Perioperative nutrition management in patients with spinal tuberculosis taking ERAS measures.

BACKGROUND AND OBJECTIVES: To explore the effect of nutrition management under ERAS concept in patients with spinal tuberculosis. METHODS AND STUDY DESIGN: The study was conducted in an orthopedic ward of a tertiary grade A special hospital in Beijing. The patients admitted from January 1, 2021 to June 27, 2023 were screened for inclusion. The qualified patients were randomized into experimental group or control group. The experimental group received perioperative nutrition management under the concept of ERAS while the control group received routine perioperative management in hospital. The data was collected on the next day of admission, the next day and the sixth day after operation, including laboratory indicators (lymphocyte count, hemoglobin level, etc), intraoperative bleeding volume, postoperative exhaust, defecation time, drainage volume, albumin infusion amount, nutritional risk score, length of stay, hospitalization costs, etc. Univariate analysis and multivariate analysis correcting for gender, age, and baseline values were performed using SPSS24.0. RESULTS: A total of 127 patients with spinal tuberculosis completed the study. Compared with the control group, the intraoperative blood loss (p=0.028) in the experimental group was significantly reduced, the postoperative exhaust time (p=0.012) and defecation time (p=0.012) were significantly shortened, and the nutritional status (p<0.001) was significantly improved. Besides, the results of multivariate analysis are robust after correcting potential confounding factors. CONCLUSIONS: Nutrition management under the concept of ERAS is helpful to reduce intraoperative bleeding, promote postoperative flatus and defecation, and improve nutritional status in patients with spinal tuberculosis, which may further improve their clinical outcome and prognosis.

Differential distribution of linezolid in diseased and nondiseased bones in patients with spinal tuberculosis.

BACKGROUND: Linezolid exhibits antibacterial activity against sensitive and drug-resistant strains of Mycobacterium tuberculosis. Knowledge on the distribution of linezolid in different types of bones in patients with spinal tuberculosis (TB) is lacking, which limits the pharmacokinetic and pharmacodynamic studies of linezolid. This study aimed to evaluate the distribution of linezolid in diseased and nondiseased bones in patients with spinal TB. METHODS: Spinal TB patients treated with linezolid-containing regimens and whose diseased and nondiseased bones were collected during surgery were enrolled retrospectively from January 2017 to February 2022. Blood, nondiseased bones, and diseased bones were collected simultaneously during the operation. Linezolid concentrations in the plasma, nondiseased bones, and diseased bones were subjected to high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Seven eligible spinal TB patients, including one rifampicin-resistant case, were enrolled. Following a 600 mg oral administration of linezolid before surgery, the median concentrations of linezolid in plasma, nondiseased bone, and diseased bone of the seven patients were 8.23, 1.01, and 2.13 mg/L, respectively. The mean ratios of linezolid concentration in nondiseased bones/plasma, diseased bones/plasma and diseased bones/nondiseased bones reached 0.26, 0.49, and 2.27, respectively. The diseased bones/plasma presented a higher mean ratio of linezolid concentration than nondiseased bones/plasma, and the difference was statistically significant (t = 2.55, p = 0.025). Pearson's correlation analysis showed the positively correlation of linezolid concentrations in diseased and nondiseased bones (r = 0.810, p = 0.027). CONCLUSIONS: Linezolid exhibits a higher concentration distribution in diseased bones than in nondiseased bones.

High expression of ARPC1B correlates with immune infiltration and poor outcomes in glioblastoma.

Objective: To investigate the role of ARPC1B in GBM and its prognostic value. Methods: mRNA and protein expression of ARPC1B in GBM was analyzed using the TCGA; TIMER2 and the HPA databases, and protein expression differences were detected using immunohistochemistry. K-M analysis and Cox regression analysis were performed on high and low ARPC1B expression groups in the TCGA database. The relationship between immune cells and ARPC1B expression was explored using the TIMER2 database. GO and KEGG analyses were conducted to investigate the functions of ARPC1B-related genes in GBM. Results: ARPC1B was highly expressed in both GBM tissues and cell lines, and it was demonstrated as a prognostic biomarker for GBM. ARPC1B expression levels showed associations with immune cell populations within the GBM microenvironment. Conclusion: ARPC1B can regulating immune infiltration in the GBM microenvironment, indicating its potential as a novel therapeutic target for GBM.

