Effector Pt9226 from Puccinia triticina Presents a Virulence Role in Wheat Line TcLr15.

Effectors are considered to be virulence factors secreted by pathogens, which play an important role during host-pathogen interactions. In this study, the candidate effector Pt9226 was cloned from genomic DNA of Puccinia triticina (Pt) pathotype THTT, and there were six exons and five introns in the 877 bp sequence, with the corresponding open reading frame of 447 bp in length, encoding a protein of 148 amino acids. There was only one polymorphic locus of I142V among the six Pt pathotypes analyzed. Bioinformatics analysis showed that Pt9226 had 96.46% homology with the hypothetical putative protein PTTG_26361 (OAV96349.1) in the Pt pathotype BBBD. RT-qPCR analyses showed that the expression of Pt9226 was induced after Pt inoculation, with a peak at 36 hpi, which was 20 times higher than the initial expression at 0 hpi, and another high expression was observed at 96 hpi. No secretory function was detected for the Pt9226-predicted signal peptide. The subcellular localization of Pt9226Δsp-GFP was found to be multiple, localized in the tobacco leaves. Pt9226 could inhibit programmed cell death (PCD) induced by BAX/INF1 in tobacco as well as DC3000-induced PCD in wheat. The transient expression of Pt9226 in 26 wheat near-isogenic lines (NILs) by a bacterial type III secretion system of Pseudomonas fluorescens EtHAn suppressed callose accumulation triggered by Ethan in wheat near-isogenic lines TcLr15, TcLr25, and TcLr30, and it also suppressed the ROS accumulation in TcLr15. RT-qPCR analysis showed that the expression of genes coded for pathogenesis-related protein TaPR1, TaPR2, and thaumatin-like protein TaTLP1, were suppressed, while the expression of PtEF-1α was induced, with 1.6 times at 72 h post inoculation, and TaSOD was induced only at 24 and 48 h compared with the control, when the Pt pathotype THTT was inoculated on a transient expression of Pt9226 in wheat TcLr15. Combining all above, Pt9226 acts as a virulence effector in the interaction between the Pt pathotype THTT and wheat.

NLR, MLR, and PLR are adverse prognostic variables for sleeve lobectomy within non-small cell lung cancer.

BACKGROUND: The goal of the research was to examine the value of peripheral blood indicators in forecasting survival and recurrence among people suffering central-type non-small cell lung cancer (NSCLC) undergoing sleeve lobectomy (SL). METHODS: Clinical information was gathered from 146 individuals suffering from NSCLC who had SL at our facility between January 2014 and May 2023. Peripheral blood neutrophil lymphocyte ratio (NLR), monocyte lymphocyte ratio (MLR), and platelet lymphocyte ratio (PLR) levels were determined by receiver operating characteristic (ROC) curve to establish the threshold points. Kaplan-Meier survival analysis was employed to evaluate the prognostic value of different groupings, and both univariate and multivariate Cox proportional hazards model (referred to as COX) were performed. RESULTS: The disease-free survival (DFS) and overall survival (OS) cutoff values were carried out via ROC analysis. Kaplan-Meier survival analysis revealed notable differences in OS for NLR (≥2.196 vs. <2.196, p = 0.0009), MLR (≥0.2763 vs. <0.2763, p = 0.0018), and PLR (≥126.11 vs. <126.11, p = 0.0354). Similarly, significant differences in DFS were observed for NLR (≥3.010 vs. <3.010, p = 0.0005), MLR (≥0.2708 vs. <0.2708, p = 0.0046), and PLR (≥126.11 vs. <126.11, p = 0.0028). Univariate Cox analysis showed that NLR (hazard ratio [HR]: 2.469; 95% confidence interval [CI]: 1.416-4.306, p < 0.001), MLR (HR: 2.192, 95% CI: 1.319-3.643, p = 0.002) and PLR (HR: 1.696, 95% CI: 1.029-2.795, p = 0.038) were correlated alongside OS. Multivariate Cox analysis showed that NLR (HR: 2.036, 95% CI: 1.072-3.864, p = 0.030) was a separate OS risk variable. Additionally, the pN stage (HR: 3.163, 95% CI: 1.660-6.027, p < 0.001), NLR (HR: 2.530, 95% CI: 1.468-4.360, p < 0.001), MLR (HR: 2.229, 95% CI: 1.260-3.944, p = 0.006) and PLR (HR: 2.249, 95% CI: 1.300-3.889, p = 0.004) were connected to DFS. Multivariate Cox analysis showed that pN stage (HR: 3.098, 95% CI: 1.619-5.928, p < 0.001) was a separate DFS risk variable. CONCLUSION: The study demonstrates that NLR, MLR, and PLR play a convenient and cost-effective role in predicting survival and recurrence among individuals alongside central-type NSCLC having SL.

