LeishVet guidelines for the practical management of canine leishmaniosis

The LeishVet group has formed recommendations designed primarily to help the veterinary clinician in the management of canine leishmaniosis. The complexity of this zoonotic infection and the wide range of its clinical manifestations, from inapparent infection to severe disease, make the management of canine leishmaniosis challenging. The recommendations were constructed by combining a comprehensive review of evidence-based studies, extensive clinical experience and critical consensus opinion discussions. The guidelines presented here in a short version with graphical topic displays suggest standardized and rational approaches to the diagnosis, treatment, follow-up, control and prevention of canine leishmaniosis. A staging system that divides the disease into four stages is aimed at assisting the clinician in determining the appropriate therapy, forecasting prognosis, and implementing follow-up steps required for the management of the leishmaniosis patient

Composti farmaceutici che inibiscono la proliferazione di adenomi ipofisari e modi d’uso che ne derivano

Si descrive l'utilizzzo di analoghi della somatostatina com inibitori della vitalità cellulare ipofisaria in vitro

Metodo per modulare la proliferazione del carcinoma midollare della tiroide (MTC)

Si descrive l'impiego di analoghi della somatostatina per modulare la proliferazione di cellule di carcinoma midollare della tiroide

Somatostatin, but not somatostatin receptor subtypes 2 and 5 selective agonists, inhibits calcitonin secretion and gene expression in the human medullary thyroid carcinoma cell line, TT.

Somatostatin (SRIH) analogs are commonly used to treat symptoms in medullary thyroid carcinoma (MTC), that expresses SRIH receptors (SSTR1 to SSTR5), as does the human MTC cell line TT. The aim of this work was to evaluate whether SRIH, SSTR2 and SSTR5-selective agonists influence calcitonin (CT) secretion and gene expression in the TT cell line. CT secretion was evaluated by chemiluminescence, and gene expression was analyzed by Northern blot. TT cell line proliferation was also assessed by [(3)H] thymidine ([(3)H]thy) incorporation and viable cell number count. SRIH significantly (p < 0.05) reduced [(3)H]thy incorporation (approx. 50 %), viable cell number (approx. 20 %), CT secretion (-30 %) and CT gene expression (approx. 2-fold). Exposure to the SSTR2-selective agonist, BIM-23120, and to the SSTR5-selective agonist, BIM-23 206, did not modify CT secretion and mRNA levels in TT cells. Thus, SRIH inhibits DNA synthesis, cell proliferation, CT secretion and CT gene expression in the TT cell line, while SSTR2 and 5 selective agonists, although influencing DNA synthesis and cell proliferation, do not modify CT gene expression, suggesting that SRIH may influence gene expression acting through SSTRs other than subtypes 2 and 5. Furthermore, these findings may explain the erratic response of MTC patients in terms of CT plasma levels to treatment with SRIH analogs, like octreotide and lanreotide, which interact mainly with SSTR2 and 5

Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line, TT

Somatostatin and its receptors (SSTR1 to SSTR5) are expressed in normal human parafollicular C cells and medullary thyroid carcinoma (MTC), but the role of SSTR subtypes in cell growth regulation is still not clear. The present study demonstrates that the human MTC cell line TT stably expresses all the SSTR subtypes and responds to SSTR2 and SSTR5 activation by subtype-selective agonists with two different patterns in terms of [(3)H]thymidine ([(3)H]thy) incorporation and cell number. The SSTR2 preferential agonists (BIM-23120, BIM-23197, BIM-23190, and BIM-23014; 10(-9)-10(-6) M), significantly suppressed [(3)H]thy incorporation (58-13%) and reduced cell proliferation (50-28%), whereas the SSTR5-selective agonist, BIM-23206 (10(-9)-10(-6) M), significantly increased [(3)H]thy incorporation in TT cells (80-175%), but failed to influence cell proliferation. SSTR2 antagonist (BIM-23627) counteracted the action of SSTR2 preferential agonists on TT cells. Furthermore, increasing concentrations of SSTR5-selective agonists, BIM-23206, dose-dependently prevented the suppression of TT cell [(3)H]thy incorporation and proliferation produced by SSTR2 preferential agonist, BIM-23120, showing an antagonism between these compounds. The following conclusions were reached: 1) the human MTC cell line TT expresses all SSTR subtypes; 2) SSTR2 activation inhibits DNA synthesis and cell proliferation, whereas SSTR5 activation increases DNA synthesis; and 3) SSTR2 preferential agonist (BIM-23120) can antagonise SSTR5-selective agonist (BIM-23206) action and vice versa. These findings suggest a tissue-specific function and a tissue-specific interaction between the two receptors

Somatostatin receptor subtype 1 selective activation reduces cell growth and calcitonin secretion in a human medullary thyroid carcinoma cell line.

