctly restrain the migration and invasion of A549 cells through inhibiting EMT process. The results of TrxR1 enzyme activity assay, ROS assay and western blotting showed that CPUL-1 influenced EMT via inducing ROS-mediated ERK/JNK signaling by inhibiting TrxR1 enzyme activity.

Conclusions: Together, proliferation suppression and anti-metastasis activity of CPUL-1 in A549 cells were demonstrated by all the evidence. Our findings highlight the great potential of phenazine compound CPUL-1 to suppress A549 cells proliferation and metastasis.
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http://dx.doi.org/10.1007/s11033-022-07733-2DOI Listing
July 2022

Comparison of learning curves for laparoendoscopic single-site myomectomy performed by 2 surgeons.

Medicine (Baltimore) 2022 Jul 1;101(26):e29830. Epub 2022 Jul 1.

Department of Gynecologic Oncology, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China.

We aimed to compare the learning curves of 2 surgeons with different endoscopic bases when performing laparoendoscopic single-site myomectomy (LESS-M). We retrospectively analyzed and compared 2 groups of patients who underwent LESS-M performed by 2 surgeons with different bases in multi-port laparoscopic surgery (MLS) from October 2019 to December 2020 at West China Second Hospital of Sichuan University. Patients' characteristics and related surgical indicators were compared, and surgeons' learning curves were analyzed using a cumulative sum analysis. All of the patients completed LESS-M without converting to MLS or laparotomy, despite Surgeon A being MLS-unqualified and Surgeon B being MLS-qualified. There were no significant differences in patients' characteristics or surgical indicators between the 2 groups (P > 0.05 for all). Surgeons A and B crossed the learning curve after 21 and 18 cases, respectively. LESS-M is safe and feasible. Approximately 20 cases are required for surgeons to achieve LESS-M proficiency, and surgeons without MLS experience can still master LESS-M.
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http://dx.doi.org/10.1097/MD.0000000000029830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9239588PMC
July 2022

Acanthocytes Identified in Huntington's Disease.

Front Neurosci 2022 6;16:913401. Epub 2022 Jun 6.

Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.

Background: Neuroacanthocytosis (NA) and Huntington's disease (HD) are neurodegenerative conditions that share clinical symptoms and imaging findings, despite their distinct genetic etiologies. Usually, the presence of acanthocytes can help narrow the differential diagnosis of a familial choreiform disorder, as the diagnosis of NA syndrome is supported by the presence of acanthocytes in peripheral blood. In this study, we demonstrate four patients who present with HD and acanthocytosis.

Methods: We retrieved the data of 40 HD patients with fresh peripheral blood screened for erythrocytes in our hospital from 2014 to 2022. Of these 40 patients, four patients with acanthocytes were recruited for this study. Patients' investigations included clinical and laboratory studies, gene sequencing, and whole-exome sequencing. Fresh peripheral blood was screened for erythrocytes by scanning electron microscopy.

Results: The four adult patients were Han Chinese and unrelated. The age ranged from 45 to 61 years, with a disease duration of 4-10 years. The main neurological features at diagnosis included progressive involuntary movements, psychiatric changes, and dementia. Genetic analysis showed an expansion at the gene. The mean proportion of acanthocytes was mild (6-10%) elevated in patient one and high (>20%) elevated in patients 2-4 by scanning electron microscopy examination.

Conclusion: Our study illustrates that HD can combine with acanthocytosis, which may expand the clinical phenotype. Even though the primary gene defect appears to be predominately directed at the brain, a peripheral defect can be seen in HD. Our study highlights the complexity and diversity of HD.
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http://dx.doi.org/10.3389/fnins.2022.913401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9208653PMC
June 2022

A computerized diagnostic model for automatically evaluating placenta accrete spectrum disorders based on the combined MR radiomics-clinical signatures.

Sci Rep 2022 Jun 16;12(1):10130. Epub 2022 Jun 16.

Department of Radiology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, People's Republic of China.

We aimed to establish a computerized diagnostic model to predict placenta accrete spectrum (PAS) disorders based on T2-weighted MR imaging. We recruited pregnant women with clinically suspected PAS disorders between January 2015 and December 2018 in our institution. All preoperative T2-weighted imaging (T2WI) MR images were manually outlined on the picture archive communication system terminal server. A nnU-Net network for automatic segmentation and the corresponding radiomics features extracted from the segmented region were applied to build a radiomics-clinical model for PAS disorders identification. Taking the surgical or pathological findings as the reference standard, we compared this computerized model's diagnostic performance in detecting PAS disorders. In the training cohort, our model combining both radiomics and clinical characteristics yielded an accuracy of 0.771, a sensitivity of 0.854, and a specificity of 0.750 in identifying PAS disorders. In the testing cohort, this model achieved a segmentation mean Dice coefficient of 0.890 and yielded an accuracy of 0.825, a sensitivity of 0.830 and a specificity of 0.822. In the external validation cohort, this computer-aided diagnostic model yielded an accuracy of 0.690, a sensitivity of 0.929 and a specificity of 0.467 in identifying placenta increta. In the present study, a machine learning model based on preoperative T2WI-based imaging had high accuracy in identifying PAS disorders in respect of surgical and histological findings.
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http://dx.doi.org/10.1038/s41598-022-14454-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9203504PMC
June 2022

Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis.

