Integrated Acetabular Prosthesis Versus Bone Grafting in Total Hip Arthroplasty for Crowe Type II and III Hip Dysplasia: A Retrospective Case-Control Study.

OBJECTIVE: Many methods of acetabular reconstruction with total hip arthroplasty (THA) for Crowe type II and III adult developmental dysplasia of the hip (DDH) acetabular bone defect have been implemented clinically. However, there was no study comparing the results of integrated acetabular prosthesis (IAP) with bone grafting (BG). This study aims to investigate the efficacy of IAP and BG for acetabular reconstruction in Crowe type II and III DDH. METHODS: The clinical data of 45 patients with unilateral Crowe type II and III DDH who underwent THA from January 2020 to January 2023 were retrospectively analyzed. The patients were divided into two groups: 25 patients using 3D-printed IAP (IAP group) and 20 patients using BG (BG group). The operation time and intraoperative blood loss were recorded. The clinical outcomes were assessed by Harris Hip Score (HHS) and full weight-bearing time. The radiological outcomes were evaluated by the radiological examination. Accordingly, intraoperative and postoperative complications were observed as well. The data between the two groups were compared by independent sample t-tests and the Mann-Whitney U rank sum test. RESULTS: There were no significant differences between the two groups in Harris Hip Score (HHS) (preoperative, 6 months postoperative, and the last follow-up), leg length discrepancy (LLD), cup inclination, cup anteversion, vertical center of rotation (V-COR), horizontal center of rotation (H-COR) (p > 0.05). The mean HHS in the IAP group was higher than in the BG group at 1 and 3 months postoperative (p < 0.001). The mean surgical time and blood loss in the IAP group were less than in the BG group (p < 0.001). The mean full weight-bearing time in the IAP group was shorter than in the BG group (p < 0.01). No complications were observed in either group during the follow-up period. CONCLUSION: IAP and BG have similar radiographic outcomes and long-term clinical efficacy in THA for Crowe type II and III DDH, but the IAP technique has higher surgical safety and facilitates the recovery of hip joint function, which is worthy of clinical promotion.

Using machine learning to develop preoperative model for lymph node metastasis in patients with bladder urothelial carcinoma.

BACKGROUND: Lymph node metastasis (LNM) is associated with worse prognosis in bladder urothelial carcinoma (BUC) patients. This study aimed to develop and validate machine learning (ML) models to preoperatively predict LNM in BUC patients treated with radical cystectomy (RC). METHODS: We retrospectively collected demographic, pathological, imaging, and laboratory information of BUC patients who underwent RC and bilateral lymphadenectomy in our institution. Patients were randomly categorized into training set and testing set. Five ML algorithms were utilized to establish prediction models. The performance of each model was assessed by the area under the receiver operating characteristic curve (AUC) and accuracy. Finally, we calculated the corresponding variable coefficients based on the optimal model to reveal the contribution of each variable to LNM. RESULTS: A total of 524 and 131 BUC patients were finally enrolled into training set and testing set, respectively. We identified that the support vector machine (SVM) model had the best prediction ability with an AUC of 0.934 (95% confidence interval [CI]: 0.903-0.964) and accuracy of 0.916 in the training set, and an AUC of 0.855 (95%CI: 0.777-0.933) and accuracy of 0.809 in the testing set. The SVM model contained 14 predictors, and positive lymph node in imaging contributed the most to the prediction of LNM in BUC patients. CONCLUSIONS: We developed and validated the ML models to preoperatively predict LNM in BUC patients treated with RC, and identified that the SVM model with 14 variables had the best performance and high levels of clinical applicability.

Exploration of the molecular biological mechanisms and review of postoperative radiotherapy cases in tenosynovial giant cell tumors.

