Immune escape of avian oncogenic Marek's disease herpesvirus and antagonistic host immune responses.

Marek's disease virus (MDV) is a highly pathogenic and oncogenic alpha herpesvirus that causes Marek's disease (MD), which is one of the most important immunosuppressive and rapid-onset neoplastic diseases in poultry. The onset of MD lymphomas and other clinical diseases can be efficiently prevented by vaccination; these vaccines are heralded as the first demonstration of a successful vaccination strategy against a cancer. However, the persistent evolution of epidemic MDV strains towards greater virulence has recently resulted in frequent outbreaks of MD in vaccinated chicken flocks worldwide. Herein, we provide an overall review focusing on the discovery and identification of the strategies by which MDV evades host immunity and attacks the immune system. We have also highlighted the decrease in the immune efficacy of current MD vaccines. The prospects, strategies and new techniques for the development of efficient MD vaccines, together with the possibilities of antiviral therapy in MD, are also discussed.

Hepatic arterial infusion therapy for advanced hepatocellular carcinoma after systemic treatment failure: Multicenter, real-world study.

AIM: The study was conducted to evaluate the feasibility and safety profile of hepatic arterial infusion chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (HAIC-FOLFOX) as an alternative therapeutic choice for patients with advanced hepatocellular carcinoma (HCC) that is refractory to systemic treatment including immune checkpoint blockades or molecular targeting agents. METHODS: Two hundred and forty five consecutive patients with advanced HCC who received HAIC-FOLFOX treatment after systemic treatment failure were retrospectively reviewed in six institutions and their survival, tumor response, and tolerance were assessed. RESULTS: The median overall survival (OS) and progression-free survival of the 209 included participants were 10.5 months (95% confidence interval [CI], 8.1-12.9) and 6.0 months (95% CI, 5.1-6.9), respectively. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, the objective response rate was 21.1%, and the disease control rate was 64.6%. Multivariate analysis of risk factors of OS were albumin-bilirubin grade (2 and 3 vs. 1, hazard ratio [HR] 1.57; 95% CI, 1.05-2.34; p = 0.028), tumor number (>3 vs. 1-3, HR 2.18; 95% CI, 1.10-4.34; p = 0.026), extrahepatic spread (present vs. absent, HR 1.61, 95% CI, 1.06-2.45; p = 0.027), synchronous systemic treatment (present vs. absent, HR 0.55, 95% CI, 0.37-0.83; p = 0.004) and treatment response (responder vs. nonresponder, HR 0.30, 95% CI, 0.17-0.53; p < 0.001). Grade 3-4 adverse events (AEs) occurred in 59 (28.2%) HCC patients. All AEs were manageable, and deaths related to hepatic artery infusion chemotherapy treatment were not observed. CONCLUSIONS: Our findings support the effectiveness and safety of HAIC-FOLFOX treatment for patients with advanced HCC who have failed systemic treatment.

Critical roles of non-coding RNAs in lifecycle and biology of Marek's disease herpesvirus.

Over the past two decades, numerous non-coding RNAs (ncRNAs) have been identified in different biological systems including virology, especially in large DNA viruses such as herpesviruses. As a representative oncogenic alphaherpesvirus, Marek's disease virus (MDV) causes an important immunosuppressive and rapid-onset neoplastic disease of poultry, namely Marek's disease (MD). Vaccinations can efficiently prevent the onset of MD lymphomas and other clinical disease, often heralded as the first successful example of vaccination-based control of cancer. MDV infection is also an excellent model for research into virally-induced tumorigenesis. Recently, great progress has been made in understanding the functions of ncRNAs in MD biology. Herein, we give a review of the discovery and identification of MDV-encoded viral miRNAs, focusing on the genomics, expression profiles, and emerging critical roles of MDV-1 miRNAs as oncogenic miRNAs (oncomiRs) or tumor suppressor genes involved in the induction of MD lymphomas. We also described the involvements of host cellular miRNAs, lincRNAs, and circRNAs participating in MDV life cycle, pathogenesis, and/or tumorigenesis. The prospects, strategies, and new techniques such as the CRISPR/Cas9-based gene editing applicable for further investigation into the ncRNA-mediated regulatory mechanisms in MDV pathogenesis/oncogenesis were also discussed, together with the possibilities of future studies on antiviral therapy and the development of new efficient MD vaccines.

