YTHDF1 promotes the osteolytic bone metastasis of breast cancer via inducing EZH2 and CDH11 translation.

Bone metastasis is common in breast cancer and more effective therapies are required, however, its molecular mechanism is poorly understood. Additionally, the role of the m6A reader YTHDF1 in bone metastasis of breast cancer has not been reported. Here, we reveal that the increased expression of YTHDF1 is clinically correlated with breast cancer bone metastases. YTHDF1 promotes migration, invasion, and osteoblast adhesion and induces osteoclast differentiation of cancer cells in vitro and vivo. Mechanically, RNA-seq, MeRIP-seq and RIP-seq analysis, and molecular biology experiments demonstrate that YTHDF1 translationally enhances EZH2 and CDH11 expression by reading m6A-enriched sites of their transcripts. Moreover, adeno-associated virus (AAV) was used to deliver shYTHDF1 (shYTHDF1-AAV) in intratibial injection models, eliciting a significant suppressive effect on breast cancer bone metastatic formation and osteolytic destruction. Overall, we uncovered that YTHDF1 promotes osteolytic bone metastases of breast cancer by inducing EZH2 and CDH11 translation.

Tau Aggregation-Dependent Lipid Peroxide Accumulation Driven by the hsa_circ_0001546/14-3-3/CAMK2D/Tau Complex Inhibits Epithelial Ovarian Cancer Peritoneal Metastasis.

Intraperitoneal dissemination is the main method of epithelial ovarian cancer (EOC) metastasis, which is related to poor prognosis and a high recurrence rate. Circular RNAs (circRNAs) are a novel class of endogenous RNAs with covalently closed loop structures that are implicated in the regulation of tumor development. In this study, hsa_circ_0001546 is downregulated in EOC primary and metastatic tissues vs. control tissues and this phenotype has a favorable effect on EOC OS and DFS. hsa_circ_0001546 can directly bind with 14-3-3 proteins to act as a chaperone molecule and has a limited positive effect on 14-3-3 protein stability. This complex recruits CAMK2D to induce the Ser324 phosphorylation of Tau proteins, changing the phosphorylation status of Tau bound to 14-3-3 and ultimately forming the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex. The existence of this complex stimulates the production of Tau aggregation, which then induces the accumulation of lipid peroxides (LPOs) and causes LPO-dependent ferroptosis. In vivo, treatment with ferrostatin-1 and TRx0237 rescued the inhibitory effect of hsa_circ_0001546 on EOC cell spreading. Therefore, based on this results, ferroptosis caused by Tau aggregation occurs in EOC cells, which is not only in Alzheimer's disease- or Parkinson's disease-related cells and this kind of ferroptosis driven by the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex is LPO-dependent rather than GPX4-dependent is hypothesized.

Efficacy of epidural esketamine on postoperative sleep quality after laparoscopic and robotic lower abdominal surgeries: a study protocol for randomised, double-blind, controlled trial.

INTRODUCTION: Postoperative sleep disturbances significantly impair postoperative recovery. The administration of intravenous esketamine has been shown to potentially improve postoperative sleep quality. However, the effectiveness of epidural esketamine in improving postoperative sleep quality remains to be elucidated. This study aims to explore the impact of both intraoperative and postoperative use of epidural esketamine on the postoperative sleep quality of patients undergoing minimally invasive lower abdominal surgeries. METHODS AND ANALYSIS: This randomised, double-blind, parallel-group, placebo-controlled trial will be conducted at the Fudan University Shanghai Cancer Centre. A total of 128 adults undergoing minimally invasive lower abdominal surgeries will be randomly allocated in a 1:1 ratio to either the esketamine group or the placebo group. In the esketamine group, epidural esketamine will be administered intraoperatively (0.2 mg/kg) and postoperatively (25 mg). Postoperatively, all patients will receive epidural analgesia. The primary outcome of the study is the incidence of poor sleep quality on the third day after surgery. The sleep quality assessment will be conducted using the Pittsburgh Sleep Quality Index and a Numeric Rating Scale of sleep. The main secondary outcomes include postoperative pain and anxiety and depression scores. The postoperative pain, both rest pain and movement pain, will be assessed using a Numerical Rating Scale within 5 days after surgery. Anxiety and depression scores will be evaluated using the Hospital Anxiety and Depression Scale both before and after the surgery. Safety outcomes will include delirium, fidgeting, hallucinations, dizziness and nightmares. The analyses will be performed in accordance with intention-to-treat principle ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Ethics Committee of the Shanghai Cancer Centre (2309281-9). Prior to participation, all patients will provide written informed consent. The results of the trial are intended to be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ChiCTR2300076862.

