Hetrombopag for the management of chemotherapy-induced thrombocytopenia in patients with advanced solid tumors: a multicenter, randomized, double-blind, placebo-controlled, phase II study.

Background: Chemotherapy-induced thrombocytopenia (CIT) increases the risk of bleeding, necessitates chemotherapy dose reductions and delays, and negatively impacts prognosis. Objectives: This study aimed to evaluate the efficacy and safety of hetrombopag for the management of CIT in patients with advanced solid tumors. Design: A multicenter, randomized, double-blind, placebo-controlled, phase II study. Methods: Patients with advanced solid tumors who experienced a chemotherapy delay of ⩾7 days due to thrombocytopenia (platelet count <75 × 109/L) were randomly assigned (1:1) to receive oral hetrombopag at an initial dose of 7.5 mg once daily or a matching placebo. The primary endpoint was the proportion of treatment responders, defined as patients resuming chemotherapy within 14 days (platelet count ⩾100 × 109/L) and not requiring a chemotherapy dose reduction of ⩾15% or a delay of ⩾4 days or rescue therapy for two consecutive cycles. Results: Between 9 October 2021 and 5 May 2022, 60 patients were randomized, with 59 receiving ⩾1 dose of assigned treatment (hetrombopag/placebo arm, n = 28/31). The proportion of treatment responders was significantly higher in the hetrombopag arm than in the placebo arm [60.7% (17/28) versus 12.9% (4/31); difference of proportion: 47.6% (95% confidence interval (CI): 26.0-69.3); odds ratio = 10.44 (95% CI: 2.82-38.65); p value (nominal) based on the Cochran-Mantel-Haenszel: <0.001)]. During the double-blind treatment period, grade 3 or higher adverse events (AEs) occurred in 35.7% (10/28) of patients with hetrombopag and 38.7% (12/31) of patients on placebo. The most common grade 3 or higher AEs were decreased neutrophil count [35.7% (10/28) versus 35.5% (11/31)] and decreased white blood cell count [17.9% (5/28) versus 19.4% (6/31)]. Serious AEs were reported in 3.6% (1/28) of patients with hetrombopag and 9.7% (3/31) of patients with placebo. Conclusion: Hetrombopag is an effective and well-tolerated alternative for managing CIT in patients with solid tumors. Trial registration: ClinicalTrials.gov identifier: NCT03976882.

A new tandem repeat-enriched lncRNA XLOC_008672 promotes gastric carcinogenesis by regulating G3BP1 expression.

Aberrant expression of forkhead box transcription factor 1 (FOXM1) plays critical roles in a variety of human malignancies and predicts poor prognosis. However, little is known about the crosstalk between FOXM1 and long noncoding RNAs (lncRNAs) in tumorigenesis. The present study identifies a previously uncharacterized lncRNA XLOC_008672 in gastric cancer (GC), which is regulated by FOXM1 and possesses multiple copies of tandem repetitive sequences. LncRNA microarrays are used to screen differentially expressed lncRNAs in FOXM1 knockdown GC cells, and then the highest fold downregulation lncRNA XLOC_008672 is screened out. Sequence analysis reveals that the new lncRNA contains 62 copies of 37-bp tandem repeats. It is transcriptionally activated by FOXM1 and functions as a downstream effector of FOXM1 in GC cells through in vitro and in vivo functional assays. Elevated expression of XLOC_008672 is found in GC tissues and indicates worse prognosis. Mechanistically, XLOC_008672 can bind to small nuclear ribonucleoprotein polypeptide A (SNRPA), thereby enhancing mRNA stability of Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) and, consequently, facilitating GC cell proliferation and migration. Our study discovers a new uncharacterized lncRNA XLOC_008672 involved in GC carcinogenesis and progression. Targeting FOXM1/XLOC_008672/SNRPA/G3BP1 signaling axis might be a promising therapeutic strategy for GC.

JAK3/STAT5 signaling-triggered upregulation of PIK3CD contributes to gastric carcinoma development.