Accurate Differentiation of Spinal Tuberculosis and Spinal Metastases Using MR-Based Deep Learning Algorithms.

Purpose: To explore the application of deep learning (DL) methods based on T2 sagittal MR images for discriminating between spinal tuberculosis (STB) and spinal metastases (SM). Patients and Methods: A total of 121 patients with histologically confirmed STB and SM across four institutions were retrospectively analyzed. Data from two institutions were used for developing deep learning models and internal validation, while the remaining institutions' data were used for external testing. Utilizing MVITV2, EfficientNet-B3, ResNet101, and ResNet34 as backbone networks, we developed four distinct DL models and evaluated their diagnostic performance based on metrics such as accuracy (ACC), area under the receiver operating characteristic curve (AUC), F1 score, and confusion matrix. Furthermore, the external test images were blindly evaluated by two spine surgeons with different levels of experience. We also used Gradient-Class Activation Maps to visualize the high-dimensional features of different DL models. Results: For the internal validation set, MVITV2 outperformed other models with an accuracy of 98.7%, F1 score of 98.6%, and AUC of 0.98. Other models followed in this order: EfficientNet-B3 (ACC: 96.1%, F1 score: 95.9%, AUC: 0.99), ResNet101 (ACC: 85.5%, F1 score: 84.8%, AUC: 0.90), and ResNet34 (ACC: 81.6%, F1 score: 80.7%, AUC: 0.85). For the external test set, MVITV2 again performed excellently with an accuracy of 91.9%, F1 score of 91.5%, and an AUC of 0.95. EfficientNet-B3 came second (ACC: 85.9, F1 score: 91.5%, AUC: 0.91), followed by ResNet101 (ACC:80.8, F1 score: 80.0%, AUC: 0.87) and ResNet34 (ACC: 78.8, F1 score: 77.9%, AUC: 0.86). Additionally, the diagnostic accuracy of the less experienced spine surgeon was 73.7%, while that of the more experienced surgeon was 88.9%. Conclusion: Deep learning based on T2WI sagittal images can help discriminate between STB and SM, and can achieve a level of diagnostic performance comparable with that produced by experienced spine surgeons.

Phaseolus vulgaris Erythroagglutinin (PHA-E)-Positive Ceruloplasmin Acts as a Potential Biomarker in Pancreatic Cancer Diagnosis.

Pancreatic cancer (PC) remains one of the top 10 causes of cancer-related death in recent years. Approximately 80% of PC patients are diagnosed at the middle or advanced stage and miss the opportunity for surgery. The demand for early diagnostic methods and reliable biomarkers is increasing, although a number of tumor markers such as CA19-9 and CEA have already been utilized in clinics. In this study, we analyzed the alteration of N-glycan of serum glycoproteins by mass spectrometry and lectin blotting. The results showed that bisecting GlcNAc structures of glycoproteins are significantly increased in PC patients' sera. With Phaseolus vulgaris Erythroagglutinin (PHA-E) lectin that specifically recognizes bisecting GlcNAc N-glycans, the serum glycoproteins bearing bisecting GlcNAc in PC patients' sera were pulled down and identified by nano-LC-MS/MS. Among them, ceruloplasmin (Cp) was screened out with a satisfied sensitivity and specificity in identifying PC from acute pancreatitis patients (AUC: 0.757) and normal healthy persons (AUC: 0.972), suggesting a close association between Cp and PC development and diagnosis. To prove that, the Cp expression in tumor tissues of PC patients was examined. The results showed that Cp was significantly upregulated in PC tissues compared to that in adjacent normal tissues. All these results suggested that PHA-E-positive Cp could be a potential PC-specific glycoprotein marker to distinguish PC patients from acute pancreatitis patients and normal persons.

Lamprey immunity protein enables early detection and recurrence monitoring for bladder cancer through recognizing Neu5Gc-modified uromodulin glycoprotein in urine.

