Heat increases the editing efficiency of human papillomavirus E2 gene by inducing upregulation of APOBEC3A and 3G

Apolipoprotein B mRNA-editing catalytic polypeptide (APOBEC) 3 proteins have been identified as potent viral DNA mutators and have broad antiviral activity. In this study, we demonstrated that apolipoprotein B mRNA-editing catalytic polypeptide 3A (A3A) and A3G expression levels were significantly upregulated in human papillomavirus (HPV)-infected cell lines and tissues. Heat treatment resulted in elevated expression of A3A and A3G in a temperature-dependent manner in HPV-infected cells. Correspondingly, HPV-infected cells heat-treated at 44 °C showed accumulated G-to-A or C-to-T mutation in HPV E2 gene. Knockdown of A3A or A3G could promote cell viability, along with the lower frequency of A/T in HPV E2 gene. In addition, regressing genital viral warts also harbored high G-to-A or C-to-T mutation in HPV E2 gene. Taken together, we demonstrate that apolipoprotein B mRNA-editing catalytic polypeptide 3 expression and editing function was heat sensitive to a certain degree, partly explaining the mechanism of action of local hyperthermia to treat viral warts

Machine learning based prediction models for analyzing risk factors in patients with acute abdominal pain: a retrospective study

BackgroundAcute abdominal pain (AAP) is a common symptom presented in the emergency department (ED), and it is crucial to have objective and accurate triage. This study aims to develop a machine learning-based prediction model for AAP triage. The goal is to identify triage indicators for critically ill patients and ensure the prompt availability of diagnostic and treatment resources.MethodsIn this study, we conducted a retrospective analysis of the medical records of patients admitted to the ED of Wuhan Puren Hospital with acute abdominal pain in 2019. To identify high-risk factors, univariate and multivariate logistic regression analyses were used with thirty-one predictor variables. Evaluation of eight machine learning triage prediction models was conducted using both test and validation cohorts to optimize the AAP triage prediction model.ResultsEleven clinical indicators with statistical significance (p < 0.05) were identified, and they were found to be associated with the severity of acute abdominal pain. Among the eight machine learning models constructed from the training and test cohorts, the model based on the artificial neural network (ANN) demonstrated the best performance, achieving an accuracy of 0.9792 and an area under the curve (AUC) of 0.9972. Further optimization results indicate that the AUC value of the ANN model could reach 0.9832 by incorporating only seven variables: history of diabetes, history of stroke, pulse, blood pressure, pale appearance, bowel sounds, and location of the pain.ConclusionThe ANN model is the most effective in predicting the triage of AAP. Furthermore, when only seven variables are considered, including history of diabetes, etc., the model still shows good predictive performance. This is helpful for the rapid clinical triage of AAP patients and the allocation of medical resources

The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma

Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by the prolyl 3- (C-P3H) and prolyl 4- (C-P4H) hydroxylases is essential for normal cell function. Here we have investigated the expression, transcriptional regulation and function of the C-P3H and C-P4H families in melanoma. We show that the CP3H family exemplified by Leprel1 and Leprel2 are subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumour suppressor function. In contrast, although there is transcriptional silencing of P4HA3 in a sub-set of melanomas, the CP4H family members P4HA1, P4HA2 and P4HA3 are often over-expressed in melanoma, expression being prognostic of worse clinical outcomes. Consistent with tumour suppressor function, ectopic expression of Leprel1 and Leprel2 inhibits melanoma proliferation, whereas P4HA2 and P4HA3 increase proliferation and particularly invasiveness of melanoma cells. Pharmacological inhibition with multiple selective C-P4H inhibitors reduces proliferation and inhibits invasiveness of melanoma cells. Together, our data identify the C-P3H and C-P4H families as potentially important regulators of melanoma growth and invasiveness and suggest that selective inhibition of C-P4H is an attractive strategy to reduce the invasive properties of melanoma cells

The Renin Angiotensin System (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin–angiotensin system (RAS) is a major physiological regulatory pathway controlling salt–water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma

Interleukin-6 and insulin-like growth factor-1 synergistically promote the progression of NSCLC