Gastric cancer (GC) is one of the most common solid cancers with high incidence and mortality worldwide. Chronic gastritis and consequent inflammatory microenvironment is known as a major cause leading to gastric carcinogenesis. Here we report that PIK3CD that encodes p110δ, a catalytic subunit of the class IA PI3Ks, is overexpressed and tumorigenic in GC and associated with tumor inflammatory microenvironment. By investigating the data from TCGA database and our immunohistochemical staining and quantitative real-time PCR results from clinical samples, we found PIK3CD exhibits higher expression level in GC tissues compared with adjacent non-tumorous stomach tissues. Genetic silencing of PIK3CD in GC cells retards proliferation and migration in vitro and tumorigenicity and metastasis in vivo. In contrast, enhanced expression of PIK3CD promotes these phenotypes in vitro. Furthermore, pharmacological inhibition of PIK3CD could reduce GC cell viability and colony formation capacities. More importantly, we reveal a relevant mechanism that PIK3CD, but not PIK3CA and PIK3CB, is transcriptionally regulated by the pro-inflammatory IL2/JAK3/STAT5 axis and tumor-infiltrating immune cells such as lymphocytes. These observations may setup a new crosstalk between tumor inflammatory microenvironment, IL2/JAK3/STAT5 signaling and PI3K/AKT signaling. Targeting PIK3CD may be a promising therapy strategy for GC.

Lumbar Endoscopic Unilateral Laminotomy With Bilateral Decompression Surgery in Severe Lumbar Stenosis Under Electrophysiological Monitoring-Focused on Full-Visualized Trephine/Osteotome.

OBJECTIVE: Although endoscopic drill has the advantages in manipulation and hemostasis, whose low efficiency and blurred vision reduce the efficacy of lumbar endoscopic unilateral laminotomy with bilateral decompression (LE-ULBD). The present study was designed to evaluate the safety and efficacy of full-visualized trephine/osteotome in the LE-ULBD surgery for severe lumbar stenosis. METHODS: Fifty-seven severe lumbar stenosis patients who underwent LE-ULBD between January 2020 to January 2023 were enrolled, who were divided into drill and visualized trephine groups. The medical records including demographics, operative duration, intraoperative electrophysiological findings, postoperative hospital stay or hospital stay, postoperative outcomes and complications were retrospectively reviewed and analyzed. RESULTS: A total of 57 patients included 15 in drill and 42 in trephine group were enrolled in the study. There was significant difference in the pre- and postoperative visual analogue scale and Oswestry Disability Index scores in both groups (p < 0.05). The mean operative duration in the trephine group (101.05 ± 12.18 minutes) was shorter than that in the drill group (134.67 ± 9.68 minutes) (p < 0.05). There was no statistical difference between the 2 groups in electrophysiological monitoring, posthospital stays, postoperative outcomes and complications. Abnormal free-electromyography (EMG) were recorded in 2 (13.3%) and 5 patients (11.9%) in the drill and trephine group. Intraoperative somatosensory evoked potential changes occurred in 3 (20%) and 3 patients (7.1%) in the drill and trephine group and all patients recovered immediately when surgery ended. No serious complications and recurrence occurred in all the patients. CONCLUSION: Full-visualized trephine/osteotome has been approved to be convenient, safe and efficient in our study, which combined with translaminar inside-out technique and EMG monitoring especially free-EMG may offer a new choice in LE-ULBD surgery for lumbar stenosis patients.

Insulin Resistance Triggers Atherosclerosis: Caveolin 1 Cooperates with PKCzeta to Block Insulin Signaling in Vascular Endothelial Cells.