Cell Mol Life Sci 2022 Jun 11;79(7):360. Epub 2022 Jun 11.

School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.

Breast cancer stem cells (BCSCs) are positively correlated with the metastasis, chemoresistance, and recurrence of breast cancer. However, there are still no drugs targeting BCSCs in clinical using for breast cancer treatment. Here, we tried to screen out small-molecule compounds targeting BCSCs from the phenazine library established by us before. We focused on the compounds without affecting cell viability and screened out three potential compounds (CPUL119, CPUL129, CPUL149) that can significantly attenuate the stemness of breast cancer cells, as evident by the decrease of stemness marker expression, CD44/CD24 subpopulation, mammary spheroid-formation ability, and tumor-initiating capacity. Additionally, these compounds suppressed the metastatic ability of breast cancer cells in vitro and in vivo. Combined with the transcriptome sequencing analysis, ferroptosis was shown on the top of the most upregulated pathways by CPUL119, CPUL129, and CPUL149, respectively. Mechanistically, we found that these three compounds could trigger ferroptosis by accumulating and sequestering iron in lysosomes through interacting with iron, and by regulating the expression of proteins (IRP2, TfR1, ferritin) engaged in iron transport and storage. Furthermore, inhibition of ferroptosis rescued the suppression of these three compounds on breast cancer cell stemness. This study suggests that CPUL119, CPUL129, and CPUL149 can specifically inhibit the stemness of breast cancer cells through triggering ferroptosis and may be the potential compounds for breast cancer treatment.
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http://dx.doi.org/10.1007/s00018-022-04384-1DOI Listing
June 2022

TuRLK1, a leucine-rich repeat receptor-like kinase, is indispensable for stripe rust resistance of YrU1 and confers broad resistance to multiple pathogens.

BMC Plant Biol 2022 Jun 8;22(1):280. Epub 2022 Jun 8.

State Key Laboratory of Ecological Control of Fujian-Taiwan Crop Pests, Key Laboratory of Ministry of Education for Genetics, Breeding and Multiple Utilization of Crops, Plant Immunity Center, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.

Background: YrU1 is a nucleotide-binding site (NBS) and leucine-rich repeat (LRR) protein (NLR), with additional ankyrin-repeat and WRKY domains and confers effective resistance to stripe rust fungus Puccinia striiformis f. sp. Tritici (Pst). YrU1 was positionally cloned in the progenitor species of the A genome of bread wheat, Tricicum urartu, recently. However, the molecular mechanism and components involved in YrU1-mediated resistance are not clear.

Results: In this study, we found that the transcript level of TuRLK1, which encodes a novel leucine-rich repeat receptor-like kinase, was up-regulated after inoculation with Pst in the presence of YrU1, through RNA-seq analysis in T. urartu accession PI428309. TuRLK1 contained only a small number of LRR motifs, and was localized in the plasma-membrane. Transient expression of TuRLK1 induced hypersensitive cell death response in N. benthamiana leaves. Silencing of TuRLK1, using barley stripe mosaic virus (BSMV)-induced gene silencing (VIGS) system in PI428309 that contains YrU1, compromised the resistance against stripe rust caused by Pst CY33, indicating that TuRLK1 was required for YrU1-activated plant immunity. Furthermore, overexpression of TuRLK1 could enhance powdery mildew resistance in bread wheat and Arabidopsis thaliana after inoculating with the corresponding pathogens.

Conclusions: Our study indicates that TuRLK1 is required for immune response mediated by the unique NLR protein YrU1, and likely plays an important role in disease resistance to other pathogens.
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http://dx.doi.org/10.1186/s12870-022-03679-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175386PMC
June 2022

eEF1A1 promotes colorectal cancer progression and predicts poor prognosis of patients.

Cancer Med 2022 May 24. Epub 2022 May 24.

