Epstein-Barr virus-derived circular RNA LMP2A induces stemness in EBV-associated gastric cancer.

Cancer stem cells (CSCs) are cancer-initiating cells that are not only a source of tumorigenesis but also the cause of tumour progression, metastasis and therapy resistance. EBV-associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer with unique clinicopathological and molecular features. However, whether CSCs exist in EBVaGC, and the tumorigenic mechanism of EBV, remains unclear. Here, NOD/SCID mice were injected subcutaneously with the EBVaGC cell line SNU719 and treated with 5-fluorouracil weekly. Successive generations of xenografts yielded a highly malignant EBVaGC cell line, SNU-4th, which displays properties of CSCs and mainly consists of CD44+ CD24- cells. In SNU-4th cells, an EBV-encoded circRNA, ebv-circLMP2A, expression increased and plays crucial roles in inducing and maintaining stemness phenotypes through targeting miR-3908/TRIM59/p53 axis. Additionally, high expression of ebv-circLMP2A is significantly associated with metastasis and poor prognosis in patients with EBVaGC. These findings not only provide evidence for the existence of CSCs in EBVaGC and elucidate the pathogenic mechanism of ebv-circLMP2A in EBVaGC, but also provide a promising therapeutic target for EBVaGC.

Promotion of Proton Conductivity by Encapsulation of Metal-Organic Polyhedra in Metal-Organic Frameworks.

A Zr-based metal-organic polyhedron (MOP) was self-assembled in a porous MOF host, DUT-68, successfully to synthesize MOP-1@DUT-68. The MOP guest (MOP-1) has a diameter of about 20 Å, larger than that of the square windows (pore sizes of ∼14 Å) of DUT-68 but smaller than that of the rhombicuboctahedral cage (27.7 Å), which means that the migration and leaching of MOP-1 could be effectively prohibited if MOP-1 is encapsulated in the MOF's cavities. The proton conductivity of MOP-1@DUT-68 is 1.14×10-3  S cm-1 (at 80 °C under 98 % relative humidity), which is three orders of magnitude higher than that of DUT-68. Compared with MOP-1⊂DUT-68, which was synthesized by impregnation, MOP-1@DUT-68 is more prone to form faster proton-conduction pathways and thus provides higher proton conductivity.

[Studies on chemical constituents of stems of Herpetospermum pedunculosum].

This project is to study chemical compositions from the stems of Herpetospermum pedunculosum. Twenty-two compounds were isolated from the 70% acetone extract of the stems of H. pedunculosum by column chromatography on Sephadex LH-20, semi-preparative HPLC and preparative TLC. Their structures were elucidated by their physicochemical properties and spectroscopic data as N-benzyltyramine(1), α-spinasterol(2),(2S)-1-O-heptatriacontanoyl glycerol(3), 5,7-dihydroxychromanone(4), methyl 2ß,3ß-dihydroxy-D:C-friedoolean-8-en-29-oate(5), p-hydroxy benzyl alcohol(6), p-hydroxybenzoate(7), p-hydroxy cinnamic acid(8), 1H-indol-3-carboxylic acid(9), rhodiocyanoside B(10), rhodiolgin(11), rhodiosin(12), 9,12,13-trihydroxy-10(E)-octadecenoic acid(13), cylo-(Tyr-Leu)(14), matteflavoside A(15), loliolide(16), 1H-indol-3-carboxaldehyde(17),(+)-dehydrovomifoliol(18), 3-hydroxy-5α,6α-epoxy-ß-ionone(19), 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxy-1-propen-1-yl)-2-methoxyphenoxy]-1-propanone(20), 7-en-nonadecanoic acid monoglyceride(21), vanillic acid(22). Compound 1 is a new natural product, while compounds 3-15 were isolated from this plant for the first time.

The analgesic efficacy of subcostal transversus abdominis plane block with Mercedes incision.

