Jennifer Barnas

The prevalence and nature of orgasmic dysfunction after radical prostatectomy.

Section Editor

Humanized Mouse Model of Ovarian Cancer Recapitulates Patient Solid Tumor Progression, Ascites Formation, and Metastasis

Ovarian cancer is the most common cause of death from gynecological cancer. Understanding the biology of this disease, particularly how tumor-associated lymphocytes and fibroblasts contribute to the progression and metastasis of the tumor, has been impeded by the lack of a suitable tumor xenograft model. We report a simple and reproducible system in which the tumor and tumor stroma are successfully engrafted into NOD-scid IL2Rγnull (NSG) mice. This is achieved by injecting tumor cell aggregates derived from fresh ovarian tumor biopsy tissues (including tumor cells, and tumor-associated lymphocytes and fibroblasts) i.p. into NSG mice. Tumor progression in these mice closely parallels many of the events that are observed in ovarian cancer patients. Tumors establish in the omentum, ovaries, liver, spleen, uterus, and pancreas. Tumor growth is initially very slow and progressive within the peritoneal cavity with an ultimate development of tumor ascites, spontaneous metastasis to the lung, increasing serum and ascites levels of CA125, and the retention of tumor-associated human fibroblasts and lymphocytes that remain functional and responsive to cytokines for prolonged periods. With this model one will be able to determine how fibroblasts and lymphocytes within the tumor microenvironment may contribute to tumor growth and metastasis, and will make it possible to evaluate the efficacy of therapies that are designed to target these cells in the tumor stroma.

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

Vasculogenic Erectile Dysfunction Is a Predictor of Abnormal Stress Echocardiography

INTRODUCTION Erectile dysfunction (ED) and atherosclerotic vascular disease have the same risk factors; furthermore, endothelial dysfunction has been shown to be a common link between these conditions. A high prevalence of silent coronary artery disease (CAD) in patients with ED has been observed. AIMS The aims of this article were to define the prevalence and identify predictors of occult obstructive CAD in patients with documented vasculogenic ED. MAIN OUTCOME MEASURES Duplex Doppler penile ultrasonography (DUS); exercise stress echocardiography; IIEF; CAD risk factors. Methods. Patients presenting with ED who had penile vascular insufficiency documented by DUS and who had no history of diabetes or symptoms of CAD were prospectively enrolled for noninvasive cardiac stress testing using exercise stress echocardiography. RESULTS Forty-nine men (mean age 517 years) with an average duration of ED of 2.52 years were evaluated. Penile arterial insufficiency was present in 94%, and venous leak in 20% of patients. Comorbidities included hypertension (51%), hyperlipidemia (41%), and smoking (35%). All patients had at least one vascular risk factor, with 40% having two, 15% three, and 15% four risk factors. Ten patients (20%) had abnormal cardiac stress test. On univariate analysis, age, IIEF-EF domain score, cavernosal artery insufficiency, presence of venous leak, and history of a first-degree relative with CAD were significant predictors. On multivariate analysis, cavernosal artery insufficiency, venous leak, and family history of CAD continued to be predictors of an abnormal stress test. CONCLUSIONS A significant proportion of men with vasculogenic ED have abnormal cardiac stress test. The greatest chance for abnormal cardiac stress test was observed in those with corporo-venocclusive dysfunction or family history of CAD. In some men presenting with ED, even without a CAD history, performing penile DUS or cardiology referral for stress testing should be considered.

Reciprocal Functional Modulation of the Activation of T Lymphocytes and Fibroblasts Derived from Human Solid Tumors

Fibroblasts are a dominant cell type in most human solid tumors. The possibility that fibroblasts have the capacity to interact with and modulate the function of tumor-associated T lymphocytes makes them a potential therapeutic target. To address this question, primary cultures of fibroblasts derived from human lung tumors were established and cultured with T cells derived from the same tumor. The tumor fibroblasts significantly enhance the production of IFN-γ and IL-17A by the tumor-associated T cells following a CD3/CD28-induced activation of the T cells. This enhancement was fibroblast cell dose-dependent and did not require direct contact between the two cell types. Tumor-associated fibroblast-conditioned media similarly enhanced both IFN-γ and IL-17A in activated T cells, and this enhancement was significantly reduced by Abs to IL-6. Conditioned media derived from activated lymphocyte cultures significantly enhanced IL-6 production by tumor fibroblasts. A similar enhancement of IFN-γ and IL-17A was observed when activated T cells from a normal donor were cultivated with skin fibroblasts derived from the same donor. These results establish that fibroblasts and autologous lymphocytes, whether derived from the tumor microenvironment or from nonmalignant tissues, have the capacity to reciprocally interact and modulate function. In contrast to other reports, fibroblasts are shown to have an immunostimulatory effect upon activated T lymphocytes. The ability of fibroblasts to enhance two T cell cytokines known to have an impact upon tumor progression suggests that fibroblasts play an important role in tumor pathogenesis that could be exploited therapeutically.

A Line 1 insertion in the Factor IX gene segregates with mild hemophilia B in dogs.

We undertook the biochemical and molecular characterization of hemophilia in a large pedigree of German wirehaired pointers. Males affected with hemophilia B had approximately 5% normal Factor IX coagulant activity and a proportional reduction of Factor IX protein concentration, indicative of a mild hemophilia B phenotype. Using Southern blot analyses and PCR amplification of genomic DNA, we discovered a large, 1.5-kb insertion in intron 5 of the Factor IX gene of an affected male. The insert consists of a 5′ truncated canine Line-1 followed by an approximately 200-bp 3′ poly (A) tract, flanked by a 15-bp direct repeat. The insert can be traced through at least five generations and segregates with the hemophilia B phenotype in this breed. This is the first description of a Factor IX mutation associated with mild hemophilia B in a non-human species and provides evidence for a recent Line-1 insertion event in the canine genome.

Etiology and Pathogenesis of Psoriatic Arthritis

The current model of psoriatic arthritis implicates both the IL-23/IL-17 axis and the tumor necrosis factor (TNF) pathways in disease pathogenesis. Although specific major histocompatibility complex class I molecules are associated with the psoriatic disease phenotype, no specific antigen or autoantibody has been identified. Instead, an array of genes may code for an autoinflammatory loop, potentially activated by mechanical stress and dysbiosis in the skin or gut. Danger signals released by innate immune cells activate a Th1 and Th17 response that leads to synovitis, enthesitis, axial inflammation, and altered bone homeostasis characterized by pathologic bone resorption and new bone formation.

p53-Associated Parkin-like cytoplasmic protein (Parc) short-interfering RNA (siRNA) alters p53 location and biology of Peyronie’s disease fibroblasts

Study Type – Aetiology (case control)
Level of Evidence 3b