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Biomedical subjects

H Soto

Publications and source records attributed to H Soto.

At least 19 recordsLinked to original sources
PubMed2001

Involvement of chemokine receptors in breast cancer metastasis.

Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1alpha and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

Actins↗
PubMed2000

Identification of a novel chemokine (CCL28), which binds CCR10 (GPR2).

We report the identification and characterization of a novel CC chemokine designated CCL28 and its receptor CCR10, known previously as orphan G-protein-coupled receptor GPR2. Human and mouse CCL28 share 83% identity at the amino acid and 76% at the nucleic acid levels. We also identified the mouse homologues of CCL28 and of CCR10, which map to mouse chromosomes 13 and 11, respectively. CCL28 is expressed in a variety of human and mouse tissues, and it appears to be predominantly produced by epithelial cells. Both human and mouse CCL28 induce calcium mobilization in human and mouse CCR10-expressing transfectants. CCL28 desensitized the calcium mobilization induced in CCR10 transfectants by CCL27, indicating that these chemokines share this new chemokine receptor. In vitro, recombinant human CCL28 displays chemotactic activity for resting CD4 or CD8 T cells.

Amino Acid Sequence↗
PubMed2000

Cutting edge: the orphan chemokine receptor G protein-coupled receptor-2 (GPR-2, CCR10) binds the skin-associated chemokine CCL27 (CTACK/ALP/ILC).

We recently reported the identification of a chemokine (CTACK), which has been renamed CCL27 according to a new systematic chemokine nomenclature. We report that CCL27 binds the previously orphan chemokine receptor GPR-2, as detected by calcium flux and chemotactic responses of GPR-2 transfectants. We renamed this receptor CCR10. Because of the skin-associated expression pattern of CCL27, we focused on the expression of CCL27 and CCR10 in normal skin compared with inflammatory and autoimmune skin diseases. CCL27 is constitutively produced by keratinocytes but can also be induced upon stimulation with TNF-alpha and IL-1beta. CCR10 is not expressed by keratinocytes and is instead expressed by melanocytes, dermal fibroblasts, and dermal microvascular endothelial cells. CCR10 was also detected in T cells as well as in skin-derived Langerhans cells. Taken together, these observations suggest a role for this novel ligand/receptor pair in both skin homeostasis as well as a potential role in inflammatory responses.

Amino Acid Sequence↗
PubMed1999

The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes.

6Ckine is an unusual chemokine capable of attracting naive T lymphocytes in vitro. It has been recently reported that lack of 6Ckine expression in lymphoid organs is a prominent characteristic of mice homozygous for the paucity of lymph node T cell (plt) mutation. These mice show reduced numbers of T cells in lymph nodes, Peyer's patches, and the white pulp of the spleen. The genetic reason for the lack of 6Ckine expression in the plt mouse, however, has remained unknown. Here we demonstrate that mouse 6Ckine is encoded by two genes, one of which is expressed in lymphoid organs and is deleted in plt mice. A second 6Ckine gene is intact and expressed in the plt mouse.

Animals↗
PubMed1999

Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3).

We have generated rat monoclonal antibodies specific for the mouse eotaxin receptor, C-C chemokine receptor 3 (CCR3). Several anti-CCR3 mAbs proved to be useful for in vivo depletion of CCR3-expressing cells and immunofluorescent staining. In vivo CCR3 mAbs of the IgG2b isotype substantially depleted blood eosinophil levels in Nippostrongyus brasiliensis-infected mice. Repeated anti-CCR3 mAb treatment in these mice significantly reduced tissue eosinophilia in the lung tissue and bronchoalveolar lavage fluid. Flow cytometry revealed that mCCR3 was expressed on eosinophils but not on stem cells, dendritic cells, or cells from the thymus, lymph node, or spleen of normal mice. Unlike human Th2 cells, mouse Th2 cells did not express detectable levels of CCR3 nor did they give a measurable response to eotaxin. None of the mAbs were antagonists or agonists of CCR3 calcium mobilization. To our knowledge, the antibodies described here are the first mAbs reported to be specific for mouse eosinophils and to be readily applicable for the detection, isolation, and in vivo depletion of eosinophils.

3T3 Cells↗
PubMed1999

Regulation of human lung fibroblast C1q-receptors by transforming growth factor-beta and tumor necrosis factor-alpha.

Transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) are two polypeptide mediators which are believed to play a role in the evolution of idiopathic pulmonary fibrosis (IPF). We have evaluated the effect of these two substances on the expression of receptors for collagen (cC1q-R) and globular (gC1q-R) domains of C1q and on type I collagen in human lung fibroblasts. Two fibroblast subpopulations differing in C1q receptor expression were obtained by culturing human lung explants in medium containing fresh human serum and heated plasma-derived serum and separating them based on C1q binding [Narayanan, Lurton and Raghu: Am J Resp Cell Mol Biol. 1998; 17:84]. The cells, referred to as HH and NL cells, respectively, were exposed to TGF-beta and TNF-alpha in serum-free conditions. The levels of mRNA were assessed by in situ hybridization and Northern analysis, and protein levels compared after SDS-polyacrylamide gel electrophoresis and Western blotting. NL cells exposed to TGF-beta and TNF-alpha contained 1.4 and 1.6 times as much cC1q-R mRNA, respectively, whereas in HH cells cC1q-R mRNA increased 2.0- and 2.4-fold. The gC1q-R mRNA levels increased to a lesser extent in both cells. These increases were not reflected in protein levels of CC1q-R and gC1q-R, which were similar to or less than controls. Both TGF-beta and TNF-alpha also increased procollagen [I] mRNA levels in both cells. Overall, TNF-alpha caused a greater increase and the degree of response by HH fibroblasts to both TGF-beta and TNF-alpha was higher than NL cells. These results indicated that TGF-beta and TNF-alpha upregulate the mRNA levels for cC1q-R and collagen and that they do not affect gC1q-R mRNA levels significantly. They also indicated different subsets of human lung fibroblasts respond differently to inflammatory mediators.

Amino Acid Sequence↗
PubMed1998

The chemokine receptor CCR8 is preferentially expressed in Th2 but not Th1 cells.

In this paper we report on the cloning and characterization of mouse CCR8. Like its human homologue, it is predominantly expressed in the thymus. In the periphery, murine CCR8 mRNA was found most abundantly expressed in activated Th2-polarized cells and in NK1.1+ CD4+ T cells. Human CCR8 is also preferentially expressed in human Th2-polarized cells and clones. This pattern of expression suggests that CCR8 is part of a Th2-specific gene expression program. The CCR8 ligands I-309 and its mouse homologue T cell activation gene 3 (TCA-3) are potent chemoattractants for Th2-polarized cells. Taken together, these observations strongly suggest that CCR8 plays a role in the control of Th2 responses, and may represent a potential target for treatment of allergic diseases.

Amino Acid Sequence↗
PubMed1998

The CC chemokine 6Ckine binds the CXC chemokine receptor CXCR3.

We cloned the mouse homologue of the chemokine receptor CXCR3, which is located in mouse chromosome X. We screened a large panel of chemokines for their ability to induce a calcium flux in mouse CXCR3-transfected cells and identified a new ligand for this receptor, the recently reported CC chemokine 6Ckine. This represents an example of a CC chemokine, which binds to a CXC chemokine receptor. Like other ligands of this receptor, 6Ckine has angiostatic properties. 6Ckine is known to chemoattract T cells. In line with this, CXCR3 is expressed preferentially in Th1 cells and in lymphoid organs of the IL-10(-/-) mouse that develops chronic colitis. Its ability to attract T cells as well as its angiostatic properties suggest that 6Ckine may be an effective anti-tumor agent.

Amino Acid Sequence↗
PubMed1997

Language guiding therapy: the case of dehydration versus volume depletion.

Indiscriminate use of the terms dehydration and volume depletion, so carefully crafted by our predecessors, risks confusion and therapeutic errors. These two conditions should be distinguished at the bedside and in how we speak to one another. Dehydration largely refers to intracellular water deficits stemming from hypertonicity and a disturbance in water metabolism. The diagnosis of dehydration cannot be established without laboratory analysis of p[Na +] or calculation of serum tonicity. In contrast, volume depletion describes the net loss of total body sodium and a reduction in intravascular volume and is best termed extracellular fluid volume depletion. The diagnosis of this condition relies principally on history, careful physical examination, and adjunctive data from laboratory studies. The pathophysiology of both dehydration and extracellular fluid volume depletion must be understood if these conditions are to be recognized and appropriately treated when they occur separately or together. There is no inclusive therapy for all situations. For example, indiscriminate treatment with 0.45% saline cannot be recommended when these conditions coexist because extracellular fluid volume depletion is often treated rapidly with 0.9% saline and dehydration is often treated more slowly with 5% dextrose.

Dehydration↗
PubMed1997

Metalloproteinase activity during growth, maturation and atresia in the ovarian follicles of the goat.

