Degradation of TRIM32 is induced by RTA for Kaposi's sarcoma-associated herpesvirus lytic replication.

TRIM32 is often aberrantly expressed in many types of cancers. Kaposi's sarcoma-associated herpesvirus (KSHV) is linked with several human malignancies, including Kaposi's sarcoma and primary effusion lymphomas (PELs). Increasing evidence has demonstrated the crucial role of KSHV lytic replication in viral tumorigenesis. However, the role of TRIM32 in herpesvirus lytic replication remains unclear. Here, we reveal that the expression of TRIM32 is upregulated by KSHV in latency, and reactivation of KSHV lytic replication leads to the inhibition of TRIM32 in PEL cells. Strikingly, RTA, the master regulator of lytic replication, interacts with TRIM32 and dramatically promotes TRIM32 for degradation via the proteasome systems. Inhibition of TRIM32 induces cell apoptosis and in turn inhibits the proliferation and colony formation of KSHV-infected PEL cells and facilitates the reactivation of KSHV lytic replication and virion production. Thus, our data imply that the degradation of TRIM32 is vital for the lytic activation of KSHV and is a potential therapeutic target for KSHV-associated cancers. IMPORTANCE: TRIM32 is associated with many cancers and viral infections; however, the role of TRIM32 in viral oncogenesis remains largely unknown. In this study, we found that the expression of TRIM32 is elevated by Kaposi's sarcoma-associated herpesvirus (KSHV) in latency, and RTA (the master regulator of lytic replication) induces TRIM32 for proteasome degradation upon viral lytic reactivation. This finding provides a potential therapeutic target for KSHV-associated cancers.

Correction: STAT6 degradation and ubiquitylated TRIML2 are essential for activation of human oncogenic herpesvirus.

[This corrects the article DOI: 10.1371/journal.ppat.1007416.].

Selective feticide in dichorionic diamniotic (DCDA) twins complicated with previable premature rupture of membrane before 24 weeks may be a safe therapeutic alternative to ongoing pregnancy.

BACKGROUND: To date, there are no clinical guidelines for dichorionic diamniotic (DCDA) twins complicated with previable premature rupture of membrane (PV-ROM) before 24 weeks of gestation. The typical management options including expectant management and/or pregnant termination, induce the risks of fetal mortality and morbidity. OBJECTIVE: To explore the feasibility selective feticide in DCDA twins complicated with PV-ROM. STUDY DESIGN: A Retrospective cohort study, enrolling 28 DCDA twins suffering from PV-ROM in a tertiary medical center from Jan 01 2012 to Jan 01 2022. The obstetric outcome was compared between selective feticide group and expectant management group. RESULTS: There were 12 cases managed expectantly and 16 underwent selective feticide. More cases suffered from oligohydramnios in expectant management group compared to selective feticide group (P = 0.008). Among 13 cases with ROM of upper sac, the mean gestational age at delivery was (33.9 ± 4.9) weeks in the selective feticide group, which was significantly higher than that in the expectant management (P = 0.038). Five fetuses (83.3%) with selective feticide delivered after 32 weeks, whereas only one (14.3%) case in expectant management group (P = 0.029). However, in the subgroup with ROM of lower sac, no significant difference of the mean gestation age at delivery between groups and none of cases delivered after 32 weeks. CONCLUSION: There was a trend towards an increase in latency interval in DCDA twins with PV-ROM following selective feticide, compared to that with expectant management. Furthermore, selective feticide in cases with PV-ROM of upper sac has a favorable outcome.

Changes in the characteristics and outcomes of high-risk pregnant women who delivered prior to and after China's universal two-child policy: a real-world retrospective study, 2010-2021.