OBJECTIVE: To date, therapies for endothelial dysfunction have primarily focused on ameliorating identified atherosclerosis (AS) risk factors rather than explicitly addressing endothelium-based mechanism. An in-depth exploration of the pathological mechanisms of endothelial injury was performed herein. METHODS: Aortic caveolin 1 (Cav1) knockdown was achieved in mice using lentivirus, and AS was induced using a high-fat diet. Mouse body weight, blood glucose, insulin, lipid parameters, aortic plaque, endothelial injury, vascular nitric oxide synthase (eNOS), injury marker, and oxidative stress were examined. The effect of Cav1 knockdown on the content of PKCzeta and PI3K/Akt/eNOS pathway-related protein levels, as well as PKCzeta binding to Akt, was studied. ZIP, a PKCzeta inhibitor, was utilized to treat HUVECs in vitro, and the effect of ZIP on cell viability, inflammatory response, oxidative stress, and Akt activation was evaluated. RESULTS: Cav1 knockdown had no significant effect on body weight or blood glucose in mice over an 8-week period, whereas drastically reduced insulin, lipid parameters, endothelial damage, E-selectin, and oxidative stress and elevated eNOS levels. Moreover, Cav1 knockdown triggered decreased PKCzeta enrichment and the activation of the PI3K/Akt/eNOS pathway. PKCzeta has a positive effect on cells without being coupled by Cav1, and ZIP had no marked influence on PKCzeta-Akt binding following Cav1/PKCzeta coupling. CONCLUSION: Cav1/PKCzeta coupling antagonizes the activation of PI3K on Akt, leading to eNOS dysfunction, insulin resistance, and endothelial cell damage.

YTHDF2 exerts tumor-suppressor roles in gastric cancer via up-regulating PPP2CA independently of m6A modification.

BACKGROUND: YTHDF2 is one of important readers of N6-methyladenosine (m6A) modification on RNA. Growing evidence implicates that YTHDF2 takes an indispensable part in the regulation of tumorigenesis and metastasis in different cancers, but its biological functions and underlying mechanisms remain elusive in gastric cancer (GC). AIM: To investigate the clinical relevance and biological function of YTHDF2 in GC. RESULTS: Compared with matched normal stomach tissues, YTHDF2 expression was markedly decreased in gastric cancer tissues. The expression level of YTHDF2 was inversely associated with gastric cancer patients' tumor size, AJCC classification and prognosis. Functionally, YTHDF2 reduction facilitated gastric cancer cell growth and migration in vitro and in vivo, whereas YTHDF2 overexpression exhibited opposite phenotypes. Mechanistically, YTHDF2 enhanced expression of PPP2CA, the catalytic subunit of PP2A (Protein phosphatase 2A), in an m6A-independent manner, and silencing of PPP2CA antagonized the anti-tumor effects caused by overexpression of YTHDF2 in GC cells. CONCLUSION: These findings demonstrate that YTHDF2 is down-regulated in GC and its down-regulation promotes GC progression via a possible mechanism involving PPP2CA expression, suggesting that YTHDF2 may be a hopeful biomarker for diagnosis and an unrevealed treatment target for GC.

A Comparative Review of the Outcome Following MVD and PBC in Patients with Trigeminal Neuralgia.

BACKGROUND: This study aims to systematically review the treatment outcomes of percutaneous balloon compression (PBC) and microvascular decompression (MVD) in patients with trigeminal neuralgia. METHODS: A systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was performed using PubMed, Embase, and Cochrane Central Registry of Controlled Trials databases. Only those articles with more than 5 years' follow-up length were included in this investigation. To uniformly assess the postoperative outcome, we defined pain relief as totally pain free, while the postoperative hospitalization and last follow-up period were defined as early and long term, respectively. The facial numbness was quantified with Barrow Neurological Institute Pain Intensity Score (BNI). RESULTS: After database searching and screening, 7,797 cases were finally included according to the criteria. The early pain relief rates were 94.1% (1,551/1,649) and 89.9% (4,962/5,482) following PBC and MVD (odds ratio [OR] = 0.603; p < 0.05), while the long-term rates were 58.1% (921/1,566) and 74.9% (4,549/6,074; OR = 2.089; p < 0.05), respectively. Although a significant higher facial numbness occurred in the PBC group in the early stage, it was mostly diminished 5 years later compared with the MVD group. At long-term follow-up, hypoacusis and facial palsy occurred more often in the MVD group (p < 0.05). CONCLUSIONS: Both MVD and PBC provide a satisfactory outcome for the patients in the long term. As a simple, safe, and reliable technique, PBC should be considered as a viable alternative.