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

Colorectal cancer (CRC) is a major leading cause of cancer mortality worldwide in which dysregulated protein synthesis plays an etiologic role. The eukaryotic elongation factor 1 A1 (eEF1A1) exerts significant effects on protein synthesis by contributing to peptide chain extension. Whereas its role in CRC remains to be investigated. In this study, we found that the mRNA and protein levels of eEF1A1 were significantly upregulated in CRC cell lines and tissues. Elevated expression of eEF1A1 was correlated with shorter overall survival in 94 CRC patients. The inhibition of proliferation and cell cycle block were observed in CRC cells after eEF1A1 downregulation. Mechanistically, weighted gene correlation network analysis and further Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that mitogen-activated protein kinases (MAPKs) signaling pathways were significantly enriched in high-eEF1A1 expression group, and the levels of phosphorylated p38/JNK/ERK MAPK were dramatically decreased after eEF1A1 downregulation. Overexpression of eEF1A1 in CRC correlated with a poor prognosis. Collectively, this study determined the oncogenic role of eEF1A1 in CRC proliferation and tumorigenesis. eEF1A1 might be a promising therapeutic target and prognostic biomarker in CRC.
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http://dx.doi.org/10.1002/cam4.4848DOI Listing
May 2022

Meta-analysis of Cd input-output fluxes in agricultural soil.

Chemosphere 2022 Sep 18;303(Pt 2):134974. Epub 2022 May 18.

Fujian Provincial Environmental Monitoring Center, Fuzhou, 350003, China.

Heavy metal pollution of agricultural soil, especially Cd, has become a global threat to food safety and human health. Analysis of Cd fluxes through different input/output pathways is widely used to predict the change of Cd content in agricultural soil, identify the critical pathways, and assist in developing effective management strategies to protect the environmental quality of agricultural soils. In the present study, literature recording input/output fluxes of Cd through different pathways in agricultural soils were investigated, with study areas primarily located in China, Japan, and Europe. Fluxes of Cd at the study sites were calculated, and comparative analyses were carried out. Results indicated that the dominant input pathway of Cd was strongly associated with the intensity of local industrial activities. Atmospheric deposition was the predominant input pathway of Cd for 75% of the study cases. Irrigation and livestock manure were also major pathways of Cd input in China. The main output pathways were influenced by the planting structure, precipitation, topography, etc. Crop harvesting and leaching to groundwater played important roles among all Cd output pathways in China, and crop harvesting alone could remove a significant amount of Cd from the soil, with an estimated average flux of 6.27 g/ha/yr. Leaching was the dominant Cd output pathway in Europe, accounting for 77%-93% of total outflux. To mitigate the accumulation of Cd in agricultural soil, standards to regulate Cd in the atmospheric environment, irrigation water, and agricultural additives should be tightened, and regulated removal and disposal of crops harvested from the heavily contaminated field should be promoted.
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http://dx.doi.org/10.1016/j.chemosphere.2022.134974DOI Listing
September 2022

2-Alkyl-anthraquinones inhibit Candida albicans biofilm via inhibiting the formation of matrix and hyphae.

Res Microbiol 2022 Jul-Sep;173(6-7):103955. Epub 2022 May 10.

State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Candida albicans can form biofilm on biotic and abiotic surfaces of medical implants to cause superficial and systemic infections under specific condition. The formation of hyphae and matrix of C. albicans are considered as probable virulence factors. We assessed the inhibitory activities of 26 anthraquinones against C. albicans biofilm formation, which were substituted by different functional groups including hydroxyl groups, amino groups, carboxyl groups, alkyl groups, and glycoside groups at C1- or C2-position. Among them, anthraquinones without substituents at other positions but only an alkyl group attached to C2-position, namely 2-alkyl-anthraquinones were determined to have significant anti-biofilm activities. Furthermore, 2-ethylanthraquinone can significantly affect genes related to extracellular matrix (PMT6 and IFD6), and hyphal formation (HWP1, ECE1 and EFG1), leading to the disrupted formation of biofilm, by detail transcriptomics analysis. We believed that 2-ethylanthraquinone could inspire more discoveries of anti-biofilm agents against C. albicans.
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http://dx.doi.org/10.1016/j.resmic.2022.103955DOI Listing
July 2022

Particle size effects in microbial characteristics in thermophilic anaerobic digestion of cattle manure containing copper oxide.

Environ Sci Pollut Res Int 2022 Apr 21. Epub 2022 Apr 21.

College of Architecture and Environment, Sichuan University, Chengdu, 610000, People's Republic of China.

