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The galectin 3 binding protein (LGALS3BP, also known as 90K) is a ubiquitous multifunctional secreted glycoprotein originally identified in cancer progression. It remains unclear how 90K functions in innate immunity during viral infections. In this study, we found that viral infections resulted in elevated levels of 90K. Further studies demonstrated that 90K expression suppressed virus replication by inducing IFN and pro-inflammatory cytokine production. Upon investigating the mechanisms behind this event, we found that 90K functions as a scaffold/adaptor protein to interact with TRAF6, TRAF3, TAK1 and TBK1. Furthermore, 90K enhanced TRAF6 and TRAF3 ubiquitination and served as a specific ubiquitination substrate of TRAF6, leading to transcription factor NF-κB, IRF3 and IRF7 translocation from the cytoplasm to the nucleus. Conclusions: 90K is a virus-induced protein capable of binding with the TRAF6 and TRAF3 complex, leading to IFN and pro-inflammatory production. [ABSTRACT FROM AUTHOR]

Hyperthermia (HT) has shown feasibility and potency as an anticancer therapy. Administration of HT in the chemotherapy has previously enhanced the cytotoxicity of drugs against pancreatic cancer. However, the drugs used when conducting these studies are substantially conventional chemotherapeutic agents that may cause unwanted side effects. Additionally, the thermal dosage in the treatment of cancer cells could also probably harm the healthy cells. The purpose of this work was to investigate the potential of the two natural polyphenolic compounds, epigallocatechin gallate (EGCG) and chlorogenic acid (CGA), as heat synergizers in the thermal treatment of the PANC-1 cells. Furthermore, we have introduced a unique strategy entitled the thermal cycling-hyperthermia (TC-HT) that is capable of providing a maximum synergy and minimal side effect with the anticancer compounds. Our results demonstrate that the combination of the TC-HT and the CGA or EGCG markedly exerts the anticancer effect against the PANC-1 cells, while none of the single treatment induced such changes. The synergistic activity was attributed to the cell cycle arrest at the G2/M phase and the induction of the ROS-dependent mitochondria-mediated apoptosis. These findings not only represent the first in vitro thermal synergistic study of natural compounds in the treatment of pancreatic cancer, but also highlight the potential of the TC-HT as an alternative strategy in thermal treatment. [ABSTRACT FROM AUTHOR]

Daily urine protein (UP) loss is a cumbersome but important measurement to guide diagnosis and treatment of renal disease. Spot urine protein-creatinine ratio (UPCR) can been applied to estimate daily proteinuria. However, the correlations between spot and 24h proteinuria remain controversial. In this cross-sectional study, simultaneous collection of 24h and spot urines were performed from 1,039 (derivation cohort) and 204 CKD patients (validation cohort) of Chang Gung Memorial Hospital, from 2007 to 2017. The correlations between spot UPCR and 24h proteinuria were compared. The mean age of patients of derivation and validation cohort was 63 and 55 years and the mean estimated glomerular filtration rate was 62 ± 35 and 59 ± 36 mL/min/m2, respectively. The correlation coefficient was 0.819 between UPCR and 24hUP. Prediction equation was derived as: Log1024hUP (g) = 0.814 x Log10UPCR (mg/mg) + 0.110 x Gender– 0.004 x Age + 0.004 x Body weight (kg) + 0.002 x CKD stage coefficient– 0.018, where CKD stage coefficient: CKD stage G1 = 1, G2 = 2, G3a = 3.1, G3b = 3.2, G4 = 4, G5 = 5. Correlation coefficient between measured and predicted 24hUP among derivation group and validation group is 0.866 and 0.915, respectively. However, the agreement of spot and daily estimates was less pronounced with proteinuria > 3g than lower values in Bland-Altman analysis. Spot UPCR can accurately predict 24hUP in patients with daily proteinuria below 3g. The development of this equation may facilitate estimation of 24hUP in the clinical practice. [ABSTRACT FROM AUTHOR]

Our appreciation for the extent of Epstein Barr virus (EBV) transcriptome complexity continues to grow through findings of EBV encoded microRNAs, new long non-coding RNAs as well as the more recent discovery of over a hundred new polyadenylated lytic transcripts. Here we report an additional layer to the EBV transcriptome through the identification of a repertoire of latent and lytic viral circular RNAs. Utilizing RNase R-sequencing with cell models representing latency types I, II, and III, we identified EBV encoded circular RNAs expressed from the latency Cp promoter involving backsplicing from the W1 and W2 exons to the C1 exon, from the EBNA BamHI U fragment exon, and from the latency long non-coding RPMS1 locus. In addition, we identified circular RNAs expressed during reactivation including backsplicing from exon 8 to exon 2 of the LMP2 gene and a highly expressed circular RNA derived from intra-exonic backsplicing within the BHLF1 gene. While expression of most of these circular RNAs was found to depend on the EBV transcriptional program utilized and the transcription levels of the associated loci, expression of LMP2 exon 8 to exon 2 circular RNA was found to be cell model specific. Altogether we identified over 30 unique EBV circRNAs candidates and we validated and determined the structural features, expression profiles and nuclear/cytoplasmic distributions of several predominant and notable viral circRNAs. Further, we show that two of the EBV circular RNAs derived from the RPMS1 locus are detected in EBV positive clinical stomach cancer specimens. This study increases the known EBV latency and lytic transcriptome repertoires to include viral circular RNAs and it provides an essential foundation and resource for investigations into the functions and roles of this new class of EBV transcripts in EBV biology and diseases. [ABSTRACT FROM AUTHOR]