Tendon Sheath Giant Cell Tumor (TGCT) is a benign tumor that primarily grows within joints and bursae. However, it has a high postoperative recurrence rate, ranging from 15% to 45%. Although radiotherapy may reduce this recurrence rate, its applicability as a standard treatment is still controversial. Furthermore, the pathogenic mechanisms of TGCT are not clear, which limits the development of effective treatment methods. The unpredictable growth and high recurrence rate of TGCT adds to the challenges of disease management. Currently, our understanding of TGCT mainly depends on pathological slice analysis due to a lack of stable cell models. In this study, we first reviewed the medical records of two female TGCT patients who had undergone radiotherapy. Then, by combining bioinformatics and machine learning, we interpreted the pathogenesis of TGCT and its associations with other diseases from multiple perspectives. Based on a deep analysis of the case data, we provided empirical support for postoperative radiotherapy in TGCT patients. Additionally, our further analysis revealed the signaling pathways of differentially expressed genes in TGCT, as well as its potential associations with osteoarthritis and synovial sarcomas.

Retracted: Marchantin M Induces Apoptosis of Prostate Cancer Cells Through Endoplasmic Reticulum Stress.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Tian-Wei Zhang, Li Xing, Jun-Long Tang, Jing-Xiao Lu, Chun-Xiao Liu. Marchantin M Induces Apoptosis of Prostate Cancer Cells Through Endoplasmic Reticulum Stress. Med Sci Monit, 2015; 21: 3570-3576. DOI: 10.12659/MSM.894476.

Intravenous metastasis of unexpected uterine sarcoma in the context of uterine fibroids: case report and literature review.

Objective: Endometrial stromal tumors are rare and complex mesenchymal tumors that often present with clinical symptoms similar to uterine leiomyomas. Due to their atypical nature, they are prone to be misdiagnosed or overlooked by healthcare professionals. This study presents a case report of an incidentally discovered endometrial stromal sarcoma with venous metastasis, which was initially misdiagnosed as a uterine leiomyoma. In addition, this study reviews previously documented cases of similar tumors. Case report: During a routine medical examination in 2016, a 50-year-old woman was diagnosed with uterine fibroids. In June 2020, she began experiencing moderate, irregular vaginal bleeding. Nevertheless, a histopathological examination indicated an endometrial stromal sarcoma with a striking amalgamation of both low-grade and high-grade features. Molecular analysis identified a rare MED12 gene mutation. The patient underwent total hysterectomy, bilateral salpingectomy, and resection of the metastatic lesions. Postoperative management included radiotherapy, chemotherapy, and hormone therapy. After completion of chemotherapy, the patient was followed up for 27 months with no evidence of tumor recurrence. Conclusion: This case report highlights the importance of pathological, immunohistochemical, and molecular aspects of this rare tumor involving the inferior vena cava and showing the presence of atypical gene mutations. The successful treatment outcome further emphasizes the importance of advances in diagnostic modalities for managing rare tumors like this.

Deep learning techniques for imaging diagnosis of renal cell carcinoma: current and emerging trends.

This study summarizes the latest achievements, challenges, and future research directions in deep learning technologies for the diagnosis of renal cell carcinoma (RCC). This is the first review of deep learning in RCC applications. This review aims to show that deep learning technologies hold great promise in the field of RCC diagnosis, and we look forward to more research results to meet us for the mutual benefit of renal cell carcinoma patients. Medical imaging plays an important role in the early detection of renal cell carcinoma (RCC), as well as in the monitoring and evaluation of RCC during treatment. The most commonly used technologies such as contrast enhanced computed tomography (CECT), ultrasound and magnetic resonance imaging (MRI) are now digitalized, allowing deep learning to be applied to them. Deep learning is one of the fastest growing fields in the direction of medical imaging, with rapidly emerging applications that have changed the traditional medical treatment paradigm. With the help of deep learning-based medical imaging tools, clinicians can diagnose and evaluate renal tumors more accurately and quickly. This paper describes the application of deep learning-based imaging techniques in RCC assessment and provides a comprehensive review.

Efficacy of concurrent chemoradiotherapy with thalidomide and S-1 for esophageal carcinoma and its influence on serum tumor markers.