Roles of bulk-, micron-, and nano-copper oxide (CuO) on methane production, microbial diversity, functions during thermophilic anaerobic digestion (AD) were investigated in this study. Results showed that bulk-, micron-, and nano-CuO promoted methane production by 27.8%, 47.6%. and 83.1% compared to the control group, respectively. Microbial community analysis demonstrated that different particle sizes could cause various shifts on bacteria community, while had little effect on archaeal diversity. Thereinto, bacteria belonging to phylum Firmicutes and Coprothermobacterota dominated in enhanced hydrolysis process in groups with nano-CuO and bulk-CuO, respectively, while micron-CuO had stronger promotion on the abundances of hydrolytic and fermentative bacteria belonging to families Peptostreptococcaceae, Caloramatoraceae, Erysipelotrichaceae, and Clostridiaceae, than other two CuO sizes. Metabolic pathways revealed that energy-related metabolism and material transformation in bacteria were only boosted by micron-CuO, and nano-CuO and bulk-CuO were important to methanogenic activity, stimulating energy consumption and methane metabolism, respectively.
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http://dx.doi.org/10.1007/s11356-022-20327-6DOI Listing
April 2022

Oxygen Reduction Reaction at Single Entity Multiwalled Carbon Nanotubes.

J Phys Chem Lett 2022 Apr 21;13(16):3748-3753. Epub 2022 Apr 21.

Department of Chemistry, Physical and Theoretical Chemistry Laboratory, Oxford University, South Parks Road, Oxford OX1 3QZ, Great Britain.

The electrocatalysis of the oxygen reduction reaction (ORR) in aqueous base (0.1 M KOH) by multiwalled carbon nanotubes (MWCNTs) is studied at the single entity level. Electroactive surface functionality is shown to facilitate significant electrocatalysis leading to peroxide formation which is seen to occur at lower potentials as compared to the voltammetric responses obtained at bare carbon macroelectrodes and at such electrodes modified with layers of carbon nanotubes.
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http://dx.doi.org/10.1021/acs.jpclett.2c00871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9059181PMC
April 2022

Editorial: Bioactive Natural Products from Microbes: Isolation, Characterization, Biosynthesis and Structure Modification.

Front Chem 2022 22;10:883652. Epub 2022 Mar 22.

Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.

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http://dx.doi.org/10.3389/fchem.2022.883652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8980275PMC
March 2022

Child and parent secondary outcomes in stepped care versus standard care treatment for childhood trauma.

J Affect Disord 2022 06 21;307:87-96. Epub 2022 Mar 21.

Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.

Introduction: Stepped care trauma-focused cognitive behavioral therapy (SC-TF-CBT) is comparable in efficacy to standard TF-CBT for child posttraumatic stress symptoms (PTSS), but less is known about the effectiveness of SC-TF-CBT on child and parent secondary outcomes. The aim of this community-based randomized clinical trial was to compare child- and caregiver-secondary outcomes among SC-TF-CBT versus TF-CBT participants.

Methods: Children (ages 4 to 12) with PTSS and their caregivers were randomly assigned to either SC-TF-CBT (n = 91) or TF-CBT (n = 92). Secondary child (internalizing and externalizing behavior problems, anger outburst and sleep disturbances) and parent outcomes (PTSS, depression symptoms, and parenting stress) were measured at baseline, post-treatment and 6- and 12-month follow-up.

Results: There were comparable changes at all-time points in child and caregiver secondary outcomes. Non-inferiority tests indicated that for completers and intent-to-treat samples, SC-TF-CBT was non-inferior to TF-CBT for all outcomes except parenting stress at 6-months. The analysis with completers did not support non-inferiority at post-treatment for internalizing and externalizing problems and at 6- and 12-month follow-up assessments for externalizing problems, but the intent-to-treat analysis did support non-inferiority.

Limitations: Limitations included modest rates of attrition, excluding in vivo component for standard TF-CBT, parent-only assessments, and no control condition.

Conclusions: SC-TF-CBT is an effective alternative treatment method although parents with high stress may need more support and children with externalizing problems may need more standard TF-CBT sessions.
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http://dx.doi.org/10.1016/j.jad.2022.03.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035131PMC
June 2022

Correction to: GATA6 suppresses migration and metastasis by regulating the miR-520b/CREB1 axis in gastric cancer.

Cell Death Dis 2022 Mar 16;13(3):243. Epub 2022 Mar 16.

State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China.

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http://dx.doi.org/10.1038/s41419-022-04702-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8927335PMC
March 2022

A CGA/EGFR/GATA2 positive feedback circuit confers chemoresistance in gastric cancer.

J Clin Invest 2022 03;132(6)

