PPM1F regulates ovarian cancer progression by affecting the dephosphorylation of ITGB1.

PPM1F has been shown to play diverse biological functions in the progression of multiple tumors. PPM1F controls the T788/T789 phosphorylation switch of ITGB1 and regulates integrin activity. However, the impacts of PPM1F and ITGB1 on ovarian cancer (OV) progression remain unclear. Whether there is such a regulatory relationship between PPM1F and ITGB1 in ovarian cancer has not been studied. Therefore, the purpose of this study is to elucidate the function and the mechanism of PPM1F in ovarian cancer. The expression level and the survival curve of PPM1F were analyzed by databases. Gain of function and loss of function were applied to explore the function of PPM1F in ovarian cancer. A tumor formation assay in nude mice showed that knockdown of PPM1F inhibited tumor formation. We tested the effect of PPM1F on ITGB1 dephosphorylation in ovarian cancer cells by co-immunoprecipitation and western blotting. Loss of function was applied to investigate the function of ITGB1 in ovarian cancer. ITGB1-mut overexpression promotes the progression of ovarian cancer. Rescue assays showed the promoting effect of ITGB1-wt on ovarian cancer is attenuated due to the dephosphorylation of ITGB1-wt by PPM1F. PPM1F and ITGB1 play an oncogene function in ovarian cancer. PPM1F regulates the phosphorylation of ITGB1, which affects the occurrence and development of ovarian cancer.

Does the limb lengthening reduce the incidence of hip dislocation in patients with neurological disorders and insufficient muscle tension who undergoing hip arthroplasty?

Background: The soft-tissue tension is closely associated with postoperative hip dislocation in patients undergoing total hip arthroplasty (THA), especially for those patients with neurological disorders and insufficient muscle tension. The aim of this study is to explore the effect of limb lengthening on the incidence of complications following THA in patients with neurological disorders and insufficient muscle tension. Methods: This retrospective analysis examines individuals with neurological disorders, such as ischemic stroke and poliomyelitis, who underwent primary total hip arthroplasty (THA) at our medical center between January 2015 and April 2021. Demographic and baseline characteristics (such as age, gender, muscle strength) were obtained from medical records. The limb length, offset and the positional parameters of both acetabular and femoral component were measured on pre- and postoperative plain radiograph. The primary outcome was the occurrence of hip dislocation. The secondary outcome included the incidence of other complications and the hip function (determined by Harris score). The correlation between the occurrence of hip dislocation and limb lengthening was analyzed. Results: A total of 258 patients were finally analyzed. The hip dislocations were identified in 35 patients (overall incidence = 13.57%). The incidence of early dislocation was lower in patients whose limb-length discrepancy (LLD) was over 20 mm (incidence = 4.1% for LLD >20 mm, 12.2% for LLD 10 mm-20 mm and 17% for LLD <10 mm). The odds ratio (OR) was 0.206 and 95% confidence interval (CI) was 0.058-0.737 (compared between LLD <10 mm and LLD >20 mm). But the no difference was identified regarding on the incidence of late dislocation among patients with different LLD. Moreover, the overall incidence of other complications was elevated in patients with LLD >20 mm (incidence = 17.58% for LLD >20 mm, 11.11% for LLD 10 mm-20 mm and 3.19% for LLD <10 mm; OR = 6.464, 95% CI = 1.768-23.640). And the Harris scores, which reflected the hip function, was gradually decreased with the increasing in LLD. In terms of the relationship between the offset and dislocation rate, it was found that increased offset discrepancy was associated with decreased dislocation incidence (incidence = 4.71% for offset discrepancy >10 mm, 12.5% for offset discrepancy 5 mm-10 mm and 17.20% for offset discrepancy <5 mm; OR = 0.238, 95% CI = 0.076-0.742). Furthermore, increased offset discrepancy also bring a reduction in late dislocation. The incidences of late dislocation were 0%, 2.5% and 10.8% for offset discrepancy >10 mm, offset discrepancy 5 mm-10 mm and 17.20% for offset discrepancy respectively. Different from that of LDD, the incidences of other complications were similar among patients with different offset discrepancy. Besides, no influence of offset discrepancy on the hip function was identified in this study. Conclusion: Unfortunately, although increasing in limb length could partially reduce early dislocation postoperatively, it could not affect the incidence of late dislocation in those patients with neurological disorders and insufficient muscle tension. Moreover, over limb lengthening was associated with other postoperative complications and worse hip function. Instead, additional offset could reduce the probability of postoperative dislocation, without increasing the incidence of other complications. Therefore, femoral stem with lower cervico-diaphyseal angle (higher offset) should be recommended to patients with neurological disorders who were in high risk of postoperative dislocation. Isolated increasing in limb length should be avoided.