Systematic characterization of Puerariae Flos metabolites in vivo and assessment of its protective mechanisms against alcoholic liver injury in a rat model.

Puerariae Flos, a representative homology plant of medicine and food for alcoholism, has a long history of clinical experience and remarkable curative effect in the treatment of alcoholic liver disease (ALD). However, its effective forms and hepatoprotective mechanisms remain unknown. In the present study, a strategy based on UPLC-QTOF MS combined with mass defect filtering technique was established for comprehensive mapping of the metabolic profile of PF in rat plasma, urine, bile, and feces after oral administration. Furthermore, the absorbed constituents into plasma and bile with a relatively high level were subjected to the network analysis, functional enrichment analysis, and molecular docking to clarify the potential mechanism. Finally, the therapeutic effect of PF on ALD and predicted mechanisms were further evaluated using a rat model of alcohol-induced liver injury and Western blot analysis. In total, 25 prototype components and 82 metabolites, including 93 flavonoids, 13 saponins, and one phenolic acid, were identified or tentatively characterized in vivo. In addition, glucuronidation, sulfation, methylation, hydroxylation, and reduction were observed as the major metabolic pathways of PF. The constructed compound-target-pathway network revealed that 11 absorbed constituents associated with the 16 relevant targets could be responsible for the protective activity of PF against ALD by regulating nine pathways attributable to glycolysis/gluconeogenesis, amino acid metabolism, and lipid regulation as well as inflammation and immune regulation. In addition, four active ingredients (6″-O-xylosyltectoridin, genistein-7-glucuronide-4'-sulfate, tectoridin-4'-sulfate, and 6″-O-xylosyltectoridin-4'-sulfate) as well as two target genes (MAO-A and PPAR-α) were screened and validated to play a crucial role with a good molecular docking score. The present results not only increase the understanding on the effective form and molecular mechanisms of PF-mediated protection against ALD but also promote better application of PF as a supplement food and herbal medicine for the treatment of ALD.

Microvascular decompression for pediatric-onset hemifacial spasm: case series and literature review.

OBJECTIVES: Pediatric hemifacial spasm has been rarely reported in the literature, which contains only 44 cases. Although microvascular decompression (MVD) has been widely regarded as effective therapy for hemifacial spasm, the etiology and surgical treatment of pediatric patients are seldom reported. We report our experience with MVD for pediatric hemifacial spasm patients and review the literature with emphasis on the difference from adults. METHODS: This retrospective report included 4 pediatric HFS patients, who underwent MVD in our department between January 2014 and May 2021 and then reviewed all the pediatric hemifacial spasm literature on "pubmed" with emphasis on the clinical data. RESULTS: Our series included 1 boy and 3 girls with an average age of 15.6 ± 3.2 years old; their onset ages were from 7 to 16 years old (11.6 ± 4.3). Three patients achieved immediate excellent outcomes and 1 achieved poor immediately and became good 6 months later. During the operation, all the 4 patients were found compressed by anterior inferior cerebellar artery (AICA). The incidence of pediatric atypical hemifacial spasm patients is 12.5% among the 48 reported cases, which is much higher than adults. Among all the reported 48 cases including ours, the singular artery neurovascular conflictions account for 27/48(56%), the singular vein and combined artery/vein conflictions in 12/48(25%) and the cisternal conflictions in 5/48(10.4%) patients. CONCLUSIONS: The etiology of pediatric hemifacial spasm is still neurovascular conflict, of which combined artery/vein and singular venous compression patterns have a higher proportion, which might explain higher incidence of pediatric atypical hemifacial spasm and less favorable postoperative outcome. Sufficient arachnoid release, full exploration and decompression along the facial nerve are necessary, which would help to increase the excellent postoperative cure rate among pediatric patients.

