Real-world TRAE association between niraparib and platinum-based chemotherapy.

Background: Pre-clinical studies showed the anti-tumor mechanisms of PARP inhibitors (PARPi) and platinum have some crossover and overlap in the DNA damage repair pathway, patients who respond to platinum-based chemotherapy are also more likely to be sensitive to PARPi. This real-world study mainly aimed to evaluate whether TRAE (treatment-related adverse event) between platinum based chemotherapy (PBC) and niraparib are also associated. Methods: Patients received niraparib as maintenance treatment or salvage therapy for advanced ovarian cancer at the First Affiliated Hospital of Gannan Medical University from January 2020 to August 2023 were included. Survival data of niraparib treatment and adverse events occurred during the last platinum-based chemotherapy cycle before starting niraparib treatment and during niraparib treatment are documented. Fisher's exact test were used for correlation analysis. Results: 1. 40 patients treated with niraparib were included in the analysis, including 31 patients treated with niraparib for 1st-line maintenance therapy, 6 patients for PSR (platinum-sensitive recurrence) maintenance therapy, and 3 patients for salvage therapy. The overall median follow-up time was 15.0 months (ranged from 2.2 months to 32.1 months). 2. Overall grade≥3 TRAE (40% vs 70%, p=0.012) including anemia (20% vs 45%, p=0.041) and neutrophil count decreased (17.5% vs 57.5%, p<0.001) was significantly lower during niraparib treatment compared to during chemotherapy. 3. Any grade TRAE (75% vs 100%, p=0.002) including white blood cell count decreased (47.5% vs 87.5%, p<0.001), red blood cell count decreased (57.5% vs 92.5%, p<0.001), anemia (55% vs 87.5%, p<0.001) and neutrophil count decreased (35% vs 85%, p<0.001) were also significantly lower in niraparib treatment group compared with chemotherapy group. No new safety signals were identified. Conclusion: 1. In this real-world practice, we observed that patients with advanced ovarian cancer who experienced any grade and grade ≥3 TRAE during chemotherapy were well tolerated when treated with niraparib, particularly the incidence of any grade and grade ≥3 anemia, and neutrophil count decreased during niraparib treatment were significantly lower compared with that during chemotherapy. 2. For patients with ovarian cancer who have experienced grade ≥3 hematological adverse reactions during prior platinum-based chemotherapy, greater attention should be paid to the monitoring and management of hematological adverse reactions during subsequent treatment with niraparib.

DNA methylation of ICAM4 and NOXO1 participate in the formation of uterine fibroids via regulating immune cell infiltration.

This atudy aimed to reveal the effect of DNA methylation on immune infiltration of uterine fibroids (UFs) and to further classify UFs based on transcriptomic characteristics. The transcriptome and DNA methylation data of UFs were collected from the GEO database. After taking the intersection of the differentially expressed genes in these two types of data, the intersection gene was used to draw ROC curves and to filtrate the candidate genes with AUC≥0.8. Immune infiltration analysis was performed in the online tool EPIC. The correlation between gene with AUC≥0.8 and the abundance of each immune cell type was calculated with |R|>0.3 and P<0.05. ConsensusClusterPlus package in R software was used to further cluster the samples of UFs. In this study, a total of 41 RNA-seq data (10 normal uterine samples and 31 UFs samples) and 34 DNA methylation data (10 from normal subjects and 24 from patients with UFs) were involved. The significantly down-regulated ICAM4, SPECC1L, and NOXO1 were the top three methylated drive genes of UFs. Therefore, NOXO1 and ICAM4 present an intimate correlation to immune cell infiltration. Besides, UFs could be clustered into two subtypes, including a TSAB1 up-regulated subtype and a FOSB up-regulated subtype. DNA methylation of ICAM4 and NOXO1 are involved in the pathogenesis of UFs via regulating immune cell infiltration. Further classification based on transcriptomic characteristics could divide UFs into sexual steroids-related and biomechanics-related subtypes, which would promote its non-invasive treatment.

IRAK-M Ablation Promotes Status Epilepticus-Induced Neuroinflammation via Activating M1 Microglia and Impairing Excitatory Synaptic Function.