The clinical management of bladder cancer (BCa) is hindered by the lack of reliable biomarkers. We aimed to investigate the potential of lamprey immunity protein (LIP), a lectin that specifically binds to multi-antennary sialylated N-glycolylneuraminic acid (Neu5Gc) structures on UMOD glycoproteins in the urine of BCa patients. Primary BCa patients had higher levels of LIP-bound Neu5Gc in urine than healthy participants and patients receiving postoperative treatment did. In addition, lectin chip assay and mass spectrometry were used to analyze the glycan chain structure, which can recognize the UMOD glycoprotein decorated with multi-antennary sialylated Neu5Gc structures. Furthermore, compared with urine samples from healthy patients (N = 2821, T/C = 0.12 ± 0.09) or benign patients (N = 360, T/C = 0.11 ± 0.08), the range of the urine T/C ratio detected using LIP test paper was 1.97 ± 0.32 in patients with bladder cancer (N = 518) with significant difference (P < 0.0001). Our results indicate that LIP may be a tool for early BCa identification, diagnosis, and monitoring. Neu5Gc-modified UMOD glycoproteins in urine and Neu5Gc-modified N-glycochains and sialyltransferases may function as potential markers in clinical trials.

CNTN-1 Upregulation Induced by Low-Dose Cisplatin Promotes Malignant Progression of Lung Adenocarcinoma Cells via Activation of Epithelial-Mesenchymal Transition.

Tumor metastasis and invasion are the main impediments to lung adenocarcinoma successful treatment. Previous studies demonstrate that chemotherapeutic agents can elevate the malignancy of cancer cells other than their therapeutic effects. In this study, the effects of transient low-dose cisplatin treatment on the malignant development of lung adenocarcinoma cells (A549) were detected, and the underlying epigenetic mechanisms were investigated. The findings showed that A549 cells exhibited epithelial-mesenchymal transition (EMT)-like phenotype along with malignant progression under the transient low-dose cisplatin treatment. Meanwhile, low-dose cisplatin was found to induce contactin-1 (CNTN-1) upregulation in A549 cells. Subsequently, we found that further overexpressing CNTN-1 in A549 cells obviously activated the EMT process in vitro and in vivo, and caused malignant development of A549 cells in vitro. Taken together, we conclude that low-dose cisplatin can activate the EMT process and resulting malignant progression through upregulating CNTN-1 in A549 cells. The findings provided new evidence that a low concentration of chemotherapeutic agents could facilitate the malignancy of carcinoma cells via activating the EMT process other than their therapeutic effects.

Gene Expression and Mutational Landscape in a PMEC Patient With Low to Intermediate-High Grade Transition.

Primary pulmonary mucoepidermoid carcinoma (PMEC) is a very rare form of lung carcinoma. Due to the low incidence, little is known about its inherent genetic variation characteristics. The uniform treatment for PMEC has not been determined. In this case, we present a 45-year-old male with stage IA PMEC. The surgical specimens contained changes from low- to intermediate-to-high grade. We performed integrative analysis of whole-exome sequencing (WES-seq) and messenger ribonucleic acid sequencing (RNA-seq) to compare the molecular changes in the different lesions. Molecular testing exhibits the specimens harboring CRTC3-MAML2 fusion. The copy number gain of PDPK1 is only present in high-grade regional specimens. We also explored the level of immune infiltration by CIBERSORT. To our knowledge, this is the first report to describe a case of PMEC in the low- to intermediate-high-grade transition with multiomics analysis.

Glycomics reveal that ST6GAL1-mediated sialylation regulates uterine lumen closure during implantation.

OBJECTIVES: Implantation failure is a major cause of prenatal mortality. The uterine lumen closure contributes to embryo adhesion to the uterus, but its underlying mechanisms are largely unknown. Our previous study has reported that endometrial fold extension can lead to uterine lumen closure in pigs. The objective of this study was to reveal molecular mechanisms of the uterine lumen closure by characterizing the molecular basis of the endometrial fold extension during implantation in pigs. MATERIALS AND METHODS: Uterine and endometrium tissues during implantation were collected in pigs. MALDI-TOF MS was used to characterize the N-glycomic profiles. Histochemistry, siRNA transfection, Western blotting, lectin immumoprecipitation, mass spectrometry and assays of wounding healing and cell aggregation were performed to investigate the molecular basis. RESULTS: We observed that uterine luminal epithelium (LE) migrated collectively during endometrial fold extension. For the first time, we identified a large number of N-glycan compositions from endometrium during implantation using MALDI-TOF MS. Notably, the α2,6-linked sialic acid and ST6GAL1 were highly expressed in uterine LE when the endometrial folds extended greatly. Subsequently, the role of ST6GAL1-mediated 2,6-sialylation in collective epithelial migration was demonstrated. Finally, we found that ST6GAL1-mediated α2,6-sialylation of E-cadherin may participate in collective migration of uterine LE. CONCLUSIONS: The study reveals a mechanism of uterine lumen closure by identifying that ST6GAL1-mediated α2,6-sialylation of cell adhesion molecules contributes to endometrial fold extension through regulating collective migration of uterine LE.

