Maladaptation after a virus host switch leads to increased activation of the pro-inflammatory NF-κB pathway.

Myxoma virus (MYXV) causes localized cutaneous fibromas in its natural hosts, tapeti and brush rabbits; however, in the European rabbit, MYXV causes the lethal disease myxomatosis. Currently, the molecular mechanisms underlying this increased virulence after cross-species transmission are poorly understood. In this study, we investigated the interaction between MYXV M156 and the host protein kinase R (PKR) to determine their crosstalk with the proinflammatory nuclear factor kappa B (NF-κB) pathway. Our results demonstrated that MYXV M156 inhibits brush rabbit PKR (bPKR) more strongly than European rabbit PKR (ePKR). This moderate ePKR inhibition could be improved by hyperactive M156 mutants. We hypothesized that the moderate inhibition of ePKR by M156 might incompletely suppress the signal transduction pathways modulated by PKR, such as the NF-κB pathway. Therefore, we analyzed NF-κB pathway activation with a luciferase-based promoter assay. The moderate inhibition of ePKR resulted in significantly higher NF-κB­dependent reporter activity than complete inhibition of bPKR. We also found a stronger induction of the NF-κB target genes TNFα and IL-6 in ePKR-expressing cells than in bPKR-expressing cells in response to M156 in both transfection and infections assays. Furthermore, a hyperactive M156 mutant did not cause ePKR-dependent NF-κB activation. These observations indicate that M156 is maladapted for ePKR inhibition, only incompletely blocking translation in these hosts, resulting in preferential depletion of short­half-life proteins, such as the NF-κB inhibitor IκBα. We speculate that this functional activation of NF-κB induced by the intermediate inhibition of ePKR by M156 may contribute to the increased virulence of MYXV in European rabbits.

Effect of Myxoma Virus Species Jump on Iberian Hare Populations.

The myxoma virus species jump from European rabbits (Oryctolagus cuniculus) to Iberian hares (Lepus granatensis) has raised concerns. We assess the decline suffered by Iberian hare populations on the Iberian Peninsula and discuss the association between the effect of myxomatosis and the average abundance index, which we estimated by using hunting bags.

High Levels of Extracellular Potassium Can Delay Myxoma Virus Replication by Preventing Release of Virions from the Endosomes.

Potassium (K+) is one of the most abundant cations in the human body. Under normal conditions, the vast majority of K+ is found within cells, and the extracellular [K+] is tightly regulated to within 3.0 to 5.0 mM. However, it has recently been shown that high levels of localized necrosis can increase the extracellular concentration of K+ to above 50 mM. This raises the possibility that elevated extracellular K+ might influence a variety of biological processes that occur within regions of necrotic tissue. For example, K+ has been shown to play a central role in the replication cycles of numerous viral families, and in cases of lytic infection, localized regions containing large numbers of necrotic cells can be formed. Here, we show that the replication of the model poxvirus myxoma virus (MYXV) is delayed by elevated levels of extracellular K+. These increased K+ concentrations alter the cellular endocytic pathway, leading to increased phagocytosis but a loss of endosomal/lysosomal segregation. This slows the release of myxoma virus particles from the endosomes, resulting in delays in genome synthesis and infectious particle formation as well as reduced viral spread. Additionally, mathematical modeling predicts that the extracellular K+ concentrations required to impact myxoma virus replication can be reached in viral lesions under a variety of conditions. Taken together, these data suggest that the extracellular [K+] plays a role in determining the outcomes of myxoma infection and that this effect could be physiologically relevant during pathogenic infection. IMPORTANCE Intracellular K+ homeostasis has been shown to play a major role in the replication of numerous viral families. However, the potential impact of altered extracellular K+ concentrations is less well understood. Our work demonstrates that increased concentrations of extracellular K+ can delay the replication cycle of the model poxvirus MYXV by inhibiting virion release from the endosomes. Additionally, mathematical modeling predicts that the levels of extracellular K+ required to impact MYXV replication can likely be reached during pathogenic infection. These results suggest that localized viral infection can alter K+ homeostasis and that these alterations might directly affect viral pathogenesis.