Pathogenicity and Pathotype Analysis of Henan Isolates of Marek's Disease Virus Reveal Long-Term Circulation of Highly Virulent MDV Variant in China.

In recent years, outbreaks of Marek's disease (MD) have been frequently reported in vaccinated chicken flocks in China. Herein, we have demonstrated that four Marek's disease virus (MDV) isolates, HN502, HN302, HN304, and HN101, are all pathogenic and oncogenic to hosts. Outstandingly, the HN302 strain induced 100% MD incidence, 54.84% mortality, and 87.10% tumor incidence, together with extensive atrophy of immune organs. Pathotyping of HN302 was performed in comparison to a standard very virulent (vv) MDV strain Md5. We found that both CVI988 and HVT vaccines significantly reduced morbidity and mortality induced by HN302 or Md5 strains, but the protection indices (PIs) provided by these two vaccines against HN302 were significantly lower (27.03%) or lower (33.33%) than that against Md5, which showed PIs of 59.89% and 54.29%, respectively. These data suggested that HN302 possesses a significant higher virulence than Md5 and at least could be designated as a vvMDV strain. Together with our previous phylogenetic analysis on MDV-1 meq genes, we have presently suggested HN302 to be a typical highly virulent MDV variant belonging to an independent Chinese branch. To our knowledge, this is the first report to provide convincible evidence to identify a pathogenic MDV variant strain with a higher virulence than Md5 in China, which may have emerged and circulating in poultry farms in China for a long time and involved in the recent MD outbreaks.

Evaluating the influence of 6MV and 10MV photon beams on cervical cancer volumetric-modulated arc therapy plans.

BACKGROUND: Cervical cancer is a common gynecological cancer among women worldwide. OBJECTIVE: To determine the effects of 6 MV and 10 MV volumetric-modulated arc therapy (VMAT) photon beams on the target volume (TV) planning and critical organs in cases of cervical cancer. METHODS: Fifty patients with carcinoma of the cervix who underwent radiotherapy were selected. The transverse diameter (T) of the cross section of the upper edge of the sacroiliac joint on computerized tomography (CT) images of the patients was measured, and the mean value was calculated as 34 cm. All patients were divided into two groups: Group A (T < 34 cm) and Group B (T > 34 cm). The VMAT plans were generated using 6 MV and 10 MV plans separately. The prescription dose was 47.5 Gy, and the daily dose was 1.9 Gy. RESULTS: In Group A, the planning target volume (PTV) dose assessment parameters of 6 MV and 10 MV plans and their homogeneity and conformity indices were not statistically significantly different. A significant difference was observed between the 6 MV and 10 MV plans for the PTV dose assessment parameters and the homogeneity index of the plans for Group B. The monitor units (MUs) of the 10 MV plans were lower than in the 6 MV plans in both Groups A and B, and the difference was statistically significant. The assessment parameter V40 Gy of both the rectum and bladder in the 6 MV plans was smaller than the corresponding parameter in the 10 MV plans in Group A; in Group B, the assessment parameter V50 Gy of the rectum in the 10 MV plans was smaller than in the 6 MV plans. CONCLUSION: When T < 34 cm, 6 MV energy is more suitable for the external irradiation of cervical cancer. When T > 34 cm, 10 MV energy is more suitable for cervical cancer radiotherapy. Therefore, 10 MV should be considered for patients with a large abdominal size.

Dosimetric analysis of postoperative radiotherapy for thymoma.

