EBV-positive Hodgkin lymphoma is associated with suppression of p21cip1/waf1 and a worse prognosis

<p>Abstract</p> <p>Background</p> <p>About 30-50% of Hodgkin lymphomas (HLs) harbor the Epstein-Barr virus (EBV), but the impact of EBV infection on clinical outcomes has been unclear. EBV-encoded small RNAs (<it>EBER</it>s) are presented in all EBV-infected cells, but their functions are still less understood.</p> <p>Results</p> <p><it>EBER1 </it>was transfected into two HL cell lines, KMH2 and L428, and microarrays were used to screen for <it>EBER1</it>-induced changes. We found that <it>EBER1 </it>suppressed <it>p21</it>^cip1/waf1transcription in HL cell lines. In addition, positive regulators of <it>p21</it>^cip1/waf1transcription, such as p53, EGR1, and STAT1, were decreased. Suppression of <it>p21</it>^cip1/waf1in the <it>EBER1</it>⁺HL cell lines was associated with increased resistance to histone deacetylase inhibitors or proteasome inhibitors, drugs known to cause apoptosis by increasing p21^cip1/waf1levels. On biopsy specimens, EBV⁺HLs had weaker expression of both p21^cip1/waf1and active caspase 3. Clinically, suppression of p21^cip1/waf1in EBV⁺HLs was associated with a worse 2-year disease-free survival rate (45% for EBV⁺HLs <it>vs</it>. 77% for EBV^-HLs, <it>p </it>= 0.002).</p> <p>Conclusion</p> <p>Although the underlying mechanisms are still relatively unclear, <it>EBER1 </it>inhibits <it>p21</it>^cip1/waf1transcription and prevents apoptosis through down-regulation of p53, EGR1, and STAT1. The anti-apoptotic activity of <it>EBER1 </it>may be important in the rescue of Reed-Sternberg cells from drug-induced apoptosis and in the clinical behaviors of EBV⁺HLs.</p

High expression FUT1 and B3GALT5 is an independent predictor of postoperative recurrence and survival in hepatocellular carcinoma.

Cancer may arise from dedifferentiation of mature cells or maturation-arrested stem cells. Previously we reported that definitive endoderm from which liver was derived, expressed Globo H, SSEA-3 and SSEA-4. In this study, we examined the expression of their biosynthetic enzymes, FUT1, FUT2, B3GALT5 and ST3GAL2, in 135 hepatocellular carcinoma (HCC) tissues by qRT-PCR. High expression of either FUT1 or B3GALT5 was significantly associated with advanced stages and poor outcome. Kaplan Meier survival analysis showed significantly shorter relapse-free survival (RFS) for those with high expression of either FUT1 or B3GALT5 (P = 0.024 and 0.001, respectively) and shorter overall survival (OS) for those with high expression of B3GALT5 (P = 0.017). Combination of FUT1 and B3GALT5 revealed that high expression of both genes had poorer RFS and OS than the others (P &lt; 0.001). Moreover, multivariable Cox regression analysis identified the combination of B3GALT5 and FUT1 as an independent predictor for RFS (HR: 2.370, 95% CI: 1.505-3.731, P &lt; 0.001) and OS (HR: 2.153, 95% CI: 1.188-3.902, P = 0.012) in HCC. In addition, the presence of Globo H, SSEA-3 and SSEA-4 in some HCC tissues and their absence in normal liver was established by immunohistochemistry staining and mass spectrometric analysis

GTPase regulator associated with the focal adhesion kinase (GRAF) transcript was down-regulated in patients with myeloid malignancies

<p>Abstract</p> <p>Background</p> <p>GTPase regulator associated with the focal adhesion kinase (<it>GRAF</it>), a putative tumor suppressor gene, is found inactivated in hematopoietic malignancies by either genetic or epigenetic abnormalities. However, the expression level of <it>GRAF </it>gene has not yet been studied in leukemia. The aim of this study was to investigate the expression level of <it>GRAF </it>gene in those patients with myeloid malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myeloid leukemia (CML).</p> <p>Methods</p> <p>The expression levels of <it>GRAF </it>transcript were determined in 94 patients using real-time quantitative PCR (RQ-PCR). Clinical and laboratory data of these patients were collected and analyzed.</p> <p>Results</p> <p>The significantly decreased level of <it>GRAF </it>transcript was observed in three myeloid malignancies compared to controls. Within AML, there was no difference in the level of <it>GRAF </it>transcript among different FAB subtypes (<it>P </it>> 0.05). Difference was not observed in the amount of <it>GRAF </it>mRNA between CML at chronic phase and controls. As CML progressed, <it>GRAF </it>transcript significantly decreased. In MDS, three cases with 5q deletion had lower <it>GRAF </it>transcript than four without 5q deletion (median 0.76 vs 2.99) (<it>P </it>> 0.05).</p> <p>Conclusion</p> <p>our results demonstrate that the <it>GRAF </it>transcript is decreased in myeloid malignancies.</p

Epstein-Barr Virus-Encoded LMP2A Induces an Epithelial–Mesenchymal Transition and Increases the Number of Side Population Stem-like Cancer Cells in Nasopharyngeal Carcinoma