Clinical characteristics and prognosis of primary thymic adenocarcinoma: A single-center retrospective analysis.

BACKGROUND: Primary thymic adenocarcinoma (PTAC) is an extremely rare disease with a poor prognosis. In the present study, we sought to analyze the clinical characteristics and prognostic factors of patients with PTAC. METHODS: A total of 14 patients with PTAC treated at our center from January 2000 to January 2019 were included in this study. We retrospectively collected information on sex, age, history of smoking, family history of cancer, comorbidities, symptoms, imaging tests, serum tumor marker levels, tumor, node, metastasis (TNM) staging, and treatment records. Follow-up information was obtained by telephone interviews or outpatient clinic visit. Univariate and multivariate Cox regression analyses were performed to investigate the clinicopathological factors associated with survival. RESULTS: Among 14 patients with PTAC, there were five males and nine females, with an average age of 48.7 ± 9.3 years. A total of 23.1% of the patients had a history of smoking. The clinical symptoms of the patients were nonspecific and seven patients had elevated levels of serum tumor markers. Surgery was performed for nine patients, among which only four received R0 resection. The median survival time of the 14 patients was 16.0 months, and the 1-, 3- and 5-year survival rates were 57.1%, 35.7% and 21.4%, respectively. TNM stage was identified as an independent prognostic factor for PTAC patients (the median survival time of stage I-IIIA vs. stage IV was 44.0 months vs. 9.0 months, p = 0.002). CONCLUSIONS: PTAC is highly aggressive malignancy with poor prognosis. Surgical treatment is feasible, but R0 resection is challenging. TNM staging is significantly associated with patient survival.

Transformation of A1/A2 Astrocytes Participates in Brain Ischemic Tolerance Induced by Cerebral Ischemic Preconditioning via Inhibiting NDRG2.

Cerebral ischemic preconditioning (CIP) has been shown to improve brain ischemic tolerance against subsequent lethal ischemia. Reactive astrocytes play important roles in cerebral ischemia-reperfusion. Recent studies have shown that reactive astrocytes can be polarized into neurotoxic A1 phenotype (C3d) and neuroprotective A2 phenotype (S100A10). However, their role in CIP remains unclear. Here, we focused on the role of N-myc downstream-regulated gene 2 (NDRG2) in regulating the transformation of A1/A2 astrocytes and promoting to brain ischemic tolerance induced by CIP. A Sprague Dawley rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) was used. Rats were divided into the following six groups: (1) sham group; (2) CIP group: left middle cerebral artery was blocked for 10 min; (3) MCAO/R group: left middle cerebral artery was blocked for 90 min; (4) CIP + MCAO/R group: CIP was performed 72 h before MCAO/R; (5) AAV-NDRG2 + CIP + MCAO/R group: adeno-associated virus (AAV) carrying NDRG2 was administered 14 days before CIP + MCAO/R; (6) AAV-Ctrl + CIP + MCAO/R group: empty control group. The rats were subjected to neurological evaluation 24 h after the above treatments, and then were sacrificed for 2, 3, 5-triphenyltetraolium chloride staining, thionin staining, immunofluorescence and western blot analysis. In CIP + MCAO/R group, the neurological deficit scores decreased, infarct volume reduced, and neuronal density increased compared with MCAO/R group. Notably, CIP significantly increased S100A10 expression and the number of S100A10+/GFAP+ cells, and also increased NDRG2 expression. MCAO/R significantly decreased S100A10 expression and the number of S100A10+/GFAP+ cells yet increased C3d expression and the number of C3d+/GFAP+ cells and NDRG2 expression, and these trends were reversed by CIP + MCAO/R. Furthermore, over-expression of NDRG2 before CIP + MCAO/R, the C3d expression and the number of C3d+/GFAP+ cells increased, while S100A10 expression and the number of S100A10+/GFAP+ cells decreased. Meanwhile, over-expression of NDRG2 blocked the CIP-induced brain ischemic tolerance. Taken together, these results suggest that CIP exerts neuroprotective effects against ischemic injury by suppressing A1 astrocyte polarization and promoting A2 astrocyte polarization via inhibiting NDRG2 expression.