Caveolin-1 knockout mice have altered serum N-glycan profile and sialyltransferase tissue expression.

Caveolin-1 (Cav-1) is a constitutive protein within caveolar membranes. Previous studies from our group and others indicated that Cav-1 could mediate N-glycosylation, α2,6-sialylation, and fucosylation in mouse hepatocarcinoma cells in vitro. However, little is known about the effect of Cav-1 expression on glycosylation modifications in vivo. In this study, the N-glycan profiles in serum from Cav-1-/- mice were investigated by lectin microarray and mass spectrometric analysis approaches. The results showed that levels of multi-antennary branched, α2,6-sialylated, and galactosylated N-glycans increased, while high-mannose typed and fucosylated N-glycans decreased in the serum of Cav-1-/- mice, compared with that of wild-type mice. Furthermore, the real-time quantitative PCR analysis indicated that α2,6-sialyltransferase gene expression decreased significantly in Cav-1-/- mouse organ tissues, but α2,3- and α2,8-sialyltransferase did not. Of them, both mRNA and protein expression levels of the ß-galactoside α2,6-sialyltransferase 1 (ST6Gal-I) had dramatically reduced in Cav-1-/- mice organ tissues, which was consistent with the α2,6-sialyl Gal/GalNAc level reduced significantly in tissues instead of serum from Cav-1-/- mice. These results provide for the first time the N-glycans profile of Cav-1-/- mice serum, which will facilitate understanding the function of Cav-1 from the perspective of glycosylation.

The Comparative Influence of 2 and 4 Weeks Preoperative Antituberculosis Treatment on Spinal Tuberculosis Surgery: A Multicenter, Prospective, Randomized Clinical Trial.

INTRODUCTION: A trade-off between successful surgery and minimizing the operation delay for patients with spinal tuberculosis (TB) is a major consideration to determine the duration of preoperational anti-TB treatment (AAT). In this study, 2 and 4 weeks preoperative AAT durations were compared for their influence on the operation outcomes. METHOD: A multicenter, prospective, randomized trial was conducted in four hospitals in China. New patients with spinal TB were recruited and randomly allocated to two groups (2 or 4 weeks' preoperative treatment) and administered the standardized first-line anti-TB drugs. The symptom changing and indicators reflecting recovery and side effects of the treatment were monitored. Patient was followed up for another 18 months after completion of treatment. RESULTS: In total, 150 eligible patients were enrolled between June 2014 and December 2016, and 13 patients were excluded after the enrollment. The remaining 137 participants were randomly allocated to the 2-week group (n = 68) or the 4-week group (n = 69). These two groups acquired similar surgical outcomes, considering wound healing rate within 3 months after the operation (94.20%, 65/69 vs 89.71%, 61/68; P = 0.333) and bony fusion rate within 6 months (98.46%, 64/65 vs 95.45%, 63/66; P = 0.317). However, the culture positive rate of pus collected during operation in the 4-week group (41.94%) was significantly lower than that of the 2-week group (60.94%, P = 0.033). No reoccurrence of disease was observed in either group during the 18-month follow-up period. CONCLUSION: Patients with spinal TB administered 2 or 4 weeks of preoperative anti-TB treatment acquired similar surgical outcomes. However, patients who underwent the operation sooner suffered 2 weeks less agony from the disease.

Bone penetration of linezolid in osteoarticular tuberculosis patients of China.