Microvascular decompression for pediatric onset trigeminal neuralgia: patterns and variation.

OBJECTIVES: Pediatric trigeminal neuralgia has been rarely reported in the literature, which were only 28 cases. Although microvascular decompression (MVD) has been widely accepted as effective therapy for trigeminal neuralgia, the etiology and surgical treatment of pediatric ones are seldom addressed. We report our experience with MVD for pediatric trigeminal neuralgia patients with emphasis on the vascular conflict patterns and surgical skills. METHODS: This retrospective report included 11 pediatric TN patients, who underwent MVD and were followed for 3-86 months. The data were retrospectively analyzed with emphasis on the clinical features. RESULTS: This series included 4 boys and 7 girls with average age of 13 ± 3.4 years old, their onset age were from 7 to 18 years old. The singular vein and combined artery/vein conflictions account for 7/11. 9 (81.8%) patients achieved immediate excellent outcomes. One recurrence was observed after 5 months and refused the second surgery. CONCLUSIONS: The etiology of pediatric onset trigeminal neuralgia is still vascular conflict, whose patterns are different from adults, of which combined artery/vein and singular venous compression patterns have a much more higher proportion. Because of the smaller operative space and fragile-thin venous wall with adhesion to other structures, it is much more difficult to decompress the trigeminal nerve among pediatric patients. Sufficient arachnoid release, full exploration, and decompression along the trigeminal nerve were necessary, which will increase the excellent rate among pediatric patients.

Treatment of Trigeminal Neuralgia with "Microvascular Decompression Plus" Technique.

Objective Although microvascular decompression (MVD) has been widely accepted as an effective treatment of trigeminal neuralgia (TN), some patients have not been cured. To improve the postoperative outcome, the surgical procedure should be further refined. Design This is a retrospective study. Setting Present study conducted at a cranial nerve disorder center. Participants Clinical data were collected from patients with TN who had undergone surgery in our center, including 685 who had undergone traditional MVD and 576 who had undergone the "MVD plus" procedure, in which any vessel attached to the trigeminal nerve was freed away ("nerve-combing"), which was followed by intraoperative neurolysis. Main Outcome Measures Postoperative outcomes and complications in the two groups were compared. Results Among patients who underwent traditional MVD, the rates of immediate relief and 1-year relief were 89.9 and 86.9%, respectively; among patients who underwent MVD plus group, these rates were 95.1 and 94.6%, respectively ( p = 0.05). Patients who underwent MVD plus initially exhibited a higher rate of facial numbness ( p < 0.05), but this finding decreased over time and reached the same level as that in the traditional MVD group within 3 months ( p > 0.05). Conclusion Sufficient MVD with nerve-combing for the treatment of TN may produce a high rate of cure with less recurrence.

Anti-Atherosclerotic Effect of Afrocyclamin A against Vascular Smooth Muscle Cells Is Mediated via p38 MAPK Signaling Pathway.

This article published in Cell J (Yakhteh), Vol 23, No 2, 2021, on pages 191-198, corresponding author and corresponding address were changed based on authors' request. The authors would like to apologies for any inconvenience caused.

Anti-Atherosclerotic Effect of Afrocyclamin A against Vascular Smooth Muscle Cells Is Mediated via p38 MAPK Signaling Pathway.