10× single-cell sequencing revealed cellular composition heterogeneity in cardiac myxoma with malignant glandular properties.

Cardiac myxoma is the most common primary cardiac tumor in adults. The histogenesis and cellular composition of myxoma are still unclear. This study aims to reveal the role of myxoma cell components and their gene expression in tumor development. We obtained single living cells by enzymatic digestion of tissues from 4 cases of surgically resected cardiac myxoma. Of course, there was 1 case of glandular myxoma and 3 cases of nonglandular myxoma. Then, 10× single-cell sequencing was performed. We identified 12 types and 11 types of cell populations in glandular myxoma and nonglandular myxoma, respectively. Heterogeneous epithelial cells are the main components of glandular myxoma. The similarities and differences in T cells in both glandular and nonglandular myxoma were analyzed by KEGG and GO. The most important finding was that there was active communication between T cells and epithelial cells. These results clarify the possible tissue occurrence and heterogeneity of cardiac myxoma and provide a theoretical basis and guidance for clinical diagnosis and treatment.

Comparative analysis of two novel complete genomes of myxoma virus vaccine strains.

Myxoma virus (MYXV) is a double-stranded DNA-containing virus of the family Poxviridae, genus Leporipoxvirus. MYXV is an important model virus for evolutionary and immunological research and a promising oncolytic. In this study, we sequenced and analyzed two complete genomes of MYXV virus vaccine strains B-82 and Rabbivac-B, which are widely used for vaccine production in Russia. Here, we first show that MYXV vaccine strains B-82 and Rabbivac-B share a common origin with the American recombinant MYXV MAV vaccine strain. In addition, our data suggest that the MYXV B-82 and Rabbivac-B strains contain a number of genes at the 5' and 3' ends that are identical to the virulent MYXV Lausanne strain. Several unique genetic signatures were identified in the M013L, M017L, M023, and M121R genes, helping to achieve high genetic resolution between vaccine strains. Overall, these findings highlight the evolutionary flexibility of certain genes in the MYXV genome and provide insights into the molecular epidemiology of the virus and subsequent vaccine development.

Myxoma with rich blood supply in the left atrium.

Cardiac myxoma is the most common primary benign cardiac tumors, mostly found in the left atrium. It was previously reported that the main component of myxoma was myxoid stroma riched in acid-mucopolysaccharide, the blood vessels in which were sparsely distributed, being characterized as hypovascular tumor by contrast echocardiography (CE) and computed tomography angiography (CTA). There are few reports of myxoma with rich blood supply and we report one in the left atrium.

Incidental finding of atrial myxoma following curative treatment for paediatric neuroblastoma.

Cardiac tumours are uncommon in the general population and even more so in the paediatric population. Here we present a case of an asymptomatic 7-year-old male with history of high-risk neuroblastoma who underwent 1-year post-treatment surveillance scan with an incidental finding of intracardiac lesion found to be an atrial myxoma.

Pulmonary embolism from right ventricular myxoma in a child with undiagnosed Carney complex.

Pediatric pulmonary embolism occurs in 8.6-57 per 100,000 hospitalised children. We report a novel case of bilateral pulmonary emboli in a child presenting with dyspnoea who was found to have large right ventricular myxoma and subsequent diagnosis of Carney complex. After resection of the right ventricular myxoma and bilateral pulmonary embolectomy, she had a full recovery and an excellent outcome.

The Role of Methylation Analysis in Distinguishing Cellular Myxoma from Low-Grade Myxofibrosarcoma.

Cellular myxoma is a benign soft tissue tumor frequently associated with GNAS mutation that may morphologically resemble low-grade myxofibrosarcoma. This study aimed to identify the undescribed methylation profile of cellular myxoma and compare it to myxofibrosarcoma. We performed molecular analysis on twenty cellular myxomas and nine myxofibrosarcomas and analyzed the results using the methylation-based DKFZ sarcoma classifier. A total of 90% of the cellular myxomas had GNAS mutations (four loci had not been previously described). Copy number variations were found in all myxofibrosarcomas but in none of the cellular myxomas. In the classifier, none of the cellular myxomas reached the 0.9 threshold. Unsupervised t-SNE analysis demonstrated that cellular myxomas form their own clusters, distinct from myxofibrosarcomas. Our study shows the diagnostic potential and the limitations of molecular analysis in cases where morphology and immunohistochemistry are not sufficient to distinguish cellular myxoma from myxofibrosarcoma, particularly regarding GNAS wild-type tumors. The DKFZ sarcoma classifier only provided a valid prediction for one myxofibrosarcoma case; this limitation could be improved by training the tool with a more considerable number of cases. Additionally, the classifier should be introduced to a broader spectrum of mesenchymal neoplasms, including benign tumors like cellular myxoma, whose distinct methylation pattern we demonstrated.