Highly Accurate Estimation of Cell Type Abundance in Bulk Tissues Based on Single-Cell Reference and Domain Adaptive Matching.

Accurately identifies the cellular composition of complex tissues, which is critical for understanding disease pathogenesis, early diagnosis, and prevention. However, current methods for deconvoluting bulk RNA sequencing (RNA-seq) typically rely on matched single-cell RNA sequencing (scRNA-seq) as a reference, which can be limiting due to differences in sequencing distribution and the potential for invalid information from single-cell references. Hence, a novel computational method named SCROAM is introduced to address these challenges. SCROAM transforms scRNA-seq and bulk RNA-seq into a shared feature space, effectively eliminating distributional differences in the latent space. Subsequently, cell-type-specific expression matrices are generated from the scRNA-seq data, facilitating the precise identification of cell types within bulk tissues. The performance of SCROAM is assessed through benchmarking against simulated and real datasets, demonstrating its accuracy and robustness. To further validate SCROAM's performance, single-cell and bulk RNA-seq experiments are conducted on mouse spinal cord tissue, with SCROAM applied to identify cell types in bulk tissue. Results indicate that SCROAM is a highly effective tool for identifying similar cell types. An integrated analysis of liver cancer and primary glioblastoma is then performed. Overall, this research offers a novel perspective for delivering precise insights into disease pathogenesis and potential therapeutic strategies.

2,3-Seco and 3-nor guaianolides fromAchillea alpina with antidiabetic activity.

In this study, we presented the isolation and characterization of eight novel seco-guaianolide sesquiterpenoids (1-8) and two known guaianolide derivatives (9 and 10), from the aerial part of Achillea alpina L.. Compounds 1-3 were identified as guaianolides bearing an oxygen insertion at the 2, 3 position, while compounds 4-8 belonged to a group of special 3-nor guaianolide sesquiterpenoids. The structural elucidation of 1-8, including their absolute configurations, were accomplished by a combination of spectroscopic data analysis and quantum electronic circular dichroism (ECD) calculations. To evaluate the potential antidiabetic activity of compounds 1-10, we investigated their effects on glucose consumption in palmitic acid (PA)-mediated HepG2-insulin resistance (IR) cells. Among the tested compounds, compound 7 demonstrated the most pronounced ability to reverse IR. Moreover, a mechanistic investigation revealed that compound 7 exerted its antidiabetic effect by reducing the production of the pro-inflammatory cytokine IL-1ß, which was achieved through the suppression of the NLRP3 pathway.