BACKGROUND: Conventional perioperative analgesic modalities (e.g. opioids, epidural analgesia) have their own drawbacks, which limit their clinical application. This study investigated the opioid-sparing effectsof the oblique subcostal transversus abdominis plane (OSTAP) blockade with ropivacaine for the patients undergoing open liver resection with a Mercedes incision. METHODS: 126 patients who were scheduled for open liver resection were enrolled in this study. Patients were randomly assigned to receive bilateral ultrasound-guided OSTAPblocks with either 0.375% ropivacaine (groupT) or 0.9% isotonic saline (group C). Both groups also received intravenous patient-controlled analgesia and intravenous 40 mg parecoxib every 12 h for a total of 3 days. Preoperative and intraoperative parameters, plus intraoperative and postoperative cumulative sufentanil consumption, were recorded. RESULTS: 70 patients were enrolled in the study finally. There were no significant differences between the two groups with respect to preoperative parameters, and surgical and anesthetic characteristics. The intraoperative sufentanil use, cumulative sufentanil consumption at 5 min after extubation, 2 h, 4 h,12 h and 24 h after operation in group T was significantly less than that in group C (P = 0.001, 0.001, 0.000, 0.000, 0.001 and 0.044, respectively). Compared with group C, postoperative NRS pain scores at rest were significantly lower at 2 h and 4 h postoperatively in group T (P = 0.04and 0.02, respectively); NRS scores at the time of coughing were also significantly lower in group T than in group C at all time points except 5 min after extubation (all P < 0.001). Furthermore, compared with group C, the number of intraoperative vasodilator use, the extubation time and the incidence of nausea was reduced in group T. CONCLUSION: Ultrasound-guided OSTAP block with ropivacaine can significantly decrease the perioperative cumulative dosage of analgesics and improve analgesic effect without obvious side effects for the patients who underwent an open liver resection with Mercedes incision when compared tothe ultrasound-guided OSTAP block with saline. TRIAL REGISTRATION: The study protocol was registered at http://www.chictr.org.cn (ChiCTR-TRC- 14004827) on February 19, 2014.

Novel multimodal analgesia regimen improves post-TACE pain in patients with hepatocellular carcinoma.

BACKGROUD: Transarterial chemoembolization (TACE) is the primary palliative treatment for patients with unresectable hepatocellular carcinoma (HCC). However, it is often accompanied by postoperative pain which hinder patient recovery. This study was to examine whether preemptive parecoxib and sufentanil-based patient controlled analgesia (PCA) could improve the pain management in patients receiving TACE for inoperable HCC. METHODS: From June to December 2016, 84 HCC patients undergoing TACE procedure were enrolled. Because of the willingness of the individuals, it is difficult to randomize the patients to different groups. We matched the patients' age, gender and pain scores, and divided the patients into the multimodal group (n = 42) and control group (n = 42). Patients in the multimodal group received 40 mg of parecoxib, 30 min before TACE, followed by 48 h of sufentanil-based PCA. Patients in the control group received a routine analgesic regimen, i.e., 5 mg of dezocine during operation, and 100 mg of tramadol or equivalent intravenous opioid according to patient's complaints and pain intensity. Postoperative pain intensity, percentage of patients as per the pain category, adverse reaction, duration of hospital stay, cost-effectiveness, and patient's satisfaction were all taken into consideration when evaluated. RESULTS: Compared to the control group, the visual analogue scale scores for pain intensity was significantly lower at 2, 4, 6, and 12 h (all P < 0.05) in the multimodal group and a noticeably lower prevalence of post-operative nausea and vomiting in the multimodal group (31.0% vs. 59.5%). Patient's satisfaction in the multimodal group was also significantly higher than that in the control group (95.2% vs. 69.0%). No significant difference was observed in the duration of hospital stay between the two groups. CONCLUSION: Preemptive parecoxib and sufentanil-based multimodal analgesia regime is a safe, efficient and cost-effective regimen for postoperative pain control in HCC patients undergoing TACE.

Sonic hedgehog signalling pathway regulates apoptosis through Smo protein in human umbilical vein endothelial cells.