Metalloproteinases are an important group of hydrolytic enzymes which participate in interstitial matrix degradation during tissue remodelling processes and therefore may be required during follicular growth and maturation. The activity of metalloproteinases (collagenases, gelatinase, and Pz-peptidase), was measured during growth, maturation and atresia of goat antral follicles. These follicles (n = 67) were separated by size and also classified into four groups: non-atretic (Group I); early atretic (Stage I) (Group II); moderately atretic (Stage II) (Group IIIa); and, late atretic (Stage III) (Group IIIb). Pz-peptidase was greater in granulosa than in thecal cells, and almost absent in follicular fluid. In non-atretic follicles, activity in granulosa cells increased with increasing follicle size, whereas activity peaked in 3-6 mm follicles in thecal cells. Atresia was associated with declining activity in thecal cells from follicles in the 3-6 mm range and in granulosa cells from the > 6 mm range. Interstitial collagenase activity was significant and similar in granulosa and thecal cell extracts and low in follicular fluid from non-atretic follicles. Activity increased significantly in thecal cells, but decreased significantly in granulosa cells from large (> 6 mm) non-atretic follicles. Atresia was associated with declining activity in both types cells and increasing activity in follicular fluid. Gelatinase activity was some times associated with five regions corresponding to molecular weights of 22.1, 30.7, 39.6, 63.8 and 71.4 kDa, and rarely at 91.3 and 81.2 kDa. Overall activity declined with atresia in thecal cells from follicles in the 3-6 mm range, but not in those > 6 mm. In granulosa cells from follicles 3-6 mm, activity varied widely with stage of atresia, while in cells from follicles > 6 mm, activity was greatly increased in atretic follicles.

Animals↗
PubMed1997

Apoptosis in proliferative glomerulonephritis: decreased apoptosis expression in lupus nephritis.

BACKGROUND: Apoptosis is a mechanism of cellular death involved in the deletion of cells in hyperplasic processes which has been observed in proliferative glomerulonephritis. Patients with systemic lupus erythematosus (SLE) are known to have defective apoptosis but there is scarce information about apoptosis in the renal lesions of this disease. The present studies were done to evaluate apoptosis in relation to the intensity of proliferation in several glomerulonephritis and the possible association between this relationship and the chronic histologic changes in lupus nephritis. METHODS: Studies were done in renal biopsies from 19 patients with lupus nephritis (types, IV, Va, Vb) classified with respect to chronicity and activity indexes, five patients with acute poststreptococcal glomerulonephritis, five with idiopathic mesangioproliferative glomerulonephritis, four with membranous glomerulonephritis, four with minimal-change nephrotic syndrome, and three patients with focal segmental sclerosis. Seven normal kidneys which could not be used for transplantation were used as a control group. Apoptosis was determined by in situ DNA nick-end labelling techniques and proliferating cells were identified with a monoclonal antibody antiproliferating cell nuclear antigen (PCNA). RESULTS: Decreased number of apoptotic cells and a high ratio of PCNA: apoptosis were observed in glomerulus and tubulointerstitium of patients with lupus nephritis when compared to other proliferative glomerulonephritis and controls. In lupus nephritis, glomerular apoptosis had a negative correlation with the chronicity index (r = -0.606 P = 0.005). The number of apoptotic cells in the glomeruli was not correlated with the number of PCNA positive cells in lupus nephritis, in contrast with a striking linear correlation observed in acute poststreptococcal nephritis (r = 0.925, P = 0.024), a disease with excellent prognosis. CONCLUSIONS: Apoptosis is decreased in proliferative lupus nephritis. Intense proliferation without increment in apoptosis (a high PCNA: apoptosis ratio) is a characteristic of lupus nephritis associated with chronic renal histological changes.

Adolescent↗
PubMed1997

Features of Schistosoma mansoni infection in SCID mice.

Features of Schistosoma mansoni infection in SCID mice, which lack functional T- and B-lymphocytes, were investigated. The retarded development of parasites as well as reduction of liver egg recovery in SCID mice was significantly lower than those in congenic counterpart C.B-17 mice. Furthermore, the rate of parasite recovery from SCID mice with primary infection was always lower than that from C.B-17 mice by 20%, showing the innate resistance to S. mansoni infection. SCID mice vaccinated with UV-attenuated S. mansoni cercariae did not show protective immunity against a homologous challenge infection. The present innate resistance exhibited in SCID mice is discussed in relation to cell mediated immunity of macrophage activation by IFN-gamma which would not involve T-lymphocytes but is initiated by IL-12 and TNF-alpha cytokines. SCID mice may provide novel information on the host-parasite relationship in schistosome infections.

Animals↗
PubMed1996

Effects of mebendazole on protein biosynthesis and secretion in human-derived fibroblast cultures.

