Structural aspects of the FOXP3 regulatory complex as an immunopharmacological target.

The forkhead family transcription factor FOXP3 plays a fundamental role in immune homeostasis. FOXP3 dysfunction in regulatory T cells (Tregs) contributes to multiple disease processes such as autoimmunity, tumor development, and viral infection. FOXP3 cooperates and associates with a group of other transcriptional factors, co-repressors and co-activators in Tregs to form one or more dynamic regulatory complexes.

Factors associated with testicular self-examination among unaffected men from multiple-case testicular cancer families.

Background: The lifetime testicular cancer (TC) risk in the general population is relatively low (~1 in 250), but men with a family history of TC are at 4 to 9 times greater risk than those without. Some health and professional organizations recommend consideration of testicular self-examination (TSE) for certain high-risk groups (e.g.

The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies.

The HER2 gene encodes the receptor tyrosine kinase HER2 and is often over-expressed or amplified in breast cancer. Up-regulation of HER2 contributes to tumor progression. Many aspects of tumor growth are favorably affected through activation of HER2 signaling.

Dyskeratosis congenita: the first NIH clinical research workshop.

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure syndrome, characterized by abnormally short telomeres and mutations in telomere biology genes. The spectrum of telomere biology disorders is growing and the clinical management of these patients is complex. A DC-specific workshop was held at the NIH on September 19, 2008; participants included physicians, patients with DC, their family members, and representatives from other support groups.

Ductal lavage in women from BRCA1/2 families: is there a future for ductal lavage in women at increased genetic risk of breast cancer?

Purpose: Ductal lavage has been used for risk stratification and biomarker development and to identify intermediate endpoints for risk-reducing intervention trials. Little is known about patient characteristics associated with obtaining nipple aspirate fluid (NAF) and adequate cell counts (> or =10 cells) in ductal lavage specimens from BRCA mutation carriers.

Methods: We evaluated patient characteristics associated with obtaining NAF and adequate cell counts in ductal lavage specimens from the largest cohort of women from BRCA families yet studied (BRCA1/2 = 146, mutation-negative = 23, untested = 2).

The International Testicular Cancer Linkage Consortium: a clinicopathologic descriptive analysis of 461 familial malignant testicular germ cell tumor kindred.

Objectives: Familial aggregation of testicular germ cell tumor (TGCT) has been reported, but it is unclear if familial TGCT represents a unique entity with distinct clinicopathologic characteristics. Here we describe a collection of familial TGCT cases from an international consortium, in an effort to elucidate any clinical characteristics that are specific to this population.

Materials And Methods: Families with >or=2 cases of TGCT enrolled at 18 of the sites participating in the International Testicular Cancer Linkage Consortium were included.

Consenting to uncertainty: challenges for informed consent to disease screening--a case study.

This paper uses chronic beryllium disease as a case study to explore some of the challenges for decision-making and some of the problems for obtaining meaningful informed consent when the interpretation of screening results is complicated by their probabilistic nature and is clouded by empirical uncertainty. Although avoidance of further beryllium exposure might seem prudent for any individual whose test results suggest heightened disease risk, we will argue that such a clinical precautionary approach is likely to be a mistake. Instead, advice on the interpretation of screening results must focus not on risk per se, but on avoidable risk, and must be carefully tailored to the individual.

Risk of cancer in first- and second-degree relatives of testicular germ cell tumor cases and controls.

Risk factors for testicular germ cell tumors (TGCT) have not been well identified; however, data suggest that risks of cancer in family members of men with TGCT is elevated. Using family history data from 738 cases and 904 controls enrolled in the U.S.

BRCA mutation-negative women from hereditary breast and ovarian cancer families: a qualitative study of the BRCA-negative experience.

Background: When women from families with a known BRCA1 or BRCA2 mutation test negative for the family mutation, it is assumed that they will transition their personal cancer risk perception from high to average risk. However, there are scant data regarding the experience of mutation-negative women after genetic testing disclosure, particularly related to the shift of risk perception from assumed mutation-positive to actual mutation-negative. This study was designed to explore cancer risk perception and the experience of being a mutation-negative woman within a known BRCA1/2 mutation-positive family.

TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3.

Expression of FOXP3, a potent gene-specific transcriptional repressor, in regulatory T cells is required to suppress autoreactive and alloreactive effector T cell function. Recent studies have shown that FOXP3 is an acetylated protein in a large nuclear complex and FOXP3 actively represses transcription by recruiting enzymatic corepressors, including histone modification enzymes. The mechanism by which extracellular stimuli regulate the FOXP3 complex ensemble is currently unknown.

Sisters in hereditary breast and ovarian cancer families: communal coping, social integration, and psychological well-being.