OBJECTIVE: The aim of this study was to investigate the expression of smoothened protein (Smo), a sonic hedgehog (Shh) signalling component, in synovium of RA and its role in the survival and apoptosis of endothelial cells. METHODS: The expression of Smo pxrotein in RA synovial tissue was examined by immunohistochemistry. Real-time PCR and western blotting techniques were employed to measure the expression of Shh signalling components in EA.hy926 endothelial cells exposed to TNF-α in the presence or absence of cyclopamine (a Smo-specific antagonist). Lastly, the effect of cyclopamine and Smo small interfering RNA on apoptosis induced by TNF-α and actinomycin D (ActD) was determined. RESULTS: We found that Smo was highly expressed in synovial tissues of RA, especially in endothelial cells, compared with the trauma group. TNF-α significantly increased the expression of Shh signalling components in EA.hy926 endothelial cells, while cyclopamine decreased the expression of Shh signalling components. EA.hy926 endothelial cells treated with various concentrations of cyclopamine (2-8 µmol/l) showed a significant decrease in cell viability and cell survival rate, and an increase in the rate of cell apoptosis compared with endothelial cells treated with TNF-α and ActD (P < 0.05). EA.hy926 endothelial cells transfected with Smo-siRNA also showed a lower cell survival rate and higher apoptotic rate, compared with cells in the control group (P < 0.05). CONCLUSION: The Shh signalling pathway plays a role in regulating endothelial cell apoptosis in a Smo-dependent manner.

Increased severity of inflammation correlates with elevated expression of TRPV1 nerve fibers and nerve growth factor on interstitial cystitis/bladder pain syndrome.

OBJECTIVES: Although evidence supports a role for inflammation in interstitial cystitis/bladder pain syndrome (IC/BPS), the mechanism remains unknown. We determined whether inflammation causes an elevated expression of nerve growth factor (NGF) and transient receptor potential vanilloid receptor subtype 1 (TRPV1) and correlated them with the symptoms. METHODS: Bladder biopsies were obtained from 53 IC/BPS patients and 27 controls, and hematoxylin and eosin staining, immunostaining and Western blotting were performed to detect inflammation, TRPV1-immunoreactive and PGP9.5-immunoreactive nerve fibers, and NGF, respectively. Symptoms were assessed using the Pelvic Pain/Urgency/Frequency (PUF) questionnaire and pain visual analogue scale scores. Suburothelial nerve fiber density was quantified and correlated with PUF scores. RESULTS: Increased severity of inflammation was correlated with a higher TRPV1-immunoreactive nerve fiber density (r = 0.4113, p = 0.0024) and higher NGF levels (r = 0.3775, p = 0.0052). Suburothelial TRPV1-immunoreactive nerve fiber density was significantly correlated with pain scores and urgency scores (r = 0.3320, p = 0.0145 and r = 0.3823, p = 0.0039, respectively). PGP9.5-immunoreactive nerve fibers were significantly increased in IC/BPS (p = 0.0193) and had a positive relationship with inflammation severity (r = 0.6138, p < 0.0001). CONCLUSIONS: Our study revealed increased severity of inflammation correlated with a higher expression of TRPV1-immunoreactive nerve fibers and NGF in IC/BPS and correlated with clinical symptoms.

Propofol induces apoptosis of hepatocellular carcinoma cells by upregulation of microRNA-199a expression.

Propofol is one of the extensively commonly used intravenous anaesthetic agents. The effects of Propofol on hepatocellular carcinoma (HCC) growth inhibition and apoptosis have been examined. The techniques used were the MTT assay, flow cytometry, real-time PCR to assess miR-199a expression, as also caspase-8 and caspase-9 activity in HepG2 cells treated with Propofol. Finally, we evaluated the effect of miR-199a on Propofol-induced anti-tumour activity using anti-miR-199a. Propofol efficiently inhibited the growth of HCC cells, but was less toxic to normal hepatic cells. It induced apoptosis and increased expression of miR-199a. Activation of caspase-8 and caspase-9 suggested that both extrinsic and intrinsic pathways are involved in Propofol-induced apoptosis. Anti-miR-199a reversed the effect of Propofol on apoptosis and activation of caspase-8 and caspase-9 in HepG2 cells. Propofol can effectively induce apoptosis of HCC cells and modulation of miR-199a possibly contributes to the anti-tumour action of Propofol. Hence, Propofol might be an effective drug for HCC.

Propofol inhibits the adhesion of hepatocellular carcinoma cells by upregulating microRNA-199a and downregulating MMP-9 expression.