BACKGROUND: In 2016, the "universal two-child" policy, allowing each couple to have two children, was introduced in China. The characteristic change of the long-term period after the implementation of the universal two-child policy was unclear. We studied trends in the obstetric characteristics and their potential impact on the rates of cesarean section and preterm birth in the era of China's universal two-child policy. METHODS: A tertiary center-based study (2010-2021) retrospectively focused single high-risk pregnancies who delivered from the one-child policy period (OCP, 2010-2015) to the universal two-child policy period (TCP, 2016-2021). A total of 39, 016 pregnancies were enrolled. Maternal demographics, complications, delivery mode and obstetric outcomes were analyzed. Furthermore, logistic regression analysis was used to explore the association between the cesarean section rate, preterm birth and implementation of the universal two-child policy, adjusting maternal age, parity, and fetal distress. RESULTS: Ultimately a total of 39,016 pregnant women met the criteria and were included in this analysis. The proportion of women with advanced maternal age (AMA) increased from 14.6% in the OCP to 31.6% in the TCP. The number of multiparous women increased 2-fold in the TCP. In addition, the overall rate of cesarean section significantly decreased over the policy change, regardless of maternal age, whereas the risk of preterm birth significantly increased in the TCP. Adjusting for maternal age, parity and fetal distress, the universal two-child policy showed a significantly favorable impact on the cesarean section rate (RR 0.745, 95%CI (0.714-0.777), P < 0.001). Compared to the OCP group, a higher increase in fetal distress and premature rupture of membranes (PROM) were observed in the TCP group. In pregnancies with AMA, there was no increase in the risk of postpartum hemorrhage, whereas more women who younger than 35 years old suffered from postpartum hemorrhage in TCP. The logistic regression model showed that the universal two-child policy was positively associated with the risk of postpartum hemorrhage (RR: 1.135, 95%CI: 1.025-1.257, P = 0.015). CONCLUSIONS: After the implementation of the universal two-child policy in China, the rate of the cesarean section significantly decreased, especially for women under 35 years old. However, the overall risk of postpartum hemorrhage increased in women under 35 years old, while there was no change in women with AMA. Under the new population policy, the prevention of postpartum hemorrhage in the young women should not be neglected.

Decoupling of the Confused Complex in Oxidation of 3,3',5,5'-Tetramethylbenzidine for the Reliable Chromogenic Bioassay.

Regulation of the reaction pathways is a perennial theme in the field of chemistry. As a typical chromogenic substrate, 3,3',5,5'-tetramethylbenzidine (TMB) generally undertakes one-electron oxidation, but the product (TMBox1) is essentially a confused complex and is unstable, which significantly hampers the clinic chromogenic bioassays for more than 50 years. Herein, we report that sodium dodecyl sulfate (SDS)-based micelles could drive the direct two-electron oxidation of TMB to the final stable TMBox2. Rather than activation of H2O2 oxidant in the one-electron TMB oxidation by common natural peroxidase, activation of the TMB substrate by SDS micelles decoupled the thermodynamically favorable complex between TMBox2 with unreacted TMB, leading to an unusual direct two-electron oxidation pathway. Mechanism studies demonstrated that the complementary spatial and electrostatic isolation effects, caused by the confined hydrophobic cavities and negatively charged outer surfaces of SDS micelles, were crucial. Further cascading with glucose oxidase, as a proof-of-concept application, allowed glucose to be more reliably measured, even in a broader range of concentrations without any conventional strong acid termination.

A System Based on Novel Parainfluenza Virus PIV5-L for Efficient Gene Delivery of B-Lymphoma Cells.

Aggressive B-cell lymphoma is one of the most common types of blood malignancy. Robust delivery of genes of interest into target cells, long-term gene expression, and minimal risk of secondary effects are highly desirable for translational medicine including gene therapy and studies on gene function. However, efficient gene delivery into viral or nonviral B-lymphoma cells remains a challenge. Here, we report a strategy for inducing foreign gene expression in B-lymphoma cells by using a vector based on the novel parainfluenza virus PIV5-L (a strain isolated from B cells) that enabled us to study and control the function of a gene product within B-lymphoma cells. Using enhanced green fluorescent protein (eGFP) as a reporter, we successfully rescued PIV5-L and established a one-step system to generate PIV5-L virus-like particles (L-VLPs) with efficient delivery into a broad spectrum of susceptible B-lymphoma cell lines, including Epstein-Barr virus (EBV)- or Kaposi's sarcoma-associated herpesvirus (KSHV)-transformed B-lymphoblastoid cells. Similar to lentiviral vector, the L-VLP highly expressed exogenous genes and remained stable for long periods without obvious negative effects on cell viability. Taken together, these data demonstrate that the PIV5-L-based system provides a potential new strategy for the delivery of desirable genes and the treatment of cancer. IMPORTANCE B-cell lymphoma is a common aggressive neoplastic disorder of lymphocytes. Delivery of genes of interest into B cells, particularly virus-mediated B-lymphoma cells, is still a challenge. In this study, we report that a system (L-VLP) based on the parainfluenza virus PIV5-L strain isolated from B cells had highly expressed exogenous genes and remained stable without obvious cell toxicity, which provides a potential new strategy for gene delivery and treatment of B-cell cancer.

