IDO is a nodal pathogenic driver of lung cancer and metastasis development.

Unlabelled: Indoleamine 2,3-dioxygenase (IDO) enzyme inhibitors have entered clinical trials for cancer treatment based on preclinical studies, indicating that they can defeat immune escape and broadly enhance other therapeutic modalities. However, clear genetic evidence of the impact of IDO on tumorigenesis in physiologic models of primary or metastatic disease is lacking. Investigating the impact of Ido1 gene disruption in mouse models of oncogenic KRAS-induced lung carcinoma and breast carcinoma-derived pulmonary metastasis, we have found that IDO deficiency resulted in reduced lung tumor burden and improved survival in both models.

Bin1 attenuation suppresses experimental colitis by enforcing intestinal barrier function.

Background: Inflammatory bowel disease (IBD) is associated with defects in intestinal barriers that rely upon cellular tight junctions. Thus, identifying genes that could be targeted to enforce tight junctions and improve barrier function may lead to new treatment strategies for IBD.

Aims: This preclinical study aimed to evaluate an hypothesized role for the tumor suppressor gene Bin1 as a modifier of the severity of experimental colitis.

Cardiac and gastrointestinal liabilities caused by deficiency in the immune modulatory enzyme indoleamine 2,3-dioxygenase.

Indoleamine 2,3-dioxygenase (IDO) modifies adaptive immunity, in part by determining the character of inflammatory responses in the tissue microenvironment. Small molecule inhibitors of IDO are being developed to treat cancer, chronic infections and other diseases, so the systemic effects of IDO disruption on inflammatory phenomena may influence the design and conduct of early phase clinical investigations of this new class of therapeutic agents. Here, we report cardiac and gastrointestinal phenotypes observed in IDO deficient mice that warrant consideration in planned assessments of the safety risks involved in clinical development of IDO inhibitors.

Kaposi sarcoma presenting as yellow-green penile plaques in a black man with HIV.

Kaposi sarcoma characteristically presents with violaceous papules, plaques, or nodules due to the vascular nature of the lesions. We present the case of a human immunodeficiency virus (HIV)-positive black man with yellow-green penile plaques. Biopsy results revealed leukoedema and slitlike vascular spaces.

Cell-cell adhesion proteins in melanocytic pilomatrix carcinoma.

Tumors of the matrix of rigid structures include matrical tumors of the hairs, nails, and teeth. These tumors share similar phenotypical and signaling features. Although benign matrical hair tumors are among the most common of these tumors, hair matrix tumors containing pigmented melanocytes are very rare.

Dietary methionine restriction improves colon tight junction barrier function and alters claudin expression pattern.

The beneficial effects of caloric restriction in increasing longevity and forestalling age-related diseases are well known. Dietary restriction of methionine also renders similar benefits. We recently showed in a renal epithelial cell culture system that reduction of culture medium methionine by 80% resulted in altered tight junctional (TJ) claudin composition and also improved epithelial barrier function (51).

Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion.

Indoleamine 2,3-dioxygenase (IDO) is generally considered to be immunosuppressive but recent findings suggest this characterization oversimplifies its role in disease pathogenesis. Recently, we showed that IDO is essential for tumor outgrowth in the classical two-stage model of inflammatory skin carcinogenesis. Here, we report that IDO loss did not exacerbate classical inflammatory responses.

Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase.

Topical application of phorbol myristate acetate (PMA) elicits intense local inflammation that facilitates outgrowth of premalignant lesions in skin after carcinogen exposure. The inflammatory response to PMA treatment activates immune stimulatory mechanisms. However, we show here that PMA exposure also induces plasmacytoid dendritic cells (pDCs) in local draining lymph nodes (dLNs) to express indoleamine 2,3 dioxygenase (IDO), which confers T cell suppressor activity on pDCs.

Expression of cadherin/catenin cell--cell adhesion molecules in a onychomatricoma.

Onychomatricoma is a rare nail tumor with a distinctive architecture. Proximally, there are serum-filled invaginations of nail matrix epithelium into the stroma, and distally, dermal protrusions perforate the nail plate. Because other matrical tumors of follicular and odontogenic origin express nuclear beta-catenin, we examined the expression of cadherin/catenin proteins in this onychomatricoma case.

Bin3 deletion causes cataracts and increased susceptibility to lymphoma during aging.

Bin3 encodes an evolutionarily conserved and ubiquitously expressed member of the BAR superfamily of curved membrane and GTPase-binding proteins, which includes the BAR, PCH/F-BAR, and I-BAR adapter proteins implicated in signal transduction and vesicular trafficking. In humans, Bin3 maps to chromosome 8p21.3, a region widely implicated in cancer suppression that is often deleted in non-Hodgkin's lymphomas and various epithelial tumors.

Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer.

Age is the major risk factor for cancer, but few genetic pathways that modify cancer incidence during aging have been described. Bin1 is a prototypic member of the BAR adapter gene family that functions in vesicle dynamics and nuclear processes. Bin1 limits oncogenesis and is often attenuated in human cancers, but its role in cancer suppression has yet to be evaluated fully in vivo.