Single-cell profiling of the microenvironment in human bone metastatic renal cell carcinoma.

Bone metastasis is of common occurrence in renal cell carcinoma with poor prognosis, but no optimal treatment approach has been established for bone metastatic renal cell carcinoma. To explore the potential therapeutic targets for bone metastatic renal cell carcinoma, we profile single cell transcriptomes of 6 primary renal cell carcinoma and 9 bone metastatic renal cell carcinoma. We also include scRNA-seq data of early-stage renal cell carcinoma, late-stage renal cell carcinoma, normal kidneys and healthy bone marrow samples in the study to better understand the bone metastasis niche. The molecular properties and dynamic changes of major cell lineages in bone metastatic environment of renal cell carcinoma are characterized. Bone metastatic renal cell carcinoma is associated with multifaceted immune deficiency together with cancer-associated fibroblasts, specifically appearance of macrophages exhibiting malignant and pro-angiogenic features. We also reveal the dominance of immune inhibitory T cells in the bone metastatic renal cell carcinoma which can be partially restored by the treatment. Trajectory analysis showes that myeloid-derived suppressor cells are progenitors of macrophages in the bone metastatic renal cell carcinoma while monocytes are their progenitors in primary tumors and healthy bone marrows. Additionally, the infiltration of immune inhibitory CD47+ T cells is observed in bone metastatic tumors, which may be a result of reduced phagocytosis by SIRPA-expressing macrophages in the bone microenvironment. Together, our results provide a systematic view of various cell types in bone metastatic renal cell carcinoma and suggest avenues for therapeutic solutions.

Anesthesia-related intervention for long-term survival and cancer recurrence following breast cancer surgery: A systematic review of prospective studies.

OBJECTIVE: Anesthesia is correlated with the prognosis of cancer surgery. However, evidence from prospective studies focusing on breast cancer is currently limited. This systematic review aimed to investigate the effect of anesthesia-related interventions on oncological outcomes following breast cancer surgery in prospective studies. METHODS: Literature searches were performed from inception to June. 2023 in the Pubmed, Web of Science, Embase, and ClinicalTrials databases. The main inclusion criteria comprised a minimum of one-year follow-up duration, with oncological outcomes as endpoints. Anesthesia-related interventions encompassed, but were not limited to, type of anesthesia, anesthetics, and analgesics. The risk of bias was assessed using the Cochrane Risk of Bias Tool. RESULTS: A total of 9 studies were included. Anesthesia-related interventions included paravertebral nerve block (3), pectoral nerve block (1), sevoflurane (2), ketorolac (2), and infiltration of lidocaine (1). Cancer recurrence, metastasis, disease-free survival, or (and) overall survival were assessed. Among all included studies, only infiltration of lidocaine was found to prolong disease-free survival and overall survival. CONCLUSION: Regional anesthesia and propofol did not improve oncological outcomes following breast cancer surgery. The anti-tumorigenic effect of ketorolac warrants future studies with larger sample sizes. Perioperative infiltration of lidocaine around the tumor may be a promising anti-tumorigenic intervention that can prolong overall survival in patients with early breast cancer.

