This work was undertaken to study the heterogeneity of GH in serum and placental and pituitary extracts and to study GH physiology in pregnant women. Two distinct monoclonal antihuman GH (anti-hGH) antibodies (MAb) coded 5B4 and K24 were selected for their high binding affinity and specificity. The 5B4 MAb recognized the epitope comprising the NH2-terminal end of hGH, and the K24 MAb recognized an internal epitope. Both MAbs were used in RIAs to measure serum GH concentrations in various circumstances, including pregnancy. The two RIAs yielded slightly different serum GH results in normal men and nonpregnant women, but the overall correlation between the data was excellent. Since the RIAs were not affected by human placental lactogen, the evolution of serum GH in pregnant women could be studied. In such women, serum GH levels progressively declined to undetectable levels during the second half of pregnancy, while a pregnancy-associated serum GH-like antigen [tentatively called human placental growth hormone (PGH)] appeared in the circulation at midpregnancy and increased thereafter up to term. PGH contained the NH2-terminal epitope of pituitary GH, but lacked the internal one. Consequently, it reacted selectively with the 5B4 MAb only. After delivery, PGH disappeared from maternal serum within 1 h. Amniotic fluid contained low GH concentrations; cord serum contained high GH levels, but no PGH. Thus, PGH appears to be secreted selectively into the maternal compartment. PGH was purified from term placenta extracts. According to its chromatographic behavior, it appears more basic than pituitary 22K and 20K GHs. Size dimorphism was demonstrated; PGH was composed of two entities of 22K and 25K, respectively. Pure PGH, obtained in small quantities by preparative electrophoresis, was found to bind to hepatic GH receptor with an apparent high potency compared to that of pituitary GH, PGH, thus, should act in vivo as a GH agonist sharing most of its biological properties. These results lead to the conclusion that PGH is likely to replace the pituitary hormone in governing maternal metabolism during the second half of pregnancy.

Currently, no evidence supports that limited ischaemia time (i.e. ≤25 min) has a higher risk of reducing renal function after PN compared to a 'zero ischaemia' technique. Several recent studies have suggested that prolonged warm ischaemia (>25-30 min) could cause an irreversible ischaemic insult to the surgically treated kidney.

Although glucocorticoids are widely used in the treatment of immunohematologic disease, their relative efficacy is uncertain. We used an animal model, which has helped to elucidate the role of splenic macrophage Fc'y receptors in the clearance of IgG-coated cells, to investigate whether each Fc'y receptor is modulated by glucocorticoids to the same extent and to examine the relative potency of three commonly used glucocorticoids. Cortisol, prednisone, and dexamethasone all impaired the clearance ofIgG-coated erythrocytes. However, dexamethasone was more effective than either prednisone or cortisol (P < 0.001). Furthermore, splenic macrophages isolated from glucocorticoid-treated animals expressed impaired Fcy receptor function. This effect was greater in macrophages isolated from dexamethasone-treated animals, as compared to either cortisol-or prednisone-treated animals (P < 0.001). To assess the effect of glucocorticoids on the two types of guinea pig splenic macrophage Fc-y receptors, FcyR1,2 and FcyR2, specific immunoglobulin isotypes were used to measure macrophage binding of IgG-sensitized erythrocytes. Cortisol and prednisone primarily affected FcyR2, whereas dexamethasone inhibited the function of both guinea pig Fcy receptors. Furthermore, dexamethasone was more effective (P < 0.01) than either prednisone or cortisol in inhibiting the ability of both receptors to bind IgG-sensitized cells. Fluorescence-activated cell sorter analysis and fluorescence microscopy with monoclonal antibodies specific for each of these two receptors demonstrated that essentially all splenic macrophages expressed both receptors, and that these glucocorticoids decreased the level of each Fcy receptor protein expressed, rather than altering receptor mobility and clustering in the macrophage membrane. The effect on both Fcy receptors was greatest with dexamethasone and least with cortisol. These studies demonstrate the significant role of guinea pig splenic macrophage (J. Clin. Invest. 1991. 88:149-157.)

Hormone-naïve prostate cancer and its castration-resistant state (CRPC) are clinically and genetically heterogeneous diseases. From initiation of prostate carcinogenesis to its evolution towards therapeutic resistance, various combinations of genetic and epigenetic events occur.Schematically, progression to CRPC could be divided in two distinct pathways, either dependent or independent of the androgen receptor activity. Nevertheless, because the better knowledge of the genetic landscape of CRPC is under way, limited clinical applications are available at the moment, underlying the usefulness of prognostic and predictive biomarkers in daily practice. Despite the promising prognostic value of circulating tumor cells, no biomarker has been currently validated as a surrogate for overall survival in CRPC patients.Inversely, considerable interest has been generated with the recent finding of the splice variant AR-V7 that allows to predict resistance to abiraterone acetate and enzalutamide.However, other predictive biomarkers would be necessary to accurately guide personalized sequencing of CRPC treatment, which now includes numerous possibilities based on the six validated drugs, without accounting for those currently under investigation in the ongoing randomized controlled trials. As a consequence, only rational sequencing, which consists in choosing an agent that is not expected to have cross-resistance with previous therapy, can be currently advised.

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CT-naïve patients treated with AA obtained a better clinical benefit in terms of effectiveness, safety and cost-effectiveness ratio than post-CT patients. The effectiveness outcomes were poorer than those reported previously in the clinical trial setting.

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A gene encoding the heat shock protein (HSP) 60 from Paracoccidioides brasiliensis (Pb) was cloned and characterized. The hsp60 gene is composed of three exons divided by two introns. Structural analysis of the promoter detected canonical sequences characteristic of regulatory regions from eukaryotic genes. The deduced amino acid sequence of the Pb hsp60 gene and the respective cloned cDNA consists of 592 residues highly homologous to other fungal HSP60 proteins. The hsp60 gene is present as a single copy in the genome, as shown by Southern blot analysis. The HSP60 protein was isolated from Pb yeast cellular extracts. N-terminal amino acid sequencing of HSP60 confirmed that the cloned hsp60 gene correlated to the predicted protein in Pb. HSP60 expression appeared to be regulated during form transition in Pb, as different levels of expression were detected in in vitro labeling of cells and northern blot analysis. The complete coding region of Pb hsp60 was fused with plasmid pGEX-4T-3 and expressed in Escherichia coli as a glutathione S-transferase-tagged recombinant protein. The protein reacted with a mouse monoclonal antibody raised to a human recombinant HSP60. Western immunoblot experiments demonstrated that the recombinant protein and the native HSP60 were recognized by sera from humans with paracoccidioidomycosis (PCM).