Epilepsy is one of the most common neurological disorders. The pro-epileptic and antiepileptic roles of microglia have recently garnered significant attention. Interleukin-1 receptor-associated kinase (IRAK)-M, an important kinase in the innate immune response, is mainly expressed in microglia and acts as a negative regulator of the TLR4 signaling pathway that mediates the anti-inflammatory effect. However, whether IRAK-M exerts a protective role in epileptogenesis as well as the molecular and cellular mechanisms underlying these processes are yet to be elucidated. An epilepsy mouse model induced by pilocarpine was used in this study. Real-time quantitative polymerase chain reaction and western blot analysis were used to analyze mRNA and protein expression levels, respectively. Whole-cell voltage-clamp recordings were employed to evaluate the glutamatergic synaptic transmission in hippocampal neurons. Immunofluorescence was utilized to show the glial cell activation and neuronal loss. Furthermore, the proportion of microglia was analyzed using flow cytometry. Seizure dynamics influenced the expression of IRAK-M. Its knockout dramatically exacerbated the seizures and the pathology in epilepsy and increased the N-methyl-d-aspartate receptor (NMDAR) expression, thereby enhancing glutamatergic synaptic transmission in hippocampal CA1 pyramidal neurons in mice. Furthermore, IRAK-M deficiency augmented hippocampal neuronal loss via a possible mechanism of NMDAR-mediated excitotoxicity. IRAK-M deletion promotes microglia toward the M1 phenotype, which resulted in high levels of proinflammatory cytokines and was accompanied by a visible increase in the expressions of key microglial polarization-related proteins, including p-STAT1, TRAF6, and SOCS1. The findings demonstrate that IRAK-M dysfunction contributes to the progression of epilepsy by increasing M1 microglial polarization and glutamatergic synaptic transmission. This is possibly related to NMDARs, particularly Grin2A and Grin2B, which suggests that IRAK-M could serve as a novel therapeutic target for the direct alleviation of epilepsy.

Comparing the clinical efficacy of three surgical methods for cesarean scar pregnancy.

BACKGROUND: We aimed to compare the clinical efficacy of three surgical methods in the treatment of various types of cesarean scar pregnancy (CSP). METHODS: Herein, 314 cases of CSP were treated in the department of Obstetrics and Gynecology of the First Affiliated Hospital of Gannan Medical University between June 2017 and June 2020. The patients were divided into three groups based on the treatment received: group A (n = 146; curettage by pituitrin combined with ultrasonic monitoring and hysteroscopy-guided surgery), group B [n = 90; curettage after methotrexate (MTX) injection into the local gestational sac], and group C (n = 78; laparoscopic, transvaginal, and transabdominal cesarean scar resection). These groups were divided into three subgroups (type I, type II, and type III) according to the CSP type of the patients. RESULTS: The intraoperative blood loss, length of hospital stay, hospitalization cost, menstrual recovery time, and serum ß-HCG normalization time were lower in groups A than in groups B or C with type I, II and III CSP (P < 0.05). Operative efficiency and Successful second pregnancy rate were higher in groups A than in groups B or C with type I and II CSP (P < 0.05). But in type III CSP, the complications were more serious in group A than group C. CONCLUSIONS: Curettage by pituitrin combined with ultrasonic monitoring and hysteroscopy-guided surgery is an effective and relatively safe treatment for patients with type I and II CSP. Laparoscopic surgery is more suitable for type III CSP.

Deep learning of endoscopic features for the assessment of neoadjuvant therapy response in locally advanced rectal cancer.

BACKGROUND: For locally advanced rectal cancer (LARC), accurate response evaluation is necessary to select complete responders after neoadjuvant therapy (NAT) for a watch-and-wait (W&W) strategy. Algorithms based on deep learning have shown great value in medical image analyses. Here we used deep learning algorithms of endoscopic images for the assessment of NAT response in LARC. METHOD: 214 LARC patients were retrospectively included in the study. After NAT, these patients underwent total mesorectal excision (TME) surgery. Among them, 51 (23.8%) of the patients achieved a pathological complete response (pCR). 160 patients from Shanghai Changzheng Hospital were regarded as primary dataset, and the other 54 patients from Zhejiang Cancer Hospital were regarded as validation dataset. ResNet-18 and DenseNet-121 were applied to train the models based on endoscopic images after NAT. Deep learning models were valid in the validation dataset and compared to manual method. RESULTS: The performances were comparable in AUC between deep learning models and manual method. For mean metrics, sensitivity (0.750 vs. 0.417) and AUC (0.716 vs. 0.601) in ResNet-18 deep learning model were higher than those in the manual method. The deep learning models were able to identify the endoscopic features associated with NAT response by the heatmaps. A diagnostic flow diagram which integrated the deep learning model to assist the clinicians in making decisions for W&W strategy was constructed. CONCLUSIONS: We created deep learning models using endoscopic features for assessment of NAT in LARC. The deep learning models achieved modest accuracies and performed comparably to manual method.

Echocardiographic evaluation of supracardiac anomalous pulmonary venous connection in children: comparison with multilayer spiral CT.