Autocrine Regulation of Interleukin-6 via the Activation of STAT3 and Akt in Cardiac Myxoma Cells.

Plasma concentrations of a pleiotropic cytokine, interleukin (IL)-6, are increased in patients with cardiac myxoma. We investigated the regulation of IL-6 in cardiac myxoma. Immunohistochemical staining and reverse transcription-polymerase chain reaction (RT-PCR) revealed that IL-6 and its receptors, IL-6 receptor (IL-6R) and gp130, co-existed in the myxoma cells. Myxoma cells were cultured, and an antibody array assay showed that a conditioned medium derived from the cultured myxoma cells contained increased amounts of IL-6. Signal transducer and activator of transcription (STAT) 3 and Akt were constitutively phosphorylated in the myxoma cells. An enzyme-linked immunosorbent assay (ELISA) showed that the myxoma cells spontaneously secreted IL-6 into the culture medium. Real-time PCR revealed that stimulation with IL-6 + soluble IL-6R (sIL6R) significantly increased IL-6 mRNA in the myxoma cells. Pharmacological inhibitors of STAT3 and Akt inhibited the IL-6 + sIL-6R-induced gene expression of IL-6 and the spontaneous secretion of IL-6. In addition, IL-6 + sIL-6R-induced translocation of phosphorylated STAT3 to the nucleus was also blocked by STAT3 inhibitors. This study has demonstrated that IL-6 increases its own production via STAT3 and Akt pathways in cardiac myxoma cells. Autocrine regulation of IL-6 may play an important role in the pathophysiology of patients with cardiac myxoma.

Renal Embolism Associated with the Atrial Myxoma: A Case Report and Literature Review.

Renal embolisms due to cardiac myxomas are extremely rare; the clinical course, treatment, and prognosis of this disease are not established. A 69-year-old Japanese woman who underwent a nephrectomy for renal cell carcinoma 3 years earlier was hospitalized with a right occipital lobe cerebral infarction. Her renal function suddenly worsened 3 days post-admission: her serum creatinine rose from 1.46 mg/dL to 6.57 mg/dL and then to 8.03 mg/dL the next day, and hemodialysis therapy was started. Abdominal computed tomography (CT) scans showed patchy non-contrasted low-density areas in the right kidney, and chest CT scans and transesophageal ultrasonography revealed a left atrial tumor. We diagnosed renal infarction due to a left atrial myxoma. Hemodialysis and anticoagulant therapy (heparin) were continued, followed by the cardiac myxoma's resection. The patient's renal function gradually improved post-surgery, and the hemodialysis was discontinued. Considering our patient and 19 other case reports of renal infarction associated with cardiac myxoma, the treatment for such a renal infarction and the outcomes differ depending on the embolus site. The poor outcome of abdominal aortic embolism requires a prompt embolectomy, whereas a branch renal artery embolism requires anticoagulation therapy to prevent thrombosis formation around the myxoma.

Divergent Evolutionary Pathways of Myxoma Virus in Australia: Virulence Phenotypes in Susceptible and Partially Resistant Rabbits Indicate Possible Selection for Transmissibility.