Influence of extent of surgical resection on post-hepatectomy shoulder pain: an observational study.

Shoulder pain frequently follows hepatectomy. However, the influence of surgical procedures on shoulder pain is unclear. In this observational study, patients who underwent hepatectomy were enrolled in Shanghai Cancer Center. Shoulder pain and surgical pain were assessed using the numeric rating scale 2 days after surgery. The incidence of shoulder pain was the outcome of the cohort study. Nested case-control analyses were further applied. Three hundred and twelve patients were finally enrolled in this study. Nested case-control analysis showed that there were no significant differences in the number of surgical segments between the two groups (P = 0.09). In addition, minor hepatectomy did not reduce the incidence of shoulder pain compared with major hepatectomy (P = 0.37). The drainage volume within 2 days after surgery was significantly more in those patients with shoulder pain (P = 0.017). In open surgery, surgical sites involving the right anterior lobe (OR (95% CI) 2.021 (1.075, 3.802), P = 0.029) and right posterior lobe (OR (95% CI) 2.322 (1.193, 4.522), P = 0.013) were both independent risk factors for shoulder pain. Left shoulder pain also occurred in patients who did not receive left lateral hepatectomy. The preventive phrenic nerve block was not suitable for post-hepatectomy shoulder pain. Stronger preventative intervention should be used in those high-risk patients.

The feedback loop of AURKA/DDX5/TMEM147-AS1/let-7 drives lipophagy to induce cisplatin resistance in epithelial ovarian cancer.

Platinum-taxane chemotherapy is the first-line standard-of-care treatment administered to patients with epithelial ovarian cancer (EOC), and faces the major challenge of cisplatin resistance. Aurora Kinase A (AURKA) is a serine/threonine kinase, acting as an oncogene by participating in microtubule formation and stabilization. In this study, we demonstrate that AURKA binds with DDX5 directly to form a transcriptional coactivator complex to induce the transcription and upregulation of an oncogenic long non-coding RNA, TMEM147-AS1, which sponges hsa-let-7b/7c-5p leading to the increasing expression of AURKA as a feedback loop. The feedback loop maintains EOC cisplatin resistance via activation of lipophagy. These findings underscore the feedback loop of AURKA/DDX5/TMEM147-AS1/let-7 provides mechanistic insights into the combined use of TMEM147-AS1 siRNA and VX-680, which can help improve EOC cisplatin treatment. Our mathematical model shows that the feedback loop has the potential to act as a biological switch to maintain on- (activated) or off- (deactivated) status, implying the possible resistance of single use of VX-680 or TMEM147-AS1 siRNA. The combined use reduces both the protein level of AURKA using TMEM147-AS1 siRNA and its kinase activity using VX-680, showing more significant effect than the use of TMEM147-AS1 siRNA or VX-680 alone, which provides a potential strategy for EOC treatment.

Incidence and risk factors for acute shoulder pain after hepatectomy: a nested case-control study.

BACKGROUND: Shoulder pain is commonly reported after hepatic surgery; however, the factors affecting post-hepatectomy shoulder pain remain unclear. This study aimed to determine the incidence and risk factors of shoulder pain after hepatectomy. METHODS: This prospective cohort study recruited 218 patients who underwent hepatic resection at our hospital from June to September 2022. Data were obtained from electronic medical records and follow-up assessments on the second postoperative day. All patients denied chronic pain before surgery. In this cohort study, patients were grouped according to the appearance of shoulder pain. Demographic information and perioperative data were compared between the two groups. The relationship between shoulder pain and independent variables was assessed using univariate binary logistic regression analysis. The potential risk factors were analyzed using multivariable binary logistic regression. RESULTS: Of the 218 patients enrolled in this cohort study, 91 (41.7%) reported shoulder pain. Patients in the case group were significantly younger than those in the control group (P = 0.001). Epidural anesthesia was used more frequently in the case group (P = 0.012). Patients over 60 years of age showed a lower incidence of shoulder pain than younger patients (P = 0.028). According to multivariable binary logistic regression analysis, advanced age and epidural anesthesia were associated with risk of shoulder pain (advanced age: odds ratio [OR] [95% confidence interval (CI)]: 0.96 [0.94, 0.99], P = 0.002; epidural anesthesia: OR [95% CI]: 2.08 [1.18, 3.69], P = 0.012). CONCLUSIONS: The incidence of acute shoulder pain after hepatectomy is 41.7%. The application of epidural anesthesia is an independent risk factor for shoulder pain after hepatectomy, whereas advanced age is a protective factor.

