Detection of a novel gammaherpesvirus (genus Rhadinovirus) in wild muntjac deer in Northern Ireland

This study represents the initial part of an investigation into the potential for non-native, wild, free-living muntjac deer (Muntiacus reevesi) to carry viruses that could be a threat to livestock. A degenerate PCR assay was used to screen a range of tissues from muntjac deer culled in Northern Ireland for the presence of herpesviral nucleic acids. This was followed by sequencing of PCR amplicons and phylogenetic analysis. We report the detection of a novel gammaherpesvirus most closely related to a type 2 ruminant rhadinovirus from mule deer. It remains to be determined if this new virus is pathogenic to deer or presents a risk to food security through the susceptibility of domestic livestock

Cancers associated with Kaposi's sarcoma (KS) in AIDS: a link between KS herpesvirus and immunoblastic lymphoma

Kaposi's sarcoma (KS), common among persons with acquired immunodeficiency syndrome (AIDS), is caused by KS herpesvirus (KSHV) but whether KSHV causes other malignancies is uncertain. Using linked United States AIDS and cancer registries, we measured the incidence of specific malignancies in persons with AIDS (4–27 months after AIDS onset). We identified associations with KSHV by calculating a relative risk: cancer incidence in persons with KS (all were KSHV-infected) divided by incidence in persons without KS. Using Poisson regression, relative risks were adjusted for human immunodeficiency virus risk group, gender, age, race, and calendar year. We included 189 159 subjects (26 972 with KS). Immunoblastic lymphoma was significantly associated with KS (506 cases; relative risks: unadjusted 2.44, 95%CI 2.00–2.96, adjusted 1.58, 95%CI 1.29–1.93). Only one immunoblastic lymphoma had pleura as primary site. None of 37 other specified malignancies (other non-Hodgkin lymphomas, haematological malignancies, solid tumours) was significantly associated with KS. In summary, the association of immunoblastic lymphoma with KS was specific among examined malignancies and remained significant after statistical adjustment. Our findings, and the previously demonstrated presence of KSHV in the histologically related primary effusion lymphoma, suggest that KSHV is involved in the pathogenesis of some immunoblastic lymphomas. © 2001 Cancer Research Campaig

Comparison of risk prediction scores for venous thromboembolism in cancer patients:A prospective cohort study

In ambulatory patients with solid cancer, routine thromboprophylaxis to prevent venous thromboembolism is not recommended. Several risk prediction scores to identify cancer patients at high risk of venous thromboembolism have been proposed, but their clinical usefulness remains a matter of debate. We evaluated and directly compared the performance of the Khorana, Vienna, PROTECHT, and CONKO scores in a multinational, prospective cohort study. Patients with advanced cancer were eligible if they were due to undergo chemotherapy or had started chemotherapy in the previous three months. The primary outcome was objectively confirmed symptomatic or incidental deep vein thrombosis or pulmonary embolism during a 6-month followup period. A total of 876 patients were enrolled, of whom 260 (30%) had not yet received chemotherapy. Fifty-three patients (6.1%) developed venous thromboembolism. The c-statistics of the scores ranged from 0.50 to 0.57. At the conventional positivity threshold of 3 points, the scores classified 13-34% of patients as high-risk; the 6-month incidence of venous thromboembolism in these patients ranged from 6.5% (95% CI: 2.8-12) for the Khorana score to 9.6% (95% CI: 6.6-13) for the PROTECHT score. High-risk patients had a significantly increased risk of venous thromboembolism when using the Vienna (subhazard ratio 1.7; 95% CI: 1.0-3.1) or PROTECHT (subhazard ratio 2.1; 95% CI: 1.23.6) scores. In conclusion, the prediction scores performed poorly in predicting venous thromboembolism in cancer patients. The Vienna CATS and PROTECHT scores appear to discriminate better between low-and high-risk patients, but further improvements are needed before they can be considered for introduction into clinical practice

Development of real-time NASBA assays with molecular beacon detection to quantify mRNA coding for HHV-8 lytic and latent genes