To characterize the ongoing evolution of myxoma virus in Australian rabbits, we used experimental infections of laboratory rabbits to determine the virulence and disease phenotypes of recent virus isolates. The viruses, collected between 2012 and 2015, fell into three lineages, one of which, lineage c, experienced a punctuated increase in evolutionary rate. All viruses were capable of causing acute death with aspects of neutropenic septicemia, characterized by minimal signs of myxomatosis, the occurrence of pulmonary edema and bacteria invasions throughout internal organs, but with no inflammatory response. For the viruses of highest virulence all rabbits usually died at this point. In more attenuated viruses, some rabbits died acutely, while others developed an amyxomatous phenotype. Rabbits that survived for longer periods developed greatly swollen cutaneous tissues with very high virus titers. This was particularly true of lineage c viruses. Unexpectedly, we identified a line of laboratory rabbits with some innate resistance to myxomatosis and used these in direct comparisons with the fully susceptible rabbit line. Importantly, the same disease phenotype occurred in both susceptible and resistant rabbits, although virulence was shifted toward more attenuated grades in resistant animals. We propose that selection against inflammation at cutaneous sites prolongs virus replication and enhances transmission, leading to the amyxomatous phenotype. In some virus backgrounds this creates an immunosuppressive state that predisposes to high virulence and acute death. The alterations in disease pathogenesis, particularly the overwhelming bacterial invasions that characterize the modern viruses, suggest that their virulence grades are not directly comparable with earlier studies. IMPORTANCE The evolution of the myxoma virus (MYXV) following its release as a biological control for European rabbits in Australia is the textbook example of the coevolution of virus virulence and host resistance. However, most of our knowledge of MYXV evolution only covers the first few decades of its spread in Australia and often with little direct connection between how changes in virus phenotype relate to those in the underlying virus genotype. By conducting detailed experimental infections of recent isolates of MYXV in different lines of laboratory rabbits, we examined the ongoing evolution of MYXV disease phenotypes. Our results reveal a wide range of phenotypes, including an amyxomatous type, as well as the impact of invasive bacteria, that in part depended on the level of rabbit host resistance. These results provide a unique insight into the complex virus and host factors that combine to shape disease phenotype and viral evolution.

Sinonasal Myxoma: A Distinct Entity or a Myxoid Variant of Desmoid Fibromatosis?

Sinonasal myxoma (SNM) is a rare benign mesenchymal tumor that arises in the sinonasal cavity or maxilla and almost exclusively affects young children. Currently, it is considered a specific entity, but its molecular characteristics have not been reported. Lesions diagnosed as SNM and odontogenic myxoma/fibromyxoma were identified from the participating institutions, and the clinicopathologic features were recorded. Immunohistochemistry for ß-catenin was performed in all cases with available tissue. Next-generation sequencing was performed in all cases with SNM. Five patients with SNM were identified, including 3 boys and 2 girls with an age range of 20-36 months (mean: 26 months). The tumors were well defined, centered in the maxillary sinus, surrounded by a rim of woven bone, and composed of a moderately cellular proliferation of spindle cells oriented in intersecting fascicles in a variably myxocollagenous stroma that contained extravasated erythrocytes. Histologically, the tumors resembled myxoid desmoid fibromatosis. Three tested cases showed nuclear expression of ß-catenin. In 3 tumors, next-generation sequencing revealed intragenic deletions of APC exons 5-6, 9 and 15, or 16, respectively, with concurrent loss of the other wild-type copy of APC predicted to result in biallelic inactivation. The deletions were identical to those that occur in desmoid fibromatosis, and copy number analysis raised the possibility that they were germline. In addition, 1 case showed the possible deletion of APC exons 12-14, and another case exhibited a CTNNB1 p. S33C mutation. Ten patients with odontogenic myxoma/fibromyxoma were identified, including 4 women and 6 men (mean age: 42 years). Seven tumors involved the mandible and 3 the maxilla. Histologically, the tumors differed from SNM, and all cases lacked nuclear expression of ß-catenin. These findings suggest that SNM represents a myxoid variant of desmoid fibromatosis that often arises in the maxilla. The APC alterations might be germline, and therefore, genetic testing of the affected patients should be considered.

The benign nature and rare occurrence of cardiac myxoma as a possible consequence of the limited cardiac proliferative/ regenerative potential: a systematic review.