Transcatheter Arterial Sclerosing Embolization for the Treatment of Giant Propranolol-Resistant Infantile Hemangiomas in the Parotid Region.

PURPOSE: To report the effectiveness and safety of transcatheter arterial sclerosing embolization (TASE) for the treatment of parotid infantile hemangiomas that did not respond appreciably to propranolol. MATERIALS AND METHODS: A total of 21 infants (12 male and 9 female) with large propranolol-resistant infantile hemangiomas in the parotid region were enrolled in this study. During TASE, the feeding arteries of the lesions were embolized using pingyangmycin-lipiodol emulsion and polyvinyl alcohol particles (300-500 µm) to reduce the blood flow rate. All children were followed up as outpatients at 2 weeks and monthly thereafter. The curative effect was evaluated at the 1- and 3-month follow-up visits. RESULTS: Nine lesions were located on the right side of the parotid gland, whereas 12 were located on the left side. The feeding arteries in all patients originated from branches of the external carotid artery. TASE was technically successful in all patients. The mean (± SD) maximal diameter of the hemangiomas significantly decreased from 6.50 cm ± 2.28 before treatment to 3.56 cm ± 1.84 at 1 month after TASE (P <. 05). Three months after TASE, the mean maximal diameter further significantly decreased to 1.94 cm ± 1.58 (P <. 05). During the follow-up period, 16 cases were rated as excellent and 5 as good; no recurrence or serious complications were noted. Minor side effects, such as slight pain, mild fever, and tissue swelling, were observed. CONCLUSIONS: TASE significantly decreased the size of the parotid hemangiomas with minor side effects during a short follow-up period.

Simulated Angiography Using a Bleomycin Mixture for Sclerotherapy of Lymphatic Malformations.

Objective: Repeat sclerotherapy of lymphatic malformations (LMs) is challenging. Accordingly, the aim of the present article is to describe a simulated angiography technique-a new method of bleomycin infusion for the treatment of LMs to achieve better outcome(s) in fewer sessions. Materials and Methods: A retrospective analysis of information housed in a prospectively collected LM database was performed. Patients with LM, revealed on imaging examination and treated using a simulated angiography technique with a bleomycin mixture, were included in the study. Visual evaluation and imaging examinations were performed to evaluate clinical improvement. Results: A total of 151 patients (82 male, 69 female; mean age, 28.29 months [range 1 month-12 years]) with LMs were included in this study. Excellent visual and radiological resolution was observed in 77% (117/151) of lesions, 17% (26/151) had significant improvement, and 8 patients exhibited a slight response. The number of procedures per patient varied from 1 to 5, and the average number of treatment sessions for LM was 1.34. Side effects included skin erythema at the injection site, local swelling, mild tenderness, and fever, which were controlled by oral antipyretics. No serious side effects were observed. Conclusions: Simulated angiography using a bleomycin mixture for sclerotherapy of LMs in children was feasible and demonstrated good effect with little trauma and less time per treatment.

MYH9 promotes cell metastasis via inducing Angiogenesis and Epithelial Mesenchymal Transition in Esophageal Squamous Cell Carcinoma.