BACKGROUND: Human herpesvirus-8 (HHV-8) is linked to the pathogenesis of Kaposi's sarcoma (KS), and the HHV-8 DNA load in peripheral blood mononuclear cells (PBMC) is associated with the clinical stage of KS. To examine the expression of HHV-8 in PBMC, four HHV-8 mRNA specific NASBA assays were developed METHODS: We have developed four quantitative nucleic acid sequence-based amplification assays (NASBA-QT) specifically to detect mRNA coding for ORF 73 (latency-associated nuclear antigen, LANA), vGCR (a membrane receptor), vBcl-2 (a viral inhibitor of apoptosis) and vIL-6 (a viral growth factor). The NASBA technique amplifies nucleic acids without thermocycling and mRNA can be amplified in a dsDNA background. A molecular beacon is used during amplification to enable real-time detection of the product. The assays were tested on PBMC samples of two AIDS-KS patients from the Amsterdam Cohort. RESULTS: For all four assays, the limit of detection (LOD) of 50 molecules and the limit of quantification (LOQ) of 100 molecules were determined using in vitro transcribed RNA. The linear dynamic range was 50 to 10(7) molecules of HHV-8 mRNA. We found HHV-8 mRNA expression in 9 out of the 10 tested samples. CONCLUSION: These real-time NASBA assays with beacon detection provide tools for further study of HHV-8 expression in patient material

Kaposi's Sarcoma-Associated Herpesvirus ORF45 Interacts with Kinesin-2 Transporting Viral Capsid-Tegument Complexes along Microtubules

Open reading frame (ORF) 45 of Kaposi's sarcoma-associated herpesvirus (KSHV) is a tegument protein. A genetic analysis with a null mutant suggested a possible role for this protein in the events leading to viral egress. In this study, ORF45 was found to interact with KIF3A, a kinesin-2 motor protein that transports cargoes along microtubules to cell periphery in a yeast two-hybrid screen. The association was confirmed by both co-immunoprecipitation and immunoflorescence approaches in primary effusion lymphoma cells following virus reactivation. ORF45 principally mediated the docking of entire viral capsid-tegument complexes onto the cargo-binding domain of KIF3A. Microtubules served as the major highways for transportation of these complexes as evidenced by drastically reduced viral titers upon treatment of cells with a microtubule depolymerizer, nocodazole. Confocal microscopic images further revealed close association of viral particles with microtubules. Inhibition of KIF3A–ORF45 interaction either by the use of a headless dominant negative (DN) mutant of KIF3A or through shRNA-mediated silencing of endogenous KIF3A expression noticeably decreased KSHV egress reflecting as appreciable reductions in the release of extracellular virions. Both these approaches, however, failed to impact HSV-1 egress, demonstrating the specificity of KIF3A in KSHV transportation. This study thus reports on transportation of KSHV viral complexes on microtubules by KIF3A, a kinesin motor thus far not implicated in virus transportation. All these findings shed light on the understudied but significant events in the KSHV life cycle, delineating a crucial role of a KSHV tegument protein in cellular transport of viral particles

Awareness of venous thromboembolism among patients with cancer: Preliminary findings from a global initiative for World Thrombosis Day

BACKGROUND Cancer-associated venous thromboembolism (CAT) has detrimental impact on patients' clinical outcomes and quality of life. Data on CAT education, communication, and awareness among the general cancer population are scanty. METHODS We present the preliminary results of an ongoing patient-centered survey including 27 items covering major spheres of CAT. The survey, available in 14 languages, was promoted and disseminated online through social networks, email newsletters, websites, and media. RESULTS As of September 20, 2022, 749 participants from 27 countries completed the survey. Overall, 61.8% (n = 460) of responders were not aware of their risk of CAT. Among those who received information on CAT, 26.2% (n = 56) were informed only at the time of CAT diagnosis. Over two thirds (69.1%, n = 501) of participants received no education on signs and symptoms of venous thromboembolism (VTE); among those who were educated about the possible clinical manifestations, 58.9% (n = 119) were given instructions to seek consultation in case of VTE suspicion. Two hundred twenty-four respondents (30.9%) had a chance to discuss the potential use of primary thromboprophylaxis with health-care providers. Just over half (58.7%, n = 309) were unaware of the risks of bleeding associated with anticoagulation, despite being involved in anticoagulant-related discussions or exposed to anticoagulants. Most responders (85%, n = 612) valued receiving CAT education as highly relevant; however, 51.7% (n = 375) expressed concerns about insufficient time spent and clarity of education received. CONCLUSIONS This ongoing survey involving cancer patients with diverse ethnic, cultural, and geographical backgrounds highlights important patient knowledge gaps. These findings warrant urgent interventions to improve education and awareness, and reduce CAT burden

Primary effusion lymphoma associated with Human Herpes Virus-8 and Epstein Barr virus in an HIV-infected woman from Kampala, Uganda: a case report

