Immune response to MMTV infection.

Mouse mammary tumor virus (MMTV) has developed a strategy of exploitation of the immune response. It infects dendritic cells and B cells and requires this infection to establish an efficient chronic infection. This allows transmission of infection to the mammary gland, production in milk and infection of the next generation via lactation. The elaborate strategy developed by MMTV utilizes several key elements of the normal immune response. Starting with the infection and activation of dendritic cells and B cells leading to the expression of a viral superantigen followed by professional superantigen-mediated priming of naive polyclonal T cells by dendritic cells and induction of superantigen-mediated T cell B cell collaboration results in long-lasting germinal center formation and production of long-lived B cells that can later carry the virus to the mammary gland epithelium. Later in life it can induce transformation of mammary gland epithelium by integrating close to proto-oncogenes leading to their overexpression. Genes encoding proteins of the Wnt-pathway are preferential targets. This review will put these effects in the context of a normal immune response and summarize important facts on MMTV biology.

Dopamine receptors on dispersed bovine anterior pituitary cells

The dopamine antagonist [3H]-domperidone-[3H]-DOM-bound to a single class of high-affinity (Kd = 1.24 +/- 0.14 nM) and saturable receptors on dispersed bovine anterior pituitary (AP) cells. The binding of [3H]-DOM was stereoselective and reversible with agonists and antagonists. Dopamine competitions for [3H]-DOM binding modeled best for a single site consistent with an interaction with a homogeneous population of receptors. The mean number of specific binding sites labeled by [3H]-DOM was 53,000 per cell in dispersed AP cells consisting of 42% lactotrophs. Dispersed bovine AP cells attached to extracellular matrix within 3 h, and prolactin secretion from these cells was effectively inhibited by dopamine. Several observations suggested that [3H]-DOM-labeled receptors on dispersed bovine AP cells were restricted to the outer plasma membrane and not internalized. These included (1) the rapid and complete dissociation of specific [3H]-DOM binding; (2) the ability of treatment with acid or proteolytic enzymes to entirely remove specifically bound [3H]-DOM, and (3) the lack of effect of metabolic inhibitors on specific [3H]-DOM binding.

Expression of genes encoding cytotoxic cell-associated serine proteases in thymocytes.

A family of homologous serine esterases designated granzyme A-H and the pore-forming protein perforin are present in cytoplasmic granules of mature peripheral cytolytic T lymphocytes and natural killer cells. In vivo, the majority of cytotoxic T cells containing these granule-associated proteins are of the CD4-CD8+ phenotype. It is generally assumed that these cells are derived from immature CD4-CD8- thymocytes. However, the precise intrathymic differentiation steps leading to functionally mature cytotoxic T cells are unclear. Thus we decided to analyze the expression of genes in the thymus which are preferentially expressed in mature cytotoxic cells, i.e. granzyme A, granzyme B, and perforin. In situ hybridization on tissue sections revealed the expression of genes coding for granzyme A and granzyme B in the thymus. No evidence was found, however, for thymocytes expressing the perforin gene. Granzyme A and granzyme B mRNA positive cells in the thymus are almost exclusively CD4-CD8- thymocytes, particularly of the CD3- IL2R- phenotype.

Association of T-zone reticular networks and conduits with ectopic lymphoid tissues in mice and humans.

Ectopic or tertiary lymphoid tissues (TLTs) are often induced at sites of chronic inflammation. They typically contain various hematopoietic cell types, high endothelial venules, and follicular dendritic cells; and are organized in lymph node-like structures. Although fibroblastic stromal cells may play a role in TLT induction and persistence, they have remained poorly defined. Herein, we report that TLTs arising during inflammation in mice and humans in a variety of tissues (eg, pancreas, kidney, liver, and salivary gland) contain stromal cell networks consisting of podoplanin(+) T-zone fibroblastic reticular cells (TRCs), distinct from follicular dendritic cells. Similar to lymph nodes, TRCs were present throughout T-cell-rich areas and had dendritic cells associated with them. They expressed lymphotoxin (LT) β receptor (LTβR), produced CCL21, and formed a functional conduit system. In rat insulin promoter-CXCL13-transgenic pancreas, the maintenance of TRC networks and conduits was partially dependent on LTβR and on lymphoid tissue inducer cells expressing LTβR ligands. In conclusion, TRCs and conduits are hallmarks of secondary lymphoid organs and of well-developed TLTs, in both mice and humans, and are likely to act as important scaffold and organizer cells of the T-cell-rich zone.