OBJECTIVE: Research suggests that fine particulate matter (PM2.5) contributes to the expansion and development of atherosclerosis. Infiltration and proliferation of vascular smooth muscle cells (VSMCs) from the blood vessel media into the intima, is an important step in the atherosclerosis pathophysiology. Afrocyclamin A, is an oleanane-type triterpene saponin, isolated from Androsace umbellate, which is commonly used in Chinese herbal medicine. In the study, we examined the effect of Afrocyclamin A on PM2.5-induced VSMCs proliferation and scrutinized possible mechanisms of action. MATERIALS AND METHODS: In the experimental study, counting Kit-8 (CCK-8) assay was used for estimation of VSMCs viability. BrdU immunofluorescence was used for estimation of VSMCs proliferation. The levels of antioxidant parameters such as malonaldehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH); proinflammatory cytokines such as interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α), nitric oxide (NO), endothelin-1 (ET-1), and vascular cell adhesion molecule-1 (VCAM-1), were estimated. The expression of proliferating cell nuclear antigen (PCNA) and phospho-p38 MAPK (p-p38 MAPK) was assessed. RESULTS: Compared to PM2.5-treated cells, in addition to reducing PM2.5-induced VSMCs proliferation, Afrocyclamin A reduced the expression of PCNA and p-p38 MAPK, down-regulated the level of TNF-α, IL-1ß, IL-6, VCAM-1, MDA and ET-1, and up-regulated SOD, GSH and NO level. Furthermore, the anti-proliferative effect of Afrocyclamin A was considerably increased following co-incubation of Afrocyclamin A with SB203580 (p38 MAPK inhibitor) in comparison with Afrocyclamin A-treated cells. CONCLUSION: Based on the results, we can conclude that Afrocyclamin A might reduce PM2.5-induced VSMCs proliferation via reduction of p38 MAPK signaling pathway.

FOXM1-induced miR-552 expression contributes to pancreatic cancer progression by targeting multiple tumor suppressor genes.

Dysregulation of microRNAs (miRNAs) plays important roles during carcinogenesis. Forkhead box M1 (FOXM1), a well-known oncogenic transcription factor, has been implicated in the progression of multiple cancer types. To find out FOXM1-induced abnormal miRNAs in pancreatic cancer, we analyzed TCGA database and figured out miR-552 as the most relevant miRNA with FOXM1. Molecular experimental results demonstrated that FOXM1 transcriptionally activated miR-552 expression by directly binding to the promoter region of miR-552. In a pancreatic cancer tissue microarray, miR-552 expression was positively correlated with FOXM1 and high expression of miR-552 could predict poor patient outcome. Functionally, overexpression of miR-552 promoted pancreatic cancer cell migration and inhibition of miR-552 attenuated this phenotype. The inhibitory effect on cell migration caused by FOXM1 knockdown could be restored by exogenous expression of miR-552. By informatics analysis, we identified three tumor suppressor genes: DACH1, PCDH10 and SMAD4, all of which were negatively associated with FOXM1 and validated as functionally relevant targets of miR-552. Taken together, our findings provide a new FOXM1-miR-552-DACH1/PCDH10/SMAD4 axis to regulate pancreatic cancer cell progression and new opportunities for therapeutic intervention against this disease.

IL-6 contributes to Nav1.3 up-regulation in trigeminal nerve following chronic constriction injury.

Background: To verify the hypothesis that the nature of trigeminal neuralgia (TN) is an ectopic impulse induced by sodium channel modulated by cytokines, we conducted an animal study using the infraorbital nerve chronic constriction injury (CCI) model in rats.Method: The expression of Nav1.3 or IL-6 in the infraorbital nerve (ION) and trigeminal ganglion (TG) were detected by western blot and immunocytochemistry after administration of antisense oligodeoxynucleotide sequence (AS), IL-6 or Anti-IL-6.Results: With intrathecal administration of AS or mismatch oligodeoxynucleotide sequence (MM) in the CCI rats, the Nav1.3-IR in ION and TG accounted for 2.2 ± 0.51% and 8.5 ± 3.1% in AS+CCI group vs. 6.9 ± 1.3% and 38.7 ± 4.8% in MM+CCI group (p < 0.05), respectively. While with local administration of IL-6 in those with sham operation, it accounted for 7.4 ± 2.1% and 45.5 ± 3.4% in IL-6+ sham group vs. 1.9 ± 0.67% and 8.1 ± 1.3% in vehicle+sham group (p < 0.05); with local administration of anti-IL-6 in CCI rats, 4.5 ± 0.78% and 32.1 ± 9.6% in Anti-IL-6+ CCI group vs 8.9 ± 2.1% and 61.4 ± 11.2% in vehicle+CCI group (p < 0.05).Discussion: We believe that the emergence of Nav1.3 from the compressed trigeminal nerve might be an important structural basis for the development of the ectopic excitability on the axon and IL-6 may play a role of necessary precondition.