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

De novo and acquired resistance are major impediments to the efficacy of conventional and targeted cancer therapy. In unselected gastric cancer (GC) patients with advanced disease, trials combining chemotherapy and an anti-EGFR monoclonal antibody have been largely unsuccessful. In an effort to identify biomarkers of resistance so as to better select patients for such trials, we screened the secretome of chemotherapy-treated human GC cell lines. We found that levels of CGA, the α-subunit of glycoprotein hormones, were markedly increased in the conditioned media of chemoresistant GC cells, and CGA immunoreactivity was enhanced in GC tissues that progressed on chemotherapy. CGA levels in plasma increased in GC patients who received chemotherapy, and this increase was correlated with reduced responsiveness to chemotherapy and poor survival. Mechanistically, secreted CGA was found to bind to EGFR and activate EGFR signaling, thereby conferring a survival advantage to GC cells. N-glycosylation of CGA at Asn52 and Asn78 is required for its stability, secretion, and interaction with EGFR. GATA2 was found to activate CGA transcription, whose increase, in turn, induced the expression and phosphorylation of GATA2 in an EGFR-dependent manner, forming a positive feedback circuit that was initiated by GATA2 autoregulation upon sublethal exposure to chemotherapy. Based on this circuit, combination strategies involving anti-EGFR therapies or targeting CGA with microRNAs (miR-708-3p and miR-761) restored chemotherapy sensitivity. These findings identify a clinically actionable CGA/EGFR/GATA2 circuit and highlight CGA as a predictive biomarker and therapeutic target in chemoresistant GC.
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http://dx.doi.org/10.1172/JCI154074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8920335PMC
March 2022

Interaction of lncRNA MIR100HG with hnRNPA2B1 facilitates mA-dependent stabilization of TCF7L2 mRNA and colorectal cancer progression.

Mol Cancer 2022 03 12;21(1):74. Epub 2022 Mar 12.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Rd, Xi'an, 710032, Shaanxi, China.

Background: Epithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG, confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown.

Methods: The correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining.

Results: The expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (mA) site of TCF7L2 mRNA in the presence of MIR100HG. TCF7L2, in turn, activated MIR100HG transcription, forming a feed forward regulatory loop. The MIR100HG/hnRNPA2B1/TCF7L2 axis was augmented in specimens from CRC patients who either developed local or distant metastasis or had disease progression that was associated with cetuximab resistance.

Conclusions: MIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop.
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http://dx.doi.org/10.1186/s12943-022-01555-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917698PMC
March 2022

Preventative Cancer Screening Rates Among Uninsured Patients in Free Clinics: A Retrospective Cohort Study of Cancer Survivors and Non-cancer Survivors.

Cancer Control 2022 Jan-Dec;29:10732748211072983

Survivorship Clinic, 25301H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Background: There is limited research on screening rates among uninsured cancer survivors. Uninsured cancer survivors are at higher risk of poorer health outcomes than the insured due to limited access to preventative screening for secondary cancers. This study examines the rates of surveillance and screening of uninsured cancer survivors and compares to uninsured patients without a cancer history seen in free clinics.

Methods: Data were collected retrospectively from electronic medical records and paper charts of patients from 10 free clinics between January 2016 and December 2018 in the Tampa Bay area. The prevalence of socioeconomic characteristics, cancer diagnoses, and screening practices were compared for cancer survivors and free clinic patients without a history of cancer. Study participants were determined to be eligible for cancer screenings based on the United States Preventive Services Task Force guidelines.

Results: Out of 13 982 uninsured patients frequenting free clinics between 2016 and 2018, 402 (2.9%) had a documented history of cancer. Out of the 285 eligible cancer survivors, 44 (15.4%) had completed age-appropriate colon cancer screening. Among the 170 female cancer survivors, 75 (44.1%) had completed breast cancer screenings, and only 5.9% (59/246) had completed cervical cancer screenings. After adjusting for age, gender, race, salary, employment status, and household size, cancer survivors were more likely to undergo colorectal cancer screening (OR: 3.59, 95% CI: 2.10-6.15) and breast cancer screening (OR: 2.13, 95% CI: 1.30-3.84) than patients without a cancer history. This difference was not seen for cervical cancer screening (OR: 0.99, 95% CI: .62-1.58).

Conclusions: Uninsured cancer survivors frequenting free clinics represent a unique population that is underrepresented in the medical literature. Our results suggest that uninsured survivors use screening services at higher rates when compared to uninsured patients without a reported cancer diagnosis. However, these rates are suboptimal when compared to national screening rates of insured cancer survivors.
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http://dx.doi.org/10.1177/10732748211072983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902193PMC
March 2022

Effect of vitamin D3 on hyperplasia of mammary glands in experimental rats.

Gland Surg 2022 Jan;11(1):136-146

Department of Ultrasound, The Second Medical Center, Chinese PLA General Hospital, Beijing, China.

Background: 1,25(OH)2D3/vitamin D3 receptor (VD3/VDR) signaling pathway can inhibit the occurrence of breast cancer in many ways. We used vitamin D3 to interfere with Hyperplasia of mammary glands (HMG) model rats, and to explore the intervention effect of vitamin D3 on HMG.

