Aberrant cellular retinol binding protein 1 (CRBP1) gene expression and promoter methylation in prostate cancer

AIMS: Retinoids are involved in cell growth, differentiation, and carcinogenesis. Their effects depend on cytosolic transport and binding to nuclear receptors. CRBP1 encodes a protein involved in this process. Because altered CRBP1 expression and promoter hypermethylation occur in several tumours, these changes were investigated in prostate tumorigenesis. METHODS: The CRBP1 promoter was assessed by methylation specific polymerase chain reaction on tissue samples from 36 radical prostatectomy specimens (paired normal tissue, adenocarcinoma, and high grade prostatic intraepithelial neoplasia (HGPIN)), 32 benign prostatic hyperplasias (BPHs), and 13 normal prostate tissue samples from cystoprostatectomies. Methylation of DNA extracted from microdissected tissue was examined blindly. CRBP1 expression was assessed by immunohistochemistry on formalin fixed, paraffin wax embedded tissue. RESULTS: Loss of CRBP1 expression was seen in 15 of 36 adenocarcinomas and 18 of 36 HGPINs. Fifteen adenocarcinomas and nine HGPINs showed overexpression, whereas the remainder showed normal expression. BPH displayed normal expression. No significant associations were found between CRBP1 expression and Gleason score or stage. CRBP1 promoter hypermethylation was found in 17 of 36 adenocarcinomas, three of 35 HGPINs, one of 36 normal prostate tissues from the same patients, none of 32 BPHs, and none of 13 normal prostate tissues from cystoprostatectomies. Loss of expression and hypermethylation of CRBP1 were not significantly associated. CONCLUSIONS: Altered CRBP1 expression and hypermethylation are common in prostate carcinoma, although CRBP1 hypermethylation is not an early event in tumorigenesis. Moreover, both adenocarcinoma and HGPIN show frequent CRBP1 overexpression. The molecular mechanisms underlying altered CRBP1 expression in prostate cancer deserve further study.     

Adenosine A(2A) receptor facilitation of hippocampal synaptic transmission is dependent on tonic A(1) receptor inhibition

Adenosine tonically inhibits synaptic transmission through actions at A(1) receptors. It also facilitates synaptic transmission, but it is unclear if this facilitation results from pre- and/or postsynaptic A(2A) receptor activation or from indirect control of inhibitory GABAergic transmission. The A(2A) receptor agonist, CGS 21680 (10 nM), facilitated synaptic transmission in the CA1 area of rat hippocampal slices (by 14%), independent of whether or not GABAergic transmission was blocked by the GABA(A) and GABA(B) receptor antagonists, picrotoxin (50 microM) and CGP 55845 (1 microM), respectively. CGS 21680 (10 nM) also inhibited paired-pulse facilitation by 12%, an effect prevented by the A(2A) receptor antagonist, ZM 241385 (20 nM). These effects of CGS 21680 (10 nM) were occluded by adenosine deaminase (2 U/ml) and were made to reappear upon direct activation of A(1) receptors with N(6)-cyclopentyladenosine (CPA, 6 nM). CGS 21680 (10 nM) only facilitated (by 17%) the K(+)-evoked release of glutamate from superfused hippocampal synaptosomes in the presence of 100 nM CPA. This effect of CGS 21680 (10 nM), in contrast to the isoproterenol (30 microM) facilitation of glutamate release, was prevented by the protein kinase C inhibitors, chelerythrine (6 microM) and bisindolylmaleimide (1 microM), but not by the protein kinase A inhibitor, H-89 (1 microM). Isoproterenol (30 microM), but not CGS 21680 (10-300 nM), enhanced synaptosomal cAMP levels, indicating that the CGS 21680-induced facilitation of glutamate release involves a cAMP-independent protein kinase C activation. To discard any direct effect of CGS 21680 on adenosine A(1) receptor, we also show that in autoradiography experiments CGS 21680 only displaced the adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentyladenosine ([(3)H]DPCPX, 0.5 nM) with an EC(50) of 1 microM in all brain areas studied and CGS 21680 (30 nM) failed to change the ability of CPA to displace DPCPX (1 nM) binding to CHO cells stably transfected with A(1) receptors.Our results suggest that A(2A) receptor agonists facilitate hippocampal synaptic transmission by attenuating the tonic effect of inhibitory presynaptic A(1) receptors located in glutamatergic nerve terminals. This might be a fine-tuning role for adenosine A(2A) receptors to allow frequency-dependent plasticity phenomena without compromising the A(1) receptor-mediated neuroprotective role of adenosine.     

