Pulmonary tumor thrombotic microangiopathy and pulmonary veno-occlusive disease in a woman with cervical cancer treated with cediranib and durvalumab

Abstract Background Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare cause of pulmonary hypertension that is associated with malignancies and is marked by the presence of non-occlusive tumor emboli and fibrocellular intimal proliferation of small pulmonary arteries leading to increased pulmonary vascular resistance and right heart failure. The diagnosis of PTTM is challenging to make pre-mortem and guidelines on treatment are lacking. Case presentation A 45-year-old woman with advanced squamous cell carcinoma of the cervix developed symptoms of dyspnea and evidence of right heart failure during a phase I clinical trial with cediranib and durvalumab. After an extensive evaluation, pre-capillary pulmonary hypertension was confirmed by right heart catheterization. Vasodilator therapy was initiated but resulted in the development of symptomatic hypoxemia and was discontinued. Despite continued supportive care, she continued to decline and was transitioned to hospice care. At autopsy, the cause of her right heart failure was found to be due to PTTM with features of pulmonary veno-occlusive disease (PVOD). Conclusion PTTM and PVOD are important diagnoses to consider in patients with a malignancy and the development of right heart failure and may be manifestations of a spectrum of similar disease processes

Mineralocorticoid Receptor (MR)trans-Activation of Inflammatory AP-1 Signaling

901 Santa Clara Avenue Alameda, CA 94501exterior, "Asaalaamu Alaikum" inscription on men's entrance door, 201

Late Multiple Organ Surge in Interferon-Regulated Target Genes Characterizes Staphylococcal Enterotoxin B Lethality

<div><p>Background</p><p>Bacterial superantigens are virulence factors that cause toxic shock syndrome. Here, the genome-wide, temporal response of mice to lethal intranasal staphylococcal enterotoxin B (SEB) challenge was investigated in six tissues.</p><p>Results</p><p>The earliest responses and largest number of affected genes occurred in peripheral blood mononuclear cells (PBMC), spleen, and lung tissues with the highest content of both T-cells and monocyte/macrophages, the direct cellular targets of SEB. In contrast, the response of liver, kidney, and heart was delayed and involved fewer genes, but revealed a dominant genetic program that was seen in all 6 tissues. Many of the 85 uniquely annotated transcripts participating in this shared genomic response have not been previously linked to SEB. Nine of the 85 genes were subsequently confirmed by RT-PCR in every tissue/organ at 24 h. These 85 transcripts, up-regulated in all tissues, annotated to the interferon (IFN)/antiviral-response and included genes belonging to the DNA/RNA sensing system, DNA damage repair, the immunoproteasome, and the ER/metabolic stress-response and apoptosis pathways. Overall, this shared program was identified as a type I and II interferon (IFN)-response and the promoters of these genes were highly enriched for IFN regulatory matrices. Several genes whose secreted products induce the IFN pathway were up-regulated at early time points in PBMCs, spleen, and/or lung. Furthermore, IFN regulatory factors including Irf1, Irf7 and Irf8, and Zbp1, a DNA sensor/transcription factor that can directly elicit an IFN innate immune response, participated in this host-wide SEB signature.</p><p>Conclusion</p><p>Global gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death. Therapies aimed at IFN-associated innate immunity may improve outcome in toxic shock syndromes.</p></div

Quantitative real-time PCR (qRT-PCR) confirmation of tissue-wide changes in gene expression.

<p>Nine genes were quantitated by qRT-PCR across all 6 tissues at 24 h. (A) Scatter plot of all genes and tissues tested comparing microarray and qRT-PCR fold-change from control. As shown by the line of identify (x  =  y), qRT-PCR typically returned higher fold-change results than microarray. Gene specific results, colored by tissue (see Legend), are shown as follows: (B) Cxcl11; (C) Herc6; (D) Irf1; (E) Irf8; (F) Irgm1; (G) Parp12; (H) Stat1; (I) Xaf1; and (J) Zbp1. All qRT-PCR results met the >1.5 fold-change cut-off for gene selection, except for measurements of Irf8 in PBMCs and spleen. However, Irf8 similarly failed selection by microarray in these tissues at 24 h. Four samples were tested per tissue. Each PBMC sample represented a pool of multiple mice while each organ sample came from an individual mouse.</p

Functional network of selected upstream-regulators and differentially expressed genes across all tissues.

<p>From among the significant nodes identified using the Ingenuity Pathway Analysis® (IPA®) Upstream Regulator tool, the following were selected for inclusion in the displayed network: 1) the T-cell receptor (TCR), as this is the primary target of staphylococcal enterotoxin B (SEB)-mediated cell activation (colored orange at the network center); 2) TNF, IL-1β, IL-2, IFNγ and IL-12B, as these are known interferon (IFN) pathway initiators that were expressed early in the peripheral blood mononuclear cells and/or spleens of the SEB challenged mice (colored blue and positioned as the inner most ring of the network); and 3) any upstream regulator that was also present on our all-tissue list of differentially expressed genes (colored in shades of red proportional to fold-change) and positioned as the next ring moving outward. The resulting network connected 70 of 79 genes recognized by IPA®. The remaining 9 genes (outside of the outermost ring) were connected manually (see text) using PubMed and STRING (<a href="http://string-db.org/newstring_cgi/" target="_blank">http://string-db.org/newstring_cgi/</a>) version 9.05, a database of known and predicted protein-protein interactions. A key defining colors, shapes, and relationships is shown. In addition, changes in gene symbols from those in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088756#pone-0088756-g001" target="_blank">Figure 1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088756#pone-0088756-t003" target="_blank">Table 3</a> are provided for clarity. Also note that IPA® frequently defaults to all-capital gene symbols that denote human genes, while elsewhere the mouse format is followed of only capitalizing the first letter.</p