BACKGROUND: Although the current conventional treatment strategies for esophageal carcinoma (EC) have been proven effective, they are often accompanied by serious adverse events. Therefore, it is still necessary to continue to explore new therapeutic strategies for EC to improve the clinical outcome of patients. AIM: To elucidate the clinical efficacy of concurrent chemoradiotherapy (CCRT) with thalidomide (THAL) and S-1 (tegafur, gimeracil, and oteracil potassium capsules) in the treatment of EC as well as its influence on serum tumor markers (STMs). METHODS: First, 62 patients with EC treated at the Zibo 148 Hospital between November 2019 and November 2022 were selected and grouped according to the received treatment. Among these, 30 patients undergoing CCRT with cis-platinum and 5-fluorouracil were assigned to the control group (Con), and 32 patients receiving CCRT with THAL and S-1 were assigned to the research group (Res). Second, inter-group comparisons were carried out with respect to curative efficacy, incidence of drug toxicities, STMs [carbohydrate antigen 125 (CA125) and macrophage inflammatory protein-3α (MIP-3α)], angiogenesis-related indicators [vascular endothelial growth factor (VEGF); VEGF receptor-1 (VEGFR-1); basic fibroblast growth factor (bFGF); angiogenin-2 (Ang-2)], and quality of life (QoL) [QoL core 30 (QLQ-C30)] after one month of treatment. RESULTS: The analysis showed no statistical difference in the overall response rate and disease control rate between the two patient cohorts; however, the incidences of grade I-II myelosuppression and gastrointestinal reactions were significantly lower in the Res than in the Con. Besides, the post-treatment CA125, MIP-3α, VEGF, VEGFR-1, bFGF, and Ang-2 Levels in the Res were markedly lower compared with the pre-treatment levels and the corresponding post-treatment levels in the Con. Furthermore, more evident improvements in QLQ-C30 scores from the dimensions of physical, role, emotional, and social functions were determined in the Res. CONCLUSION: The above results demonstrate the effectiveness of THAL + S-1 CCRT for EC, which contributes to mild side effects and significant reduction of CA125, MIP-3α, VEGF, VEGFR-1, bFGF, and Ang-2 Levels, thus inhibiting tumors from malignant progression and enhancing patients' QoL.

Migrated Hem-o-Lok clips in the neobladder with giant stone formation: a case report.

INTRODUCTION: Neobladder urolithiasis is a rare but important delaying complication of orthotopic urinary diversion. We report a case of Hem-o-Lok (HOLC) migration into the neobladder with giant stone formation after orthotopic neobladder cystectomy. CASE REPORT: We report a case of a 57-year-old man with frequent urination and occasional discharge of stones 3 years after a laparoscopic orthotopic neobladder cystectomy. Computed tomography revealed a large round 3.5 cm calculus. An endoscopic neocystolitholapaxy was performed, and a Hem-o-Lok was found in the center of the stone. CONCLUSION: We described the case presentation, treatment and analysis of etiology of stone formation to avoid such complication.

Multi-robot task assignment for serving people quarantined in multiple hotels during COVID-19 pandemic.

Background: Efficiently combating with the coronavirus disease 2019 (COVID-19) has been challenging for medics, police and other service providers. To reduce human interaction, multi-robot systems are promising for performing various missions such as disinfection, monitoring, temperature measurement and delivering goods to people quarantined in prescribed homes and hotels. This paper studies the task assignment problem for multiple dispersed homogeneous robots to visit a set of prescribed hotels to perform tasks such as body temperature assessment or oropharyngeal swabs for people quarantined in the hotels while trying to minimize the robots' total operation time. Each robot can move to multiple hotels sequentially within its limited maximum operation time to provide the service. Methods: The task assignment problem generalizes the multiple traveling salesman problem, which is an NP-hard problem. The main contributions of the paper are twofold: (I) a lower bound on the robots' total operation time to serve all the people has been found based on graph theory, which can be used to approximately evaluate the optimality of an assignment solution; (II) several efficient marginal-cost-based task assignment algorithms are designed to assign the hotel-serving tasks to the robots. Results: In the Monte Carlo simulations where different numbers of robots need to serve the people quarantined in 30 and 90 hotels, the designed task assignment algorithms can quickly (around 30 ms) calculate near-optimal assignment solutions (within 1.15 times of the optimal value). Conclusions: Numerical simulations show that the algorithms can lead to solutions that are close to the optimal compared with the competitive genetic algorithm and greedy algorithm.