Potential role of lnc-METRNL-1 in the occurrence and prognosis of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of the head and neck with poor prognosis. This study aimed to explore the role of lnc-METRNL-1 in occurrence and prognosis of OSCC patients. Expression of lnc-METRNL-1 was compared between OSCC samples and paracancerous samples from The Cancer Genome Atlas (TCGA) database. Additionally, the lnc-METRNL-1 expression in cell lines was detected by using qRT-PCR. The overall survival (OS) was estimated based on the Kaplan-Meier and the immune cell infiltration was evaluated using CIBERSORT. Significantly enriched biological pathways were identified by Gene-set enrichment analysis (GSEA). Differential expression analysis was done in edgeR package. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of differential expression genes were conducted using DAVID version 6.8. The lnc-METRNL-1 expression in OSCC was significantly lower than that in paracancerous samples, and patients with low lnc-METRNL-1 expression had poorer OS. Additionally, lnc-METRNL-1 was significantly down-regulated in OSCC cell lines compared with normal cell line. High expression of lnc-METRNL-1 was closely associated with the activation of several tumor metabolic and metabolism-related pathways. Besides, aberrant lnc-METRNL-1 expression was found to be related to the differential infiltration of immune cells in tumor tissue, such as regulatory T cells, and Macrophages. Low lnc-METRNL-1 expression was probably a poor prognostic biomarker for OSCC patients. Moreover, the potential role of lnc-METRNL-1 in the onset of OSCC was partly revealed. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03674-0.

Patient-Reported Outcome-Based Prediction for Postdischarge Complications after Lung Surgery.

BACKGROUND: Patients undergoing lung tumor surgery may experience various complications after discharge from the hospital. Using patient-reported outcomes (PROs), this study attempted to identify relevant indicators of postdischarge complications after lung tumor surgery and develop a predictive nomogram model to evaluate the risk for individual patients. METHODS: Patients who underwent lung tumor surgery between December 2021 and June 2022 were included in this study. PROs were assessed using the Perioperative Symptom Assessment for Lung Surgery scale and were assessed preoperatively at baseline, on postoperative day 1 (POD1) 1 to POD4, and then weekly until the fourth week. A random forest machine learning prediction model was built to rank the importance of each PRO score of patients on POD1 to POD4. We then selected the top 10 variables in terms of importance for the multivariable logistic regression analysis. Finally, a nomogram was developed. RESULTS: PROs, including coughing (POD3 and POD4), daily activity (POD1), and pain (POD1 and POD2), were associated with postdischarge complications in patients undergoing lung tumor surgery. The predictive model showed good performance in estimating the risk of postdischarge complications, with an area under the curve of 0.833 (95% confidence interval: 0.753-0.912), while maintaining good calibration and clinical value. CONCLUSION: We found that PRO scores on POD1 to POD4 were associated with postdischarge complications after lung tumor surgery, and we developed a helpful nomogram model to predict the risk of postdischarge complications.

Morphine poisoning in a patient with malignant peritoneal mesothelioma: A case report.

Pain is one of the most common symptoms of malignant peritoneal mesothelioma. Therefore, analgesia serves an indispensable role in the treatment of this condition. Morphine is a representative opioid, which is widely used in clinical practice; however, excessive or unreasonable application can cause poisoning. Few cases of morphine poisoning have been reported, and cases of morphine poisoning in patients with malignant peritoneal mesothelioma are even more rare. Here, we present a case of morphine poisoning in a patient with malignant peritoneal mesothelioma. The patient had a high abdominal tumor load, hepatorenal insufficiency, and was treated with a combination of morphine and the sedative benzodiazepine, eventually leading to morphine poisoning. Therefore, for cancer pain, omni-directional and whole-process management should be emphasized. In patients with hepatorenal insufficiency, those treated with morphine combined with benzodiazepines, or those with a high abdominal tumor load, attention should be paid to drug absorption, excretion and interaction, and the drug dose during administration should be reduced to avoid drug poisoning. If poisoning symptoms occur, timely measures should be taken to reduce poison absorption and increase poison excretion, and antagonists should be used to reverse the poisoning and reduce the damage caused.