Objective To explore the clinical value of transthoracic echocardiography (TTE) in the differentiation of Supracardiac Anomalous Pulmonary Venous Connection (SAPVC) in children. Materials and methods A total of 118 children with concurrent TTE and CT databases of cases diagnosed with SAPVCs were included. We analyzed the consistency between the two for the ability to diagnose the classification of SAPVC, drainage sites, ectopic pulmonary veins and the segments of superior vena cava (SVC). Results The consistency between TTE and CT in diagnosing the existence of SAPVC and the classification were 88.1% (95% CI: 80.9-93.4%) and 91.0% (95% CI: 84.1-95.6%), respectively. The error rate of partial type diagnosed by TTE was significantly higher than that of total and mixed type (20.5% vs. 2.8%, P = 0.003). The consistency between TTE and CT to determine drainage sites was 91.9% (95% CI: 85.2-96.2%). TTE had a significantly higher error rate in determining pulmonary vein drainage to the SVC than in those draining into the left innominate vein (17.5 vs. 2.5%, P = 0.007). The consistency of TTE and CT in judging the number of veins was 87.4% (95% CI: 79.7-92.9%). The error rate in determining the presence of 2 and 5 ectopic pulmonary veins was significantly higher than those of 1 and 4 veins (P < 0.05). Conclusion TTE for diagnosing partial SAPVC and identifying the drainage site of SVC has a high error rate of misdiagnosis and missed diagnosis. The extra attention should be given to these factors in clinical practice to improve the accuracy of TTE in diagnosing SAPVC.

MicroRNA-133b Inhibits nTumor Cell Proliferation, Migration and Invasion by Targeting SUMO1 in Endometrial Carcinoma.

Objectives: An increasing number of studies have confirmed that microRNAs (miRNAs/miRs), as oncogenes or tumor suppressor genes, play an important regulatory role in the occurrence and development of numerous types of cancer. The aim of the present study was to investigate the potential role and mechanism of miR-133b and small ubiquitin like modifier 1 (SUMO1) in the development of endometrial carcinoma (EC). Methods: First, Venn diagrams are used to identify the differential expressions of miRNAs in EC from GSE35794 and GSE25405 datasets. Next, we conduct a series of functional tests, including Cell Counting Kit-8, wound healing, and transwell and matrigel assays. Then, a bioinformatics tool, is used to identify downstream target genes of miR-133b and to verify the predicted results by RT-qPCR, Western blotting and double luciferase reporter gene analysis. Finally, in order to further study whether the cellular function of miR-133b is mediated by the expression of SUMO1, rescue experiments were carried out. Results: The results of bioinformatics studies showed that the expression of miR-133b was down-regulated in EC tissues, and the expression level of miR-133b was lower in patients with high grade, different histology or menopausal status. The results of functional assay showed that overexpression of miR-133b reduced cell proliferation, migration and invasion. On the contrary, miR-133b silence has the opposite effect. SUMO1 was the direct target of miR-133b and was negatively regulated by miR-133b. The decrease of SUMO1mRNA expression inhibited the proliferation, migration and invasion of EC cells, and reversed the effect of miR-133b on EC cells. Conclusion: The findings from the present study suggested that miR-133b may be a tumor suppressor gene and a potential therapeutic target for the treatment of EC.

SODA: Detecting COVID-19 in Chest X-rays with Semi-supervised Open Set Domain Adaptation.

Due to the shortage of COVID-19 viral testing kits, radiology is used to complement the screening process. Deep learning methods are promising in automatically detecting COVID-19 disease in chest x-ray images. Most of these works first train a Convolutional Neural Network (CNN) on an existing large-scale chest x-ray image dataset and then fine-tune the model on the newly collected COVID-19 chest x-ray dataset, often at a much smaller scale. However, simple fine-tuning may lead to poor performance due to two issues, firstly the large domain shift present in chest x-ray datasets and secondly the relatively small scale of the COVID-19 chest x-ray dataset. In an attempt to address these issues, we formulate the problem of COVID-19 chest x-ray image classification in a semi-supervised open set domain adaptation setting and propose a novel domain adaptation method, Semi-supervised Open set Domain Adversarial network (SODA). SODA is designed to align the data distributions across different domains in the general domain space and also in the common subspace of source and target data. In our experiments, SODA achieves a leading classification performance compared with recent state-of-the-art models in separating COVID-19 with common pneumonia. We also present results showing that SODA produces better pathology localizations.

Betulinic acid induces apoptosis and impairs migration and invasion in a mouse model of ovarian cancer.

