HLA-G1, but Not HLA-G3, Suppresses Human Monocyte/Macrophage-mediated Swine Endothelial Cell Lysis.

The inhibitory function of HLA-G1, a class Ib molecule, on monocyte/macrophage-mediated cytotoxicity was examined. The expression of inhibitory receptors that interact with HLA-G, immunoglobulin-like transcript 2 (ILT2), ILT4, and KIR2DL4 (CD158d) on in vitro-generated macrophages obtained from peripheral blood mononuclear cells and the phorbol 12-myristate 13-acetate (PMA)-activated THP-1 cells were examined by flow cytometry. cDNAs of HLA-G1, HLA-G3, HLA-E, and human ß2-microglobulin were prepared, transfected into pig endothelial cells (PECs), and macrophage- and the THP-1 cell-mediated PEC cytolysis was then assessed. In vitro-generated macrophages expressed not only ILT2 and ILT4 but CD158d as well. The transgenic HLA-G1 on PEC indicated a significant suppression in macrophage-mediated cytotoxicity, which was equivalent to that of transgenic HLA-E. HLA-G1 was clearly expressed on the cell surface of PEC, whereas the levels of HLA-G3 were much lower and remained in the intracellular space. On the other hand, the PMA-activated THP-1 cell was less expressed these inhibitory molecules than in vitro-generated macrophages. Therefore, the HLA-G1 on PECs showed a significant but relatively smaller suppression to THP-1 cell-mediated cytotoxicity compared to in vitro-generated macrophages. These results indicate that by generating HLA-G1, but not HLA-G3, transgenic pigs can protect porcine grafts from monocyte/macrophage-mediated cytotoxicity.

A missense mutation in podocin leads to early and severe renal disease in mice.

Mutations in the NPHS2 gene, encoding podocin, are responsible for familial autosomal recessive and sporadic cases of steroid-resistant nephrotic syndrome. We have successfully generated a mouse model in which the common p.R138Q mutation found in nephrotic patients is expressed in the kidney. Homozygous mice express the mutant protein, which is mislocated to the cytoplasm, along with a portion of the nephrin pool. These mice die within the first month of life, but their survival depends on the genetic background. Albuminuria manifests early and leads to progressive renal insufficiency, characterized histologically by diffuse mesangiolysis and mesangial sclerosis, endothelial lesions along with podocyte abnormalities such as widespread foot process effacement. Gene expression profiling revealed marked differences between these and the podocin-null mice, including significant perturbations of podocyte-expressed genes such as Cd2ap, Vegfa and the transcription factors Lmx1b and Zhx2. Upregulation of Serpine1 and Tgfb1 implicates these as potential mediators of disease progression in these mice. This mouse model of nephrotic syndrome may serve as a valuable tool in studies of in vivo intracellular protein trafficking of podocyte proteins, as well as testing therapeutic modalities aimed at correcting the targeting of mutant proteins.

[Progesterone receptors in the prognosis after therapy of pre- and post-menopausal patients with squamous intraepithelial lesions and cancer of the uterine cervix]. / Receptores a progesterona en el pronóstico de la terapia en pacientes pre y posmenopáusicas con lesiones escamosas intraepiteliales y por cáncer cérvico uterino.

The objective of this study was to know if there is a correlation in contents progesterone receptors (RPg) in biopsies from patients pre and postmenopausal, with normal cervix, Low-Grade squamous intraepithelial lesions (LGESIL) and High-Grade (HGSIL), and invasive cancer. Sixty three patients with abnormal cytology; colposcopy was carried out and two biopsies were taken from the suspicious lesion, they were sent for histopathological study, and for RPg; both studies were correlated later. Both pre and postmenopausal with LGSIL, the RPg the mean values were 16.81 fmol/mg, protein, and values negative, respectively. With regard to HGSIL, the RPg content, the mean values was 20.31 fmol/mg, protein in pre-menopausal patients, whereas it was 3.8 fmol/mg, protein in postmenopausal patients. It was seen that RPg concentration is higher in invasive cancer than to LGSIL and HGSIL patients in pre and postmenopausal. It is concluded that this study on quantification to RPg receptor level measurement may well be to select poor prognostic groups of patients for inclusion in the management of squamous intraepithelial lesions and invasive cancer.

Ribozymes: biology, biochemistry, and implications for clinical medicine.