Treatment of Acetabular Bone Defect in Revision of Total Hip Arthroplasty Using 3D Printed Tantalum Acetabular Augment.

OBJECTIVE: The treatment of acetabular defects is one of the most difficult challenges of revision of total hip arthroplasty (RTHA), and tantalum is regarded as a promising bone substitute material. This study aims to investigate the effectiveness of 3D printed acetabular augment used in RTHA for the treatment of acetabular bone defect. METHODS: A retrospective analysis of the clinical data of seven patients who had undergone RTHA was carried out using 3D printed acetabular augment from January 2017 to December 2018. The CT data of the patients were exported to Mimics 21.0 software (Materialise, Leuven, Belgium), and the acetabular bone defect augment were designed, printed and then implanted during operation. The postoperative Harris score, visual analogue scale (VAS) score and prosthesis position were observed to evaluate the clinical outcome. A I-test was used for preoperative and postoperative comparison of the paired-design dataset. RESULTS: A firm attachment of the bone augment to the acetabulum during operation without any complications was found during the follow-up time 2.8-4.3 years. The VAS score of all patients was found 6.9 ± 1.4 before operation and was 0.7 ± 0.7 at the last follow-up (P ≤ 0.001), and the Harris hip scores, were 31.9 ± 10.3 and 73.3 ± 12.8 before operation, and at the last follow-up (P ≤ 0.001), respectively. Moreover, no loosening sign between the bone defect augment and the acetabulum was observed during the entire implantation period. CONCLUSION: 3D printed acetabular augment is effective in reconstructing the acetabulum following an acetabular bone defect revision, which enhances the hip joint function and eventually makes a satisfactory stable prosthetic.

Identification of Hub Genes and Biomarkers between Hyperandrogen and Normoandrogen Polycystic Ovary Syndrome by Bioinformatics Analysis.

BACKGROUND: The common and divergent genetic mechanisms of hyperandrogen (HA) and normoandrogen (NA) polycystic ovary syndrome (PCOS) are currently unknown. OBJECTIVE: This study aimed to explore the hub genes and potential mechanisms of HA and NA PCOS through bioinformatics analysis. METHODS: The GSE137684 dataset was downloaded from the Gene Expression Omnibus (GEO) database. The co-expressed genes and differentially expressed genes (DEGs) between HA and NA PCOS samples were functionally annotated by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The protein-protein interaction (PPI) network of the DEGs was constructed and visualized using STRING and Cytoscape, respectively, and the hub genes were screened using the Cytohubba plug-in. The transcription factors (TFs) of these hub genes were identified with the JASPAR database, and the hub gene-TF regulatory network was constructed. RESULTS: A total of 327 DEGs, including 191 upregulated and 136 downregulated genes, were identified in HA PCOS relative to NA PCOS. Ten hub genes were screened, of which MYC, CAV1, and HGF were mainly enriched in the Proteoglycans in the cancer pathway. In addition, 47 TFs were identified that were found to be involved in the regulation of hub genes. CONCLUSION: MYC, CAV1, and HGF are potential diagnostic biomarkers and therapeutic targets for HA PCOS.