Clinical efficacy and acceptability of remote fetal heart rate self-monitoring in Southern China.

BACKGROUND: Compared to traditional fetal heart rate monitoring (FHR) for the outpatients in clinic, remote FHR monitoring shows real-time assessment of fetal wellbeing at home. The clinical function of remote FHR monitoring in pregnant wome in outpatient is still unclear. OBJECTIVE: To explore the feasibility of remote FHR self-monitoring in singleton pregnant women from southern China. STUDY DESIGN: This prospective cohort study was conducted at one tertiary center in southern China. Pregnant women used a mobile cardiotocogram device to measure the FHR at least once a week until delivery in the remote group. For the control group, pregnant women underwent traditional FHR monitoring once a week in the outpatient clinic. The rate of cesarean section, risk of postpartum hemorrhage and adverse neonatal outcomes were compared between the two groups. All the pregnant women completed a questionnaire survey to evaluate their acquisition of remote FHR self-monitoring. RESULTS: Approximately 500 women were recruited in the remote FHR self-monitoring group (remote group), and 567 women were recruited in the traditional FHR monitoring group (control group). The women in the remote FHR monitoring group were more likely to be nulliparous (P < 0.001), more likely to have a higher education level (P < 0.001) and more likely to be at high risk (P = 0.003). There was no significant difference in the risk of cesarean section (P = 0.068) or postpartum hemorrhage (P = 0.836) between the two groups. No difference in fetal complications was observed across groups, with the exception of the incidence of NICU stays, which was higher in the remote group (12.0% vs. 8.3%, P = 0.044). The questionnaire survey showed that the interval time (P = 0.001) and cost (P = 0.010) of fetal heart rate monitoring were lower in the remote group. Regarding age, prepregnancy BMI, risk factors, education level, maternal risk and household income, senior high school (OR 2.86, 95% CI 1.67-4.90, P < 0.001), undergraduate (OR 2.96, 95% CI 1.73-5.06, P < 0.001), advanced maternal age (OR 1.42, 95% CI 1.07-1.89, P = 0.015) and high-risk pregnancy (OR 1.61, 95% CI 1.11-2.35, P = 0.013) were independent factors for pregnant women to choose remote fetal monitoring. Multiparty (OR 0.33, 95% CI 0.21-0.51, P < 0.001), full-time motherhood (OR 0.47, 95% CI 0.33-0.678, P < 0.001) and high household income (OR 0.67, 95% CI 0.50-0.88, P = 0.004) were negatively correlated with the choice of remote FHR self-monitoring. CONCLUSION: Remote FHR self-monitoring technology has a lower cost and shows potential clinical efficacy for the outpatient setting in southern China. This approach does not increase the risk of cesarean section or adverse neonatal outcomes. It is acceptable among nulliparous pregnant women with a high education level, high household income or high risk. Further research is needed to assess the impact of this technology on obstetric outcomes in different health settings.

Rational of topical photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) for treatment of endocervical canal low-grade squamous intraepithelial lesion with high-risk human papillomavirus infection.

BACKGROUND: The detection and continuous monitoring of low-grade squamous intraepithelial lesions (LSIL) within the endocervical canal pose considerable challenges, and the effectiveness of ablation treatment is also constrained. In this context, the potential efficacy of 5-aminolevulinic acid photodynamic therapy (5-ALA PDT) in targeting these concealed lesions merits exploration. The present study undertakes a comprehensive analysis of the clinical effectiveness and safety aspects associated with the utilization of 5-ALA PDT. METHODS: A retrospective analysis was conducted on a cohort of 13 patients who were diagnosed with LSIL within the endocervical canal, concomitant with high-risk human papillomavirus (hrHPV) infection. These patients were subjected to treatment with 5-ALA PDT and subsequently monitored over a period of 3-6 months following the intervention. RESULTS: The study cohort comprised 13 patients, among whom 4 presented with isolated lesions within the endocervical canal, 5 exhibited LSIL involving both the endocervical canal and the cervix vaginal portion, 3 displayed LSIL within the endocervical canal in conjunction with vaginal involvement, and 1 patient demonstrated lesions across all three of these anatomical sites. All identified lesions underwent therapeutic intervention via 5-ALA PDT. Before treatment initiation, 9 patients returned positive results in the liquid-based cytologic test (LBC), 4 displayed concurrent multiple hrHPV infections, and 5 manifested infections specifically with HPV 16/18. Subsequent to the application of 5-ALA PDT, regression was observed in the LBC results of all patients, with only 3 individuals retaining a singular type of hrHPV infection. Adverse reactions following treatment encompassed mild aberrant vaginal secretions and mild to moderately pronounced distending abdominal discomfort, all of which were remitted within a span of 7 days. CONCLUSIONS: Within the context of LSIL within the endocervical canal in association with hrHPV infection, the findings affirm the efficacy and safety of 5-ALA PDT as a viable therapeutic modality.