ZIM3 activation of CCL25 expression in pulmonary metastatic nodules of osteosarcoma recruits M2 macrophages to promote metastatic growth.

Tumor-associated macrophages (TAMs) play an important role in tumor growth and metastasis. However, the involvement of TAMs infiltration in pulmonary osteosarcoma (OS) metastasis remains poorly understood. Therefore, the effect of OS cells on macrophages migration was investigated by in vivo and in vitro experiments to evaluate the infiltration and mechanism of TAMs in pulmonary OS metastases. The results showed that the zinc finger protein ZIM3 was upregulated in OS cells than in osteoblasts and activated the expression of CCL25, which subsequently promoted the migration of M2 macrophages. CCL25 or ZIM3 silencing in OS cells inhibited the infiltration of M2 macrophages and the formation of pulmonary metastatic nodules in a mouse model of pulmonary OS metastasis and prolonged the survival of the mice. Furthermore, bioinformatics analyses revealed that CCL25 and ZIM3 expressions are negatively correlated with the prognosis of OS patients. In conclusion, this study found that a large number of M2 TAMs were recruited into pulmonary metastatic nodules of OS through the activation of the ZIM3-CCL25 axis in OS cells, thereby facilitating OS metastasis. Therefore, the suppression of ZIM3-CCL25-induced recruitment of M2 TAMs to the metastatic sites might be considered as a therapeutic approach to inhibit the growth of pulmonary OS metastases.

Targeted therapy for multiple gene mutations in multiple metastases of advanced gastric cancer: a case report.

In China, gastric cancer is the second most common cause of cancer-related death, after lung cancer. At present, the morbidity and mortality rates of gastric cancer are increasing, and targeted therapy for gastric cancer has become a research hotspot. Herein, we report a patient with multiple metastases from advanced gastric cancer. After identifying MET gene amplification, initial treatment induced regression of the tumor. However, in later stages, due to the overexpression or mutation of HER-2, KRAS, TP53, and other genes, the targeted drug therapy became ineffective, and the disease progressed rapidly, leading to the death of the patient.

Clinical characteristics and prognostic factors of pulmonary sarcomatoid carcinoma.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a kind of rare lung cancer. We aim to analyze the clinical characteristics and prognostic factors of patients with PSC. Methods: From January 1, 2006 to December 31, 2015, 119 patients in the Cancer Hospital Chinese Academy of Medical Sciences were diagnosed with PSC, and they received treatment. We retrospectively collected information on gender, age, body mass index (BMI), symptoms, family history, smoking history, tumor size, tumor location, tumor diameter, tumor-node-metastasis (TNM), pathological type, and other factors to analyze the relationship between these factors and 1-, 3-, 5-year, and overall survival (OS). Results: Male patients who had a smoking history (n=76) comprised the main group of PSC. Median patient age was 60.67±10.50 years (range, 26-89 years). The majority of these patients (n=82) presented with respiratory symptoms. The median survival of patients who died of PSC was 11.87 months (6.38-21.48 months). The 1-, 3-, and 5-year survival rates were 61.3%, 34.5%, and 31.9%, respectively. Patients with a lower T stage and without lymph node metastasis and distant metastasis had a better OS (P<0.05). Other clinical characteristics and the difference in treatments did not influence the prognosis significantly (P>0.05). Conclusions: PSC is a rare malignant neoplasm of the lung with poor prognosis. Surgery is a major therapeutic method for this disease entity. TNM-stage is the main factors affecting prognosis.

Postoperative Patient-Reported Outcomes after Uniportal Video-Assisted Thoracoscopic Surgery Using the Perioperative Symptom Assessment for Lung Surgery Scale.