BACKGROUND: Propofol is one of the extensively and commonly used intravenous anesthetics and has the ability to influence the proliferation, motility, and invasiveness of many cancer cells. In this study, the effects of propofol on hepatocellular carcinoma cells invasion ability were examined. METHODS: We assessed the invasion ability of HepG2 cells in vitro by determining enzyme activity and protein expression of MMP-9 using gelatin zymography assay and Western blot. The real-time PCR was used to evaluate the effect of propofol on microRNA-199a (miR-199a) expression, and miR-199a-2 precursor to evaluate whether over-expression of miR-199a can affect MMP-9 expression. Finally, the effect of miR-199a on propofol-induced anti-tumor activity using anti-miR-199a was assessed. RESULTS: Propofol significantly elevated the expression of miR-199a and inhibited the invasiveness of HepG2 cells. Propofol also efficiently decreased enzyme activity and protein expression of MMP-9. Moreover, the over-expression of miR-199a decreased MMP-9 protein level. Interestingly, the neutralization of miR-199a by anti-miR-199a antibody reversed the effect of propofol on alleviation of tumor invasiveness and inhibition of MMP-9 activity in HepG2 cells. CONCLUSION: Propofol decreases hepatocellular carcinoma cell invasiveness, which is partly due to the down-regulation of MMP-9 expression by miR-199a.

Expressions of Osteopontin (OPN), ανß3 and Pim-1 Associated with Poor Prognosis in Non-small Cell Lung Cancer (NSCLC).

OBJECTIVE: To examine the expressions of osteopontin (OPN), (α) (ν) (ß) (3) and Pim-1 in non-small cell lung cancer (NSCLC), and investigate their potential pathogenic roles in the development of NSCLC. METHODS: Immunohistochemistry was used to examine the expressions of OPN, (α) (ν) (ß) (3) and Pim-1 in cohort (136 cases) of NSCLC samples and their adjacent normal lung tissue specimens. Statistical analysis was performed to evaluate the relationships among expressions of OPN, (α) (ν) (ß) (3) and Pim-1 and their associations with patients clinico- pathological parameters. RESULTS: The expressions of OPN and Pim-1 were predominantly observed in cytoplasm. The expression of (α) (ν) (ß) (3) was mostly detected in cytoplasm and/or membrane. In NSCLC samples, the positive rates of OPN, (α) (ν) (ß) (3) and Pim-1 expressions were 68.4% (93/136), 77.2% (105/136) and 57.4% (78/136), respectively. In normal lung tissues, in contrast, the positive rates of OPN, (α) (ν) (ß) (3) and Pim-1 were 24.0% (12/50), 26.0% (13/50) and 16.0% (8/50), respectively. There were significant differences of the positive expression rates of OPN, (α) (ν) (ß) (3) and Pim-1 between NSCLCs samples and normal lung tissues (P<0.01). In addition, the positive expression of OPN, (α) (ν) (ß) (3) and Pim-1 in NSCLCs samples was significantly associated with increased pathological grade, lymph node metastasis and advanced clinical stage (P<0.01), and they were independent of other clinicopathological parameters (P>0.05). Furthermore, a significantly positive correlation between the expression of OPN and (α) (ν) (ß) (3) (r=0.38, P<0.01), OPN and Pim-1 (r=0.37, P<0.01), or (α) (ν) (ß) (3) and Pim-1 (r=0.20, P<0.05) was evaluated in our NSCLC cohort. CONCLUSION: OPN, (α) (ν) (ß) (3) and Pim-1 proteins are frequently overexpressed in NSCLC, and they may play important roles in the development and/or progression of NSCLC.

Hypoxia-induced ebv-circLMP2A promotes angiogenesis in EBV-associated gastric carcinoma through the KHSRP/VHL/HIF1α/VEGFA pathway.

EBV-encoded circular RNA LMP2A (ebv-circLMP2A) was found to be expressed in EBV-associated gastric carcinoma (EBVaGC) and associated with distant metastasis and poor prognosis. Angiogenesis is a key step in tumor invasion and metastasis and plays a crucial role in tumor progression. However, it is unclear whether and how ebv-circLMP2A is involved in angiogenesis. In this study, we showed that MVD, HIF1α, and VEGFA expression was increased in EBVaGC mouse xenografts with high expression of ebv-circLMP2A. The expression of ebv-circLMP2A was positively correlated with MVD, HIF1α, and VEGFA expression in clinical samples of EBVaGC. Knockdown of ebv-circLMP2A repressed tube formation and migration of HUVECs and decreased VEGFA and HIF1α expression in cancer cells under hypoxia, while ectopic expression of ebv-circLMP2A reversed these effects. Additionally, knockdown of HIF1α blocked the upregulation of ebv-circLMP2A by hypoxia, and ebv-circLMP2A interacted with KHSRP to enhance KHSRP-mediated decay of VHL mRNA, leading to the accumulation of HIF1α under hypoxia. There was a positive feedback loop between HIF1α and ebv-circLMP2A that promotes angiogenesis under hypoxia. ebv-circLMP2A was essential in regulating tumor angiogenesis in EBVaGC and might provide a valuable therapeutic target for EBVaGC.

ebv-circRPMS1 promotes the progression of EBV-associated gastric carcinoma via Sam68-dependent activation of METTL3.

