Left Atrial High-grade Sarcoma With Focal Osteosarcomatous Differentiation.

Approximately 75% of cardiac tumors are benign, and 25% are malignant cardiac tumors. Of these, sarcomas are extremely rare and have been described in isolated case reports. Due to its rarity, there is no published guideline for the management of this pathological entity. We present a case of an 85-year-old female who presented to our hospital with a chief complaint of shortness of breath and pinpointed left-sided chest pain. Computed tomography of the chest showed a filling defect in the left atrium concerning a mass versus thrombus. A transesophageal echocardiogram showed a 4 cm multi-lobular echogenic mass with calcifications in the left atrium likely arising from the pulmonary vein suspicious for malignancy. Cardiovascular surgery department scheduled the patient for surgical debulking/removal via a minimally invasive approach. The specimen was reported to be multi-lobular and was resected in several fragments of tan, fleshy, and somewhat gelatinous appearing tissue in aggregate. Histopathology showed spindle cell malignant neoplasm with small foci of bone and cartilaginous formation, suggestive of osteosarcoma. Expert consultation at John Hopkins reported this to be a high-grade sarcoma with focal osteosarcomatous differentiation. Cardiac synovial sarcomas are less than 0.1% of all primary cardiac tumors reported in the literature. Cardiac synovial sarcomas are not extensively described in literature due to their low incidence and prevalence. Thus, it is important to report cases and follow outcomes. This case reports an extremely rare diagnosis that has been reported in less than seven case reports.

Cocaine enhances HIV-1 infectivity in monocyte derived dendritic cells by suppressing microRNA-155.

Cocaine and other drugs of abuse increase HIV-induced immunopathogenesis; and neurobiological mechanisms of cocaine addiction implicate a key role for microRNAs (miRNAs), single-stranded non-coding RNAs that regulate gene expression and defend against viruses. In fact, HIV defends against miRNAs by actively suppressing the expression of polycistronic miRNA cluster miRNA-17/92, which encodes miRNAs including miR-20a. IFN-g production by natural killer cells is regulated by miR-155 and this miRNA is also critical to dendritic cell (DC) maturation. However, the impact of cocaine on miR-155 expression and subsequent HIV replication is unknown. We examined the impact of cocaine on two miRNAs, miR-20a and miR-155, which are integral to HIV replication, and immune activation. Using miRNA isolation and analysis, RNA interference, quantitative real time PCR, and reporter assays we explored the effects of cocaine on miR-155 and miR-20 in the context of HIV infection. Here we demonstrate using monocyte-derived dendritic cells (MDCCs) that cocaine significantly inhibited miR-155 and miR-20a expression in a dose dependent manner. Cocaine and HIV synergized to lower miR-155 and miR-20a in MDDCs by 90%. Cocaine treatment elevated LTR-mediated transcription and PU.1 levels in MDCCs. But in context of HIV infection, PU.1 was reduced in MDDCs regardless of cocaine presence. Cocaine increased DC-SIGN and and decreased CD83 expression in MDDC, respectively. Overall, we show that cocaine inhibited miR-155 and prevented maturation of MDDCs; potentially, resulting in increased susceptibility to HIV-1. Our findings could lead to the development of novel miRNA-based therapeutic strategies targeting HIV infected cocaine abusers.

MicroRNA: implications in HIV, a brief overview.

MicroRNAs (miRNAs) are 20-22 nucleotide length noncoding RNA molecules that represent key regulators of many normal cellular functions. miRNAs undergo two processing steps which transform a long primary transcript into the mature miRNA. Available literatures demonstrate the association between alterations in the expression of miRNAs and the progression of numerous human disorders. Even though significant advances have been made, many fundamental questions about their expression and function still remain unanswered. Identifying factors that block the negative action of drugs of abuse on the miRNAs could help in identifying new therapeutic strategies. In this review, we briefly discuss the importance of miRNAs on HIV, strategies used by virus to avoid the cells' antiviral miRNA defenses, and how HIV might control and regulate host cell genes by encoding viral miRNAs.

HIV-1 Tat upregulates expression of histone deacetylase-2 (HDAC2) in human neurons: implication for HIV-associated neurocognitive disorder (HAND).

Histone deacetylases (HDACs) play a pivotal role in epigenetic regulation of transcription and homeostasis of protein acetylation in histones and other proteins involved in chromatin remodeling. Histone hypoacetylation and transcriptional dysfunction have been shown to be associated with a variety of neurodegenerative diseases. More recently, neuron specific overexpression of HDAC2 has been shown to modulate synaptic plasticity and learning behavior in mice. However, the role of HDAC2 in development of HIV-associated neurocognitive disorders (HAND) is not reported. Herein we report that HIV-1 Tat protein upregulate HDAC2 expression in neuronal cells leading to transcriptional repression of genes involved in synaptic plasticity and neuronal function thereby contributing to the progression of HAND. Our results indicate upregulation of HDAC2 by Tat treatment in dose and time dependant manner by human neuroblastoma SK-N-MC cells and primary human neurons. Further, HDAC2 overexpression was associated with concomitant downregulation in CREB and CaMKIIa genes that are known to regulate neuronal activity. These observed effects were completely blocked by HDAC2 inhibition. These results for the first time suggest the possible role of HDAC2 in development of HAND. Therefore, use of HDAC2 specific inhibitor in combination with HAART may be of therapeutic value in treatment of neurocognitive disorders observed in HIV-1 infected individuals.

Interactive role of human immunodeficiency virus type 1 (HIV-1) clade-specific Tat protein and cocaine in blood-brain barrier dysfunction: implications for HIV-1-associated neurocognitive disorder.

In recent years, increasing interest has emerged to assess the human immunodeficiency virus type 1 (HIV-1) clade C viral pathogenesis due to its anticipated spread in the United States and other western countries. Previous studies suggest that clade C is less neuropathogenic than clade B; however, the underlying mechanism is poorly understood. Additionally, the interactive role of drugs of abuse such as cocaine on clade C-associated neuropathogenesis has not been reported. In the current study, we hypothesize that HIV-1 clade-specific Tat proteins exert differential effects on blood-brain barrier (BBB) integrity and cocaine further differentially aggravates the BBB dysfunction. We evaluated the effect of Tat B and Tat C and/or cocaine on the BBB integrity using an in vitro model constructed with primary human brain microvascular endothelial cells (HBMECs) and astrocytes. The BBB membrane integrity was measured by transendothelial electrical resistance (TEER) and paracellular permeability was measured by fluorescein isothiocyanate (FITC)-dextran transport assay and monocytes transmigration across the BBB. Results indicate that Tat B disrupts BBB integrity to a greater extent compared to Tat C and cocaine further differentially exacerbates the BBB dysfunction. This BBB dysfunction was associated with altered expression of tight junction proteins zona occuldens (ZO-1) and junctional adhesion molecule (JAM)-2. Thus, these results for the first time delineate the differential role of Tat B and Tat C and/or cocaine in BBB dysfunction, which may be correlated with the clade-specific differences observed in HIV-1-associated neurological disorders.