BACKGROUND: Linezolid presents strong antimicrobial activity against multidrug-resistant (MDR) pulmonary tuberculosis (TB), but its application in osteoarticular tuberculosis treatment remains understudied. Our objective was to analyze the bone penetration efficiency of linezolid in osteoarticular TB patients. METHODS: Osteoarticular TB patients, treated with 600 mg q 24 h linezolid-containing regimens and undergoing surgery, were prospectively and consecutively enrolled. One dose linezolid was administered before surgery. Blood and bone samples were collected simultaneously during operation, and their linezolid concentrations were then detected using high-performance liquid chromatography-tandem mass spectrometry. Pus samples were subjected to mycobacterial culture and GeneXpert MTB/RIF assay. The minimum inhibition concentrations (MICs) and drug susceptibility testing were performed with the recovered isolates. RESULTS: A total of 36 eligible osteoarticular TB patients were enrolled, including five MDR/rifampicin-resistant cases. All the 12 recovered isolates had MICs ≤0.5 µg/mL for linezolid. Mean concentrations in plasma, collected 100-510 min after the preoperative dosing, were 10.43 ± 4.83 µg/mL (range 3.29-22.26 µg/mL), and median concentrations in bone were 3.93 µg/mL (range 0.61-16.34 µg/mL). The median bone/plasma penetration ratio was 0.42 (range 0.14-0.95 µg/mL). Linezolid concentration in bone had a linear correlation with the drug concentration in plasma (r = 0.7873, p < 0.0001), while plasma concentration could explain 61.98% of the variation of concentration in bone (R2 = 0.6198). Notably, stratification analysis by sampling time demonstrated that samples collected 200-510 min after dosing had very good linear relationships between their bone and plasma concentrations (r = 0.9323). CONCLUSIONS: Linezolid penetrates from blood to bone efficiently, and the penetration further stabilizes ∼3 h after dosing.

SATB2 knockdown decreases hypoxia-induced autophagy and stemness in oral squamous cell carcinoma.

Increasing evidence has suggested that special AT-rich sequence-binding protein 2 (SATB2) may be involved in the progression of numerous types of human cancer; however, the biological function of SATB2 in oral squamous cell carcinoma (OSCC) occurrence and progression remains relatively unknown. The present study aimed to investigate the potential role of SATB2 in the regulation of biological characteristics of OSSC during hypoxia. The expression of SATB2 in SCC9 cells was knocked down using small interfering RNA. Western blotting was used to determine the protein expression levels of SATB2, autophagy-related proteins microtubule-associated protein light chain (LC)3-I/II and Beclin-1, and stemness markers such as Oct-4 (POU class 5 homeobox 1), Sox-2 (SRY-box 2) and Nanog (nanog homeobox). Transmission electron microscopy and monodansylcadaverine staining were used to detect the presence of autophagosomes. Furthermore, the self-renewal capacity of cells was analyzed using colony forming assays; the cell proliferative, migratory and invasive ability were evaluated using CCK-8, wound healing and Transwell assays, respectively; and the cell cycle distribution and rate of apoptosis were detected using flow cytometry. The expression levels of SATB2, autophagy-related proteins and stemness markers were significantly increased in SCC9 cells following hypoxic treatment. Meanwhile, the genetic knockdown of SATB2 inhibited hypoxia-mediated autophagy by decreasing the expression levels of Beclin-1, and preventing the conversion of LC3-I to LC3-II and the accumulation of autophagosomes. The knockdown of SATB2 also inhibited the hypoxia-induced colony-forming ability and the expression of stemness markers. Functionally, it also inhibited the proliferative, migratory and invasive abilities of SCC9 cells, while inducing apoptosis and cell cycle arrest under hypoxia. In conclusion, the present study suggested that SATB2 may function as an oncogene in OSCC cells, and targeting SATB2 may be a potential therapeutic strategy for the treatment of OSCC.

Distribution of Linezolid in Tuberculosis Lesions in Patients with Spinal Multidrug-Resistant Tuberculosis.

