Effects of vitamin D3 and cyclosporin A on HgCl2-induced autoimmunity in Brown Norway rats

BACKGROUND.: Mercuric chloride (HgCl₂ induces a lymphoproliferative disorderand autoimmune glomerulonephritis in Brown Norway (BN) rats.This syndrome is the consequence of T cell-dependent polyclonalB cell activation and autoantibody production. We have previouslyshown that HgCl₂-induced autoimmune perturbations can be preventedin BN rats by the administration of cyclosporin A (CsA). Themost potent vitamin D₃ metabolite 1,25(OH)₂ D₃ (Vit D₃) sharescertain immunomodulatory properties with CsA. We therefore choseto compare the effects of Vit D₃ to those of CsA in BN ratstreated with HgCl₂ in order to establish whether Vit D₃ eitheralone or in combination with CsA can attenuate an autoimmunesyndrome in vivo. METHODS.: BN rats were treated with HgCl₂ according to a standard protocol.Subgroups of rats were also given CsA alone, Vit D₃ or syntheticanalogues of Vit D₃ alone, or combinations of both agents. Differentdoses and routes of administration were compared. The followingmarkers of disease activity were evaluated: mortality, peakproteinuria, serum IgE concentrations, and renal immunoglobulindeposition. RESULTS.: Disease activity was markedly attenuated in all rats treatedwith CsA alone. Vit D₃ and certain of its synthetic analoguesadministered alone also tempered the autoimmune process, butto a lesser extent than did CsA. The effect of CsA alone wasso potent, that no additive or synergistic effects could bedemonstrated when CsA was administered in combination with VitD₃. CONCLUSIONS.: Despite similar described immunomodulatory effects in vitro,CsA is clearly more effective than Vit D₃ in preventing HgCl₂autoimmune disease in BN rats. This suggests that there is adifference in the cellular targets of these two agents in vivo,and/or a difference in the potency with which HgCl2-triggeredimmune activation is suppressed.     

Mean lifetime of microtubules attached to nucleating sites.

A simple two-phase (cap; no cap) macroscopic model describing the kinetic behavior at a labile tip of a microtubule has been proposed [Hill, T. L. (1984) Proc. Natl. Acad. Sci. USA 81, 6728-6732]. In the model, a microtubule exists either in a slowly growing phase (first-order rate constant, alpha) characterized by the existence of a GTP-tubulin cap at the growing tip; or the same microtubule exists in a rapidly shrinking phase (first-order rate constant, beta), which is entered if/when the GTP-tubulin cap is lost through a fluctuation, thus exposing GDP-tubulin subunits, which constitute the body of the microtubule. Transition between the two phases--i.e., loss of a cap (first-order rate constant, k) or formation of a new cap (first-order rate constant, k') occurs very infrequently and in a stochastic manner. In vitro experiments with centrosome-nucleated microtubules by Mitchison and Kirschner and Monte Carlo kinetic simulations, based on a realistic set of microscopic rate constants that apply to the end of a microtubule, suggest this alternation between two "quasimacroscopic" phases. In this paper, I outline the calculation of the mean lifetime of a microtubule nucleated on a centrosome by using Hill's model. For a microtubule M units long in the slowly growing phase, the mean lifetime for complete depolymerization is [M(k + k') + alpha + beta](beta k - alpha k')-1, provided that beta k greater than alpha k'. If the microtubule is in the rapidly shrinking phase, then the mean lifetime is M(k + k')(beta k - alpha k')-1, provided that beta k greater than alpha k'. In case beta k less than alpha k', the microtubule grows indefinitely, and the mean lifetime is infinite.     

Second malignant tumors in patients with laryngeal carcinoma: diagnosis, treatment, and prevention

Although the survival rates reported for patients with larynx carcinoma are quite good, there is a risk of developing second malignant tumors (SMT) in this population. The prognosis for SMT is poor, particularly with tumors of the lung and esophagus. The Rochester series was analyzed for larynx stage and specific SMT sites, possible common etiologic factors, and survival of the population as a whole, as well as for the SMT group. From a total of 235 patients with larynx carcinoma and a median follow-up of 10 years, 50 patients with 61 SMT were identified. The overall incidence of developing a SMT was 21%, with 44% of the SMT in the lung. The median survival from SMT diagnosis was 8.74 months and the 2-year survival was only 26%. More than twice as many SMT were observed than would be expected in the population at risk, with an observed-to-expected ratio (OER) for lung SMT of 5.3, and 8 times as many head and neck SMT occurring in our population. These SMT are not treatment related but are most likely caused by a combination of exposure to a common carcinogen, that is, tobacco smoke and alcohol, and to inherent factors, notably "condemned mucosa syndrome." Follow-up procedures, from the perspective of SMT development in larynx cancer patients, are addressed in an attempt to improve survival. The focus of this study is the high incidence of lung primaries that could be mistaken for metastatic disease, which is relatively uncommon in early larynx cancer patients.     