Epstein-Barr virus (EBV) is a tumor virus that is associated with a variety of neoplasms, including EBV-associated gastric carcinoma (EBVaGC). Recently, EBV was reported to generate various circular RNAs (circRNAs). CircRNAs are important regulators of tumorigenesis by modulating the malignant behaviors of tumor cells. However, to date, the functions of ebv-circRNAs in EBVaGC remain poorly understood. In the present study, we observed high ebv-circRPMS1 expression in EBVaGC and showed that ebv-circRPMS1 promoted the proliferation, migration, and invasion and inhibited the apoptosis of EBVaGC cells. In addition, METTL3 was upregulated in GC cells overexpressing ebv-circRPMS1. Mechanistically, ebv-circRPMS1 bound to Sam68 to facilitate its physical interaction with the METTL3 promotor, resulting in the transactivation of METTL3 and cancer progression. In clinical EBVaGC samples, ebv-circRPMS1 was associated with distant metastasis and a poor prognosis. Based on these findings, ebv-circRPMS1 contributed to EBVaGC progression by recruiting Sam68 to the METTL3 promoter to induce METTL3 expression. ebv-circRPMS1, Sam68, and METTL3 might serve as therapeutic targets for EBVaGC.

Aberrant upregulation of 14-3-3Æ¡ expression serves as an inferior prognostic biomarker for gastric cancer.

BACKGROUND: 14-3-3Æ¡ is an intracellular, phosphoserine binding protein and proposed to be involved in tumorigenesis. However, the expression dynamics of 14-3-3Æ¡ and its clinicopathological/prognostic significance in human tumors are still controversial. METHODS: The method of immunohistochemistry (IHC) and Western blot were utilized to examine the protein expression of 14-3-3Æ¡ in gastric cancer and paired normal adjacent gastric mucosal tissues. Receive operating characteristic (ROC) curve analysis was employed to determine a cutoff score for 14-3-3Æ¡ expression in a training set (n = 66). For validation, the ROC-derived cutoff score was subjected to analysis of the association of 14-3-3Æ¡ expression with patient outcome and clinical characteristics in a testing set (n = 86) and overall patients (n = 152). RESULTS: The expression frequency and expression levels of 14-3-3Æ¡ were significantly higher in gastric cancer than in normal gastric mucosal tissues. Correlation analysis demonstrated that high expression of 14-3-3Æ¡ in gastric cancer was significantly correlated with clinical stage and tumor invasion. Furthermore, in the testing set and overall patients, Kaplan-Meier analysis showed that elevated 14-3-3Æ¡ expression predicted poorer overall survival (OS) and progression-free survival (PFS). Importantly, high 14-3-3Æ¡ expression was also associated with shortened survival time in stage III and stage IV gastric cancer patients. Multivariate analyses revealed that 14-3-3Æ¡ expression was an independent prognostic parameter in gastric cancer. CONCLUSIONS: These findings provide evidence that high expression of 14-3-3Æ¡ may be important in the tumor progression and servers as an independent molecular marker for poor prognosis of gastric cancer. Thus, overexpression of 14-3-3Æ¡ identifies patients at high risk and is a novel therapeutic molecular target for this tumor.

Chinese Association for the Study of Pain: Expert consensus on diagnosis and treatment for lumbar disc herniation.

Lumbar disc herniation is a common disease in the clinical context and does great harm to either the physical or mental health of patients suffering from this disease. Many guidelines and consensus for the diagnosis and treatment of lumbar disc herniation have been published domestically and internationally. According to the expert consensus, clinicians could adopt tailored and personalized diagnosis and treatment management strategies for lumbar disc herniation patients.

Association of distinctive Epstein-Barr virus variants with gastric carcinoma in Guangzhou, southern China.