Cell adhesion protein expression in melanocytic matricoma.

Melanocytic matricoma is a rare neoplasm thought to recapitulate the hair follicle in anagen. The tumor forms a nodule in the dermis containing basaloid, intermediate and shadow cells admixed with pigmented melanocytes dispersed as single dendritic cells. Because cadherins and catenins are crucial in the development of hair tumors, we examined the expression of E(epithelial)-, P(placental)-, N(nerve)-cadherin and beta-catenin in a melanocytic matricoma.

Bin1 attenuation in breast cancer is correlated to nodal metastasis and reduced survival.

Clinical outcomes in breast cancer are likely influenced by modifier genes that affect tumor dormancy versus progression. The Bin1 gene encodes a nucleocytosolic adapter protein that suppresses neoplastic cell transformation and that is often attenuated in human breast carcinoma. Recent mouse genetic studies indicate that Bin1 loss cooperates with ras activation to drive progression of mammary carcinoma, establishing Bin1 as a negative modifier of tumor progression in breast cancer.

Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression.

Genes that modify oncogenesis may influence dormancy versus progression in cancer, thereby affecting clinical outcomes. The Bin1 gene encodes a nucleocytosolic adapter protein that interacts with and suppresses the cell transforming activity of Myc. Bin1 is often attenuated in breast cancer but its ability to negatively modify oncogenesis or progression in this context has not been gauged directly.

Silent corticotroph cell pituitary adenoma in a struma ovarii.

This is the first report of a silent corticotroph cell pituitary adenoma arising in a struma ovarii. The patient, a 79-year-old woman, was found to have an asymptomatic left-sided adnexal mass confirmed by vaginal sonography to be a complex cystic and solid tumor. Pathological analysis demonstrated an 8-cm partially cystic struma ovarii in which there was a focus of predominantly basophilic adenohypophyseal cells arranged in a diffuse pattern, adjacent to mature neural tissue containing numerous Herring bodies.

Ultrastructural immunolocalization of IGF-1 and insulin receptors in rat pituitary culture: evidence of a functional interaction between gonadotroph and lactotroph cells.

We have investigated the expression of receptors for insulin and insulin-like growth factor 1 (IGF-1) in rat pituitary cells in vitro and examined the morphological and proliferative changes induced in adenohypophyseal cells by insulin and IGF-1. The proliferation of lactotrophs was determined by double-immunostaining for bromodeoxyuridine and prolactin. Incubation with insulin (10, 100 or 1000 ng/ml) or IGF-1 (5, 30 or 100 ng/ml) for 48 or 72 h significantly increased the number of lactotrophs undergoing mitosis.

Differential expression of N-cadherin distinguishes a subset of metastasizing desmoplastic melanomas.

Desmoplastic melanoma is a variant of spindle cell melanoma considered at low risk for distant metastases when compared with other forms of melanoma. The emphasis in the differential diagnosis of desmoplastic melanomas has been placed mostly in distinguishing it from scars and other benign spindle cell proliferations. In contrast, recognizing a subset of desmoplastic melanomas with higher metastatic potential has proven more difficult.

Soluble p-cadherin found in human semen.

Cadherins constitute a family of calcium-dependent cell-cell adhesion molecules. P (placental)-cadherin is a 118-kd protein expressed by basal cells in epithelial tissues. P-cadherin also has been described as a soluble protein in certain biological fluids, including human serum and breast milk.

Overexpression of neural cell adhesion molecule in regenerative muscle fibers in 3-hydroxy-3-methylglutaryl coenzyme: A reductase inhibitor-induced rhabdomyolysis.

Skeletal muscle degeneration is a side effect of cholesterol-lowering hydroxymethylglutaryl coenzyme A reductase inhibitors. The expression of the cell-cell adhesion proteins, neural cell adhesion molecule and neural-cadherin was studied in a case of rhabdomyolysis induced by the hydroxymethylglutaryl coenzyme A reductase inhibitor cerivastatin. Neural cell adhesion molecule and N-cadherin participate in the interactions of muscle cells during skeletal myogenesis.

Targeted disruption of the murine Bin1/Amphiphysin II gene does not disable endocytosis but results in embryonic cardiomyopathy with aberrant myofibril formation.

The mammalian Bin1/Amphiphysin II gene encodes an assortment of alternatively spliced adapter proteins that exhibit markedly divergent expression and subcellular localization profiles. Bin1 proteins have been implicated in a variety of different cellular processes, including endocytosis, actin cytoskeletal organization, transcription, and stress responses. To gain insight into the physiological functions of the Bin1 gene, we have disrupted it by homologous recombination in the mouse.

Soluble fragment of P-cadherin adhesion protein found in human milk.

Classical cadherins such as E- and P-cadherin are transmembrane proteins that mediate specific cell-to-cell adhesion and are important to tissue development and function. Cadherin function can be modulated by various means, including proteolytic cleavage of the extracellular adhesion domain from the cells' surface, yielding large soluble fragments termed (soluble) sE- or sP-cadherin. In people with certain carcinomas, sE-cadherin can be detected at elevated levels in the serum and sometimes can serve as a prognostic marker.