Clinical Efficacy and Safety Analysis of PD-1/PD-L1 Inhibitor vs. Chemotherapy in the Treatment of Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Objective: To systematically evaluate the efficacy and safety of pembrolizumab (PD-1/PD-L inhibitor) and adjuvant chemotherapy to treat NSCLC and provide evidence-based reference for clinical use. Methods: By searching the Cochrane Library, EMBASE, PubMed, and Web of Science, according to the inclusion criteria, literature selection, data extraction, and quality evaluation were carried out for the included literature. The I 2 test was used to evaluate heterogeneity between studies, and the meta-analysis was performed using RevMan 5.3 software provided by Cochrane. Results: Finally, 14 relevant documents meeting the standards were included. It is a statistical difference in one-year survival rate [OR = 1.50, 95% CI (1.28, 1.76), P < 0.00001, I 2 = 0%, Z = 4.99]; overall response rate[OR =1.57, 95% CI (1.29, 1.90), P < 0.00001, I 2 = 0%, Z = 4.58]; progression-free survival [OR = 2.99, 95% CI (2.29, 3.91), P < 0.00001, I 2 = 26%, Z = 8.00]; and overall survival [OR = 1.38, 95% CI (1.07, 1.78), P = 0.01, I 2 = 46%, Z = 2.50] and reduces the incidence of adverse drug reactions [OR = 2.54, 95% CI (1.99, 3.25), P < 0.00001, I 2 = 69%, Z = 7.43]. Conclusion: Pembrolizumab adjuvant chemotherapy is effective in the treatment of advanced NSCLC, but attention should be paid to the occurrence of adverse reactions in clinical. Due to the limitations of the methodology included in the study, this conclusion required more validation of large-sample RCT.

FEK self-assembled peptide hydrogels facilitate primary hepatocytes culture and pharmacokinetics screening.

A FEFEFKFK (FEK, F, phenylalaninyl; E, glutamyl; K, lysinyl)-based self-assembling peptide hydrogel (FEK-SAPH) was developed to replace sandwich culture (SC) for improved culture of primary hepatocytes in vitro. Under neutral conditions, FEK self-assembles to form ß-sheet nanofibers, which in turn form FEK-SAPH. For the culture of rat primary hepatocytes (RPH), the use of FEK-SAPH simplified operation steps and promoted excellent cell-cell interactions while maintaining the SC-related RPH polarity trend. Compared with SC, FEK-SAPH cultured RPH for 14 days, the bile duct network was formed, the secretion of albumin and urea was improved, and the metabolic clearance rate based on cytochrome P450 (CYPs) was comparable. In FEK-SAPH culture, the expression level of the biliary efflux transporter bile salt export pump increased by 230.7%, while the biliary excretion index value of deuterium-labeled sodium taurocholate (d8-TCA) differed slightly from the SC value (72% and 77%, respectively, p = .0195). The inhibitory effect of cholestasis drugs on FEK-SAPH was significantly higher than that of SC. In FEK-SAPH, hepatoprotective drugs were more effective in antagonizing hepatotoxicity induced by lithocholic acid (LCA). FEK-SAPH cultured RPH with hepatoprotective drugs can better recover from LCA-induced damage. In summary, FEK-SAPH can be used as a substitute for SC for pharmacokinetic screening to evaluate the drug absorption, disposition, metabolism, excretion, and toxicity (ADMET) in hepatocytes.

Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway.

Farnesoid X receptor (FXR) plays an indispensable role in liver homeostasis and has been a promising drug target for hepatic diseases. However, the concerns of undesired biological actions limit the clinical applications of FXR agonists. To reveal the intrinsic mechanism of FXR agonist-induce hepatotoxicity, two typical FXR agonists with different structures (obeticholic acid (OCA) and Px-102) were investigated in the present study. By detecting MMP, ROS, and ATP and analyzing the fate of cells, we found that both OCA and Px-102 reduced the mitochondrial function of hepatocytes and promoted cell apoptosis. Gene ablation or inhibition of FXR or SHP ameliorated the cytotoxicities of OCA and Px-102, which indicated the adverse actions of FXR/SHP activation including down-regulation of phosphorylation of PI3K/AKT and functional hepatic genes. The dose-related injurious effects of OCA (10 mg/kg and 30 mg/kg) and Px-102 (5 mg/kg and 15 mg/kg) on the liver were confirmed on a high-fat diet mouse model. The decrease of hepatocyte-specific genes and augmenter of liver regeneration in the liver caused by OCA or Px-102 suggested an imbalance of liver regeneration and a disruption of hepatic functions. Exploration of intestinally biased FXR agonists or combination of FXR agonist with apoptosis inhibitor may be more beneficial strategies for liver diseases.