Non-muscle myosin heavy chain 9 (MYH9) is one novel low frequency mutated gene identified in esophageal squamous cell carcinoma (ESCC) using next-generation sequencing. However, its clinical relevance, potential function and mechanisms remain elusive. Methods: Genomic sequencing datas from 104 esophageal squamous cell carcinoma (ESCC) cases were screened a series of low frequency mutant genes. MYH9 was selected to further analyze its clinical significance, function and PCR-array was performed to explore its potential mechanism. Results: MHY9 is a low frequency mutant gene with a mutation frequency of 2.88% in ESCC. Immunohistochemical analysis showed that MYH9 expression was significantly higher in ESCC tumor tissues, and the expression levels were associated with lymph node metastasis of ESCC patients. Moreover, we found that MYH9 knock-down led to inhibition of cell migration and invasion. PCR-array showed MYH9 knockdown led to a significant change of genes expression associated with angiogenesis and epithelial-to-mesenchymal transition (EMT). This observation is further confirmed in TCGA database of LUSC (lung squamous cell carcinoma), CESC (cervical squamous cell carcinomas) and HNSC (head and neck squamous cell carcinoma). Conclusions: Collectively, our study identifies a novel role and mechanism of MYH9, highlights a significance of MYH9 as a metastatic biomarker, and offers potential therapeutic targets for ESCC patients harboring MYH9 mutations.

Nosocomial cross-infection of hypervirulent Listeria monocytogenes sequence type 87 in China.

BACKGROUND: To investigate the epidemiological and phenotypic characteristics and molecular relatedness of L. monocytogenes, which were cultured from the blood and cerebrospinal fluid (CSF) samples isolated from two neonates. METHODS: In the present case study, two infected neonates were interviewed and epidemiological investigation performed. The phenotypic characteristics and molecular relatedness of L. monocytogenes was characterized by serotyping, pulsed-field gel electrophoresis and whole-genome sequencing (WGS). RESULTS: The field investigation found that the two neonates were born in the same hospital (Hospital B) and admitted to the neonatal department through different channels within half an hour by different nurses, where they were weighed and placed in different but adjacent incubators. Then they were cared for by the same group of nurses that evening. It is worth noting that there was no record of sanitation of the neonatal incubator of neonate-1. The serotype of the two isolated L. monocytogenes were 1/2b, with an indistinguishable pulsotypes and were sequence type (ST) 87. WGS showed that there were no core SNP differences identified. In order to explore the genomic traits associated with L. monocytogenes virulence genes, we identified the Listeria pathogenicity island 4 and found that the genome was devoid of any stress islands. There are no positive results from the environmental samples. Considering the genomic data together with epidemiological evidence and clinical symptoms, insufficient surface cleaning along with the nursing staff caring for these neonates was considered as cross-infection factors. CONCLUSIONS: To our knowledge, this is the first report of a nosocomial cross-infection of L. monocytogenes ST87 between two neonates, which carries the recently identified gene cluster expressing the cellobiose-family phosphotransferase system (PTS-LIPI-4) between two neonates. The test results of environmental samples in the hospital indicate that strict sterilization and patient isolation measures cannot be emphasized enough in neonatal nursing.

Do children need a longer time to shed SARS-CoV-2 in stool than adults?

SARS-CoV-2 can be shed in the stool of patients in the recovery phase. Children show a longer shedding time than adults. We analyzed the possible causes of this finding and recommend that a negative stool sample be included in a patient's discharge criteria.

RNSCLC-PRSP software to predict the prognostic risk and survival in patients with resected T1-3N0-2 M0 non-small cell lung cancer.