Methods: We divided 42 female rats into six groups randomly: blank control group, hyperplasia model group, negative control group, and vitamin D3 (VD3) groups of low-dose (LVD, 5 µg/kg), medium-dose (MVD, 10 µg/kg), and high-dose (HVD, 20 µg/kg). We established HMG model in all groups except for the blank control group, then different dose of VD3 was intraperitoneal injected for VD3 groups and normal saline (NS) was given to the negative control group. After the experiment, the body weights, heights and diameters of nipples, and the thickness of the mammary gland of rats were measured. The serum content of sex hormone and VD3 were detected by enzyme-linked immunosorbent assay (ELISA). The tissues of mammary glands were analyzed by hematoxylin and eosin (HE) stain, and the expression of estrogen receptor α (ERα), progesterone receptor (PR), and VDR were detected by immunohistochemical (IHC) stain. Similarly, the total protein expression of ERα, PR, and VDR were measured by western blot.

Results: Compared with the hyperplasia group, rats in the VD3 groups displayed a marked decrease of the thickness of the mammary glands and the height and diameter of the nipples. The serum estrogen (E2), testosterone (T), luteinizing hormone (LH), and VD3 was markedly decreased in all VD3 groups (P<0.05). The IHC results showed that ERα and PR was decreased in all three VD3 groups; however, VDR was increased. Western blot demonstrated that both ERα and PR were reduced in VD3 groups, while the VDR level was significantly enhanced. Overall, the findings suggested that VD3 could be used in HMG treatment.

Conclusions: Supplementation of VD3 could markedly decrease the mammary gland thickness, nipple diameter, and nipple height of rats, accompanied by the decrease of serum E2, T, and LH. Intervention with VD3 can lead to decreased expression of ERa and PR, in conjunction with the increase of VDR.
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http://dx.doi.org/10.21037/gs-21-851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8825506PMC
January 2022

Blockade of GCH1/BH4 Axis Activates Ferritinophagy to Mitigate the Resistance of Colorectal Cancer to Erastin-Induced Ferroptosis.

Front Cell Dev Biol 2022 10;10:810327. Epub 2022 Feb 10.

Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Ferroptosis, a type of cell death triggered by excessive accumulation of iron-dependent lipid peroxidation, possesses an excellent potential in cancer treatment. However, many colorectal cancer (CRC) cell lines are resistant to ferroptosis induced by erastin and RSL3, the classical ferroptotic inducers. Moreover, the underlying mechanism of resistance remains poorly elucidated. This study sought to discover the major factor contributing to ferroptosis resistance in CRC. The study findings will help design strategies for triggering ferroptosis for application in individualized tumor therapy. Here, we show that tetrahydrobiopterin (BH4) determines the sensitivity of CRC cells to ferroptosis induced by erastin. GTP cyclohydrolase-1 (GCH1) is the first rate-limiting enzyme of BH4. Genetic or pharmacological inhibition of GCH1 decreased BH4 and assisted erastin in cell death induction, lipid peroxidation enhancement, and ferrous iron accumulation. BH4 supplementation completely inhibited ferroptotic features resulting from GCH1 knockdown. Unexpectedly, GCH1 knockdown failed to enhance RSL3-induced cell death in CRC. Mechanistically, GCH1 knockdown drastically activated ferritinophagy during erastin treatment rather than RSL3 treatment. Administration of an autophagy inhibitor reversed erastin resistance in GCH1-knockdown cells. GCH1 inhibitor and erastin co-treatment synergistically inhibited tumor growth in CRC. Overall, our results identified GCH1/BH4 metabolism as a burgeoning ferroptosis defense mechanism in CRC. Inhibiting GCH1/BH4 metabolism promoted erastin-induced ferroptosis by activating ferritinophagy, suggesting that combining GCH1 inhibitors with erastin in the treatment of CRC is a novel therapeutic strategy.
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http://dx.doi.org/10.3389/fcell.2022.810327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8866854PMC
February 2022

Electro-oxidation of amino-functionalized multiwalled carbon nanotubes.

Chem Sci 2022 Feb 10;13(5):1355-1366. Epub 2022 Jan 10.

Department of Chemistry, Physical and Theoretical Chemistry Laboratory, Oxford University South Parks Road Oxford OX1 3QZ UK

We report the electrochemistry of amino-functionalized multiwalled carbon nanotubes (MWCNTs-NH) in the pH range from 0.3 to 6.4 using quantitative cyclic voltammetry (CV) and single entity electrochemistry measurements, making comparison with non-functionalized MWCNTs. CV showed the latter to both catalyze the solvent (water) decomposition and to undergo irreversible electro-oxidation forming oxygen containing surface functionality. The MWCNTs-NH additionally undergo an irreversible oxidation to an extent which is dependent on the pH of the solution, reflecting the variable amount of deprotonated amino groups present as a function of pH. Nano-impact experiments conducted at the single particle level confirmed the oxidation of both types of MWCNTs, showing agreement with the CV. The p of the amino groups in MWCNTs was determined both electrochemical methods giving consistent values of 2.5.
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http://dx.doi.org/10.1039/d1sc06122dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809411PMC
February 2022

Stepped Care Versus Standard Care for Children After Trauma: A Randomized Non-Inferiority Clinical Trial.