Linezolid has strong antimicrobial activity against the multidrug-resistant (MDR) strains of Mycobacterium tuberculosis Little is known about the distribution of linezolid in tuberculosis (TB) lesions in patients with MDR-TB. The aim of this study was to evaluate the distribution of linezolid in TB lesions in patients with spinal MDR-TB. Nine patients with spinal MDR-TB were enrolled prospectively from August 2019 to February 2020. The patients received a linezolid-containing anti-TB treatment regimen and needed surgery for the removal of TB lesions. During the operation, nine blood samples, eight diseased bone tissue samples, seven pus samples, and four granulation tissue samples were collected simultaneously and 2 h after the oral administration of 600 mg of linezolid. Linezolid concentrations in plasma, diseased bone tissue, pus, and granulation tissue samples were subjected to high-performance liquid chromatography-tandem mass spectrometry. At sample collection, the mean concentrations of linezolid in plasma, diseased bone tissue, pus, and granulation tissue samples of the nine patients were 11.14 ± 5.82, 5.94 ± 4.27, 11.09 ± 4.58, and 14.08 ± 10.61 mg/liter, respectively. The mean ratios of linezolid concentration in diseased bone/plasma, pus/plasma, and granulation/plasma were 53.84%, 91.69%, and 103.57%, respectively. The mean ratios of linezolid concentration in pus/plasma and granulation/plasma were higher than those in diseased bone/plasma, and the difference was statistically significant (t = -2.810, P = 0.015; t = -4.901, P = 0.001). In conclusion, linezolid had different concentration distributions in different types of TB-infected tissues in patients with spinal MDR-TB.

Role of fucosyltransferase IV in the migration and invasion of human melanoma cells.

Malignant melanoma is one of the most aggressive human tumor types, mainly due to its high invasion capability, metastatic properties, and the absence of effective treatments. Glycosylation serves a pivotal role in the migration and invasion of melanoma. However, differences in glycosylation between high and low metastatic melanoma cells and how these regulate migration and invasion by altering the expression of fucosyltransferases (FUTs) remain unclear. In the present study, matrix-assisted laser desorption/ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS) analysis revealed that the composition profiling of fucosylated N-glycans differed between high metastatic C8161 and low metastatic A375P cells. Further analysis revealed that FUT4 expression was significantly increased in C8161 cells. Melanoma tissue arrays further demonstrated that FUT4 was overexpressed in metastatic samples. Altered FUT4 expression was accompanied by a change in the migration and invasion capacity of the cells. In addition, the migration and invasion potential of melanoma cells were decreased in C8161 and increased in A375P cells upon altering FUT4 expression levels by small interfering RNA or complementary DNA transfection. Furthermore, regulating FUT4 expression markedly modulated the activity of the phosphoinositide-3-kinase/Akt (PI3K/Akt) signaling pathway, which affected melanoma cell migration and invasion. In conclusion, FUT4 is a novel biomarker and regulator of the migration and invasion of melanoma cells and may serve as a therapeutic target for melanoma.

Functional analysis of long-chain non-coding RNA in oral squamous cell carcinoma.

BACKGROUND: This study aimed to investigate the expression profile of long-chain non-coding RNA (lncRNA) in oral squamous cell carcinoma (OSCC) and to explore the biological functions of differentially expressed lncRNA in the cancer tissues as compared with adjacent normal tissues, and the differentially expressed lncRNAs related to OSCC were screened. METHODS: High-throughput lncRNA microarray assay was used to detect the expression of lncRNA and mRNA in the OSCC tissues and adjacent normal tissues from five patients. The expression profiles of the lncRNA and mRNA in the cancer tissues and adjacent normal tissues were analyzed and the differentially expressed lncRNA and mRNAs were identified. The differentially expressed mRNA was analyzed with GO, Pathway and disease annotation enrichment database, and the mRNAs related to the tumor and the lncRNA-mRNA co-expression network were employed to screen the key lncRNA related to the occurrence and development of OSCC. RESULTS: A total of 3,022 differentially expressed lncRNAs and 4,364 differentially expressed mRNAs were identified in the OSCC tissues as compared with adjacent normal tissues. A further analysis revealed 130 major differentially expressed mRNAs related to the tumor. When the correlation was >0.99 or <-0.99 and P value was <0.05, there were 73 differentially expressed mRNA in case of mRNA /lncRNA co-expression. The intersection of two gene symbols resulted in the nine lncRNAs closely related to the OSCC, in which five showed up-regulation and six had down-regulation. Based on the co-expression of the lncRNAs and mRNAs (correlation 40.99 or correlation -0.99 and P value <0.05), there were differentially expressed mRNAs with co-expression with lncRNA. CONCLUSIONS: The differentially expressed lncRNAs identified in this study are related to the occurrence and development of OSCC. This may provide new therapeutic targets and biomarkers for OSCC and is also helpful for further investigation of pathogenesis of OSCC.