Primary Sjögren's syndrome (SS) and malignant lymphoma. A retrospective cohort study of 55 patients with SS.

The aim of this study was to assess the prevalence of malignant lymphomas in patients with long-standing primary Sjögren's syndrome (pSS). We retrospectively studied a cohort of 55 patients with pSS over a mean follow-up period of 12 years. Five patients (9%) developed malignant lymphoma. The interval between the diagnoses of SS and lymphoma ranged from four to 12 years (mean = 6.5 years). The lymphoma arose in the lymph nodes in two cases, the parotid gland in one case, the lacrimal gland in one case, and the lung in one case. All five cases were B-cell low-grade lymphomas. Among our SS patients, those with extraglandular manifestations and/or a mixed cryoglobulin were at increased risk for lymphoma development. Secondary lymphoma carried a poor prognosis in our study. Three of the six SS patients who died during the follow-up period had lymphoma.

Trilateral retinoblastoma: neuroimaging characteristics and value of routine brain screening on admission.

Trilateral retinoblastoma (TRb) is a rare disease associating intraocular retinoblastoma with intracranial primitive neuroectodermal tumor. Treatment is difficult and prognosis is poor. This multicenter study evaluates clinical findings and MR imaging characteristics of associated intracranial tumors in Rb patients. Clinical data of 17 patients (16 TRb and 1 quadrilateral Rb patients) included time intervals between Rb and TRb diagnosis and presence of baseline brain-imaging (BBI). Two reviewers reviewed all images individually and one reviewer per center evaluated their images. Consensus was reached during a joint scoring session. Studies were reviewed for tumor location, size and imaging characteristics (signal intensity (SI) on T1- and T2-weighted images, enhancement pattern and cystic appearance). Of 18 intracranial tumors, 78 % were located in the pineal gland and 22 % suprasellar. All tumors showed well-defined borders with mostly heterogenous enhancement (72 %) and isointense SI on T1- (78 %) and T2-weighted images (72 %) compared to gray matter. The majority of pineal TRbs showed a cystic component (57 %). TRb detected synchronously with the intraocular tumors on BBI (n = 7) were significantly smaller (P = 0.02), and mainly asymptomatic than TRb detected later on (n = 10). Overall, 5-year-survival of TRb patients detected on BBI was 67 % (95 % CI 29-100 %) compared to 11 % (95 % CI 0-32 %) for the group with delayed diagnosis. TRb mainly develops in the pineal gland and frequently presents with a cystic appearance that could be misinterpreted as benign pineal cysts. Routine BBI in all newly diagnosed Rb patients can detect TRb at a subclinical stage.

The role of focal therapy in the management of localised prostate cancer: a systematic review.

CONTEXT: The incidence of localised prostate cancer is increasing worldwide. In light of recent evidence, current, radical, whole-gland treatments for organ-confined disease have being questioned with respect to their side effects, cancer control, and cost. Focal therapy may be an effective alternative strategy. OBJECTIVE: To systematically review the existing literature on baseline characteristics of the target population; preoperative evaluation to localise disease; and perioperative, functional, and disease control outcomes following focal therapy. EVIDENCE ACQUISITION: Medline (through PubMed), Embase, Web of Science, and Cochrane Review databases were searched from inception to 31 October 2012. In addition, registered but not yet published trials were retrieved. Studies evaluating tissue-preserving therapies in men with biopsy-proven prostate cancer in the primary or salvage setting were included. EVIDENCE SYNTHESIS: A total of 2350 cases were treated to date across 30 studies. Most studies were retrospective with variable standards of reporting, although there was an increasing number of prospective registered trials. Focal therapy was mainly delivered to men with low and intermediate disease, although some high-risk cases were treated that had known, unilateral, significant cancer. In most of the cases, biopsy findings were correlated to specific preoperative imaging, such as multiparametric magnetic resonance imaging or Doppler ultrasound to determine eligibility. Follow-up varied between 0 and 11.1 yr. In treatment-naïve prostates, pad-free continence ranged from 95% to 100%, erectile function ranged from 54% to 100%, and absence of clinically significant cancer ranged from 83% to 100%. In focal salvage cases for radiotherapy failure, the same outcomes were achieved in 87.2-100%, 29-40%, and 92% of cases, respectively. Biochemical disease-free survival was reported using a number of definitions that were not validated in the focal-therapy setting. CONCLUSIONS: Our systematic review highlights that, when focal therapy is delivered with intention to treat, the perioperative, functional, and disease control outcomes are encouraging within a short- to medium-term follow-up. Focal therapy is a strategy by which the overtreatment burden of the current prostate cancer pathway could be reduced, but robust comparative effectiveness studies are now required.