The oncogenic role and regulatory mechanism of ACAA2 in human ovarian cancer.

Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial ß oxidation, which plays an important role in fatty acid metabolism. The expression of ACAA2 is closely related to the occurrence and malignant progression of tumors. However, the function of ACAA2 in ovarian cancer is unclear. The expression level and prognostic value of ACAA2 were analyzed by databases. Gain and loss of function were carried out to explore the function of ACAA2 in ovarian cancer. RNA-seq and bioinformatics methods were applied to illustrate the regulatory mechanism of ACAA2. ACAA2 overexpression promoted the growth, proliferation, migration, and invasion of ovarian cancer, and ACAA2 knockdown inhibited the malignant progression of ovarian cancer as well as the ability of subcutaneous tumor formation in nude mice. At the same time, we found that OGT can induce glycosylation modification of ACAA2 and regulate the karyoplasmic distribution of ACAA2. OGT plays a vital role in ovarian cancer as a function of oncogenes. In addition, through RNA-seq sequencing, we found that ACAA2 regulates the expression of DIXDC1. ACAA2 regulated the malignant progression of ovarian cancer through the WNT/ß-Catenin signaling pathway probably. ACAA2 is an oncogene in ovarian cancer and has the potential to be a target for ovarian cancer therapy.

LncRNA GAS5-hnRNPK axis inhibited ovarian cancer progression via inhibition of AKT signaling in ovarian cancer cells.

BACKGROUND: The incidence of ovarian cancer ranks third among gynecologic malignancies, but the mortality rate ranks first. METHODS: The expression of GAS5 is low in ovarian cancer and is associated with the low survival of ovarian cancer patients according to public ovarian cancer databases. GAS5 overexpression inhibited ovarian malignancy by affecting the proliferation and migratory abilities in OVCAR3 and A2780 cells. GAS5 overexpression increased the rate of cell apoptosis, and the cells were blocked in the G1 phase as assessed by flow cytometry. RESULTS: We found that hnRNPK was a potential target gene, which was regulated negatively by GAS5 based on RNA-pulldown and mass spectrometry analysis. Mechanistically, GAS5 affected the inhibition of the PI3K/AKT/mTOR pathways and bound the protein of hnRNPK, which influenced hnRNPK stability. Furthermore, rescue assays demonstrated hnRNPK was significantly involved in the progression of ovarian cancer. CONCLUSIONS: Our study showed one of the mechanisms that GAS5 inhibited ovarian cancer metastasis by down-regulating hnRNPK expression, and GAS5 can be used to predict the prognosis of ovarian cancer patients.

Effectiveness of Needle Aspiration versus Surgical Excision for Symptomatic Synovial Cysts of the Hip: A Single-Center, Retrospective Study.

