SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer.

Expression of the SASH1 protein is reduced in a range of human cancers and has been implicated in apoptotic cancer cell death. This study investigated whether increasing SASH1 expression could be a useful therapeutic strategy in breast cancer. Ectopic SASH1 expression increased apoptosis in 7/8 breast cancer cell lines.

Novel highly specific anti-periostin antibodies uncover the functional importance of the fascilin 1-1 domain and highlight preferential expression of periostin in aggressive breast cancer.

Periostin (POSTN), a secreted homodimeric protein that binds integrins αvβ3, αvβ5, and α6β4, was originally found to be expressed in fetal tissues and in the adult upon injury particularly bone fractures due to its role in remodelling and repair. Recently it was found to be over-expressed in human breast cancer and a variety of other tumour types including head and neck squamous cell carcinoma, where its overexpression correlates with increased tumour invasion. Progress in studying its functional role in tumour pathogenesis has been hampered by the paucity of antibodies for its specific and sensitive detection.

CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor.

Ag receptors used for cancer immunotherapy are often directed against tumor-associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor-associated Ag that shows low expression in many normal tissues.

A modified γ-retrovirus vector for X-linked severe combined immunodeficiency.

Background: In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1.

Methods: We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc).

Protocol for the examination of specimens from patients with pheochromocytomas and extra-adrenal paragangliomas.

During the last decade there have been revolutionary breakthroughs in understanding the biology of pheochromocytomas and extra-adrenal paragangliomas. Discoveries of new susceptibility genes and genotype-phenotype correlations have led to the realization that appropriate patient care requires a complete integration of clinical, genetic, biochemical, imaging, and pathology findings. Clinical practice has in many cases not kept pace with the rate of discovery, underscoring a need for updated procedures for evaluation of patient specimens and reporting of data.

Pathology of the adrenal cortex: a reappraisal of the past 25 years focusing on adrenal cortical tumors.

A reappraisal of the major advances in the diagnostic pathology of adrenal cortical lesions and tumors in the last 25 years is presented, with special reference to the definition of malignancy in primary adrenal cancer and its variants. Slightly more than 25 years ago, Weiss proposed his diagnostic scoring system for adrenal cortical carcinoma. This represented a milestone for adrenal pathologists and the starting point for further modifications of the system, either through minor changes in the scoring procedure itself or concentrating on some particular Weiss criterion such as mitotic index, integrated into alternative scoring schemes or algorithms that are currently under validation.

Phase I study protocol for ex vivo lentiviral gene therapy for the inherited skin disease, Netherton syndrome.

Netherton syndrome (NS) is a serious inherited skin disorder caused by mutations in the serine protease inhibitor Kazal type 5 gene (SPINK5), which encodes for a serine protease inhibitor lymphoepithelial Kazal type-related inhibitor (LEKTI). Patients with NS have defective keratinization, hair shaft defects, recurrent infections, atopy, and a predisposition to skin malignancies. Historically, 1 in 10 infants has died before their first birthday.

Diagnostic and molecular aspects of adrenal cortical tumors.

Adrenal cortical diseases are relatively rare but tumors are the most common in diagnostic practice. This is reflected by the content of this review. By studying familial syndromes in which they occur more frequently and the pathways involved in steroidogenesis and cortical growth, the molecular genetics of these tumors is being unraveled.

Phase I study protocol for ex-vivo lentiviral gene therapy for the inherited skin disease, Netherton Syndrome.

Netherton syndrome (NS) is a serious inherited skin disorder caused by mutations in the gene SPINK5 (serine protease inhibitor Kazal type 5) which encodes for a serine protease inhibitor LEKTI (lymphoepithelial Kazal type-related inhibitor). Patients with NS have defective keratinization, hair shaft defects, recurrent infections, atopy and a predisposition to skin malignancies. Historically, one in ten infants has died before their first birthday.

Tumor heterogeneity in a follicular carcinoma of thyroid: a study by comparative genomic hybridization.

We report a follicular carcinoma of thyroid that showed a range of histologic appearances, with microfollicular, macrofollicular/pseudopapillary, oncocytic, and poorly differentiated areas. We used comparative genomic hybridization to detect the major DNA copy number changes in each component, in order to study the inter-relationships among them. All showed gains in 11q and 17q, suggesting that these were early events in the development of the tumor, and these were the only changes in the follicular component.