Purpose: We estimated the volume of vestibular schwannomas by an ice cream cone formula using thin-sliced magnetic resonance images (MRI) and compared the estimation accuracy among different estimating formulas and between different models. Methods: The study was approved by a local institutional review board. A total of 100 patients with vestibular schwannomas examined by MRI between January 2011 and November 2015 were enrolled retrospectively. Informed consent was waived. Volumes of vestibular schwannomas were estimated by cuboidal, ellipsoidal, and spherical formulas based on a one-component model, and cuboidal, ellipsoidal, Linskey’s, and ice cream cone formulas based on a two-component model. The estimated volumes were compared to the volumes measured by planimetry. Intraobserver reproducibility and interobserver agreement was tested. Estimation error, including absolute percentage error (APE) and percentage error (PE), was calculated. Statistical analysis included intraclass correlation coefficient (ICC), linear regression analysis, one-way analysis of variance, and paired t-tests with P < 0.05 considered statistically significant. Results: Overall tumor size was 4.80 ± 6.8 mL (mean ±standard deviation). All ICCs were no less than 0.992, suggestive of high intraobserver reproducibility and high interobserver agreement. Cuboidal formulas significantly overestimated the tumor volume by a factor of 1.9 to 2.4 (P ≤ 0.001). The one-component ellipsoidal and spherical formulas overestimated the tumor volume with an APE of 20.3% and 29.2%, respectively. The two-component ice cream cone method, and ellipsoidal and Linskey’s formulas significantly reduced the APE to 11.0%, 10.1%, and 12.5%, respectively (all P < 0.001). Conclusion: The ice cream cone method and other two-component formulas including the ellipsoidal and Linskey’s formulas allow for estimation of vestibular schwannoma volume more accurately than all one-component formulas. [ABSTRACT FROM AUTHOR]

Purpose: Ischemia-reperfusion injury (IRI) is associated with significant patient mortality and morbidity. The complex cascade of IRI is incompletely understood, but inflammation is known to be a key mediator. In addition to the predominant innate immune responses, previous research has also indicated that αβ T cells contribute to IRI in various organ models. The aim of this study was to clarify the role αβ T cells play in IRI to the gut. Methods: Adult wild-type (WT) and αβ T cell-deficient mice were subjected to acute intestinal IRI with 30min ischemia followed by 4h reperfusion. The gene expression of pro-inflammatory cytokines was measured by qPCR, and the influx of leukocyte subpopulations in the gut was assessed via flow cytometry and histology. Pro-inflammatory cytokines in the serum were measured, and transaminases were assessed as an indicator of distant organ IRI. Results: Intestinal IRI led to an increased expression of pro-inflammatory cytokines in the gut tissue and an influx of leukocytes that predominantly consisted of neutrophils and macrophages. Furthermore, intestinal IRI increased serum IL-6, TNF-α, and ALT/AST levels. The αβ T cell-deficient mice did not exhibit a more significant increase in pro-inflammatory cytokines in the gut or serum following IR than the WT mice. There was also no difference between WT- and αβ T cell-deficient mice in terms of neutrophil infiltration or macrophage activation. Furthermore, the increase in transaminases was equal in both groups indicating that the level of distant organ injury was comparable. Conclusion: An increasing body of evidence demonstrates that αβ T cells play a key role in IRI. In the gut, however, αβ T cells are not pivotal in the first hours following acute IRI as deficiency does not impact cytokine production, neutrophil recruitment, macrophage activation, or distant organ injury. Thus, αβ T cells may be considered innocent bystanders during the acute phase of intestinal IRI. [ABSTRACT FROM AUTHOR]

Apoptosis plays a dual role in cancer development and malignancy. The role of apoptosis-related caspases in cancer remains controversial, particularly in oral tongue squamous cell carcinoma (OTSCC). In this study, we examined the protein levels of cleaved caspase-3, caspase-3, caspase-8, and caspase-9 on tissue microarrays consisting of samples from 246 OTSCC patients by immunohistochemistry. Wilcoxon signed-rank test indicated that the protein levels of cleaved caspase-3, caspase-3, caspase-8, and caspase-9 in tumor tissues were significantly higher compared to those in adjacent normal tissues (all p<0.001). The expression level of caspase-8 in tumors was elevated in patients with lymph node invasion. Moreover, positive expression of cleaved caspase-3 was associated with shorter disease-free survival (DFS) in OTSCC patients with moderate differentiation and lymph node invasion. Combination of either positive cleaved caspase-3 or higher caspase-3 expression or both was associated with poor DFS. Interestingly, stratification analysis showed that co-expression levels of positive cleaved caspase-3 or/and higher caspase-3 were associated with better disease-specific survival in patients with advanced stages of the disease, such as large tumor size and lymph node invasion, whereas it was associated with poor DFS in OTSCC patients with moderate cell differentiation and small tumor size. Taken together, cleaved caspase-3 and caspase-3/8/9 could be biomarkers for tumorigenesis in OTSCC patients. The co-expression level of cleaved caspase-3 and caspase-3 might be a prognostic biomarker for OTSCC patients, particular in those patients with certain tumor stages and cell differentiation status. [ABSTRACT FROM AUTHOR]

Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination. [ABSTRACT FROM AUTHOR]