BACKGROUND This study was performed to evaluate the clinical effectiveness of needle aspiration vs surgical excision for symptomatic synovial cysts of the hip. MATERIAL AND METHODS This retrospective study analyzed the clinical data of patients diagnosed with synovial cysts of the hip and treated in a single-center hospital from January 2012 to April 2022. Patients receiving needle aspiration were assigned to group A and those treated with surgery were assigned to group B. Demographic characteristics, etiology, symptoms, cyst location, postoperative complications and recurrence, Harris Hip Score (HHS) and Visual Analog Scale of Pain (VAS) scores before treatment and at 3, 6, and 12 months after treatment were recorded to assess hip function in both groups. RESULTS This study recruited 44 patients, with 18 patients in group A and 26 in group B, and the 2 arms were well-balanced in terms of baseline patient profiles. Needle aspiration resulted in significantly better pain mitigation for patients at 24 h, 48 h, and 72 h after treatment vs surgical interventions (P<0.05). Needle joint aspiration resulted in significantly better function restoration of the hip joint than surgery at 3 months after treatment, as evidenced by the lower HHS score of 85.31±13.16 in group A vs 78.51±11.66 in group B (P=0.002). Surgery was associated with a significantly lower incidence of disease relapse (0.00%) vs needle aspiration (27.7%) (P=0.004). CONCLUSIONS Needle aspiration in the treatment of symptomatic synovial cysts of the hip causes less damage to the soft tissue and leads to faster recovery in the short term than surgical resection. Surgical resection has a lower recurrence rate and better long-term efficacy.

Comparison of Outcomes Following Total Hip Arthroplasty Between Patients Diagnosed with Association Research Circulation Osseous (ARCO) Stage III and Stage IV Osteonecrosis of the Femoral Head: A Retrospective Study of 302 Patients.

BACKGROUND This retrospective study from a single center aimed to compare outcomes following total hip arthroplasty (THA) in 302 patients diagnosed with Association Research Circulation Osseous (ARCO) stage III and stage IV osteonecrosis of the femoral head (ONFH). MATERIAL AND METHODS The study included 302 patients who underwent THA for ONFH between January 2018 and September 2021. Patient groups included ARCO stage III (n=145) and ARCO stage IV (n=157). Outcomes measured included duration of disease, operative time, intraoperative blood volume, postoperative length of hospital stay, pain measured by the visual analog scale (VAS) score, Harris hip score (HHS), and forgotten joint score (FJS). RESULTS Patients with ARCO stage III ONFH had a significantly shorter operative time (P=0.009), shorter length of hospital stay (P=0.021), and reduced volume of intraoperative bleeding (P=0.021) compared with patients with ARCO stage IV ONFH. There were no significant differences in disease duration (P=0.310), postoperative complications (P=0.07), preoperative (P=0.086, P=0.156) and postoperative (P=0.062, P=0.173) HHS and VAS scores, respectively. Patients with stage III ONFH reported significantly higher FJS scores at 3 months, 6 months, and 1 year after THA. CONCLUSIONS Patients who underwent hip arthroplasty for ARCO stage III femoral head necrosis experienced shorter operative time and hospital stay, less intraoperative bleeding, and better restoration of hip function than those with ARCO stage IV. Moreover, stage III patients were more prone to "forget" their hip arthroplasty experience within 1 year of surgery.

Integrating cell interaction with transcription factors to obtain a robust gene panel for prognostic prediction and therapies in cholangiocarcinoma.

Objective: The efficacy of immunotherapy for cholangiocarcinoma (CCA) is blocked by a high degree of tumor heterogeneity. Cell communication contributes to heterogeneity in the tumor microenvironment. This study aimed to explore critical cell signaling and biomarkers induced via cell communication during immune exhaustion in CCA. Methods: We constructed empirical Bayes and Markov random field models eLBP to determine transcription factors, interacting genes, and associated signaling pathways involved in cell-cell communication using single-cell RNAseq data. We then analyzed the mechanism of immune exhaustion during CCA progression. Results: We found that VEGFA-positive macrophages with high levels of LGALS9 could interact with HAVCR2 to promote the exhaustion of CD8+ T cells in CCA. Transcription factors SPI1 and IRF1 can upregulate the expression of LGALS9 in VEGFA-positive macrophages. Subsequently, we obtained a panel containing 54 genes through the model, which identified subtype S2 with high expression of immune checkpoint genes that are suitable for immunotherapy. Moreover, we found that patients with subtype S2 with a higher mutation ratio of MUC16 had immune-exhausted genes, such as HAVCR2 and TIGIT. Finally, we constructed a nine-gene eLBP-LASSO-COX risk model, which was designated the tumor microenvironment risk score (TMRS). Conclusion: Cell communication-related genes can be used as important markers for predicting patient prognosis and immunotherapy responses. The TMRS panel is a reliable tool for prognostic prediction and chemotherapeutic decision-making in CCA.