Previous results of our group revealed that mebendazole, a broad spectrum anthelmintic drug with antimicrotubular properties, used for the treatment of liver cirrhosis, decreased total collagen content and biosynthesis in liver upon treatment. In the present study, we have evaluated the effects of mebendazole (5-50 micrograms/mL) on protein synthesis, secretion, and deposition in human-derived fibroblast cultures. The results showed a decrease in cell viability (18.5 +/- 0.9%) at 50 micrograms/mL. [3H]Thymidine incorporation diminished gradually with increasing mebendazole concentrations, reaching a plateau (53.67%) between 30 and 50 micrograms/mL. In late logarithmic phase cultures, the drug caused a decrease of [3H]proline incorporation (43.10%) and collagen biosynthesis (58.61%) in the extracellular matrix. This correlated with an increase in radioactivity in total proteins (51.28%) of the intracellular fraction. Similar results were obtained when mebendazole was assayed in post-confluent fibroblast cultures. The electrophoretic patterns of the extracellular matrix showed a decrease of radioactive collagenous components (alpha chains and beta dimers). By contrast, in the intracellular fraction an increase of radioactive collagen precursors (pro alpha chains) was observed. Immunofluorescence studies and immunotransfer analysis, using polyclonal anti-type I collagen antibodies, revealed an accumulation of intracellular collagen which included: collagen pro alpha chains, alpha chains, and low molecular weight peptides. The results obtained suggest that mebendazole interferes with the transcellular mobilization of proteins, resulting in a decrease of secretion and deposition of extracellular matrix proteins, and an accumulation of intracellular collagenous components. The intracellular accumulation of newly synthesized proteins could cause a feedback regulation in fibroblast cultures.

Antinematodal Agents↗
PubMed1992

Accuracy of frozen-section diagnosis at surgery in clinical stage I and II endometrial carcinoma.

OBJECTIVES: The purpose of our study was to determine if frozen section accurately identifies certain poor prognostic pathologic factors in endometrial carcinoma that are known to be associated with pelvic and paraaortic nodal metastasis, including deep myometrial invasion, poorly differentiated tumor, cervical invasion, adnexal involvement, and poor histologic type. STUDY DESIGN: The frozen-section pathologic results of 199 patients with clinical stage I and II endometrial cancer were retrospectively compared with permanent-section pathologic findings. RESULTS: The depth of myometrial invasion (superficial third vs deep two thirds) was accurately determined by frozen-section diagnosis at surgery in 181 of 199 cases (91.0%). The sensitivity of frozen-section diagnosis for deep myometrial invasion was 82.7%, and the specificity was 89.1%. The following tumor characteristics were accurately determined on frozen section at surgery: poorly differentiated tumor (95.0%), cervical invasion (94.0%), adnexal involvement (98.5%), and histologic type (94.0%). Frozen section underestimated deep myometrial invasion in 17.3% of patients with this characteristic and poorly differentiated tumor in 26.3% when compared with permanent-section diagnosis. In patients with unfavorable histologic types, papillary serous and adenosquamous carcinomas were the most commonly misdiagnosed histologic types by frozen section at surgery (70.6%). However, when the preoperative curettage pathologic findings were included, these inaccuracies in tumor grade and histologic type dropped to 15.8% and 35.3%, respectively. Only 13 of 199 patients (6.5%) were not correctly identified by frozen section at surgery as having poor prognostic pathologic features. CONCLUSION: Frozen section diagnosis at surgery is an important procedure that enables the surgeon to identify patients at high risk for pelvic and paraaortic nodal metastasis.

Adenocarcinoma↗
PubMed1985

Chédiak-Higashi syndrome in a Venezuelan black child.

One case of Chédiak-Higashi syndrome (CHS) in a black male child, born to a consanguineous couple from a rural village in the State of Falcón, is described. At birth the child had marked skin depigmentation and ash-gray hair. A few months later he developed an almost normal black skin color. The diagnosis of CHS was established by the presence of large peroxidase-positive granules in his leukocytes. Neutrophils showed decreased chemotaxis and lack of digestive capacity against Candida albicans. Unusual features included extreme rarity of CHS in blacks, progressive repigmentation of the skin, and an early benign evolution. A high consanguinity index in the village from which this patient originated raised the possibility of the presence of a new cluster of this disease in Venezuela.

Black or African American↗
PubMed1980

Collagen-bound collagenase.

The presence of collagenase bound to collagen extracted and purified from several animal and human sources by a standard procedure has been confirmed by different methods. Polyacrylamide (10%) gel electrophoresis at pH 8.1 of intact or "spontaneously"degraded neutral salt soluble collagen results in the separation of two components: the upper one says at the origin and represents collagen or collagen ragments, whereas the lower protein component contains no collagen, often preserves specific collagenolytic activity, and migrates as a single band in SDS/polyacrylamide electrophoresis. With lower polyacrylamide gel concentration the electrophoretic separation of the two components is less clear. Removal of the lower protein component from collagen solutions by two different methods (TCA-ethanol purification cycles and pepsin digestion) results in concomitant loss of their "spontaneous" instability. Eluates of the lower protein component stimulate the heterologous production of a monospecific antibody capable of inhibiting the collagenolytic activity of homologous crude collagenase preparations. It is suggested that collagen-bound collagenase is not an artifact of the extraction procedure but rather a physiological reality, probably corresponding in the living animal to the enzyme closely associated with extracellular collagen fibers, revealed by immunohistochemical methods.

Animals↗