USP32 promotes tumorigenesis and chemoresistance in gastric carcinoma via upregulation of SMAD2.

USP32, a member of the ubiquitin-specific proteases family, has been implicated in the development of breast cancer and small lung cancer. However, its biological functions and clinical significance in gastric cancer (GC) remain unclear. In the present study, we reported that knockdown or depletion of USP32 significantly inhibited GC cell proliferation and migration in vitro and in vivo, indicating that USP32 functions as an oncogene in GC. Importantly, results from immunohistochemical staining in a tissue microarray revealed that USP32 was upregulated in GC tissues compared with paracancerous tissues. Further analyses showed that high expression of USP32 was closely related with high T-staging and poor outcomes of GC patients. Mechanistically, USP32 silencing caused a decrease in the expression of SMAD2, which resulted in the inhibitory effects of GC cells on growth, motility, and chemoresistance to cisplatin. Therefore, our findings strongly suggest the involvement of USP32 in GC progression and provide a potential target for future therapy of GC.

Is it necessary to approach the compressed vertebra bilaterally during the process of PKP?

OBJECTIVE: To assess the clinical and radiological outcomes following unilateral or bilateral approach in percutaneous kyphoplasty (PKP) for treatment of osteoporotic vertebral compression fractures (OVCF). DESIGN: Prospective comparative study. SETTING: University affiliated hospital. PARICIPANTS: From 2012 through 2016, those MRI-diagnosed single-level lumbar OVCF patients. INTERVENTIONS: They were randomly assigned for treatment with unilateral or bilateral PKP. OUTCOME MEASURES: We assessed the patient' health status with the Oswestry Disability Index (ODI) questionnaire. Anteroposterior and lateral standing radiographs were obtained to measure the vertebral height and kyphotic angle of the vertebral body in all patients. RESULTS: Eighty-five patients were finally enrolled in this investigation, including 42 in the unilateral and 43 in the bilateral group. The operation time, PMMA volume, radiation dose was 25.6 ± 4.2 minutes, 6.2 ± 3.5 ml and 0.88 ± 0.28 mSv in the unilateral group, while 36.6 ± 8.7 minutes, 8.5 ± 2.2 ml and 1.89 ± 1.05 mSv in the bilateral group, respectively (P < 0.05). The postoperative VAS and ODI were 2.7 ± 1.2 and 19.8 ± 6.4 compared to preoperative 8.7 ± 1.6 and 35.2 ± 4.3 in unilateral group, while 2.6 ± 1.3 and 19.7 ± 2.6 compared to preoperative 8.5 ± 1.3 and 36.7 ± 3.6 in bilateral group, respectively (P > 0.05). CONCLUSION: Both bilateral and unilateral PKP are relatively safe and provide effective treatment for patients with painful OVCF. However, unilateral PKP need less radiation dose, operation time and PMMA volume.

KLF4-Mediated CDH3 Upregulation Suppresses Human Hepatoma Cell Growth and Migration via GSK-3ß Signaling.