Health Communication through Chinese Media on E-Cigarette: A Topic Modeling Approach.

BACKGROUND: Electronic cigarettes (e-cigarettes) have been a newsworthy topic in China. E-cigarettes are receiving greater consumer attention due to the rise of the Chinese e-cigarettes industry. In the past decade, e-cigarettes have been widely debated across the media, particularly their identity and their health effects. OBJECTIVE: this study aims to (1) find the key topics in e-cigarette news and (2) provide suggestions for future media strategies to improve health communication. METHOD: We collected Chinese e-cigarettes news from 1 November 2015 to 31 October 2020, in the Huike (WiseSearch) database, using "e-cigarettes" (Chinese: "") as the keyword. We used the Jieba package in python to perform the data cleaning process and the Dirichlet allocation (LDA) topic modeling method to generate major themes of the health communication through news content. MAIN FINDING: through an analysis of 1584 news articles on e-cigarettes, this paper finds 26 topics covered with 4 themes as regulations and control (n = 475, 30%), minor protection (n = 436, 27.5%), industry activities (n = 404, 25.5%), and health effects (n = 269, 17%). The peak and decline of the number of news articles are affected by time and related regulations. CONCLUSION: the main themes of Chinese news content on e-cigarettes are regulations and control, and minor protection. Newspapers should shoulder the responsibilities and play an important role in health communication with balanced coverage.

High Uniformity and Enhancement Au@AgNS 3D Substrates for the Diagnosis of Breast Cancer.

Breast cancer appears to be one of the leading causes of cancer-related morbidity and mortality for women worldwide. The accurate and rapid diagnosis of breast cancer is hence critical for the treatment and prognosis of patients. With the vibrational fingerprint information and high detection sensitivity, surface-enhanced Raman spectroscopy (SERS) has been extensively applied in biomedicine. Here, an optimized bimetallic nanosphere (Au@Ag NS) 3D substrate was fabricated for the aim of the diagnosis of breast cancer based on the SERS analysis of the extracellular metabolites. The unique stacking mode of 3D Au@Ag NSs provided multiple plasmonic hot spots according to the theoretical calculations of the electromagnetic field distribution. The low relative standard deviation (RSD = 2.7%) and high enhancement factor (EF = 1.42 × 105) proved the uniformity and high sensitivity. More importantly, the normal breast cells and breast cancer cells could be readily distinguished from the corresponding SERS spectra based on the extracellular metabolites. Furthermore, the clear clusters of SERS spectra from MCF-7 and MDA-MB-231 extracellular metabolites in the orthogonal partial least-squares discriminant analysis plot indicate the distinct metabolic fingerprint between breast cancer cells, which imply their potential clinical application in the diagnosis of breast cancer.