J Am Acad Child Adolesc Psychiatry 2022 Aug 12;61(8):1010-1022.e4. Epub 2022 Jan 12.

Baylor College of Medicine, Houston, Texas.

Objective: Trauma-focused cognitive-behavioral therapy (TF-CBT) is an evidence-based therapist-led treatment for children after trauma. Parents often experience barriers to treatment engagement, including cost. Stepped care TF-CBT (SC-TF-CBT) was developed as an alternative delivery system. Step One is a parent-led therapist-assisted treatment. Step Two provides therapist-led TF-CBT for children who did not benefit from Step One and require more intensive treatment. This study compared SC-TF-CBT to standard TF-CBT in a community-based non-inferiority trial.

Method: A total of 183 children (aged 4-12 years) experiencing posttraumatic stress symptoms (PTSS) and their caregivers were randomly assigned to SC-TF-CBT or standard TF-CBT within 6 community clinics. Assessments occurred at baseline, mid- and posttreatment, and 6 and 12 months. Primary outcomes included PTSS and impairment. Secondary outcomes included severity, diagnostic status, remission, and response. Treatment cost, acceptability, and satisfaction were measured. Difference and non-inferiority tests were applied.

Results: SC-TF-CBT participants changed at rates comparable to participants in TF-CBT for primary and secondary measures. SC-TF-CBT was non-inferior to TF-CBT for PTSS, impairment, and severity at all time points except for impairment at the 6-month assessment. Attrition did not differ between treatment arms (132 participants were completers). Baseline treatment acceptability was lower for SC-TF-CBT parents, although there was no difference in expected treatment improvements or treatment satisfaction at posttreatment. Based on regression estimates, total costs were 38.4% lower for SC-TF-CBT compared to TF-CBT, whereas recurring costs were 53.7% lower.

Conclusion: Stepped Care TF-CBT provides an alternative way to deliver treatment for some children and parents, with reduced cost for providers and parents.

Clinical Trial Registration Information: Stepped Care for Children after Trauma: Optimizing Treatment; https://clinicaltrials.gov; NCT02537678.
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http://dx.doi.org/10.1016/j.jaac.2021.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9273807PMC
August 2022

TMSF-Net: Multi-series fusion network with treeconnect for colorectal tumor segmentation.

Comput Methods Programs Biomed 2022 Mar 31;215:106613. Epub 2021 Dec 31.

The Department of Anorectal Surgery, The First Hospital of China Medical University, Shenyang 110122, China. Electronic address:

Purpose: Colorectal tumors are common clinical diseases. Automatic segmentation of colorectal tumors captured in computed tomography (CT) images can provide numerous possibilities for computer-assisted treatment. Obtaining large datasets is expensive, and completing labeling is time- and manpower-consuming. To solve the challenge using a limited pathological dataset, this paper proposes a multi-series fusion network with treeconnect (TMSF-Net), which can automatically achieve colorectal tumor segmentation using CT images.

Methods: To drive the TMSF-Net, three-series enhanced CT images were collected from all patients to improve the data characteristics. In the TMSF-Net, the coding path was designed as a three-branch structure to realize the feature extraction of the different series. Subsequently, the three branches were merged to start the feature analysis in the decoding path. To achieve the objective of feature fusion, different layers in the decoding path fused feature maps from the upper layer in the encoding path to achieve a cross-scale fusion. In addition, to reduce the problem of parameter redundancy, this study adopted a three-dimensional treeconnect to complete data connection on three branches.

Results: A total of 22 cases were conducted by ablation and comparative experiments to test the TMSF-Net. The results showed that the TMSF-Net can improve the network performance by multiseries fusion, and its expressiveness is better than many classic networks.

Conclusion: The TMSF-Net is a many-to-one structure network, which can enhance the network learning ability and improve the analysis of potential features. Therefore, it yields good results in colorectal tumor segmentation. It can provide a new direction for neural network models based on feature fusion.
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http://dx.doi.org/10.1016/j.cmpb.2021.106613DOI Listing
March 2022

The Temporal Pattern of Arterial Stiffness during Aging: A Large-Scale Cross-Sectional Study.

J Diabetes Res 2021 10;2021:3243135. Epub 2021 Dec 10.

Department of Biostatistics and Epidemiology, College of Public Health, University of South Florida, Tampa, FL 33612, USA.