Medullary thyroid carcinoma (MTC) is a rare and aggressive tumor and so far medical therapy has provided inconclusive results. In the human MTC cell line TT, expressing all somatostatin (SST) receptor subtypes, cell proliferation decreases with SST and SST receptor subtype 2 (sst(2)), but not sst(5), selective agonist treatment, whereas calcitonin (CT) expression and secretion are reduced by SST, but not by sst(2) and sst(5) agonists. The effectiveness of two new SST analogs, BIM-23926 and BIM-23745, selectively interacting with sst(1), was investigated in the TT cell line. DNA synthesis is significantly reduced by BIM-23926 (27-40% at 10(-10)-10(-6)M) and BIM-23745 (32-90% at 10(-8)-10(-6)M). Viable cell number is also significantly reduced by both BIM-23926 (40% at 10(-12)-10(-6)M) and BIM-23745 ( approximately 40% at 10(-10)-10(-6)M). Treatment with sst(1)-selective agonists significantly reduces CT secretion and gene expression, with a reduction of CREB phosphorylation. These findings suggest that potent sst(1)-selective agonists could have a therapeutic role in MTC

Role of complex Cyclin D1/Cdk4 in somatostatin subtype 2 receptor-mediated inhibition of cell proliferation of a medullary thyroid carcinoma cell line in vitro.

Somatostatin (SRIH) inhibits cell proliferation by interacting with five distinct SRIH receptor subtypes (SSTRs) activating several pathways in many tissues. We previously demonstrated that SRIH, by activating Src homology-2-containing protein, inhibits cell proliferation of the human medullary thyroid carcinoma cell line, TT, which expresses all SSTRs. However, the effects of SRIH on cell cycle proteins have not been investigated so far. We therefore evaluated the effects of SRIH and a selective SSTR2 agonist on cell cycle protein expression, mainly focusing on cyclin D1 and its associated kinases. Our data show that SRIH and the selective SSTR2 agonist, BIM-23120, reduce cell proliferation and DNA synthesis as well as induce a delay of the cell cycle in G(2)/M phase. Moreover, treatment with both SRIH and BIM-23120 decreases cyclin D1 levels, with a parallel increase in phosphocyclin D1 levels, suggesting protein degradation. Moreover, our data show an increase in glycogen synthase kinase-3beta activity, which triggers phosphorylation-dependent cyclin D1 degradation. Indeed, we observed a reduction in cyclin D1 protein half-life under treatment with SRIH or the SSTR2 selective agonist. A reduction in cdk4 protein levels is also observed with a parallel reduction in Rb phosphorylation levels at Ser-780. Our data indicate that the subtype 2 receptor-mediated antiproliferative effect of SRIH on TT cell proliferation may be exerted through a decrease in cyclin D1 levels

Role of complex Cdk4/Cyclin D1 in somatostatin subtype 2 receptor-mediated inhibition of cell proliferation of a medullary thyroid carcinoma cell line in vitro

Somatostatin (SRIH) inhibits cell proliferation by interacting with five distinct SRIH receptor subtypes (SSTR) by several pathways in many tissues. We previously demonstrated that SRIH, by activating SHP-1, inhibits cell proliferation of the human Medullary Thyroid Carcinoma (MTC) cell line, TT, which expresses all SSTR. However, the effects of SRIH on cell cycle proteins have not been investigated, so far. We therefore investigated the effects of SRIH and of a selective SSTR2 agonist on cell cycle protein expression, mainly focusing on Cyclin D1 and its associated kinases. TT cells were serum starved for 48 h and then treated with SRIF or with a selective SSTR2 agonist, BIM-23120 for up to 60 h. Cell proliferation was verified by a colorimentric assay and by [3H]thymidine incorporation. Moreover, cell cycle progression was studied by cytofluorimetry. Cell cycle protein expression at different time points was investigated by Western blot. Cyclin D1 expression was also investigated by quantitative RT-PCR. Our data show that SRIH and the selective SSTR2 agonist, BIM-23120, reduce cell proliferation and DNA synthesis, as well as induce a delay of the cell cycle in G2/M phase. Moreover, treatment with SRIH or with BIM-23120 decreases Cyclin D1 and cdk4 protein levels, with a parallel reduction in Rb phosphorylation levels at Ser-780. These data indicate that the subtype 2 receptor-mediated antiproliferative effect of SRIH on TT cell proliferation may be exerted through a decrease in Cyclin D1 levels, and further underline the importance of SSTR2 in mediating the antiproliferative effects of SRIH, indicating a direct and strong effect on Cyclin D1-cdk4 comple