Cellular heterogeneity and transcriptomic profiles during intrahepatic cholangiocarcinoma initiation and progression.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is not fully investigated, and how stromal cells contribute to ICC formation is poorly understood. We aimed to uncover ICC origin, cellular heterogeneity, and critical modulators during ICC initiation/progression, and to decipher how fibroblast and endothelial cells in the stromal compartment favor ICC progression. APPROACH AND RESULTS: We performed single-cell RNA sequencing (scRNA-seq) using AKT/Notch intracellular domain-induced mouse ICC tissues at early, middle, and late stages. We analyzed the transcriptomic landscape, cellular classification and evolution, and intercellular communication during ICC initiation/progression. We confirmed the findings using quantitative real-time PCR, western blotting, immunohistochemistry or immunofluorescence, and gene knockout/knockdown analysis. We identified stress-responding and proliferating subpopulations in late-stage mouse ICC tissues and validated them using human scRNA-seq data sets. By integrating weighted correlation network analysis and protein-protein interaction through least absolute shrinkage and selection operator regression, we identified zinc finger, MIZ-type containing 1 (Zmiz1) and Y box protein 1 (Ybx1) as core transcription factors required by stress-responding and proliferating ICC cells, respectively. Knockout of either one led to the blockade of ICC initiation/progression. Using two other ICC mouse models (YAP/AKT, KRAS/p19) and human ICC scRNA-seq data sets, we confirmed the orchestrating roles of Zmiz1 and Ybx1 in ICC occurrence and development. In addition, hes family bHLH transcription factor 1, cofilin 1, and inhibitor of DNA binding 1 were identified as driver genes for ICC. Moreover, periportal liver sinusoidal endothelial cells could differentiate into tip endothelial cells to promote ICC development, and this was Dll4-Notch4-Efnb2 signaling-dependent. CONCLUSIONS: Stress-responding and ICC proliferating subtypes were identified, and Zmiz1 and Ybx1 were revealed as core transcription factors in these subtypes. Fibroblast-endothelial cell interaction promotes ICC development.

Integrating bulk and single-cell RNA sequencing reveals cellular heterogeneity and immune infiltration in hepatocellular carcinoma.

Efficacy of immunotherapy in hepatocellular carcinoma (HCC) is blocked by its high degree of inter- and intra-tumor heterogeneity and immunosuppressive tumor microenvironment. However, the correlation between tumor heterogeneity and immunosuppressive microenvironment in HCC has not been well addressed. Here, we endeavored to dissect inter- and intra-tumor heterogeneity in HCC and uncover how they contribute to the immunosuppressive microenvironment. We performed consensus molecular subtyping with non-negative matrix factorization (NMF) clustering to stratify the inter-heterogeneity profile of HCC tumors. We grouped HCC tumors from the Cancer Genome Atlas (TCGA) patients into three subtypes (S1, S2 and S3), where S1 was characterized as a 'hot tumor' profile with high expression level of T cell genes and rate of immune scores. S2 was characterized as a 'cold tumor' profile with the highest tumor purity score, and S3 as an 'immunosuppressed tumor' profile with the poorest prognosis and a high expression level of immunosuppressive genes such as cytotoxic T-lymphocyte-associated protein-4, TIGIT, and PDCD1. Moreover, we combined weighted gene co-expression network analysis and single-cell regulatory network inference and clustering (SCENIC) in the single-cell dataset of the S3-like subtype (CS3) and identified a transcription factor, BATF, which could upregulate immunosuppressive genes. Finally, we identified a cell interaction network in which a myeloid-derived suppressor cell-like macrophage subtype could promote the formation of immunosuppressive T-cells.

Structures of capsid and capsid-associated tegument complex inside the Epstein-Barr virus.

As the first discovered human cancer virus, Epstein-Barr virus (EBV) causes Burkitt's lymphoma and nasopharyngeal carcinoma. Isolating virions for determining high-resolution structures has been hindered by latency-a hallmark of EBV infection-and atomic structures are thus available only for recombinantly expressed EBV proteins. In the present study, by symmetry relaxation and subparticle reconstruction, we have determined near-atomic-resolution structures of the EBV capsid with an asymmetrically attached DNA-translocating portal and capsid-associated tegument complexes from cryogenic electron microscopy images of just 2,048 EBV virions obtained by chemical induction. The resulting atomic models reveal structural plasticity among the 20 conformers of the major capsid protein, 2 conformers of the small capsid protein (SCP), 4 conformers of the triplex monomer proteins and 2 conformers of the triplex dimer proteins. Plasticity reaches the greatest level at the capsid-tegument interfaces involving SCP and capsid-associated tegument complexes (CATC): SCPs crown pentons/hexons and mediate tegument protein binding, and CATCs bind and rotate all five periportal triplexes, but notably only about one peri-penton triplex. These results offer insights into the EBV capsid assembly and a mechanism for recruiting cell-regulating factors into the tegument compartment as 'cargoes', and should inform future anti-EBV strategies.