Lymphomes des annexes de l'oeil au cours du syndrome de Gougerot-Sjögren [Lymphomas of the ocular adnexa in Gougerot-Sjögren syndrome. Apropos of 4 cases].

The risk of malignant B cell lymphoma is increased in Sjögren's syndrome (SS). Orbital localization seems infrequent. We report 4 cases of malignant lymphoma (ML) occurring in 4 women aged 47 to 77 years, with primary SS in 3 cases, located to the conjunctiva in 2 cases, the lacrymal gland in 1 case and the eyelid in 1 case. The interval between the diagnosis of SS and orbital ML varied from 6 months to 15 years. All 4 lymphomas were of the B cell type, low histopathologic grade, with monoclonal gammopathy in 1 case. Extraocular lymphoma was initially present in 1 case. ML remained localized in 2 cases with a follow-up of 4 and 6 years. Two patients treated by excisional biopsy alone are in complete remission 3 and 6 years later. The 2 other patients treated with orbital radiotherapy and chemotherapy died rapidly (transformation into a high grade malignancy in 1 case). We conclude that clinical, immunopathologic features, as well as prognosis and treatment of ocular adnexa ML in SS are similar to those of primary ML without SS.

Transplantation of a human mammary carcinoma cell line (BT 20) into nude mice.

Cell suspensions of a human mammary carcinoma cellline (BT 20), wh en injected subcutaneously into nude athymie mice (BALB/c NujNu), produced tumor nodules at the injection site. Subsequent seriai transM plantations also gave rise to neoplastic nodules after latency periods averaging 3 weeks. The nodules displayed morphologie and functional characteristics comparable to those of the original tumor cells. Metastases, however, were not observed in any of the tumor-bearing mice.

CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is of pivotal importance for self-tolerance, with deficiency or unfavorable polymorphisms leading to autoimmune disease. Tolerance to self-antigens is achieved through thymic deletion of highly autoreactive conventional T (Tconv) cells and generation of FoxP3(+) regulatory T (Treg) cells. The main costimulatory molecule, CD28, augments the negative selection of Tconv cells and promotes the generation of FoxP3(+) Treg cells. The role of its antagonistic homolog CTLA-4, however, remains a topic of debate. To address this topic, we investigated the thymic development of T cells in the presence and absence of CTLA-4 in a T-cell receptor (TCR) transgenic mouse model specific for the myelin basic protein peptide Ac1-9. We reveal that CTLA-4 is expressed in the corticomedullary region of the thymus. Its absence alters the response of CD4(+)CD8(-) thymocytes to self-antigen recognition, which affects the quantity of the Treg cells generated and broadens the repertoire of peripheral Tconv cells. T-cell repertoire alteration after deletion of CTLA-4 results from changes in TCR Vα and Jα segment selection as well as CDR3α composition in Tconv and Treg cells. CTLA-4, therefore, regulates the early development of self-reactive T cells in the thymus and plays a key role in central tolerance.

Circulating EM66 is a highly sensitive marker for the diagnosis and follow-up of pheochromocytoma.