The signaling pathways of interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1) play an important role in the progression of lung cancer, and this study aimed to explore whether they can synergistically promote the progression of non-small cell lung cancer (NSCLC). We found that IL-6, glycoprotein 130 (GP130), IGF-1 and IGF-1R were highly expressed in NSCLC (p = .000), and there was the correlation between GP130, IGF-1, and IGF-1R (p < .01). The overall survival of patients with the co-expression of GP130 and IGF-1R was significantly shorter (p = .0360). Co-stimulation of IL-6 and IGF-1 resulted in significantly enhanced in cell proliferation, (p < .05), invasion (p < .05), cycle (p < .05), apoptosis (p < .05), and the expression of signal molecules (GP130, IGF-1R, p-AKT, and p-ERK1/2) (all p < .05) in NSCLC cells. This experiment revealed that IL-6 and IGF-1 can synergistically promote the progression of NSCLC. The high expression of GP130 and IGF-1R is an independent risk factor for poor prognosis patients, and it is helpful to find a more accurate target for targeted therapy in NSCLC

Data_Sheet_1_Effect of 18F-DCFPyL PET on changes in management of patients with prostate cancer: a systematic review and meta-analysis.docx

PurposeProstate-specific membrane antigen (PSMA)-targeted imaging has gained increasing interest in its application in prostate cancer lesion detection. Compared with 68Galium (68Ga), 18Fluoride (18F)-labeled imaging agent has easier syntheses, lower price, and a longer half-time. 2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid positron emission tomography (18F-DCFPyL PET) has been recently approved by the U.S. Food and Drug Administration. Several studies have proven its superiority to conventional imaging techniques in detecting prostate cancer lesions. However, the impact of 18F-DCFPyL PET on the management of patients with prostate cancer is not well established. Thus, we performed a systematic review and meta-analysis of available data to evaluate the impact of 18F-DCFPyL PET on the management of patients with prostate cancer.MethodsThe PubMed, Embase, Scopus, and Cochrane databases were searched up to April 2024. Studies that reported the proportion of changes in management after 18F-DCFPyL PET was performed in patients with prostate cancer were included. The Grading of Recommendations Assessment, Development, and Evaluation system was used for the quality evaluation of the included studies. The proportion of changes in management was pooled using a random effects model. Meta-regression analyses were performed to assess the potential correlation between the PET positivity and management changes.ResultsFourteen studies (3,078 patients with prostate cancer) were included in our review and analysis. The pooled percentage of management changes was 43.5% (95% confidence interval [CI]: 33–54%). In patients with biochemical recurrent and for primary staging, the pooled percentage was 50% (95% CI: 39–60%) and 22% (95% CI: 15–29%), respectively. In the meta-regression analyses, PET positivity was detected as a significant predictor of management change (p = 0.0023).Conclusion18F-DCFPyL PET significantly affects the management of patients with prostate cancer. Higher PET positivity rate significantly correlated with a higher proportion of management changes in patients with prostate cancer. However, more studies are still needed to confirm the important role of 18F-DCFPyL PET in the management of prostate cancer.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#myprospero, CRD42022339178.</p

MCL-1 Inhibitor S63845 Distinctively Affects Intramedullary and Extramedullary Hematopoiesis

Conventional chemotherapy for killing cancer cells using cytotoxic drugs suffers from low selectivity, significant toxicity, and a narrow therapeutic index. Hyper-specific targeted drugs achieve precise destruction of tumors by inhibiting molecular pathways that are critical to tumor growth. Myeloid cell leukemia 1 (MCL-1), an important pro-survival protein in the BCL-2 family, is a promising antitumor target. In this study, we chose to investigate the effects of S63845, a small-molecule inhibitor that targets MCL-1, on the normal hematopoietic system. A mouse model of hematopoietic injury was constructed, and the effects of the inhibitor on the hematopoietic system of mice were evaluated via routine blood tests and flow cytometry. The results showed that S63845 affected the hematopoiesis of various lineages in the early stage of action, causing extramedullary compensatory hematopoiesis in the myeloid and megakaryocytic lineages. The maturation of the erythroid lineage in the intramedullary and extramedullary segments was blocked to varying degrees, and both the intramedullary and extramedullary lymphoid lineages were inhibited. This study provides a complete description of the effects of MCL-1 inhibitor on the intramedullary and extramedullary hematopoietic lineages, which is important for the selection of combinations of antitumor drugs and the prevention of adverse hematopoiesis-related effects