PURPOSE: To compare the dosimetric differences between intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) in the treatment of male and female thymoma. MATERIAL AND METHODS: This single-institutional analysis included 20 patients with thymoma treated with RT between January 2017 and December 2020. Twenty patients were retrospectively planned for IMRT (IMRT1 with an average field angle of 216°, 288°, 0°, 72°,and 144°; IMRT2 with fan-shaped field angles of 280°, 320°, 0°, 40°, and 80°) and VMAT (VMAT1 with two arcs ranging form 280° to 80°,clockwise and then counterclockwise; VMAT2 with two 360° arcs). The plans for all investigated RT modalities were optimized for a prescriptional dose of 50Gy and fractional dose of 2.0Gy. Planning target volume (PTV) and organs-at-risk (OARs: heart, breasts, lungs, spinal cord, and esophagus) dosimetric parameters were compared. RESULTS: All plans met the preparation aims for all the included metrics. There was little difference in the median values of PTV parameters (D2%, D98%, Dmean, homogeneity index[HI], and conformity index [CI]). The CI of the VMAT2 plan was the closest to 1 in both therapy groups. The monitor unit (MU) of IMRT2 and the estimated total delivery time of VMAT1 were the lowest in both therapy groups and were statistically significant. In the male group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) for VMAT1 were the lowest and showed statistical significance. In the female group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) and bilateral breast parameters (Dmean, V5Gy, V10Gy, and V20Gy) of IMRT2 were the lowest and showed statistical significance. CONCLUSIONS: In male thymoma patients undergoing postoperative RT (PORT) treatment, the choice of fan-shaped VMAT may be a better option for protecting the lungs. For female thymoma patients receiving PORT, fan-shaped IMRT can better protect the lungs and breasts. The fan-shaped field performed better than the average and the full arc fields in PORT for thymoma.

Virus-encoded miR-155 ortholog in Marek's disease virus promotes cell proliferation via suppressing apoptosis by targeting tumor suppressor WWOX.

Marek's disease virus serotype 1 (MDV-1) is an important oncogenic α-herpesvirus that induces immunosuppressive and rapid-onset T-cell lymphomatous disease in poultry commonly referred to as Marek's disease (MD). As an excellent biomodel for the study of virally-induced cancers in natural hosts, MDV-1 encoded microRNAs (miRNAs) have been previously demonstrated with the potential roles to act as critical regulators in virus replication, latency, pathogenesis and especially in oncogenesis. Similar to the oncogenic γ-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV), miR-M4-5p, the cellular microRNA-155 (miR-155) ortholog encoded by MDV-1, is also involved in MD oncogenesis. In lymphoblastoid cell lines derived from MDV-induced T-cell lymphomas, miR-M4-5p has been shown to be highly expressed and participate in inducing MD lymphomagenesis by regulating multiple signal pathways. Herein we report the new identification of the host WW domain-containing oxidoreductase (WWOX) as a biological target for miR-M4-5p. Further experiments revealed that as a critical oncomiRNA, miR-M4-5p promotes the proliferations of both chicken embryo fibroblast (CEF) and MSB-1 cells via suppressing cell apoptosis by targeting WWOX, a well-known tumor suppressor. Our data presents a novel insight in elucidating the regulatory mechanisms mediated by the viral analog of miR-155 that potentially contribute to MD tumorigenesis.

Marek's Disease Virus (Gallid alphaherpesvirus 2)-Encoded miR-M2-5p Simultaneously Promotes Cell Proliferation and Suppresses Apoptosis Through RBM24 and MYOD1-Mediated Signaling Pathways.

MicroRNAs (miRNAs) have been demonstrated for their involvement in virus biology and pathogenesis, including functioning as key determinants of virally-induced cancers. As an important oncogenic α-herpesvirus affecting poultry health, Marek's disease virus serotype 1 [Gallid alphaherpesvirus 2 (GaHV-2)] induces rapid-onset T-cell lymphomatous disease commonly referred to as Marek's disease (MD), an excellent biological model for the study of virally-induced cancer in the natural hosts. Previously, we have demonstrated that GaHV-2-encoded miRNAs (especially those within the Meq-cluster) have the potential to act as critical regulators of multiple processes such as virus replication, latency, pathogenesis, and/or oncogenesis. In addition to miR-M4-5p (miR-155 homolog) and miR-M3-5p, we have recently found that miR-M2-5p possibly participate in inducing MD lymphomagenesis. Here, we report the identification of two tumor suppressors, the RNA-binding protein 24 (RBM24) and myogenic differentiation 1 (MYOD1), being two biological targets for miR-M2-5p. Our experiments revealed that as a critical miRNA, miR-M2-5p promotes cell proliferation via regulating the RBM24-mediated p63 overexpression and MYOD1-mediated IGF2 signaling and suppresses apoptosis by targeting the MYOD1-mediated Caspase-3 signaling pathway. Our data present a new strategy of a single viral miRNA exerting dual role to potentially participate in the virally-induced T-cell lymphomagenesis by simultaneously promoting the cell proliferation and suppressing apoptosis.