Masseter Muscle Metastasis of Renal Cell Carcinoma: A Case Report and Literature Review.

BACKGROUND: Patients with renal cell carcinoma are often troubled by metastases, but masseter muscle metastases are particularly rare. CASE PRESENTATION: We reported a 76-year-old male who did not show any recurrence and metastasis after the nephrectomy until 5 years later. The metastatic mass was found with the protrusion of masseter muscle area. Computed tomography and ultrasonography indicated a hypervascular mass, and pathology confirmed the masseter muscle metastasis of renal cell carcinoma. Complete metastasectomy was performed with the preserval of facial function and appearance. No local recurrence or distant metastasis was found in follow-up. CONCLUSION: Our report indicates masseter muscle can be a metastatic site of renal cell carcinoma, regardless of its rarity. Long-term comprehensive surveillance is needed for patients with renal cell carcinoma. Muscle metastases can disguise as benign mass, while multiple imaging and pathology are important in identifying their sources. If possible, complete metastasectomy with function retention is recommended for masseter muscle metastases.

Tonkinensine B induces apoptosis through mitochondrial dysfunction and inactivation of the PI3K/AKT pathway in triple-negative breast cancer cells.

OBJECTIVES: Tonkinensine B, a novel compound with cytisine-pterocarpan skeleton isolated from the root of Sophora tonkinensis Gagnep, was reported to have a significant antitumor effect. The effect and intrinsic mechanism of tonkinensine B on tumour need to be further investigated. METHODS: With the help of cell cytotoxicity, the effect of tonkinensine B on MDA-MB-231 cells was investigated. By observing mitochondrial function changes, the intrinsic mechanism was further studied. The levels of key apoptosis-associated proteins Bcl-2, Bax, caspase-9, caspase-3 and AKT in MDA-MB-231 cells were analysed to determine whether tonkinensine B caused apoptosis via the mitochondrial pathway. KEY FINDINGS: After treated with tonkinensine B, MDA-MB-231 cells multiplication was repressed, and the decreased mitochondrial membrane potential, loss of ATP synthesis and elevated ROS generation were detected. Furthermore, the proportions of Bax/Bcl-2, cleaved caspase-3 and caspase-9 proteins production were up-regulated, indicating that tonkinensine B acted on intrinsic mitochondrial-mediated apoptosis pathway. In addition, tonkinensine B also reduced phosphorylation levels of AKT, and thus the activation of apoptosis might likewise be correlated with the inhibition of the PI3K/AKT pathway. CONCLUSIONS: Tonkinensine B may be a hopeful candidate for human triple-negative breast cancer, and further structural optimization is expected to improve its anti-tumour activity.

USF1-mediated upregulation of lncRNA GAS6-AS2 facilitates osteosarcoma progression through miR-934/BCAT1 axis.

Long noncoding RNAs (lncRNAs) have been certified as important regulators in tumorigenesis. LncRNA GAS6-AS2 (GAS6-AS2) was a newly identified tumor-related lncRNA, and its dysregulation and oncogenic effects in melanoma and bladder cancer had been reported in previous studies. However, the expression pattern and potential function of GAS6-AS2 in osteosarcoma (OS) have not been investigated. In this study, we identified a novel OS-related lncRNA GAS6-AS2. We found that GAS6-AS2 was distinctly upregulated in both OS specimens and cell lines. Distinct up-regulation of GAS6-AS2 in OS was correlated with advanced clinical stages and shorter survivals. In addition, USF1 could directly bind to the GAS6-AS2 promoter and contribute to its overexpression. Furthermore, GAS6-AS2 knockdown caused tumor suppressive effects via reducing cellular proliferation, migration and invasion, and promoting OS cell apoptosis. Besides, GAS6-AS2 directly bound to miR-934 and downregulated its expression. Mechanistically, GAS6-AS2 positively regulated the expression of BCAT1 through sponging miR-934. Taken together, our data illustrated how GAS6-AS2 played an oncogenic role in OS and might offer a potential therapeutic target for treating OS.