Objective: We investigated the association between psychological distress and indices of social integration and communal coping among sisters from hereditary breast and ovarian cancer (HBOC) families.

Sample And Methods: Sixty-five sisters from 31 HBOC families completed the Brief Symptom Inventory-18 and the Colored Eco-Genetic Relationship Map, which identified members of participants' social support networks. Hierarchical linear models were used for all analyses to account for the clustering of sisters within families.

FOXP3 and its partners: structural and biochemical insights into the regulation of FOXP3 activity.

Forkhead box protein P3 (FOXP3) contributes to a unique transcriptional signature and serves as a functional marker of CD4(+)CD25(+) natural regulatory T cells. Dysfunction of FOXP3 in human is associated with fatal autoimmune disease known as immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) or X-linked autoimmunity-allergic disregulation syndrome (XLAAD). FOXP3 also can act as a breast tumor suppressor of the v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog (avian)) (Her2/neu) gene.

Non-invasive, ultra-sensitive, high-throughput assays to quantify rare biomarkers in the blood.

Many diseases are easier to treat and control when detected at an early stage of disease progression. Often, disease-related antigens or biomarkers are shed from the primary site and present in the blood. Unfortunately, there are very few tests capable of detecting these rare biomarkers in the blood.

Polymersomes: a new multi-functional tool for cancer diagnosis and therapy.

Nanoparticles are being developed as delivery vehicles for therapeutic pharmaceuticals and contrast imaging agents. Polymersomes (mesoscopic polymer vesicles) possess a number of attractive biomaterial properties that make them ideal for these applications. Synthetic control over block copolymer chemistry enables tunable design of polymersome material properties.

Modulation of biomolecular interactions with complex-binding small molecules.

Although numerous biomolecular interactions have been identified as potential targets for the development of therapeutic agents, modulation of these interactions with small molecules has historically been considered an extremely difficult task. This difficulty is largely due to the low effectiveness of the traditionally used competitive approaches in which inhibitors are designed and screened for their ability to block biomolecules from establishing contacts with their targets. We propose a novel approach to modulate biomolecular interactions by de novo structure-based design of noncompetitive small molecules that bind to the intermolecular complexes and make molecular contacts with both interacting partners.

Mechanisms of resistance to ErbB-targeted cancer therapeutics.

The ErbB receptors, such as EGFR, have been intensely pursued as targets for cancer therapeutics. However, a large percentage of patients who are initially responsive to ErbB-targeted therapies experience tumor recurrence and become refractory to therapy. In this issue of the JCI, Guix et al.

Familial and genetic risk of transitional cell carcinoma of the urinary tract.

Environmental exposures, including tobacco smoke and occupational exposure to aromatic amines, have been implicated in bladder cancer etiology. However, the pathogenesis of urinary bladder transitional cell carcinoma remains incompletely defined. In epidemiologic studies, family history confers a 2-fold increase in bladder cancer risk, but it is uncertain whether this represents evidence of a genetic and/or a shared environmental basis for familial aggregation.

No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study.

Background: The transforming growth factor beta-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-beta, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population.

Methods: To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers.

Testicular cancer and genetics knowledge among familial testicular cancer family members.

Purpose: It was our aim to determine baseline levels of testicular cancer and genetics knowledge among members of families with Familial Testicular Cancer (FTC).

Methods: This is a sub-study of an ongoing National Cancer Institute (NCI) multidisciplinary, etiologically-focused, cross-sectional study of FTC. We evaluated 258 male and female participants including testicular cancer (TC) survivors, blood relatives and spouses to assess factors associated with a Genetic Knowledge Scale (GKS) and Testicular Cancer Knowledge Scale (TCKS).

Complementary and alternative medicine use among women at increased genetic risk of breast and ovarian cancer.

Background: Complementary and alternative medicine (CAM) use is well documented among breast cancer patients and survivors, but little evidence is available to describe rates and patterns of use among women at increased genetic risk of breast cancer.

Methods: A pre-visit telephone interview was conducted to ascertain CAM use among the BRCA mutation carriers enrolled in a high-risk breast cancer screening study. Participants were asked to report on their use of thirteen therapies within the year prior to enrollment into the study.

Human glucocorticoid-induced TNF receptor ligand regulates its signaling activity through multiple oligomerization states.

Ligation between glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand (GITRL) provides an undefined signal that renders CD4(+)CD25(-) effector T cells resistant to the inhibitory effects of CD4(+)CD25(+) regulatory T cells. To understand the structural basis of GITRL function, we have expressed and purified the extracellular domain of human GITR ligand in Escherichia coli. Chromotography and cross-linking studies indicate that human GITRL (hGITRL) exists as dimers and trimers in solution and also can form a supercluster.