BACKGROUND: The clinical outcomes of patients with resected T1-3N0-2M0 non-small cell lung cancer (NSCLC) with the same tumor-node-metastasis (TNM) stage are diverse. Although other prognostic factors and prognostic prediction tools have been reported in many published studies, a convenient, accurate and specific prognostic prediction software for clinicians has not been developed. The purpose of our research was to develop this type of software that can analyze subdivided T and N staging and additional factors to predict prognostic risk and the corresponding mean and median survival time and 1-5-year survival rates of patients with resected T1-3N0-2M0 NSCLC. RESULTS: Using a Cox proportional hazard regression model, we determined the independent prognostic factors and obtained a prognostic index (PI) eq. PI = ∑ßixi.=0.379X1-0.403X2-0.267X51-0.167X61-0.298X62 + 0.460X71 + 0.617X72-0.344X81-0.105X91-0.243X92 + 0.305X101 + 0.508X102 + 0.754X103 + 0.143X111 + 0.170X112 + 0.434X113-0.327X122-0.247X123 + 0.517X133 + 0.340X134 + 0.457X143 + 0.419X144 + 0.407X145. Using the PI equation, we determined the PI value of every patient. According to the quantile of the PI value, patients were divided into three risk groups: low-, intermediate-, and high-risk groups with significantly different survival rates. Meanwhile, we obtained the mean and median survival times and 1-5-year survival rates of the three groups. We developed the RNSCLC-PRSP software which is freely available on the web at http://www.rnsclcpps.com with all major browsers supported to determine the prognostic risk and associated survival of patients with resected T1-3N0-2 M0 non-small cell lung cancer. CONCLUSIONS: After prognostic factor analysis, prognostic risk grouping and corresponding survival assessment, we developed a novel software program. It is practical and convenient for clinicians to evaluate the prognostic risk and corresponding survival of patients with resected T1-3N0-2M0 NSCLC. Additionally, it has guiding significance for clinicians to make decisions about complementary treatment for patients.

Ubiquitin-specific protease 44 inhibits cell growth by suppressing AKT signaling in non-small cell lung cancer.

Ubiquitin-specific protease 44 (USP44) has been reported as a tumor suppressor or promoter in some tumors, but its function in non-small cell lung cancer (NSCLC) is still unclear. In this study, USP44 was found significantly downregulated in both of NSCLC tissues and cell lines, and low expression of USP44 predicted a poor prognosis for NSCLC patients. Overexpression of USP44 markedly downregulated the expression levels of Cyclin D1 and CDK4, but upregulated p53 expression, as a result of which, suppressing the cell growth of NSCLC cells. Further studies indicated that overexpression of USP44 significantly inhibited the phosphorylation of AKT, and its down-stream signals, including mTOR and P70S6K. Moreover, overexpression of USP44 increased PTEN protein but not its mRNA levels, which suggested that USP44 inhibited AKT signaling by stabilizing PTEN in NSCLC cells. In conclusion, we demonstrated that USP44 showed prior evidence of a tumor suppressive function in NSCLC cells, and inhibited NSCLC cell growth by suppressing AKT signaling, suggesting that USP44 could be as a novel target for NSCLC therapy.

[Mutation analysis of the RUNX2 gene in a family with cleidocranial dysplasia].

OBJECTIVE: To analyze the mutations of the RUNX2 gene in a family with cleidocranial dysplasia (CCD). METHODS: The general health status of family members with CCD was investigated through propositus verification method. Oral specialized examination and radiological examination were performed. The peripheral venous blood of the proband and her parents and sisters was collected. Genomic DNA was extracted, and the RUNX2 gene from this DNA was amplified by polymerase chain reaction (PCR). DNA sequences were analyzed with the Blastn program. RESULTS: After Blastn analysis, heterozygous C to T transition mutation at nucleotide 568 occurred in exon 2, which converted arginine to tryptophane at codon 190 (c.568C>T, CGG-->TGG). CONCLUSION: RUNX2 gene is responsible for the CCD in the Chinese family under study. The c.568C>T mutation is the molecular basis of the CCD in the family.

[Cleidocranial dysplasia: two cases report and signature analysis].

Two cases of cleidocranial dysplasia(CCD) were reported and the characteristics of CCD were analyzed. The propositus verification method was used to family members for general health and oral specialized examination. All patients expressed developmental abnormality of crania, teeth and clavicle.