Betulinic acid (BA) was verified to possess plenty of biological activities including anti-tumor, anti-inflammatory and so on. In our research, we studied the growth inhibition, apoptosis promotion and metastasis resistance of ovarian cancer cells by BA. The result showed that BA showed a time- and dose-dependent inhibitory effect on ovarian cancer cell lines. SKOV3 cell line proliferation has a concentration- and time-dependently, which may be inhibited by BA. Furthermore, BA inhibited the metastasis of tumor cells remarkably by inhibiting epithelial-mesenchymal transition process. Beyond that, the weight and volume of subcutaneous tumor was distinctly suppressed by administration of BA in tumor-bearing mice of SKOV3 cells. Pathological and immunohistochemical tests showed that Ki-67+ and MMP-2+ cells were dramatically decreased after BA administration, indicating that BA can not only suppress proliferation, but also inhibit migration of tumor cells. Taken together, BA can be a valuable candidate drug for the treatment of ovarian cancer. PRACTICAL APPLICATIONS: Betulinic acid (BA) isolated from natural plants such as fenugreek, eucalyptus bulb and mulberry has been reported with many biological activities. Results from this study revealed that in vitro and in vivo BA-induced apoptosis and inhibited migration and invasion of human ovarian cancer cells. Therefore, BA from natural plants may be developed as a potential drug for inhibition the development of ovarian cancer cells.

Iodine load reduction in dual-energy spectral CT portal venography with low energy images combined with adaptive statistical iterative reconstruction.

OBJECTIVE: To study the application of using low energy images combined with adaptive statistical iterative reconstruction (ASiR) in dual-energy spectral CT portal venography (CTPV) to reduce iodine load. METHODS: 41 patients for CTPV were prospectively and randomly divided into two groups. Group A ( n = 21) used conventional 120 kVp scanning protocol with contrast dose at 0.6 gI/kg while group B ( n = 20) used dual-energy spectral imaging with reduced contrast dose at 0.3 gI/kg. The 120 kVp images in Group A and 50 keV images in Group B were reconstructed with 40% ASiR. The contrast-to-noise ratio of portal vein was calculated. The image quality and the numbers of intrahepatic portal vein branches were evaluated by two experienced radiologists using a 5-point scoring system. RESULTS: Group B reduced iodine load by 52% compared to Group A (17.21 ± 3.30 gI vs 35.80 ± 6.18 gI, p < 0.001). All images in both groups were acceptable for diagnosis. CT values and standard deviations in portal veins of Group B were higher than Group A (all p < 0.05); There were no statistical differences in contrast-to-noise ratio, image quality score and the number of observed portal vein branches between the two groups (all p > 0.05), and the two observers had excellent agreement in image quality assessment (all κ > 0.75). CONCLUSION: The use of 50 keV images in dual-energy spectral CTPV with ASiR reduces total iodine load by 52% while maintaining good image quality. ADVANCES IN KNOWLEDGE: Spectral CT images combined with ASiR can be used in low contrast dose CTPV portal venography to maintain image quality and reduce contrast dose.

Preliminary study on the differentiation between parapelvic cyst and hydronephrosis with non-calculous using only pre-contrast dual-energy spectral CT scans.

OBJECTIVE: To investigate the value of using the quantitative parameters from only the pre-contrast dual-energy spectral CT imaging for distinguishing between parapelvic cyst and hydronephrosis with non-calculous (HNC). METHODS: This retrospective study was approved by the institutional review board. 28 patients with parapelvic cyst and 24 patients with HNC who underwent standard pre-contrast and multiphase contrast-enhanced dual-energy spectral CT imaging were retrospectively identified. The parapelvic cyst and HNC were identified using the contrast-enhanced scans, and their CT number in the 70-keV monochromatic images, effective atomic number (Zeff), iodine concentration (IC) and water concentration in the pre-contrast images were measured. The slope of the spectral curve (λ) was calculated. The difference in the measurements between parapelvic cyst and HNC was statistically analyzed using SPSS® v. 19.0 (IBM Corp., New York, NY; formerly SPSS Inc., Chicago, IL) statistical software. Receiver-operating characteristic analysis was performed to assess the diagnostic performance. RESULTS: The CT numbers in the 70-keV images, Zeff and IC values were statistically different between parapelvic cyst and HNC (all p < 0.05). The sensitivity, specificity and accuracy of these parameters for distinguishing between parapelvic cyst and HNC were 89.2%, 73.3% and 82.1%; 86.5%, 43.3% and 67.2%; 91.9%, 40.0% and 68.7%; and 64.9%, 73.3% and 83.6%, respectively, and the combined specificity was 92.9%. There was no statistical difference in λ between the two groups (p > 0.05). CONCLUSION: The quantitative parameters obtained in the pre-contrast dual-energy spectral CT imaging may be used to differentiate between parapelvic cyst and HNC. Advances in knowledge: The pre-contrast dual-energy spectral CT scans may be used to screen parapelvic cysts for patients who are asymptomatic, thereby avoiding contrast-enhanced CT or CT urography examination for these patients to reduce ionizing radiation dose and contrast dose.