An in vivo Octreoscan-negative adrenal pheochromocytoma expresses somatostatin receptors and responds to somatostatin analogs treatment in vitro.

A 52-yr-old woman presented with hypertension, elevated urinary vanillylmandelic acid, metanephrines, normetanephrines, and plasma chromogranin A (CgA), but normal urinary catecholamine levels. Abdominal ultrasonography and subsequent MRI imaging showed a 3 cm nodular lesion of the right adrenal gland also visualized by 123I-meta-iodobenzylguanidine scintigraphy consistent with a pheochromocytoma (PC). Her OctreoScan was negative. The patient underwent right adrenalectomy and histological examination showed a PC. The adrenal medulla tissue was examined for somatostatin (SRIH) receptor subtypes 1 to 5 (SSTR1 to 5) expression by RT-PCR. Cultured tumor cells were treated with either SRIH, Lanreotide (Lan), or an SSTR2 (BIM-23 120) or SSTR5 (BIM-23 206) selective agonist. CgA secretion was measured in the medium by ELISA and catecholamine levels by HPLC after 6h. Cell viability was assessed after 48h. RT-PCR analysis showed that SSTR1, 2, 3 and 4 were expressed. CgA secretion was significantly reduced by SRIH (- 80 %), Lan (- 35%), and the SSTR2 selective agonist (- 65 %). Norepinephrine secretion was reduced by SRIH (- 66 %), Lan (- 40 %), and BIM-23 120 (- 70 %). Epinephrine and dopamine secretion was also inhibited by treatment with SRIH (- 90 % and - 93 %, respectively) and BIM-23 120 (- 33 % and - 75 %, respectively) but not by Lan. Cell viability was also significantly reduced by SRIH (- 30 %), Lan (- 10 %), and the SSTR2 selective agonist (- 20 %). The SSTR5 selective agonist did not modify either CgA and catecholamine secretion or cell viability. Our data show that SSTRs may be present in a PC although OctreoScan is negative in vivo, and that SRIH and its analogs may reduce both differentiated and proliferative functions in chromaffin cells in vitro. These findings suggest that SRIH analogs with enhanced SSTR2 affinity might be useful in the medical therapy of PC, even when an OctreoScan is negative

Somatostatin receptor subtype 1 selective activation in human growth hormone- and prolactin-secreting pituitary adenomas: effects on cell viability, growth hormone and prolactin secretion.

Somatostatin (SRIF) analogs interacting with SRIF receptor subtype (SSTR) 2 and SSTR5 are known to reduce secretion in GH-secreting pituitary adenomas. We investigated the effects of SRIF and a SSTR1 selective agonist, BIM-23926, on GH and prolactin (PRL) secretion and cell viability in primary cultures deriving from 15 GH- and PRL-secreting adenomas expressing SSTR1. Quantitative RT-PCR showed SSTR1 mRNA mean levels of 6 +/- 2.2 x 10(4) molecules/ microg reverse-transcribed total RNA. SSTR2 and SSTR5 were frequently expressed (93.3%), on the contrary of SSTR3 (53.3%) and SSTR4 (6.7%). GH secretion was significantly reduced by SRIF and BIM-23926 (45 +/- 8.6% and 32 +/- 18.1% inhibition, respectively) as well as PRL secretion (16.1 +/- 4% and 19.7 +/- 3.5% inhibition, respectively). After treatment with SRIF and BIM-23926, cell viability was significantly reduced by 17.5 +/- 5% and 20 +/- 3.9%, respectively. SSTR1 mRNA levels correlated with the degree of GH and PRL secretion inhibition. These results demonstrate that SSTR1 selective activation inhibits hormone secretion and cell viability in GH- and PRL-secreting adenomas in vitro and suggest that SRIF analogs with affinity for SSTR1 may be useful to control hormone hypersecretion and reduce neoplastic growth of pituitary adenomas