This study aimed to use a new special inventory for lung surgery patients to evaluate postoperative symptoms and functional status and to identify factors that may affect these after uniportal video-assisted thoracoscopic surgery (VATS). In this single-center longitudinal cohort observational study, we used a new scale, the perioperative symptom assessment for lung surgery (PSA-Lung), to evaluate the recovery from symptoms and the functional status of patients undergoing uniportal VATS. We divided patients into two groups, according to patients' symptom scores, and compared the clinical characteristics between the two groups under each item. Then, we conducted a qualitative interview regarding coughing in postoperative week 4. Exactly 104 patients were enrolled in this study. The two highest-scoring patient-reported outcome (PRO) items were "shortness of breath" and "coughing" in the fourth week after surgery. Thirty-one patients reported that "coughing" severely influenced their lives in postoperative week 4. Using the PSA-Lung inventory, we found that "shortness of breath" was the worst symptom in postoperative week 4. Although "coughing" was not the most important symptom in the early postoperative period, it affected some patients' lives in postoperative week 4. Therefore, further research is required to determine the optimal cut-off point for coughing.

Clinical course and management of insidious adrenal crisis manifested initially as hyperpyrexia secondary to pembrolizumab: Case reports and literature review.

Immune checkpoint inhibitors (ICIs) are novel drugs with a dramatic survival benefit in patients with advanced malignancies. With the widespread use, several immune-related adverse events (irAEs) have emerged, which may be life-threatening. Herein we report two patients with adrenal crisis who received anti-programmed cell death protein 1 (PD-1) (pembrolizumab) therapy. Several reports of secondary adrenal insufficiency caused by pembrolizumab exist, including during treatment or late onset. Severe adrenal insufficiency according to the Common Terminology Criteria for Adverse Events (CTCAE) has rarely been described in the literature, since it initially manifests as high-grade fever. The two male patients developed adrenal crisis that was first characterized by hyperpyrexia accompanied by abdominal symptoms. These initial manifestations confused the clinicians who misdiagnosed them as infection. Timely identification, hydrocortisone pulse therapy, and fluid resuscitation improved the patients' condition. Compliance with the standardized treatment approach and course can prevent or relieve the crisis as soon as possible. Assessment of relevant laboratory test results and patient education, including when to use stress-dose hydrocortisone and guidance on route of administration, can reduce the incidence of adrenal crisis. We report these two cases and have evaluated the literature on previously reported cases to improve our understanding of this condition and offer a more scientific approach to diagnosis and treatment options.

Germacranolide- and guaianolide-type sesquiterpenoids from Achillea alpina L. reduce insulin resistance in palmitic acid-treated HepG2 cells via inhibition of the NLRP3 inflammasome pathway.

Chemical investigation on the aerial part of Achillea alpina L. led to the isolation of twenty sesquiterpenoids. The structures of the undescribed achigermalides A-H were determined by extensive spectroscopic analysis, including NMR, HRESIMS, UV and IR, and their absolute configurations were established by computational electronic circular dichroism (ECD) method. The X-ray crystal structure for 8α-angeloxy-1ß,2ß:4ß,5ß-diepoxy-10ß-hydroxy-6ßH,7αH,11ßH-12,6α-guaianolide was reported for the first time. Glucose consumption was analyzed to investigate the effect of all compounds on palmitic acid (PA)-mediated insulin resistance (IR) in HepG2 cells, and achigermalides D-F, desacetylherbohde A, and 4E,10E-3-(2-methylbutyroyloxy)-germacra-4,10(1)-diene-12,6α-olide appreciably enhanced the glucose consumption at low concentrations of 1.56-6.25 µM. Moreover, achigermalide D decreased the expression of IL-1ß and the generation of reactive oxygen species (ROS), and also down-regulated the protein levels of TXNIP, NLRP3, caspase-1 and NF-κB in the Western blot analysis, suggesting achigermalide D mediated IR via the suppression of NLRP3 inflammasome pathway.

Osteosarcoma exocytosis of soluble LGALS3BP mediates macrophages toward a tumoricidal phenotype.