Update on tumours of the adrenal cortex, phaeochromocytoma and extra-adrenal paraganglioma.

This review covers aspects of adrenal cortical tumours, phaeochromocytoma and extra-adrenal paragangliomas. Relevant clinical and epidemiological information is included. It is now known that about 30% of paragangliomas occur in a familial setting and these new aspects of the genetic background are presented.

A diagnostic approach to adrenal cortical lesions.

The adrenal gland is not a common specimen in surgical pathology practice as, until recently, adrenal tumors were recognized in life only if associated with hypersecretion of hormones or evidence of malignancy. However, adrenal nodules are not uncommon at autopsy, and the number of these found in life is now increasing as they are identified when the abdomen is scanned for the investigation of other diseases using computed tomography or magnetic resonance imaging. It is therefore becoming increasingly important for the surgical pathologist to be aware of the range of pathology in the gland and to understand how to approach the specimens.

Lesions of the adrenal cortex.

Context: In surgical pathology practice adrenal cortical tumors are rare. However, in autopsy series adrenal cortical nodules are found frequently. These are now being identified more commonly in life when the abdomen is scanned for other disease.

Histopathology and immunohistochemistry of adrenal medullary tumors and paragangliomas.

Paragangliomas arise from sympathetic or parasympathetic paraganglia and should now be defined by their site and type. The term pheochromocytoma is reserved for intra-adrenal tumors. This short review discusses the gross and microscopic features, the immunohistochemical profile, the problem of recognizing malignant potential, and the rare instances where a differential diagnosis has to be considered.

CD8alpha/alpha homodimers fail to function as co-receptor for a CD8-dependent TCR.

In this study, we have started to dissect the molecular basis of CD8 dependence of a high and low avidity CTL clone specific for the same peptide epitope. Using anti-CD8alpha and anti-CD8beta antibodies, we found that cytotoxicity and IFN-gamma production by high but not by low avidity CTL was strongly CD8 dependent. We isolated the TCR genes of both types of CTL clones and used retroviral gene transfer to analyse the function of these TCR in primary T cells of wild-type and CD8beta-deficient mice.

Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.

The First International Symposium on Pheochromocytoma, held in October 2005, included discussions about developments concerning these rare catecholamine-producing tumors. Recommendations were made during the symposium for biochemical diagnosis, localization, genetics, and treatment. Measurement of plasma or urinary fractionated metanephrines, the most accurate screening approach, was recommended as the first-line test for diagnosis; reference intervals should favor sensitivity over specificity.

Assessment of malignancy in adrenal cortical tumors.

The roles of the pathologist in assessing adrenal cortical tumors are, first, to differentiate adenoma from carcinoma, and, second, to assess prognosis when the diagnosis of malignancy is made. How easy is it to achieve these goals with standard histology and immunohistochemistry, and to what extent can molecular analysis help?

Pathology of pheochromocytoma and extra-adrenal paraganglioma.

The 2004 WHO classification of endocrine tumors defines pheochromocytoma as a tumor arising from chromaffin cells in the adrenal medulla. Closely related tumors in extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. A pheochromocytoma is an intra-adrenal sympathetic paraganglioma.

Capture and generation of adenovirus specific T cells for adoptive immunotherapy.

Adenoviral infections represent a major cause of morbidity and mortality following haematopoietic stem cell transplantation. Current anti-viral agents are virostatic and it is evident that elimination of adenovirus (ADV) infection is only achieved by recovery of cellular immunity. Using an interferon-gamma (IFN-gamma) secretion and capture assay to isolate ADV-specific T cells, followed by a 2 week expansion and restimulation protocol, we generated ADV T cells that may be used for cellular immunotherapy.

Identification of adrenocorticotropin receptor messenger ribonucleic acid in the human pituitary and its loss of expression in pituitary adenomas.

The ACTH receptor (ACTH-R) is the second member of the melanocortin (MC-2) receptor family that includes five seven-transmembrane G protein-coupled receptors and has been shown to be predominantly expressed in the adrenal cortex. It has been postulated that ACTH may regulate its own secretion through ultra-short-loop feedback within the pituitary. ACTH-secreting adenomas are characterized by resistance to glucocorticoid feedback, and they may have dysregulated ACTH feedback.