Insight into Iron Leaching from an Ascorbate-Oxidase-like Fe-N-C Nanozyme and Oxygen Reduction Selectivity.

Ascorbate (H2 A) is a well-known antioxidant to protect cellular components from free radical damage and has also emerged as a pro-oxidant in cancer therapies. However, such "contradictory" mechanisms underlying H2 A oxidation are not well understood. Herein, we report Fe leaching during catalytic H2 A oxidation using an Fe-N-C nanozyme as a ferritin mimic and its influence on the selectivity of the oxygen reduction reaction (ORR). Owing to the heterogeneity, the Fe-Nx sites in Fe-N-C primarily catalyzed H2 A oxidation and 4 e- ORR via an iron-oxo intermediate. Nonetheless, trace O2 ⋅- produced by marginal N-C sites through 2 e- ORR accumulated and attacked Fe-Nx sites, leading to the linear leakage of unstable Fe ions up to 420 ppb when the H2 A concentration increased to 2 mM. As a result, a substantial fraction (ca. 40 %) of the N-C sites on Fe-N-C were activated, and a new 2+2 e- ORR path was finally enabled, along with Fenton-type H2 A oxidation. Consequently, after Fe ions diffused into the bulk solution, the ORR at the N-C sites stopped at H2 O2 production, which was the origin of the pro-oxidant effect of H2 A.

Rapid establishment of murine gastrointestinal organoids using mechanical isolation method.

Gastrointestinal (GI) diseases, including pathological dysplasia, inflammation, neoplasia and injury, suffer millions of patients globally per year. Organoids, three-dimensional cell mass structures supported by biomaterials in dishes, are currently used as a research model for diseases of the small intestine. However, the traditional enzymatic-digestion method for establishing small-intestinal organoids (EnzyOs) is time consuming and often loses the bulk of crypts, a more efficient and reliable method needs to be developed. In this study, using mouse GI organoids as a model, we formulated a rapid mechanical isolation method that could efficiently isolate and culture villi-crypts into small intestinal organoids (MechOs). Primary duodenum organoids generated by MechOs displayed three types of morphology: spheroid, semi-budding and budding, while EnzyOs produced much less budding. Moreover, primary duodenum organoids from MechOs could be subcultured and presented similar gene expression profiles of small intestine specific markers as that from EnzyOs. Importantly, the MechOs method could also be used to generate other types of organoids derived from the stomach, jejunum-ileum, sigmoid-rectum and bile cysts. Taken together, the results show that MechOs could efficiently and economically generate digestive system organoids, providing a potential basis of epithelial organoids for the clinical treatment of gastroenterological diseases.

STUB1 is targeted by the SUMO-interacting motif of EBNA1 to maintain Epstein-Barr Virus latency.