BACKGROUND: Cardiac Myxoma is a primary tumor of heart. Its origins, rarity of the occurrence of primary cardiac tumors and how it may be related to limited cardiac regenerative potential, are not yet entirely known. This study investigates the key cardiac genes/ transcription factors (TFs) and signaling pathways to understand these important questions. METHODS: Databases including PubMed, MEDLINE, and Google Scholar were searched for published articles without any date restrictions, involving cardiac myxoma, cardiac genes/TFs/signaling pathways and their roles in cardiogenesis, proliferation, differentiation, key interactions and tumorigenesis, with focus on cardiomyocytes. RESULTS: The cardiac genetic landscape is governed by a very tight control between proliferation and differentiation-related genes/TFs/pathways. Cardiac myxoma originates possibly as a consequence of dysregulations in the gene expression of differentiation regulators including Tbx5, GATA4, HAND1/2, MYOCD, HOPX, BMPs. Such dysregulations switch the expression of cardiomyocytes into progenitor-like state in cardiac myxoma development by dysregulating Isl1, Baf60 complex, Wnt, FGF, Notch, Mef2c and others. The Nkx2-5 and MSX2 contribute predominantly to both proliferation and differentiation of Cardiac Progenitor Cells (CPCs), may possibly serve roles based on the microenvironment and the direction of cell circuitry in cardiac tumorigenesis. The Nkx2-5 in cardiac myxoma may serve to limit progression of tumorigenesis as it has massive control over the proliferation of CPCs. The cardiac cell type-specific genetic programming plays governing role in controlling the tumorigenesis and regenerative potential. CONCLUSION: The cardiomyocytes have very limited proliferative and regenerative potential. They survive for long periods of time and tightly maintain the gene expression of differentiation genes such as Tbx5, GATA4 that interact with tumor suppressors (TS) and exert TS like effect. The total effect such gene expression exerts is responsible for the rare occurrence and benign nature of primary cardiac tumors. This prevents the progression of tumorigenesis. But this also limits the regenerative and proliferative potential of cardiomyocytes. Cardiac Myxoma develops as a consequence of dysregulations in these key genes which revert the cells towards progenitor-like state, hallmark of CM. The CM development in carney complex also signifies the role of TS in cardiac cells.

Cortical ischemic lesions from atrial myxoma as a mimic of disease activity in an RRMS antiCD20-treated patient.

Cortical lesions (CLs) detected with double inversion recovery (DIR) magnetic resonance imaging (MRI) are very helpful in differentiating multiple sclerosis (MS) from other neuroinflammatory diseases of the central nervous system (CNS), that is, neuromyelitis optica spectrum disorders (NMOSDs). Furthermore, CLs are closely related to motor and cognitive impairment. We report a case of a 48-year-old female MS patient who developed several CLs during anti-CD20 therapy. Some CLs disappeared during follow-up MRIs. In the suspicion of a treatment failure, the screening for the autologous hematopoietic stem cell transplant (AHSCT) was performed with the evidence of an atrial myxoma. In MS patients with new CLs, a comorbid ischemic pathology should be considered and carefully investigated.

Quantifying resistance to myxomatosis in wild rabbits produces novel evolutionary insights.

Wild rabbits in Australia developed genetic resistance to the myxoma virus, which was introduced as a biological control agent. However, little is known about the rate at which this evolutionary change occurred. We collated data from challenge trials that estimated rabbit resistance to myxomatosis in Australia and expressed resistance on a continuous scale, enabling trends in its development to be assessed over 45 years up to 1995. Resistance initially increased rapidly, followed by a plateau lasting ten years, before a second rapid increase occurred associated with the introduction of European rabbit fleas as myxoma virus vectors. By contrast, in the United Kingdom, where rabbit flea vectors were already present when the myxoma virus initially spread, resistance developed more slowly. No estimates of rabbit resistance to myxomatosis have been made for almost 30 years, despite other highly lethal rabbit pathogens becoming established worldwide. Continued testing of wild-caught rabbits in Australia to determine current levels of resistance to myxomatosis is recommended to assess its current effectiveness for managing pest rabbits. Given the economic and environmental significance of invasive rabbits, it would be remiss to manage such biological resources and ecosystem services poorly.

A rare case of cutaneous myxoma with trichofolliculoma-like features.