P-cadherin (CDH3), a classical cell adhesion molecule involved in tissue integrity and cell localization, has been implicated in many types of cancer. However, little is known about its function and regulatory mechanism in hepatocellular carcinoma (HCC). Here we report that CDH3 was positively regulated by kr¨uppel-like transcription factor 4 (KLF4), which is a crucial tumor suppressor gene in HCC, at mRNA level in HCC cell lines. Luciferase reporter assay and chromatin immunoprecipitation assay indicated that KLF4 directly bound to CDH3 promoter and transcriptionally activated CDH3 expression. Consistently, CDH3 expression was closely related with KLF4 expression in patients' samples and both proteins exhibited a downregulated expression pattern in cancer samples. Functionally, enforced CDH3 expression suppressed and silenced CDH3 expression promoted HCC cell growth and migration in vitro. Mechanistically, we observed that GSK-3ß was regulated by CDH3 and may function as a possible downstream effector of CDH3. Knockdown of GSK-3ß showed a similar phenotype with CDH3 silencing. Taken together, these findings establish the KLF4/CDH3/GSK-3ß axis as an important regulatory mechanism in HCC development.

B-cell lymphoma-2-associated transcription factor 1 is overexpressed and contributes to sorafenib resistance in hepatocellular carcinoma.

AIM: B-cell lymphoma-2-associated transcription factor 1 (BCLAF1) is involved in various biological processes including tumorigenesis, but its function and expression in hepatocellular carcinoma (HCC) is little known, and its clinical value in HCC has not yet been defined. METHODS: The protein level of BCLAF1 in HCC specimens and paired adjacent normal tissues was examined by immunohistochemical staining. The effects of BCLAF1 on autophagy in HCC cells were detected by confocal microscopy, transmission electron microscopy, and western blot analysis. Cell proliferation and tumorigenicity assays were carried out in vitro and in vivo. Flow cytometry assay was used to determine the apoptosis level of HCC cells. The correlation of BCLAF1 and sorafenib resistance in HCC was analyzed by the Kaplan-Meier survival method. RESULTS: High expression of BCLAF1 was found in HCC tissues compared with adjacent normal tissues, and higher BCLAF1 expression was correlated with higher tumor-node-metastasis stage, worse differentiation, and worse prognosis of HCC patients. BCLAF1 could induce autophagy in HCC cells in response to starvation and BCLAF1-mediated autophagy could enhance cell proliferation and impede cell apoptosis under stress conditions. Animal experiments indicated that BCLAF1 promoted tumorigenicity of HCC cells in vivo. More importantly, high expression of BCLAF1 might contribute to sorafenib resistance in HCC patients. CONCLUSIONS: BCLAF1 is a potential oncogene in HCC by inducing autophagy to maintain tumor cell growth in response to stress conditions, and it could serve as a potential biomarker for predicting the prognosis of HCC patients and screening patients who are suitable for sorafenib therapy.

SSeCKS/Gravin/AKAP12 Inhibits PKCζ-Mediated Reduction of ERK5 Transactivation to Prevent Endotoxin-Induced Vascular dysfunction.

SSeCKS/Gravin/AKAP12 is a protein kinase C (PKC) substrate that inhibits the activity of PKC through binding with it. SSeCKS is expressed in vascular endothelial cells (ECs). The atypical PKC isoform ζ (PKCζ) is a pathologic mediator of endothelial dysfunction. However, the functional significance of SSeCKS/PKCζ dimerization in the vascular endothelium remains poorly understood. Given this background, we investigated the effects of SSeCKS on endothelial dysfunction and elucidated the possible mechanism involved. Vascular endothelial dysfunction and inflammatory changes were induced by treatment with bacterial endotoxin lipopolysaccharide (LPS, a vascular endothelial toxicity inducer). LPS can increase the level of SSeCKS. However, we also found that depletion of SSeCKS aggravated the LPS-induced vascular endothelial dysfunction, upregulated pro-inflammatory proteins and phosphorylation level of PKCζ, increased ROS formation, decreased extracellular-signal-regulated kinase 5 (ERK5) transcriptional activity, and reduced eNOS expression. Further examination revealed that depletion of SSeCKS increased PKCζ/ERK5 dimerization. These findings provide preliminary evidence that the expression of SSeCKS induced by LPS, as a negative feedback mechanism, has the potential to improve endothelium-dependent relaxation in vascular disease conditions by inhibiting PKCζ-mediated reduction of ERK5 transactivation.