To investigate the clinicopathologic features, Epstein-Barr virus (EBV) latency pattern and genome polymorphism of EBV-associated gastric carcinoma (EBVaGC) in Guangzhou, an endemic area of nasopharyngeal carcinoma (NPC), an in situ hybridization assay of EBV-encoded small RNA-1 (EBER-1) was used to identify the presence of EBV in 676 consecutive gastric carcinoma cases. EBV-encoded proteins EBNA1, EBNA2, LMP1, and ZEBRA were detected by immunohistochemistry. EBV genome polymorphism was also analyzed by PCR and DNA sequencing. Of the 676 cases, 45 EBV-positive cases (6.7%) were identified, including 37 (8.5%) male and 8 (3.3%) female cases. EBNA1 was detected in 42 cases (93.3%), while EBNA2, LMP1, and ZEBRA were all negative. In the EBV genome polymorphism analysis, type A strain, prototype F, type I, XhoI-, and del-LMP1 variants were predominant among EBVaGC patients, accounting for 44 (97.8%), 37 (82.2%), 45 (100%), 34 (75.6%), and 42 (93.3%) cases, respectively. Moreover, a new hotspot mutation in the BamHI-W1/I1 boundary region (148,972 T --> C) was found in 39 (86.7%) of the 45 cases. The predominant EBV variants in EBVaGC in Guangzhou are prototype F, type I, and XhoI-, which are different from those in NPC in this area (predominant variant-type "f") and in EBVaGC in Latin American countries (predominant type "i" and XhoI+), suggesting that the EBV variants are not only geographically distributed but also disease restricted, and the pathogenic role of EBV in different EBV associated epithelial malignancies in different areas may be distinct.

Effects of low central venous pressure during preanhepatic phase on blood loss and liver and renal function in liver transplantation.

BACKGROUND: Although the low central venous pressure (LCVP) technique is used to decrease blood loss during liver resection, its efficacy and safety during transplant procedures are still debatable. Our study aimed to assess the effects of this technique and its clinical safety for recipients undergoing liver transplantation. METHODS: Eighty-six adult patients were randomly divided into a LCVP group and a control group. In the LCVP group, CVP was maintained below 5 mmHg or 40% lower than baseline during the preanhepatic phase by limiting infusion volume, manipulating the patient's posture, and administration of somatostatin and nitroglycerine. Recipients in the control group received standard care. Hemodynamics, blood loss, liver function, and renal function of the two groups were compared perioperatively. RESULTS: A lower CVP was maintained in the LCVP group during the preanhepatic phase, resulting in a significant decrease in blood loss (1922 +/- 1429 vs. 3111 +/- 1833 ml, P < 0.05) and transfusion volume (1200 +/- 800 vs. 2400 +/- 1200 ml, P < 0.05) intraoperatively. Compared with the control group, the LCVP group had a significantly lower mean arterial pressure at 2 h after the start of the operation (74 +/- 11 vs. 84 +/- 14 mmHg, P < 0.05), a lower lactate value at the end of the operation (5.9 +/- 3.0 vs. 7.2 +/- 3.0 mmol/l, P < 0.05), and a better preservation of liver function after the declamping of the portal vein. There were no significant differences in perioperative renal function and postoperative complications between the groups. CONCLUSIONS: The LCVP technique during the preanhepatic phase reduced intraoperative blood loss, protected liver function, and had no detrimental effects on renal function in LT.

[Clinicopathologic features and protein expression study of Epstein-Barr virus-associated gastric carcinoma in Guangzhou].