Latent Epstein-Barr virus (EBV) infection is strongly associated with several malignancies, including B-cell lymphomas and epithelial tumors. EBNA1 is a key antigen expressed in all EBV-associated tumors during latency that is required for maintenance of the EBV episome DNA and the regulation of viral gene transcription. However, the mechanism utilized by EBV to maintain latent infection at the levels of posttranslational regulation remains largely unclear. Here, we report that EBNA1 contains two SUMO-interacting motifs (SIM2 and SIM3), and mutation of SIM2, but not SIM3, dramatically disrupts the EBNA1 dimerization, while SIM3 contributes to the polySUMO2 modification of EBNA1 at lysine 477 in vitro. Proteomic and immunoprecipitation analyses further reveal that the SIM3 motif is required for the EBNA1-mediated inhibitory effects on SUMO2-modified STUB1, SUMO2-mediated degradation of USP7, and SUMO1-modified KAP1. Deletion of the EBNASIM motif leads to functional loss of both EBNA1-mediated viral episome maintenance and lytic gene silencing. Importantly, hypoxic stress induces the SUMO2 modification of EBNA1, and in turn the dissociation of EBNA1 with STUB1, KAP1 and USP7 to increase the SUMO1 modification of both STUB1 and KAP1 for reactivation of lytic replication. Therefore, the EBNA1SIM motif plays an essential role in EBV latency and is a potential therapeutic target against EBV-associated cancers.

Comprehensive role of SARS-CoV-2 spike glycoprotein in regulating host signaling pathway.

Since the outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, global public health and the economy have suffered unprecedented damage. Based on the increasing related literature, the characteristics and pathogenic mechanisms of the virus, and epidemiological and clinical features of the disease are being rapidly discovered. The spike glycoprotein (S protein), as a key antigen of SARS-CoV-2 for developing vaccines, antibodies, and drug targets, has been shown to play an important role in viral entry, tissue tropism, and pathogenesis. In this review, we summarize the molecular mechanisms of interaction between S protein and host factors, especially receptor-mediated viral modulation of host signaling pathways, and highlight the progression of potential therapeutic targets, prophylactic and therapeutic agents for prevention and treatment of SARS-CoV-2 infection.

Identification of viral SIM-SUMO2-interaction inhibitors for treating primary effusion lymphoma.

Primary effusion lymphoma (PEL) is an aggressive B-cell malignancy without effective treatment, and caused by the infection of Kaposi's sarcoma-associated herpesvirus (KSHV), predominantly in its latent form. Previously we showed that the SUMO2-interacting motif within the viral latency-associated nuclear antigen (LANASIM) is essential for establishment and maintenance of KSHV latency. Here, we developed a luciferase based live-cell reporter system to screen inhibitors selectively targeting the interaction between LANASIM and SUMO2. Cambogin, a bioactive natural product isolated from the Garcinia genus (a traditional herbal medicine used for cancer treatment), was obtained from the reporter system screening to efficiently inhibit the association of SUMO2 with LANASIM, in turn reducing the viral episome DNA copy number for establishment and maintenance of KSHV latent infection at a low concentration (nM). Importantly, Cambogin treatments not only specifically inhibited proliferation of KSHV-latently infected cells in vitro, but also induced regression of PEL tumors in a xenograft mouse model. This study has identified Cambogin as a novel therapeutic agent for treating PEL as well as eliminating persistent infection of oncogenic herpesvirus.

Lactate Induces Production of the tRNAHis Half to Promote B-lymphoblastic Cell Proliferation.

High plasma lactate is emerging as a critical regulator in development and progression of many human malignancies. Small RNAs derived from cleavage of mature tRNAs have been implicated in many cellular stresses, but the detailed mechanisms that respond to lactic acid (LA; acidic lactate) are not well defined. Here, using an Epstein-Barr virus (EBV)-immortalized B lymphoblastic cell line (LCL) as a model, we report that LA induces cleavage of mature tRNA at the anticodon loop, particularly production of three 5'-tRNA halves (5'-HisGUG, 5'-ValAAC, and 5'-GlyGCC), along with increased expression of RNA polymerase III and angiogenin (ANG). Of these, only the 5'-HisGUG half binds to the chromatin regulator argonaute-2 (AGO2) instead of the AGO1 protein for stability. Notably, the levels of ANG and 5'-HisGUG half expression in peripheral blood mononuclear cells from B cell lymphoma patients are tightly correlated with lactate dehydrogenase (LDH; a lactate indicator) in plasma. Silencing production of the 5'-HisGUG half by small interfering RNA or inhibition of ANG significantly reduces colony formation and growth of LA-induced tumor cells in vitro and in vivo using a murine xenograft model. Overall, our findings identify a novel molecular therapeutic target for the diagnosis and treatment of B cell lymphoma.

Tim-1 alleviates lupus nephritis-induced podocyte injury via regulating autophagy.