Thrombin enhancement of interleukin-1 and tumor necrosis factor-alpha induced polymorphonuclear leukocyte migration.

BACKGROUND: Cytokines such as IL-1 alpha and tumor necrosis factor-alpha (TNF-alpha) activate vascular endothelium to express leukocyte adhesion molecules that promote polymorphonuclear leukocyte (PMNL) migration and to synthesize tissue factor, thus making the endothelium a procoagulant surface. alpha-Thrombin, generated during coagulation, also activates endothelial cells. Since all these processes are likely involved in inflammation, the effect of alpha-thrombin on PMNL interaction with cytokine activated endothelium was investigated. EXPERIMENTAL DESIGN: Human umbilical vein endothelium was grown on polycarbonate filters to investigate the effects interleukin-1 alpha (IL-1 alpha), TNF-alpha, and alpha-thrombin on PMNL transendothelial migration quantitated with 51Cr-labeled PMNL, and on endothelial monolayer permeability, quantitated with 125I-labeled albumin (HSA). To evaluate the expression of endothelial-leukocyte adhesion molecules, enzyme-linked immunosorbent assay was performed on human umbilical vein endothelium monolayers. The effect of thrombin on PMNL accumulation and plasma exudation in inflammation was studied in a rabbit dermal model, using 51Cr-labeled blood leukocytes and [125I]HSA respectively. RESULTS: On resting human umbilical vein endothelium, alpha-thrombin induced a transient increase (2.5- to 4-fold) in monolayer permeability lasting 30 minutes. Slight but significant transendothelial migration of 51Cr-labeled PMNL was induced by alpha-thrombin (7.4 +/- 0.6% of cells added, unstimulated = 1.9 +/- 0.4%), although this response was less than that induced by f-norLeu-Leu-Phe (17%), IL-1 alpha (29%) or TNF-alpha (21%). alpha-Thrombin enhanced the initial rate of IL-1, TNF-alpha and f-norLeu-Leu-Phe induced PMNL transendothelial migration in an additive or supradditive manner (e.g., with IL-1 alpha+alpha-thrombin, migration was 58% greater than additive at 15 to 30 minutes, p < 0.001). Catalytically inactivated alpha-thrombin, D-phenylalanyl-L-propyl-L-arginine chloromethyl ketone and diisopropyl-fluorophosphate alpha-thrombin, did not enhance migration or permeability. In dermal inflammation in rabbits, alpha-thrombin (10 units/site) induced an increase in plasma protein exudation, with only a mild infiltration of PMNL. However, alpha-thrombin synergistically enhanced the PMNL infiltration induced by IL-1 alpha, TNF-alpha, but not that induced by zymosan activated plasma (C5a) or IL-8 (neutrophil-activating peptide-1). These measurements were confirmed histologically. Investigations into the mechanisms of the enhancement of PMNL migration indicated that individually vascular permeability changes, prostaglandins, platelet activating factor, and P-selectin expression did not account for the observation effects. CONCLUSIONS: Alpha-thrombin may have a role in synergistically enhancing PMNL infiltration at sites of inflammation, in part via enzymatic action on the cytokine activated endothelium. The mechanisms involved in this effect are likely a complex interaction.     

Sesquiterpene Lactones in the Molluscidal Extract of Eremanthus glomerulatus

The eremantholides 1A, 1B, 1E, 1G, 1H, 1J and the germacranolides 2A, B were found in the molluscidal extract from EREMANTHUS GLOMERULATUS L.     

Cesarean Delivery and Risk of Excess Weight Among Brazilian Preschool Children

Maternal and Child Health Journal - To study the relationship between cesarean Delivery (CD) and overweight in preschool children, considering the presence of birth aspects and demographic...     

The influence of photobiomodulation on the temperature of the brachial biceps during muscle fatigue protocol

Lasers in Medical Science - Physical activity raises body temperature. However, the literature does not contain studies about whether the employment of hotobiomodulation (PMB) could significantly...     