This study aimed to elucidate the interactions between osteosarcoma (OS) and M1 macrophages infiltrated into the tumor microenvironment and to explore the underlying mechanisms whereby M1 macrophages influence the growth of OS, so that novel treatments of OS can be developed. A transwell co-culture system, an indirect conditioned medium culture system and two orthotopic bearing OS models were established to assess for the interplay between M1 macrophages and OS. We found that the co-culture of M1 macrophages with OS cells significantly inhibited the growth of the tumor cells by inducing apoptosis. Furthermore, HSPA1L secreted by M1 macrophages exerted this anti-tumor effect through the IRAK1 and IRAK4 pathways. LGALS3BP secreted by OS cells bound to the ligand LGALS3 on M1 macrophages and thereby induced the secretion of Hspa11 via Akt phosphorylation. In vivo experiments demonstrated that the culture supernatant of OS-stimulated M1 macrophages significantly inhibited the growth of OS, whereas silencing Lgals3bp promoted the progression of OS. In conclusion, OS modifies the phenotype of tumor-associated macrophages (TAMs) and thereby influences the apoptosis of OS cells through soluble factors. The modulation of TAMs may be a promising and effective therapeutic approach in OS.

Actein Antagonizes Oral Squamous Cell Carcinoma Proliferation through Activating FoxO1.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is among the most prevalent head and neck malignancies globally, and it is associated with high mortality rates. Actein is one of the primary active components extractable from the rhizomes of Cimicifuga foetida. This study aimed to evaluate the anti-OSCC effects of actein and evaluate the potential underlying mechanisms. METHODS AND RESULTS: CCK-8 cell proliferation experiments demonstrated significant dose- and time-dependent anti-OSCC effects of actein, while actein had weak cytotoxic effects on normal oral cell lines. Flow cytometry for cell cycle evaluation revealed that actein could induce cell cycle arrest at the G1 phase among OSCC cell lines. In our Annexin V/PI double staining apoptosis analysis, actein induced significant apoptosis among OSCC cells, with upregulation of Bax and downregulation of Bcl-2. Our mechanistic study implicated the involvement of the Akt/FoxO1 pathway in the anti-OSCC effects of actein. Akt1 and Akt2 expression significantly decreased in association with the FoxO1 upregulation. Furthermore, Bim and p21 were significantly upregulated, while survivin expression was downregulated. Finally, actein treatment was associated with significant p-Akt downregulation and p-FoxO1 upregulation in OSCC cells, demonstrating the validated roles of Akt/FoxO1 in actein-mediated OSCC cell apoptosis and cell cycle arrest. FoxO1 knockdown significantly reversed the anti-OSCC effects of actein. Additionally, a xenograft model indicated that actein could inhibit OSCC cell growth in vivo. CONCLUSIONS: Our findings demonstrated that actein could be a strong anti-OSCC candidate. Further evaluations of its safety and effectiveness are necessary before it can be considered for clinical use.

LINGO-1 regulates Wnt5a signaling during neural stem and progenitor cell differentiation by modulating miR-15b-3p levels.