It has been recently reported that a side population of cells in nasopharyngeal carcinoma (NPC) displayed characteristics of stem-like cancer cells. However, the molecular mechanisms underlying the modulation of such stem-like cell populations in NPC remain unclear. Epstein-Barr virus was the first identified human tumor virus to be associated with various malignancies, most notably NPC. LMP2A, the Epstein-Barr virus encoded latent protein, has been reported to play roles in oncogenic processes. We report by immunostaining in our current study that LMP2A is overexpressed in 57.6% of the nasopharyngeal carcinoma tumors sampled and is mainly localized at the tumor invasive front. We found also in NPC cells that the exogenous expression of LMP2A greatly increases their invasive/migratory ability, induces epithelial–mesenchymal transition (EMT)-like cellular marker alterations, and stimulates stem cell side populations and the expression of stem cell markers. In addition, LMP2A enhances the transforming ability of cancer cells in both colony formation and soft agar assays, as well as the self-renewal ability of stem-like cancer cells in a spherical culture assay. Additionally, LMP2A increases the number of cancer initiating cells in a xenograft tumor formation assay. More importantly, the endogenous expression of LMP2A positively correlates with the expression of ABCG2 in NPC samples. Finally, we demonstrate that Akt inhibitor (V) greatly decreases the size of the stem cell side populations in LMP2A-expressing cells. Taken together, our data indicate that LMP2A induces EMT and stem-like cell self-renewal in NPC, suggesting a novel mechanism by which Epstein-Barr virus induces the initiation, metastasis and recurrence of NPC

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Biomechanical Characteristics for Identifying the Cutting Direction of Professional Soccer Players

[[abstract]](1) Background: To understand the movement characteristics of soccer players when cutting in two directions (45_ for the right and left cutting movements) through biomechanical analysis of the lower limbs to identify the cutting direction of the attacker; (2) Methods: A motion analysis system was used to capture the movements of 12 male professional soccer players dribbling to the left and right. Kinematics of the players’ cutting were analyzed, and the paired t-test was used for statistics, with a significant level of _ = 0.05; (3) Results: When cutting towards the right, the height of the hip joint during the run-up was low (effect size, ES = 0.41, p = 0.031) at 91.8 _ 7.0 cm. When cutting towards the left, the value was 94.6 _ 6.7 cm. While cutting, the front foot was abducted by 4.3 _ 4.0_ at landing when cutting towards the right and adducted by 2.7 _ 5.1_ when cutting towards the left (ES = 0.38, p = 0.003); (4) Conclusions: When the attacker carries out the cutting action while approaching the defender, the cutting direction may be predicted by observing the attacker’s hip and foot movements.[[notice]]補正完

Meta-tetrahydroxyphenyl chlorine mediated photodynamic therapy inhibits the migration and invasion of a nasopharyngeal carcinoma KJ-1 cell line

Different photosensitizer-mediated photodynamic therapy (PDT) has different intracellular cytotoxic cascades. Previous reports showed that 5-aminolevulinic acid (5-ALA)-mediated PDT suppressed the migration and invasion of head and neck cancer cells. Unlike from 5-ALA, which mainly targets the mitochondria of cells, meta-tetrahydroxyphenyl chlorin (m-THPC) mainly accumulates in the endoplasmic reticulum and Golgi complex. Does m-THPC PDT inhibit the migration and invasion of cancer cells? Methods: The effect of m-THPC PDT with a sublethal dose sufficient to kill around 20% of cells on the migration and invasion of a nasopharyngeal carcinoma KJ-1 cell line was studied by wound healing and Matrigel invasion assays. Results: In the wound healing assay, the migration distance of KJ-1 cells decreased significantly from 0.71 ± 0.02 mm in the control cells to 0.31 ± 0.03 mm in the PDT-treated cells 24 hours after light treatment (p < 0.05) and the migration distance also decreased significantly from 1.02 ± 0.07 mm in the control cells to 0.32 ± 0.04 mm in the PDT-treated cells 48 hours after treatment (p < 0.05). In the Matrigel invasion assay, the number of the invaded KJ-1 cells in PDT treated group was also statistically significantly less than those without PDT treatment (p < 0.05). Conclusion: This study demonstrates that a sublethal dose of m-THPC PDT inhibits the migration and invasion of nasopharyngeal carcinoma cells in vitro

Establishment of calculated panel reactive antibody and its potential benefits in improving the kidney allocation strategy in Taiwan

Background/Purpose: Renal transplant candidates who are highly sensitized to human leukocyte antigens (HLAs) tend to wait longer to find a matched donor and have poor outcomes. Most organ-sharing programs prioritize highly sensitized patients in the allocation scoring system. The HLA sensitization status is traditionally evaluated by the panel-reactive antibody (PRA) assay. However, this assay is method dependent and does not consider the ethnic differences in HLA frequencies. A calculated PRA (cPRA), based on a population's HLA frequency and patients' unacceptable antigens (UAs), correctly estimates the percentage of donors suitable for candidates. The Taiwan Organ Registry and Sharing Center does not prioritize sensitized patients. We propose that the incorporation of the cPRA and UAs into the renal allocation program will improve the local kidney allocation policy. Methods: We established a cPRA calculator using 6146 Taiwanese HLA-A, -B, -C, -DR, and -DQ phenotypes. We performed simulated allocation based on the concept of acceptable mismatch for 76 candidates with cPRA values exceeding 80%. Results: We analyzed 138 waitlisted renal transplant candidates at our hospital, and we determined that the concordance rate of the cPRA and PRA for highly sensitized (%PRA > 80%) candidates was 92.5%, which decreased to 20% for those with %PRA < 80%. We matched 76 highly sensitized patients based on acceptable mismatch with the HLA phenotypes of 93 cadaver donors. Forty-six patients (61%) found at least one suitable donor. Conclusion: The application of the cPRA and acceptable mismatch can benefit highly sensitized patients and reduce positive lymphocyte cytotoxicity crossmatch. Keywords: Kidney transplantation, Human leukocyte antigen, CPR