INTRODUCTION: Lupus nephritis (LN) is a complication of systemic lupus erythematosus (SLE) which seriously threatens the health of people. Tim-1 is known to be associated with the pathogenesis of SLE. However, the role of Tim-1 in LN is still unclear. AIM OF THE STUDY: To explore the expression and the potential regulatory molecular mechanism of Tim-1 in LN-induced podocyte injury. MATERIAL AND METHODS: An in vivo model of LN was established to detect the expression of Tim-1, inflammatory cytokines and autophagy-related proteins. Podocytes were treated with immunoglobulin G (IgG) to establish the LN in vitro model and then treated with an autophagy inhibitor. RT-qPCR and western blot were performed to investigate the effect of Tim-1 on inflammatory responses as well as autophagy in podocytes. The function of Tim-1 in IgG-induced podocytes was detected by CCK-8 and flow cytometry, respectively. RESULTS: Tim-1, L3BII/L3BI ratio and inflammatory cytokines were upregulated in LN mice. Tim-1 notably inhibited IgG-induced inflammatory responses in podocytes via reducing tumor necrosis factor α (TNF-α), interleukin (IL)-6 and IL-1ß expression, and it could protect podocytes against LN-induced injury via inducing autophagy. Meanwhile, Tim-1 significantly promoted the proliferation of IgG-induced podocytes via inhibiting apoptosis. The autophagy inhibitor reversed the effect of Tim-1 on inflammatory cytokines and autophagy-related proteins in IgG-treated podocytes. CONCLUSIONS: Tim-1 protects podocytes against LN-induced injury via mediating autophagy, which might serve as a new target for the treatment of LN.

STAT6 degradation and ubiquitylated TRIML2 are essential for activation of human oncogenic herpesvirus.

Aberrations in STAT6-mediated signaling are linked to the development of multiple cancer types. Increasing evidence has shown that activation of human oncogenic herpesvirus lytic replication is crucial for viral tumorigenesis. However, the role of STAT6 in herpesvirus lytic replication remains elusive. Here, by using Kaposi's sarcoma-associated herpesvirus (KSHV) as a model, we revealed that RTA, the master regulator of lytic replication, interacts with STAT6 and promotes lysine 48 (K48) and K63-linked ubiquitylation of STAT6 for degradation via the proteasome and lysosome systems. Moreover, degradation of STAT6 is dramatically associated with the increased ubiquitylated form of tripartite motif family like 2 (TRIML2, a tumor suppressor) for prolonged cell survival and virion production, which is also commonly observed in lytic activation of Epstein-Barr virus, herpes simplex virus 1 and cytomegalovirus. These results suggest that degradation of STAT6 is important for the lytic activation of KSHV and as such, may be an attractive therapeutic target.

Effective Trapping of Polysulfides Using Functionalized Thin-Walled Porous Carbon Nanotubes as Sulfur Hosts for Lithium-Sulfur Batteries.

Owing to their high aspect ratios and structures of high-mechanical-strength conductive scaffolds, carbon nanotubes (CNTs) are considered to be one of the most promising hosts for sulfur in lithium-sulfur batteries (LSBs). However, traditional CNTs with impermeable walls are not conducive to the penetration of sulfur, resulting in a large number of sulfur exposures to the electrolyte. Therefore, it is difficult to effectively limit the shuttle effect of polysulfides. Here, a kind of thin-walled porous amorphous carbon nanotube (HCNT) is adopted as the host for sulfur in LSBs. To further alleviate the shuttle effect, oxygen-containing functional groups (OCFGs) are introduced to modify HCNTs to form HOCNTs. The S/HOCNT composite with the embedded structure is successfully constructed. The S/HOCNT cathode demonstrates glorious cycling and rate performance (798.5 mAh g-1 at 0.2 C after 100 cycles and 511.6 mAh g-1 at 1 C after 500 cycles). The excellent electrochemical performance of S/HOCNT can be attributed to the embedded structure of sulfur in HOCNTs, which avoids direct contact with the electrolytes and strong bonding action of OCFGs and polysulfides, effectively limiting the shuttle effect of polysulfides.

Lactic Acid Downregulates Viral MicroRNA To Promote Epstein-Barr Virus-Immortalized B Lymphoblastic Cell Adhesion and Growth.