BACKGROUND: Manipulation of neural stem and progenitor cells (NSPCs) is critical for the successful treatment of spinal cord injury (SCI) by NSPC transplantation, since their differentiation into neurons and oligodendrocytes can be inhibited by factors present in inflamed myelin. In this study, we examined the effects of LINGO-1 on spinal cord-derived NSPC (sp-NSPC) differentiation, the underlying mechanisms of action, and the functional recovery of mice after transplantation of manipulated cells. METHODS: sp-NSPCs were harvested from female adult C57/BL6 mice after SCI induced with an NYU impactor. These cells were infected with lentiviral vectors containing LINGO-1 shRNA sequence or a scrambled control and transplanted into SCI mice. Tuj-1- and GFAP-positive cells were assessed by immunofluorescence staining. Wnt5a, p-JNK, JNK, and ß-catenin expression was determined by Western blot and RT-qPCR. miRNAs were sequenced to detect changes in miRNA expression. Motor function was evaluated 0-35 days post-surgery by means of the Basso Mouse Scale (BMS) and by the rotarod performance test. RESULTS: We discovered that LINGO-1 shRNA increased neuronal differentiation of sp-NSPCs while decreasing astrocyte differentiation. These effects were accompanied by elevated Wnt5a protein expression, but unexpectedly, no changes in Wnt5a mRNA levels. miRNA-sequence analysis demonstrated that miR-15b-3p was a downstream mediator of LINGO-1 which suppressed Wnt5a expression. Transplantation of LINGO-1 shRNA-treated sp-NSPCs into SCI mice promoted neural differentiation, wound compaction, and motor function recovery. CONCLUSIONS: LINGO-1 shRNA promotes neural differentiation of sp-NSPCs and Wnt5a expression, probably by downregulating miR-15b-3p. Transplantation of LINGO-1 shRNA-treated NSPCs promotes recovery of motor function after SCI, highlighting its potential as a target for SCI treatment.

A four-hypoxia-genes-based prognostic signature for oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common maligancies of the head and neck. The prognosis was is significantly different among OSCC patients. This study aims to identify new biomarkers to establish a prognostic model to predict the survival of OSCC patients. METHODS: The mRNA expression and corresponding clinical information of OSCC patients were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus. Additionally, a total of 26 hypoxia-related genes were also obtained from a previous study. Univariate Cox regression analysis and LASSO Cox regression analysis were performed to screen the optimal hypoxia-related genes which were associated with the prognosis of OSCC. to establish the predictive model (Risk Score) was established for estimating the patient's overall survival (OS). Multivariate Cox regression analysis was used to determine whether the Risk Score was an independent prognostic factor. Based on all the independent prognostic factors, nomogram was established to predict the OS probability of OSCC patients. The relative proportion of 22 immune cell types in each patient was evaluated by CIBERSORT software. RESULTS: We determined that a total of four hypoxia-related genes including ALDOA, P4HA1, PGK1 and VEGFA were significantly associated with the prognosis of OSCC patients. The nomogram established based on all the independent factors could reliably predict the long-term OS of OSCC patients. In addition, our resluts indicated that the inferior prognosis of OSCC patients with high Risk Score might be related to the immunosuppressive microenvironments. CONCLUSION: This study shows that high expression of hypoxia-related genes including ALDOA, P4HA1, PGK1 and VEGFA is associated with poor prognosis in OSCC patients, and they can be used as potential markers for predicting prognosis in OSCC patients.

Nomogram for predicting the overall survival of the patients with oesophageal signet ring cell carcinoma.

BACKGROUND: The purpose of this study was to explore the prognostic factors of oesophageal signet ring cell (SRC) carcinoma and to construct a nomogram for predicting the outcome of SRC carcinoma of oesophagus. METHODS: A total of 968 cases of oesophageal SRC carcinoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016. Cases were divided into training cohort and validation cohort. Univariate and multivariable Cox analyses was performed to select the predictors of overall survival (OS for the nomogram. The performance of nomogram was validated with Harrell's concordance index (C-index), calibration curves and decision curve analysis (DCA). RESULTS: The 1- and 5-year OS in the training cohort were 0.446 and 0.146, respectively, and the 1- and 5-year OS in the validation cohort were 0.459 and 0.138. The independent prognostic factors for establishing the nomogram were marital status, invasion of the surrounding tissue, lymph node metastasis, distant metastasis, surgery and chemotherapy. The Harrell's c-index value of the training cohort and validation cohort were 0.723 and 0.708. In the calibration curves, the predicted survival probability and the actual survival probability have a considerable consistency. DCA indicated the favourable potential clinical utility of the nomogram. CONCLUSIONS: A nomogram to predict the OS of patients with oesophageal SRC carcinoma was established. The validation of the nomogram fully demonstrates its great performance.