Ribozymes are a class of ribonucleic acid (RNA) molecules that possess enzymatic properties. Upon binding to complementary nucleic acid strands, catalytic degradation takes place via a cleavage reaction. In effect, inactivation of susceptible substrate RNA molecules takes place at a catalytic rate and with a high degree of substrate specificity. This article reviews the biology and biochemistry of this class of molecules and its potential applications in clinical medicine.

[Reductive effect of the sesquiterpenic lactone "Helenalin " and its metallic derivatives in the formation of the estradiol receptor complex in breast tumor tissue]. / Efecto reductor de la lactona sesquiterpénica "Helenalina" y sus derivados metálicos en la formación del complejo estradiol receptor en tejido tumoral mamario.

Chemotherapy for systemic therapy in breast cancer has been widely used, and has been supported by many varied compounds with different origins and different compositions. Nevertheless, all of them produce several side adverse effects which must be taken into account. For this reason we must study new possibilities in which the administered drug acts selectively on the tumour cell without injuring healthy tissue. For studying its effect, a gamma lactone called "Helenaline" and its metalic derivates He-Co, He-Hg and He-Cu were studied, which chemical composition allows them to react with -SH residues present in the tumour cell receptors, which when interspaced by a previous reaction, could modify its structural composition and finally its affinity by the hormone. The inhibition effect for formation of estradiol-receptor complex in breast tumour tissue using Helenaline 12 n M and 126 n M was studied, obtaining 14% and 56% inhibition effect respectively. When He-Co, He-Hg and He-Cu effect was studied, this effect was raised obtaining 11%, 10.5% and 60% with 12 nM and 44.5%, 74.4% and 86% with 126 nM respectively.

[Infiltrating duct breast carcinoma: the role of estradiol and progesterone receptors]. / Carcinoma mamario ductal infiltrante. Papel de los receptores a estradiol y progesterona.

The content of receptors to estradiol (ER) and progesterone (PgR) was studied in hormone-dependent tumours from pre- and postmenopausal patients with an infiltrating ductal type of mammary cancer in clinical stage III. The receptors concentration was correlated with the response endocrine treatment. (ER) and (PgR) demonstrated values in the ranges 11-275 and 11-76 femtomoles/mg protein respectively. According to the type of receptor found, four different groups were found, the group (ER+) (PgR+) was found in 25% and 26% of the pre- and postmenopausal patients respectively, 31% and 27% demonstrated the group (ER+) (PgR-). The combination (ER-) (PgR+) was present in 21% of premenopausal women and 16% in the postmenopausal conditions. 23% and 31 of the pre- and postmenopausal women presented (ER-) (PgR-) respectively. Patients, to whom tamoxifen was administered, were those who demonstrated the following receptor groups: (ER+) (PgR+), (ER+) (PgR-) and (ER-) (PgR+). Following therapeutic treatment those surviving without tumoural activity, were those who demonstrated higher estrogen receptor values. The concentration of (ER) was observed to be decreased by 29% in patients who presented distant metastasis and in the cases with local metastasis, (ER) showed at 54% decrease with respect to (ER) values from symptomatic patients. The concentration of (PgR) remained constant in all the aforementioned groups.

[Estradiol, progesterone, and dexamethasone receptors in infiltrating ductal carcinoma]. / Receptores a estradiol, progesterona y dexametazona en carcinoma ductal infiltrante.

The concentration of receptor to estradiol (E-R) progesterone (Pg-R) and dexamethasone (G-R) was studied, by the dextran coated charcoal method in the cytosol of the mammary gland tissue from patients with infiltrating ductal carcinoma. The study was done in one hundred cases. 45% of these patients were postmenopausic and 55% premenopausic, with average ages of 66 and 37 years respectively. Their first pregnancy occurred on average at 24 years and they had 3-4 gestations, 45% breast-fed for a minimum period of six months and menarche at 13 years. The specific union found in the tumours was considered "receptor positive" were in the range of 10 to 181 femtomoles/mg. The "Receptor negative" tumour was considered to have a specific union less than 10 femtomoles/mg protein. On using E-R as a marker to predict the hormonal treatment it was found in this study that 56% of these patients demonstrated R-E+ and was absent in 44%. Simultaneous determination of E-R and Pg-R, raised the number of patients presenting specific receptors to 70% and on determining E-R, Pg-R and G-R, in the same tumours as markers of hormone dependence, the number of patients that presented them, increased to 77%. Finally 23% of these patients did not contain E-R, Pg-R or G-R. When the values of R-E+ were grouped according to the menstrual state of the patient, it was found that the high values of R-E+ corresponded to the postmenopausic patients. No relation was found between the concentration of R-Pg+ and R-G+ and the patient's menstrual state.