Management of functioning pediatric adrenal tumors

AimThe aim of this study is to present our experience in the management of hormonally active adrenal tumors in children.Material and methodsWe did a retrospective chart review of all children with hormonally active adrenal tumors evaluated at the endocrinology clinic and operated at our institution between 1983 and 2019.ResultsThere were 75 patients included in the study, 58 with adrenocortical tumors (ACTs) and 17 with pheochromocytomas (PCCs). Within the group of patients with ACTs, there were 41 females and 17 males. The mean age was 58.3 (SD: 87.9; range: 9–211) months. The clinical manifestation of the tumor's hormonal activity was virilization in 37 cases, Cushing syndrome in 5, and mixed in 16. A positive family history was present in 11 patients (18.9%). The mean tumor size was 48.2 (SD: 22.4; range: 7–120) mm. The pathological diagnosis was adenoma in 42 cases, carcinoma in 15 cases, and macronodular hyperplasia in 1. Median follow-up was 192 (range: 50–290) months. Tumor recurrence occurred in 6 patients (10.3%), and there were three disease-related deaths (5%). Within the group of patients with PCCs, there were 11 males and 6 females. The mean age was 146.7 (SD: 71.2; range: 60–216) months. A positive family history was present in 7 patients (41.2%). The mean tumor size was 36.6 (SD: 16.7; range: 7–120) mm. The pheochromocytoma was classified as benign in 15 cases and as malignant in 2. During a median follow-up of 180 (range: 127–300) months, recurrence was observed in 6 cases (35.3%) and disease-related death in 1 case (5.9%).ConclusionsProper diagnosis and management at our referral center were associated with a high cure rate, even in cases of malignant tumors. Familial surveillance is highly recommended.Level of evidenceLevel IV.     

Ectopic T cell receptor expression causes B cell immunodeficiency in transgenic mice

Mice expressing transgenic T cell receptors (TCR) are used to explore important questions in immunity. However, transgene expression may have unexpected effects. We previously reported a B cell immunodeficiency, comprising decreased B cell numbers and diminished antibody responses, in mice that express a transgenic TCR specific for nicotinic acetylcholine receptor; the mice were generated using cassette vectors designed specifically for transgenic TCR expression [see Kouskoff et al. J. Immunol. Methods 1995. 180: 273-280]. We now show data suggesting that this defect is due to the expression and accumulation of TCR alpha and beta chains inside B cells and induction of an endoplasmic reticulum stress response, causing apoptosis at the pre B-I and later B cell stage. Thus, inappropriate transgene expression can profoundly affect B cells, leading to a previously undescribed mechanism of immunodeficiency.     

Percutaneous transluminal coronary angioplasty - Histopathological analysis of nine necropsy cases

Summary From 1982 to 1984 nine of 300 patients undergoing transluminal coronary angioplasty died. The nine coronary arteries and one saphenous aorto-coronary by-pass graft affected by angioplasty were studied by light microscopy. The following types of lesions were found, frequently in association: rupture of the plaque, circumscribed or reaching to the intimal layer or extending beyond it, dissections (fissures) between arterial layers, intra-plaque haemorrhage, plaque emboli and thrombosis. In two cases the therapeutic approach was considered to be clinically and pathologically successful; the patients survived 24 h (case 6) and forty days (case 4). Case 6 which presented recent lesions indicative of success showed, in contrast with the other non-successful cases, rupture affecting not only the initimal layer but also deeper structures of the arterial wall. There were also more extensive fissures. Case 4 which presented late alterations indicative of success showed a plaque fracture whose borders were kept apart by fibrous tissue. In conclusion, we believe that angioplasty allows the re-establishment of arterial blood flow by provoking deep intimal and medial rupture producing a small fissure between the arterial layers and a widening of the lumen; in cases with good late results these alterations cicatrize leaving a wider arterial lumen.     

Glaucolide B, A Molluscicidal Sesquiterpene Lactone, and Other Constituents of Vernonia eremophila

The sesquiterpene lactone glaucolide B was isolated from the molluscicidal extract of VERNONIA EREMOPHILA Mart, and shown to be responsible for the molluscicidal activity. Hydrogenolysis of glaucolide B resulted in the disappearance of the activity. Other inactive constituents of the extract were 3,7-dimethoxy-5,3',4'-trihydroxyflavone and two transformation products, possibly artefacts, of glaucolide B. Glaucolide B exhibited strong antimicrobial activity against B, CEREUS and moderate activity against S. AURENS, but was inactive in several other systems.