Brachial-ankle pulse wave velocity (baPWV) is a noninvasive clinical test that provides quantification for the stiffness of both the aorta and peripheral arteries by measuring the brachial and tibial arterial wave velocities. The temporal pattern of baPWV values during aging was investigated in this paper. A gradual increase in baPWV with respect to age was observed, suggesting an increase in the stiffness of arterial vessels as age increases. The baPWV value, defined as the absolute value of the difference between bilateral baPWV, also showed a positive correlation with aging. Many underlying physiological conditions such as hyperlipidemia, hypertension, diabetes, and hyperglycemia have previously been shown to elevate baPWV and contribute to the decline of arterial function. The effect of factors including biological sex, blood pressure, and blood glucose levels on the baPWV temporal pattern were also investigated. Between the ages of 18 and 50, men in the study had significantly higher baPWV readings than females of comparable age on average. However, after the age of 50, mean baPWV values increased at a greater rate in females than in males. In addition, blood pressure and blood glucose were shown to be associated with baPWV values. The results will improve existing prediction models for future cardiovascular episodes induced by arterial hardening in different age groups.
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http://dx.doi.org/10.1155/2021/3243135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683198PMC
March 2022

The Role of Ferroptosis Signature in Overall Survival and Chemotherapy of Pancreatic Adenocarcinoma.

DNA Cell Biol 2022 Feb 13;41(2):116-127. Epub 2021 Dec 13.

Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Studies have shown that ferroptosis, an iron-dependent regulated cell death, is related to prognosis and chemotherapy, but the role of ferroptosis in pancreatic adenocarcinoma (PAAD) is still unclear. We aimed at constructing a ferroptosis-related gene (FRGs) model to predict the PAAD patients' overall survival (OS) and at exploring their values in chemotherapy. We downloaded the mRNA-sequencing data and corresponding clinical data of patients with PAAD from The Cancer Genome Atlas. Lasso-penalized Cox regression analysis was utilized to construct a prognostic risk model, including spermidine/spermine N1-acetyltransferase 1 (SAT1), SAT2, TFRC, SLC39A8, MAP1LC3A, ALOX15, and PROM2. Receiver operating characteristic curves were used to evaluate the prognostic model. International Cancer Genome Consortium cohorts were used to validate this model. Then, we used Genomics of Drug Sensitivity in Cancer and Gene Expression Omnibus databases to analyze the correlation between FRGs and drug sensitivity. Notably, SAT1 showed significant influence in cisplatin and gemcitabine resistance. Finally, in vitro experiments demonstrated that the combination of gemcitabine and cisplatin could induce ferroptosis in AsPC1 cells, probably through elevated SAT1 expression. Taken together, Our 7-gene signature has significant values in predicting the PAAD patients' OS, and it may help inform the clinical treatment of PAAD.
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http://dx.doi.org/10.1089/dna.2021.0594DOI Listing
February 2022

miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN.

Cancers (Basel) 2021 Nov 15;13(22). Epub 2021 Nov 15.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China.

Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.
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http://dx.doi.org/10.3390/cancers13225710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616371PMC
November 2021

The Prognostic Value of Circulating Tumor DNA in Ovarian Cancer: A Meta-Analysis.

Authors:
Yuanyuan Lu Li Li

Technol Cancer Res Treat 2021 Jan-Dec;20:15330338211043784

117981Guangxi Medical University Affiliated Cancer Hospital, Nanning, Guangxi, China.

Studies have shown that circulating tumor DNA (ctDNA) indicates a poor prognosis in ovarian cancer. In this study, meta-analysis was used to assess the relationship between ctDNA and the prognosis of patients with epithelial ovarian cancer. The clinical trials included in this study were obtained via a search of PubMed, the Cochrane Library, the Web of Science and Embase between the period of establishment and March 2020. We selected clinical studies using qualitative or quantitative ctDNA methods to analyse the prognosis of ovarian epithelial cancer, screened the studies according to the determined inclusion and exclusion criteria, and used the modified JADAD score scale and NOS scale for evaluation, with OS (overall survival) and PFS (progression-free survival) as end events. The Cochrane Evaluation Tool was used to evaluate the quality of the randomized controlled trials. Stata 15.0 software was used to combine the effect ratio (hazard ratio, HR) and its 95% confidence interval (CI). In addition, a source analysis of ctDNA specimens, an analysis of ctDNA detection methods and a subgroup and sensitivity analysis of FIGO staging were performed. A total of 8 studies were included in this meta-analysis, and ctDNA was found to be an independent risk factor for patients with epithelial ovarian cancer (OS: HR = 2.36, 95% CI [1.76,3.17],  < .001; PFS: HR = 2.51, 95% CI [1.83,3.45]). The results of our analysis suggested that ctDNA is a potential biomarker that can be used to evaluate the prognosis of patients with ovarian cancer.
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http://dx.doi.org/10.1177/15330338211043784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649094PMC
February 2022
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