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Cervical cancer remains one of the most lethal gynecological malignancies. However, biomarkers for more precise patient care are an unmet need. Herein, the concentration of 285 plasma cell-free DNA (cfDNA) samples are analyzed from 84 cervical patients and the clinical significance of cfDNA fragmentomic characteristics across the neoadjuvant chemotherapy (NACT) treatment. Patients with poor NACT response exhibit a significantly greater escalation in cfDNA levels following the initial cycle of treatment, in comparison to patients with a favorable response. Distinctive end motif profiles and promoter coverages of cfDNA in initial plasma are observed between patients with differing NACT responses. Notably, the DNASE1L3 analysis further demonstrates the intrinsic association between cfDNA characteristics and chemotherapy resistance. The cfDNA and motif ratios show a good discriminative capacity for predicting non-responders from responders (area under the curve (AUC) > 0.8). In addition, transcriptional start sites (TSS) coverages around promoters discern the alteration of biological processes associated with chemotherapy resistance and reflect the potential value in predicting chemotherapy response. These findings in predictive biomarkers may optimize treatment selection, minimize unnecessary treatment, and assist in establishing personalized treatment strategies for cervical cancer patients., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Human papillomavirus (HPV) integration and high expression of HPV oncogenes (E6 and E7) are important mechanisms for HPV carcinogenesis in cervical cancer. However, the relationship between HPV integration and HPV E6 spliced transcripts, as well as the underlying mechanisms of HPV integration in carcinogenesis after HPV E6 splicing remains unclear. We analyzed HPV-coiled-coil domain containing 106 (CCDC106) integration samples to characterize the roles of HPV integration, E6 spliceosome I (E6*I), and high CCDC106 expression in cervical carcinogenesis. We found that E6 was alternatively spliced into the E6*I transcript in HPV-CCDC016 integration samples with low p53 expression, in contrast to the role of E6*I in preventing p53 degradation in cervical cancer cells. In addition, CCDC106 was highly expressed after HPV-CCDC106 integration, and interacted with p53, resulting in p53 degradation and cervical cancer cell progression in vitro and in vivo. Importantly, when E6*I was highly expressed in cervical cancer cells, overexpression of CCDC106 independently degraded p53 and promoted cervical cancer cell progression. In this study, we explored the underlying mechanisms of HPV-CCDC106 integration in HPV carcinogenesis after HPV E6 splicing, which should provide insight into host genome dysregulation in cervical carcinogenesis., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Increased ovarian fibrosis and an expanded stromal cell compartment are the main characteristics of aging ovaries. However, the molecular mechanisms and the key factor of stromal cells underlying ovarian aging remain unclear. Here, we explored single-cell transcriptomic data of ovaries from the adult mouse (4,363 cells), young (1,122 cells), and aged (1,479 cells) non-human primates (NHPs) to identify expression patterns of stromal cells between young and old ovaries. An increased number of stromal cells (p = 0.0386) was observed in aged ovaries of NHPs, with enrichment processes related to the collagen-containing extracellular matrix. In addition, differentially expressed genes of stromal cells between young and old ovaries were regulated by ESR1 (p = 7.94E-08) and AR (p = 1.99E-05). Among them, EGFR was identified as the common target and was highly expressed (p = 7.69E-39) in old ovaries. In human ovaries, the correlated genes of EGFR were associated with the process of the cell-substrate junction. Silencing of EGFR in human ovarian stromal cells led to the reduction of cell-substrate junction via regulating phosphorylation modification of the AKT-mTOR signaling pathway and stromal cell marker genes. Overall, we identified high levels of EGFR for stromal cells in ovarian aging, which provides insight into the cell type-specific molecular mechanisms underlying ovarian aging at single-cell resolution., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Non-gestational choriocarcinoma (NGC) is a rare subtype of choriocarcinoma differing in origin and phenotypic characteristics compared to gestational choriocarcinoma (GC). This study aimed to analyze the molecular biology of GC and NGC and evaluate genetic anomalies of choriocarcinoma subtypes. DNA was extracted and paired from tumor-normal tissue of one NGC and one GC (control) patient for whole-exome sequencing. To further understand the role of DNAJB9 , a p53 regulator mutated in the NGC tumor, on p53 upregulation in choriocarcinoma, CRISPR/Cas9 was used to induce DNAJB9 site-specific mutations in choriocarcinoma cells JEG-3. We hypothesized that DNAJB9 dysfunction would result in p53 overexpression. Sequencing revealed the GC tumor contained > 7 times more somatic mutations than the NGC tumor. Missense (98.86% vs. 94.97%), stop-gain (0.57% vs. 0.93%), and frameshift mutations (0.57% vs. 4.10%) were observed in the GC and NGC samples, respectively ( x 2 = 24.63, P < 0.00001). The transition substitution rate was 67.54% and 55.71% in the GC and NGC samples, while the transversion substitution rate was 32.46% and 44.29% in the GC and NGC samples, respectively ( x 2 = 11.56, P < 0.000673). Pathway enrichment analysis revealed ECM-receptor interaction and graft-versus-host disease were most enriched in the GC and NGC tumors, respectively. In vitro investigations showed that DNAJB9 mRNA and protein levels were downregulated in Cas9- DNAJB9 -sgRNA transfected cells compared to the control ( P < 0.001), while p53 protein levels were upregulated. Our findings display the genetic distinctness of choriocarcinoma subtypes, especially NGC, and further highlight the relationship between p53 and DNAJB9 in choriocarcinoma cells, laying the foundation for further investigations., Competing Interests: None., (AJTR Copyright © 2019.)

Objective: The purpose of this retrospective study was to investigate the role of 18F-Fluorodeoxyglucose Positron Emission Tomography ( 18 F-FDG PET/CT) and evaluate if combined elevated serum tumor markers levels improve the accuracy of 18 F-FDG PET/CT in detecting recurrence of cervical squamous cell carcinoma. Methods: A total number of 42 patients who were treated for cervical squamous cell carcinoma and had underwent 18 F-FDG PET/CT for suspected recurrence of cervical cancer were retrospectively reviewed in this study and their clinical, pathological and serological data were collected and analyzed. The clinical value of combining 18 F-FDG PET/CT with serum tumor markers was investigated. Results: Among the 42 patients, 18 F-FDG PET/CT was true positive in 25 (59.5%), false positive in 5 (11.9%), true negative in 12 (28.5%) and false negative in none. The overall patient-based sensitivity, specificity, accuracy, positive predictive value and negative predictive value of 18 F-FDG PET/CT in detecting recurrent cervical cancer were 100%, 70.6, 88.1%, 83.3%, and 100%, respectively. The accuracy of 18 F-FDG PET/CT with combined squamous cell carcinoma antigen (SCC Ag) and carcinoembryonic antigen (CEA) elevation was 100% compared to only SCC Ag elevation and only CEA elevation, 90% and 33.3%, respectively. The positive predictive value of a positive 18 F-FDG PET/CT with combined SCC Ag and CEA elevation was 100% for detection of recurrent cervical cancer. Also, the negative predictive value of a negative 18 F-FDG PET/CT combined with normal SCC Ag and CEA levels was 100%. Conclusion: 18 F-FDG PET/CT is highly sensitive in the diagnosis of recurrent cervical cancer. When 18 F-FDG PET/CT is associated with both SCC Ag and CEA elevation or only SCC Ag elevation, the accuracy is increased but not when associated with only CEA elevation. Positive 18 F-FDG PET/CT associated with both tumor markers elevation can precisely predict recurrence. Moreover, normal levels of both tumor markers with a negative 18 F-FDG PET/CT result may clinically reassure that a recurrence is absent., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.