Lymphopenia in Esophageal Squamous Cell Carcinoma: Relationship to Malnutrition, Various Disease Parameters, and Response to Concurrent Chemoradiotherapy.

BACKGROUND: Lymphopenia occurs commonly in esophageal squamous cell carcinoma (ESCC) and may influence treatment outcomes. We aimed to examine its association with treatment response and tumor progression in patients with locally advanced ESCC treated with concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: A total of 286 patients with stage II-IVa ESCC treated with CCRT between 2015 and 2017 were analyzed. Total lymphocyte counts were assessed at baseline, weekly, and 4 weeks after CCRT. Pretreatment lymphopenia was defined as total lymphocyte count <1,000 cells per mm3 at diagnosis, and treatment-related lymphopenia was defined as total lymphocyte count <200 cells per mm3 with 6 weeks after starting CCRT. Univariate and multivariate logistic regression methods were used to analyze factors associated treatment-related lymphopenia and treatment response. RESULTS: Lymphopenia was observed in 44 patients (15.4%) at initial diagnosis. Pretreatment lymphopenia was significantly associated with greater tumor length, worse T status, body mass index ≤18.5 kg/m2, and weight loss ≥3 kg in the previous 3 months. Six weeks after starting CCRT, 89 patients (31%) developed treatment-related lymphopenia. Tumor progression and cancer-related death were more frequently observed in treatment-related lymphopenia group than those without (76.4% vs. 52.8% and 58.4% vs. 39.6%). A complete response (CR) was achieved in 62 patients (21.7%). In multivariate analysis, treatment-related lymphopenia was significantly associated with lack of clinical CR, and older age, lower tumor location, greater tumor length, and larger planning target volume were independent predictors of treatment-related lymphopenia. CONCLUSION: Treatment-related lymphopenia during CCRT is an independent predictor for poor treatment response in ESCC. IMPLICATIONS FOR PRACTICE: A total of 286 patients with locally advanced esophageal squamous cell carcinoma were treated with concurrent chemoradiotherapy (CCRT), and treatment-related lymphopenia occurred in 31% of patients within 6 weeks from the start of CCRT. Treatment-related lymphopenia was significantly associated with lack of treatment response, and older age, lower tumor location, greater tumor length, and larger planning target volume were independent predictors of treatment-related lymphopenia. Lymphocyte count is an inexpensive biomarker that may be easily used by clinicians to identify patients who are most likely to benefit from CCRT.

[Regulation of c-fos gene expression in hepatic stellate cells by transforming growth factor beta].

OBJECTIVE: To investigate the effects of transforming growth factor beta (TGF ) on c-fos gene expression in hepatic stellate cells. METHODS: Hepatic stellate cells (HSC-T6) were cultured in the medium containing different concentrations of TGF (0.2, 1, and 5 ng/ml), and cells were collected at different time points of incubation (8, 24, 48, and 72 h). The total RNA of the HSCs was isolated and c-fos gene expression level were measured by reverse transcription polymerase chain reaction. RESULTS: c-fos gene expression levels of HSCs cultured in the presence of low (0.2 ng/ml), moderate (1 ng/ml) and high (5 ng/ml) concentrations of TGF for 8, 24, 48 and 72 h were significantly greater than those of control group. The c-fos gene expression levels of HSCs increased gradually with the increment of TGF concentration, and significant differences in c-fos gene expression were found between the 3TGF groups. CONCLUSION: TGF strongly up-regulates c-fos gene expression in hepatic stellate cells.