High plasma lactate is associated with poor prognosis of many malignancies, but its role in virally mediated cancer progression and underlying molecular mechanisms are unclear. Epstein-Barr virus (EBV), the first human oncogenic virus, causes several cancers, including B-cell lymphoma. Here, we report that lactate dehydrogenase A (LDH-A) expression and lactate production are elevated in EBV-immortalized B lymphoblastic cells, and lactic acid (LA; acidic lactate) at low concentration triggers EBV-infected B-cell adhesion, morphological changes, and proliferation in vitro and in vivo Moreover, LA-induced responses of EBV-infected B cells uniquely occurs in viral latency type III, and it is dramatically associated with the inhibition of global viral microRNAs, particularly the miR-BHRF1 cluster, and the high expression of SMAD3, JUN, and COL1A genes. The introduction of miR-BHRF1-1 blocks the LA-induced effects of EBV-infected B cells. Thus, this may be a novel mechanism to explain EBV-immortalized B lymphoblastic cell malignancy in an LA microenvironment.IMPORTANCE The tumor microenvironment is complicated, and lactate, which is created by cell metabolism, contributes to an acidic microenvironment that facilitates cancer progression. However, how LA operates in virus-associated cancers is unclear. Thus, we studied how EBV (the first tumor virus identified in humans; it is associated with many cancers) upregulates the expression of LDH-A and lactate production in B lymphoma cells. Elevated LA induces adhesion and the growth of EBV-infected B cells by inhibiting viral microRNA transcription. Thus, we offer a novel understanding of how EBV utilizes an acidic microenvironment to promote cancer development.

Nuclear Localization and Cleavage of STAT6 Is Induced by Kaposi's Sarcoma-Associated Herpesvirus for Viral Latency.

Emerging evidence implies that STAT6 plays an important role in both the adaptive and innate immune responses to virus infection. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic γ-herpesvirus agent associated with several human malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphomas (PELs). Previously, we demonstrated that KSHV blocks IL-4-induced STAT6 phosphorylation and retains a basal IL-13/STAT6 constitutive activation for cell survival and proliferation. However, the mechanism by which KSHV regulates STAT6 remains largely unknown. Here, we found that KSHV-encoded LANA interacts with STAT6 and promotes nuclear localization of STAT6 independent of the tyrosine 641-phosphorylation state. Moreover, nuclear localization of STAT6 is also dramatically increased in KS tissue. The latent antigen LANA induces serine protease-mediated cleavage of STAT6 in the nucleus, where the cleaved STAT6 lacking transactivation domain functions as a dominant-negative regulator to repress transcription of Replication and Transcription Activator (RTA) and in turn shut off viral lytic replication. Blockade of STAT6 by small interference RNA dramatically enhances expression of RTA, and in turn reduces KSHV-infected endothelial cell growth and colony formation. Taken together, these results suggest that nuclear localization and cleavage of STAT6 is important for modulating the viral latency and pathogenesis of KSHV.

High prevalence and correlates of human herpesvirus-6A in nevocytic nevus and seborrheic diseases: Implication from a pilot study of skin patient tissues in Shanghai.

Skin disorders vary greatly in symptom and severity, and the causes of these disorders are largely unknown. Human herpesvirus (HHV) has been shown to cause many diseases. However, the prevalence and correlation of each HHV infection with different skin disorders remains obscure. To reveal the potential link of a certain type of skin disease with herpesvirus infection, a total of 272 patient tissues with inflammatory or neoplastic skin diseases including 7 subtypes in Shanghai, China, were investigated. We found that the overall prevalence of HHV-6A in inflammatory or neoplastic skin tissues is the most common (40.3%), followed by Epstein-Barr virus (17.6%), Kaposi's sarcoma-associated herpesvirus (KSHV; 9.2%), HHV-6B (4.4%), human cytomegalovirus (1.1%), and varicella-zoster virus (0.7%); albeit the co-infection of HHV-6A, Epstein-Barr virus, and KSHV presents to a less extent and none of HSV-1, HSV-2, or HHV-7 were detected. Moreover, HHV-6A infection is highly associated with nevocytic nevus and seborrheic dermatitis/keratosis diseases, which mainly occur in the head and the neck or the lower limb. Despite no significant difference among the HHV infections in different age groups of skin patient tissues, the distribution of KSHV infection was exclusively and significantly higher (~3.7-fold) in male skin patients.