We have previously demonstrated that measurement of tissue concentration of the novel secretogranin II-derived peptide EM66 may help to discriminate between benign and malignant pheochromocytomas. The aim of the present study was to characterize EM66 in plasma and urine of healthy volunteers and pheochromocytoma patients, in order to further evaluate the usefulness of this peptide as a circulating marker for the management of the tumors. HPLC analysis of plasma and urine samples demonstrated that the EM66-immunoreactive material coeluted with the recombinant peptide. In healthy volunteers, plasma and urinary EM66 levels were, respectively, 2.6 (1.9-3.7) ng/ml and 2.9 (1.9-4.6) ng/ml. In patients with pheochromocytoma, plasma EM66 levels were 10-fold higher than those of healthy volunteers (26.9 (7.3-44) ng/ml), and returned to normal values after removal of the tumor. In contrast, urinary EM66 levels were not significantly different from those of healthy volunteers (3.2 (2.2-3.9) ng/ml). Measurement of total or free plasma metanephrines and 24 hr urinary metanephrines in our series of patients revealed that these tests, taken separately, are less sensitive than the EM66 determination. Pheochromocytes in primary culture secreted high levels of EM66, suggesting that the chromaffin tumor was actually responsible for the increased plasma peptide concentrations in the patients. These data indicate that EM66 is secreted in the general circulation and that elevated plasma EM66 levels are correlated with the occurrence of pheochromocytoma. Thus, EM66 is a sensitive plasma marker that should be considered as a complementary tool in the management of pheochromocytoma.

Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

Health technology assessment in evolution - focal therapy in localised prostate cancer.

Focal therapy in prostate cancer aims to treat only the part of the gland harboring clinically significant disease while preserving the rest of the tissue. This approach may substantially reduce treatment-related toxicity without compromising disease control outcomes. Short- to medium-term functional and oncological results in prospective interventional studies are promising, but comparative effectiveness research against standard of care is required to incorporate focal therapy among standard options. In this review, we discuss the actual stage of assessment and results of sources of energy commonly used to deliver focal therapy. We also provide our viewpoint on how the field will evolve in the near future.

Extrafollicular plasmablast B cells play a key role in carrying retroviral infection to peripheral organs.

B cells can either differentiate in germinal centers or in extrafollicular compartments of secondary lymphoid organs. Here we show the migration properties of B cells after differentiation in murine peripheral lymph node infected with mouse mammary tumor virus. Naive B cells become activated, infected, and carry integrated retroviral DNA sequences. After production of a retroviral superantigen, the infected B cells receive cognate T cell help and differentiate along the two main differentiation pathways analogous to classical Ag responses. The extrafollicular differentiation peaks on day 6 of mouse mammary tumor virus infection, and the follicular one becomes detectable after day 10. B cells participating in this immune response carry a retroviral DNA marker that can be detected by using semiquantitative PCR. We determined the migration patterns of B cells having taken part in the T cell-B cell interaction from the draining lymph node to different tissues. Waves of immigration and retention of infected cells in secondary lymphoid organs, mammary gland, salivary gland, skin, lung, and liver were observed correlating with the two peaks of B cell differentiation in the draining lymph node. Other organs revealed immigration of infected cells at later time points. The migration properties were correlated with a strong up-regulation of alpha(4)beta(1) integrin expression. These results show the migration properties of B cells during an immune response and demonstrate that a large proportion of extrafolliculary differentiating plasmablasts can escape local cell death and carry the retroviral infection to peripheral organs.

Xerostomía: diagnóstico y tratamiento

La xerostomía o disminución de la cantidad de saliva en la cavidad bucal suele tener una serie de consecuencias: unas directas, tales como el aumento en la incidencia de caries y enfermedad periodontal, y otras indirectas, como la dificultad en la masticación o la mala adaptación de las prótesis. De ahí la importancia de una correcta lubrificación salival de la cavidad bucal. En el presente trabajo se realiza una revisión de los problemas ocasionados por la xerostomía, así como de su diagnóstico y tratamiento, aspectos éstos un tanto conflictivos, debido a la dificultad de objetivar la sintomatología y de conseguir resultados duraderos.