OBJECTIVE: To investigate the prevalence of Epstein-Barr virus (EBV)-associated gastric carcinomas in Guangzhou, their clinicopathologic features and related protein expressions including DNMT1, p16, and cyclin D1. METHOD: A total of 676 cases of EBV-associated gastric carcinoma were included in the study. The presence of EBV-encoded small RNA1 (EBER1), a marker for EBV infection, was analyzed by in-situ hybridization using formalin-fixed and paraffin-embedded tumor samples. Expression of EBV-encoded proteins, DNMT1, p16 and cyclin D1 were detected by immunohistochemistry. RESULTS: Forty-five of 676 gastric carcinomas showed EBER intranuclear positivity in all tumor cells. EBV involvement was significantly more frequent among the male than the female patients, especially in tumors of less differentiated types (diffuse type) and involving the upper stomach (P < 0.05). EBNA1 and LMP2A expression were detected in 42 (93.3%) and 24 (53.3%) cases, respectively. None expressed EBNA2, LMP1, and ZEBRA. Among 45 cases of EBV associated gastric carcinomas, DNMT1, p16 and cyclin D1 expression were seen in 35 (77.8%), 10 (22.2%), and 29 (64.4%) cases, respectively. In contrast, among 40 EBV negative gastric carcinomas, expression of the three proteins were 20 (50.0%), 25 (62.5%) and 12 (30.0%), respectively. The difference of expression of the three proteins between the two groups was significant (P < 0.05). Expression of p16 correlated with the depth of the tumor invasion. Correlated protein expression was seen between LMP2A and DNMT1, between DNMT1 and p16, and between p16 and cyclin D1 (P < 0.05). CONCLUSIONS: EBV associated gastric carcinoma accounts for 6.7% of gastric carcinomas in Guangzhou with the Latency I pattern in some cases and between Latency I and II in others. The correlated expression of LMP2A, DNMT1, p16 and cyclin D1 may contribute to the pathogenesis of EBV associated gastric carcinomas.

Intrathecal delivery of hydromorphone vs morphine for refractory cancer pain: a multicenter, randomized, single-blind, controlled noninferiority trial.

Hydromorphone is an alternative to morphine for intrathecal drug delivery system to treat refractory cancer pain; however, there is not enough clinical evidence to prove it. In our study, 233 patients from 12 different pain management centers across China were enrolled, 121 and 112 in the intrathecal hydromorphone (ITHM) and intrathecal morphine (ITMO) groups, respectively. The primary outcome was the clinical success rate, which was defined as ratio of patients achieving ≥50% pain relief. The noninferiority margin was defined as -0.15. Other outcomes included daily visual analogue scale score, breakthrough pain (BTP) incidence, intrathecal dose change, and patient-controlled analgesia bolus count change, GAD-7/PHQ-9. Clinical success was achieved in 85 and 79 of the 121 ITHM patients (70.2%) and 112 ITMO patients (70.5%), respectively. Compared to the corresponding baseline findings, significantly decreased visual analogue scale scores and BTP incidence were noted in both groups. The dose change rate decreased and increased with time in the ITHM and ITMO groups, respectively (ITHM -3.33% vs ITMO 35.4%, P < 0.01, t test) from the third week. The patient-controlled analgesia bolus change rate was lower in the ITHM group than in the ITMO group (ITHM -19.88% vs ITMO 7.79%, P < 0.01, t test) from first week. Our result shows that ITHM is noninferior to ITMO on pain relief to treat refractory cancer pain, however, at different doses and that the doses of morphine tended to increase, whereas those of hydromorphone decreased over time. Hydromorphone offers advantage over morphine in controlling BTP.

The implication of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric carcinoma.

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct entity that has conspicuously inflammatory infiltration compared with EBV-negative gastric carcinoma. To date, the local immune status in EBVaGC and its relationship with patient prognosis and apoptosis of tumor cells are largely unknown. In this study, we evaluated the density of different types of tumor-infiltrating lymphocytes (TILs) in 53 EBVaGCs and 67 EBV-negative gastric carcinomas and analyzed its relationship with patient outcomes and apoptosis of tumor cells in EBVaGC. The average number of CD3+ total T cells, CD8+ T cells, CD79α+ B cells, CD56+ natural killer cells, Fascin+ dendritic cells (DCs), and FoxP3+ Tregs and the average proportions of Ki-67, interleukin 1ß, granzyme B, interferon γ, and interleukin 10 in TILs were higher in EBVaGC, and CD8+ T cells were the predominant constituent cells of TILs in EBVaGC. Patients with higher numbers of CD3+ total T cells, CD8+ T cells, CD79α+ B cells, and Fascin+ DCs survived longer in EBVaGC, and CD8+ T cells and Fascin+ DCs were independent prognostic factors for patient survival. Besides, CD8+ T cells were positively correlated with apoptotic index of tumor cells. However, the apoptosis of tumor cells was lower, and the expression of survivin and NF-κBp65 in tumor cells was up-regulated in EBVaGC. These findings suggested that CD3+ total T cells, CD8+ T cells, CD79α+ B cells, and Fascin+ DCs predict a better prognosis in EBVaGC; CD8+ T cells might through a nonapoptotic pathway eliminate tumor cells, thereby improving the patient prognosis.