Carney complex is a rare genetic disorder associated with a number of cutaneous lesions, especially cutaneous myxomas. We present a rare case of cutaneous myxoma (superficial angiomyxoma) with trichofolliculoma-like features in a patient with Carney complex, and explore how the associated histopathology provides critical context for elucidating the etiology of this benign neoplasm.

Atrial septal hematogenous cyst with calcification mimicking myxoma: A rare case.

A 61-year-old female presented with right atrial mass during physical examination. Contrast-enhanced left heart echocardiography revealed a mass with the size of 32*23 mm in the right atrium, attached to the atrial septum; there was a certain degree of activity and deformation. MRI showed a mass of about 35*22 mm in the right atrium adjacent to the atrial septum, which was diagnosed with right atrial myxoma. Intraoperative TEE showed that the mass was located in the atrial septum close to the inferior vena cava and spontaneous echo contrast with hyperechoic images within the mass. The lesion was resected under cardiopulmonary bypass. Pathological examination revealed that the filling defect was an atrial septal hematogenous cyst with calcification.

Echocardiography in cardioembolic stroke prevention.

Stroke is a leading cause of mortality and disability, and cardiac embolism accounts for one-third of all ischaemic strokes. Thirty per cent of strokes are cryptogenic. In this setting, echocardiography is essential in the diagnosis, treatment, and prevention of embolic stroke of undetermined source since it is a widely available, safe, and inexpensive tool. Transthoracic echocardiography and transoesophageal echocardiography, furthermore, are proven to change therapeutic management leading to initiation of anti-coagulation, anti-microbial therapy, patent foramen ovale (PFO) closure, or cardiac tumour resection. The most common cardioembolic sources include left atrial appendage thrombus, left ventricular thrombus, vegetations in endocarditis, paradoxical embolization in PFO, prosthesis thrombosis, and intracardiac tumours. Although the presence of a cardioembolic source only represents a risk factor for an ischaemic stroke, it could not assure the certain or the unique cause of the event. The purpose of this review is to underline the importance of echocardiography and overview the main sources of cardiac embolism and the echocardiographic features.

Clinical characteristics, management, and outcomes of pulmonary valve myxoma: systematic review of published case reports.

BACKGROUND: Cardiac myxoma is the most common type of primary cardiac tumor, with the majority located in the atrial wall. The tumor is attached to valvular structures in a few cases, of which the pulmonary valve is the least affected. Pulmonary valve myxoma may have different clinical manifestations from the more common cardiac myxomas because of its vital position. A misdiagnosis of these types of cardiac myxoma may be detrimental to the care and well-being of patients. Therefore, this systematic review aims to define the clinical characteristics of pulmonary valve myxoma and how this differs from a more common cardiac myxoma. METHODS: Employed literature was obtained from PubMed, ScienceDirect, Scopus, Springer, and ProQuest without a publication year limit on August 23, 2022. The keyword was "pulmonary valve myxoma." Inclusion criteria were as follows: (1) case report or series, (2) available individual patient data, and (3) myxoma that is attached to pulmonary valve structures with no evidence of metastasis. Non-English language or nonhuman subject studies were excluded. Johanna Briggs Institute checklists were used for the risk of bias assessment. Data are presented descriptively. RESULTS: This review included 9 case reports from 2237 articles. All cases show a low risk of bias. Pulmonary valve myxoma is dominated by males (5:4), and the patient's median age is 57 years with a bimodal distribution in pediatric and geriatric populations. The clinical manifestation of pulmonary valve myxoma is often unspecified or asymptomatic. However, systolic murmur in the pulmonary valve area is heard in 67% of cases. Echocardiography remains the diagnostic modality of choice in the majority of cases. Tumor attached to the pulmonary cusps or annulus and extended to adjacent tissues in all cases. Therefore, valve replacement or adjacent tissue reconstructions are required in 77% of cases. The recurrence and mortality are considerably high, with 33% and 22% cases, respectively. CONCLUSIONS: Pulmonary valve myxoma is more common in males with a bimodal age distribution, and its outcomes seem worse than usual cardiac myxomas. Increasing awareness of its clinical symptoms, early diagnosis, and complete myxoma resection before the presence of congestive heart failure symptoms are important in achieving excellent outcomes. A firm embolization blockade is needed to prevent myxoma recurrence.