Estradiol regulates the expression of CD45 splicing isoforms in lymphocytes.

CD45, a common leukocyte antigen expressed on the surface of all nucleated hematopoietic cells, indicates the developmental stage and functional status of lymphocytes by its alternative splicing isoforms. Estrogen is correlated with the immune activity of lymphocytes and is involved in the sex bias of several human autoimmune diseases, but the effect of estrogen on the expression of the CD45 splicing isoforms remains unknown. In the present study, a potential estrogen response element was identified on the opposite strand of the CD45 gene by bioinformatics software prediction. The results from RT-qPCR results showed that the expression levels of CD45RO isoform and CD45 antisense RNA were increased after the lymphocytes were treated with 10 nM 17beta-estradiol, and this effect of 17beta-estradiol was reversed when the lymphocytes were cotreated with an estrogen receptor antagonist. Moreover, bisulfite sequencing PCR showed that CD45 DNA methylation in lymphocytes was increased after the treatment with 10 nM 17beta-estradiol. In conclusion, estradiol regulated the expression of CD45 in an estrogen receptor-dependent manner and was associated with CD45 antisense RNA and DNA methylation. The results helped elucidate the regulatory mechanism of the expression of CD45 isoforms and the correlation between estrogen levels and immune activity in females.

Analysis of the role of DAMTC in lung adenocarcinoma cells based on the DNA microarrays.

The present study aimed to investigate the effect of 7, 8-diacetoxy-4-methylcoumarin (DAMTC) on lung adenocarcinoma cells (A549) and analyze the molecular mechanism underlying DAMTC-treated lung adenocarcinoma. Gene expression profile GSE29698 was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) in 3 DAMTC-treated A549 samples were analyzed and compared with 3 DAMTC-untreated samples using the limma package. Gene Ontology (GO) and pathway enrichment analyses of DEGs were performed, followed by the functional annotation and protein-protein interaction (PPI) network construction. Finally, pathway crosstalk analysis was conducted. A total of 500 upregulated and 389 downregulated DEGs were identified. The upregulated and downregulated DEGs were enriched in different GO terms and pathways, including metabolic process, p53 signaling pathway and metabolic pathways. A total of 9 DEGs were determined to have node degrees >16 in the PPI network, including interleukin 6 (IL6), MDM2 oncogene, E3 ubiquitin protein ligase (MDM2), cell division cycle 42 (CDC42) and MYC associated factor X (MAX). Furthermore, numerous DEGs were identified to function as transcription factors and tumor suppressor genes, including histone deacetylase 3 and MAX. Additionally, apoptosis, tight junction, and endocytosis pathway were determined to cross-talk with small cell and non-small cell lung cancer. The DEGs (IL6, MDM2, CDC42 and MAX) involved in different pathways, including the p53 signaling pathway and endocytosis, may be the potential targets for DAMTC in lung adenocarcinoma. The elucidation of the underlying mechanism of the DAMTC effect may make it a potential drug.

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models.

Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC50, 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase-related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography (PET) imaging of microdosed 11C-labeled AZD1390 (Kp,uu, 0.33). AZD1390 blocks ATM-dependent DDR pathway activity and combines with radiation to induce G2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induced tumor regressions and increased animal survival compared to IR treatment alone. We established a pharmacokinetic-pharmacodynamic-efficacy relationship by correlating free brain concentrations, tumor phospho-ATM/phospho-Rad50 inhibition, apoptotic biomarker (cleaved caspase-3) induction, tumor regression, and survival. On the basis of the data presented here, AZD1390 is now in early clinical development for use as a radiosensitizer in central nervous system malignancies.