The Turner syndrome research registry: Creating equipoise between investigators and participants

To address knowledge gaps about Turner syndrome (TS) associated disease mechanisms, the Turner Syndrome Society of the United States created the Turner Syndrome Research Registry (TSRR), a patient‐powered registry for girls and women with TS. More than 600 participants, parents or guardians completed a 33‐item foundational survey that included questions about demographics, medical conditions, psychological conditions, sexuality, hormonal therapy, patient and provider knowledge about TS, and patient satisfaction. The TSRR platform is engineered to allow individuals living with rare conditions and investigators to work side‐by‐side. The purpose of this article is to introduce the concept, architecture, and currently available content of the TSRR, in anticipation of inviting proposals to utilize registry resources.     

Inhibition of TGF-beta modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma

A pathologically elevated interstitial fluid pressure (IFP) is a characteristic of both clinical and experimental carcinoma. The soluble TGF-beta receptor type II-murine Fc:IgG2A chimeric protein (Fc:TbetaRII) lowers IFP in the KAT-4 experimental model for anaplastic thyroid carcinoma. Analyses of messenger RNA (mRNA) expressions by Affymetrix microarrays and RNase protection assays, as well as of protein expressions identified tumor macrophages as targets for Fc:TbetaRII. Treatment with Fc:TbetaRII reduced albumin extravasation, increased coverage of alpha-smooth muscle actin-positive cells and reduced expression of NG2, a marker of activated pericytes, in KAT-4 carcinoma blood vessels. Specific inhibition of interleukin-1 (IL-1), a major cytokine produced by activated macrophages, lowered carcinoma IFP to a similar degree as Fc:TbetaRII but had no significant effect on the parameters of blood vessel maturation. Neither Fc:TbetaRII nor inhibition of IL-1 changed blood vessel density. Finally, pretreatment of KAT-4 carcinomas with Fc:TbetaRII increased the antitumor efficacy of doxorubicin. Our data emphasize a potential role of tumor macrophages in carcinoma physiology and identify these cells as potential stromal targets for treatment aimed to improve efficacy of chemotherapy.     

Intertubular growth in pure seminomas: associations with poor prognostic parameters

Clinical stage I seminomas are effectively treated with surgery raising concerns as to when to give adjuvant radiation therapy given the risk of secondary malignancies. A recent randomized trial found tumor size and rete testis invasion to be the strongest predictors of relapse in clinical stage I seminomas. These 2 parameters may be surrogate measures of tumor volume. Intertubular seminoma (ITS) of the testis describes the presence of neoplastic germ cells within the interstitium of the testis. These cells are detected away from the main macroscopic mass. Because ITS can infiltrate in a 3-dimensional fashion, it may also represent a measure of tumor volume not usually noted in standard pathology reporting. The goal of this study was to determine the incidence of ITS in pure seminomas and its association with other prognostic parameters. One hundred twenty consecutive pure seminomas surgically removed between 1998 and 2003 were evaluated. ITS was defined as the presence of an interstitial or intertubular growth pattern of tumor cells, which was noncontiguous with the main tumor and present at least 3 high-power fields away from the tumor mass. The average tumor size was 3.4 cm. Of the entire cohort of patients, which included pathological stages T1 through T3, 11% had invasion through the tunica albuginea, 51% had rete testis invasion, 51% had lymphovascular invasion, 93% had associated intratubular germ-cell neoplasia, and 36% had ITS. ITS was significantly associated with rete testis invasion ( P = .001). Logistic regression analysis looking at ITS, tumor size, patient age, and lymphovascular invasion revealed that only ITS was associated with rete testis invasion (RR, 4.1, P < .0001). ITS is present in a significant proportion of pure seminomas and has a significant association with rete testis invasion. The presence of ITS may therefore be an important prognostic factor, not only because it alters the calculated size of the tumor but also because it has an association with rete testis invasion.     

Regulator T Cells: Specific for Antigen and/or Antigen Receptors?

Adaptive immune responses are regulated by many different molecular and cellular effectors. Regulator T cells are coming to their rights again, and these T cells seem to have ordinary α/β T‐cell receptors (TCRs) and to develop in the thymus. Autoimmune responses are tightly regulated by such regulatory T cells, a phenomenon which is beneficial to the host in autoimmune situations. However, the regulation of autoimmune responses to tumour cells is harmful to the host, as this regulation delays the defence against the outgrowth of neoblastic cells. In the present review, we discuss whether regulatory T cells are specific for antigen and/or for antigen receptors. Our interest in these phenomena comes from the findings that T cells produce many more TCR‐α and TCR‐β chains than are necessary for surface membrane expression of TCR‐αβ heterodimers with CD3 complexes. Excess TCR chains are degraded by the proteasomes, and TCR peptides thus become available to the assembly pathway of major histocompatibility complex class I molecules. Consequently, do T cells express two different identification markers on the cell membrane, the TCR‐αβ clonotype for recognition by B‐cell receptors and clonotypic TCR‐αβ peptides for recognition by T cells?