ST3Gal IV Mediates the Growth and Proliferation of Cervical Cancer Cells In Vitro and In Vivo Via the Notch/p21/CDKs Pathway.

ST3Gal IV is one of the principal sialyltransferases responsible for the biosynthesis of α2, 3-sialic acid to the termini N-glycans or O-glycans of glycoproteins and glycolipids. It has been reported that ST3Gal IV expression is associated with gastric carcinoma, pancreatic adenocarcinoma and breast cancer. While the expression and functions of ST3Gal IV in cervical cancer are still poorly understood. In this study, we found that ST3Gal IV was downregulated in human cervical cancer tissues compared to normal cervix tissues, and ST3Gal IV expression was negatively associated with the pathological grade of cervical cancer. ST3Gal IV upregulation inhibited the growth and proliferation of cervical cancer HeLa and SiHa cells in vitro and in vivo. Furthermore, ST3Gal IV overexpression enhanced the expression of several Notch pathway components such as Jagged1, Notch1, Hes1 and Hey1, while cell cycle protein expression like Cyclin D1, Cyclin E1, CDK2 and CDK4 were decreased. These results indicate that expression of ST3Gal IV is reduced in cervical cancer and plays a negative role in cell proliferation via Notch/p21/CDKs signaling pathway. Thus, sialyltransferase ST3Gal IV might be a target for the diagnosis and therapy of cervical cancer.

Dynasore potentiates c-Met inhibitors against hepatocellular carcinoma through destabilizing c-Met.

c-Met receptor is frequently overexpressed in hepatocellular carcinoma and thus considered as an attractive target for pharmacological intervention with small molecule tyrosine kinase inhibitors. Albeit with the development of multiple c-Met inhibitors, none reached clinical application in the treatment of hepatoma so far. To improve the efficacy of c-Met inhibitors towards hepatocellular carcinoma, we investigated the combined effects of the dynamin inhibitor dynasore with several c-Met inhibitors, including tivantinib, PHA-665752, and JNJ-38877605. We provide several lines of evidence that dynasore enhanced the inhibitory effects of these inhibitors on hepatoma cell proliferation and migration, accompanied with increased cell cycle arrest and apoptosis. Mechanically, the combinatorial treatments decreased c-Met levels and hence markedly disrupted downstream signaling, as revealed by the dramatically declined phosphorylation of AKT and MEK. Taken together, our findings demonstrate that the candidate agent dynasore potentiated the inhibitory effects of c-Met inhibitors against hepatoma cells and will shed light on the development of novel therapeutic strategies to target c-Met in the clinical management of hepatocellular carcinoma patients.

Endocytic degradation of ErbB2 mediates the effectiveness of neratinib in the suppression of ErbB2-positive ovarian cancer.

The tyrosine kinase receptor ErbB2 is frequently found to be overexpressed in multiple cancer types. Targeted therapeutic approaches against ErbB2 have shown promising results and received FDA approvals in the treatment of breast cancer. However, this approach has not been granted in ovarian cancers till now. In order to assess the validity of ErbB2-targeted therapy in ovarian cancer, we investigated the effectiveness of two FDA-approved tyrosine kinase inhibitors of ErbB2, lapatinib and neratinib, on the growth of ovarian cancers. We observed that both lapatinib and neratinib displayed inhibitory effects towards the proliferation and migration of ErbB2-positive ovarian cancer cells in vitro, with neratinib showing stronger suppression in general. Neratinib treatment led to the reduction of ErbB2 protein levels, with concomitant attenuation of the phosphorylation of AKT, MEK, and ERK1/2. Immunofluorescence assays revealed that neratinib induced the internalization and lysosomal degradation of ErbB2, which was accompanied by its hyperubiquitylation. Lapatinib and neratinib also repressed the in vivo growth of SKOV3 cells, and neratinib downregulated ErbB2 levels in xenograft tumors to cause potent inhibition. Therefore, the ubiquitylation-mediated endocytic degradation of ErbB2 incurred by neratinib treatment conferred potent inhibition of ovarian cancer growth. Clinical investigations of neratinib in ErbB2-positive ovarian cancer are warranted.