<p>Abstract</p> <p>Introduction</p> <p>Primary effusion lymphoma is a recently recognized entity of AIDS related non-Hodgkin lymphomas. Despite Africa being greatly affected by the HIV/AIDS pandemic, an extensive MEDLINE/PubMed search failed to find any report of primary effusion lymphoma in sub-Saharan Africa. To our knowledge this is the first report of primary effusion lymphoma in sub-Saharan Africa. We report the clinical, cytomorphologic and immunohistochemical findings of a patient with primary effusion lymphoma.</p> <p>Case presentation</p> <p>A 70-year-old newly diagnosed HIV-positive Ugandan African woman presented with a three-month history of cough, fever, weight loss and drenching night sweats. Three weeks prior to admission she developed right sided chest pain and difficulty in breathing. On examination she had bilateral pleural effusions.</p> <p>Haematoxylin and eosin stained cytologic sections of the formalin-fixed paraffin-embedded cell block made from the pleural fluid were processed in the Department of Pathology, Makerere University, College of Health Sciences, Kampala, Uganda. Immunohistochemistry was done at the Institute of Haematology and Oncology "L and A Seragnoli", Bologna University School of Medicine, Bologna, Italy, using alkaline phosphatase anti-alkaline phosphatase method. <it>In situ </it>hybridization was used for detection of Epstein-Barr virus.</p> <p>The tumor cells were CD45+, CD30+, CD38+, HHV-8 LANA-1+; but were negative for CD3-, CD20-, CD19-, and CD79a- and EBV RNA+ on <it>in situ </it>hybridization. CD138 and Ki-67 were not evaluable. Our patient tested HIV positive and her CD4 cell count was 127/μL.</p> <p>Conclusions</p> <p>A definitive diagnosis of primary effusion lymphoma rests on finding a proliferation of large immunoblastic, plasmacytoid and anaplastic cells; HHV-8 in the tumor cells, an immunophenotype that is CD45+, pan B-cell marker negative and lymphocyte activated marker positive. It is essential for clinicians and pathologists to have a high index of suspicion of primary effusion lymphoma when handling HIV positive patients who have effusions without palpable tumor masses. Basic immunohistochemistry is essential for definitive diagnosis.</p

Immunosenescence and lymphomagenesis

One of the most important determinants of aging-related changes is a complex biological process emerged recently and called \u201cimmunosenescence\u201d. Immunosenescence refers to the inability of an aging immune system to produce an appropriate and effective response to challenge. This immune dysregulation may manifest as increased susceptibility to infection, cancer, autoimmune disease, and vaccine failure. At present, the relationship between immunosenescence and lymphoma in elderly patients is not defined in a satisfactory way. This review presents a brief overview of the interplay between aging, cancer and lymphoma, and the key topic of immunosenescence is addressed in the context of two main lymphoma groups, namely Non Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL). Epstein Barr Virus (EBV) plays a central role in the onset of neoplastic lymphoproliferation associated with immunological changes in aging, although the pathophysiology varies vastly among different disease entities. The interaction between immune dysfunction, immunosenescence and Epstein Barr Virus (EBV) infection appears to differ between NHL and HL, as well as between NHL subtypes

Kaposi's Sarcoma Herpesvirus Upregulates Aurora A Expression to Promote p53 Phosphorylation and Ubiquitylation

Aberrant expression of Aurora A kinase has been frequently implicated in many cancers and contributes to chromosome instability and phosphorylation-mediated ubiquitylation and degradation of p53 for tumorigenesis. Previous studies showed that p53 is degraded by Kaposi's sarcoma herpesvirus (KSHV) encoded latency-associated nuclear antigen (LANA) through its SOCS-box (suppressor of cytokine signaling, LANASOCS) motif-mediated recruitment of the EC5S ubiquitin complex. Here we demonstrate that Aurora A transcriptional expression is upregulated by LANA and markedly elevated in both Kaposi's sarcoma tissue and human primary cells infected with KSHV. Moreover, reintroduction of Aurora A dramatically enhances the binding affinity of p53 with LANA and LANASOCS-mediated ubiquitylation of p53 which requires phosphorylation on Ser215 and Ser315. Small hairpin RNA or a dominant negative mutant of Aurora A kinase efficiently disrupts LANA-induced p53 ubiquitylation and degradation, and leads to induction of p53 transcriptional and apoptotic activities. These studies provide new insights into the mechanisms by which LANA can upregulate expression of a cellular oncogene and simultaneously destabilize the activities of the p53 tumor suppressor in KSHV-associated human cancers