Human chorionic gonadotropin as an angiogenic factor in breast cancer during pregnancy

Breast cancer associated with pregnancy is defined as the one in which the diagnosis is made in a pregnancy or within one year of delivery. Breast cancer is the second most common malignancy during pregnancy and it is generally considered to have a worse prognosis than the one that is not associated with pregnancy. The average patient is between 32 and 38 years of age. Steroid hormone receptor-positive cell populations comprise 80% of breast cancers, however, estrogen receptor levels in pregnancy-associated tumors are often low or absent. Extensive laboratory data suggest that angiogenesis plays an essential role in breast cancer development, invasion, and metastasis. One of the most powerful stimulatory factors, vascular endothelial growth factor (VEGF), functions in autocrine/paracrine pathways. Current research, generally has validated the poor prognosis and early relapse that are associated with increasing microvessel density, which is related to VEGF expression in tumoral cells. During pregnancy, human chorionic gonadotropin (hCG) induces neovascularization in various tissues, one of them being the placenta. Its receptors have been detected in epithelial cells in breast carcinoma tissue, and breast cancer cell lines. According to this premise the hCG normally produced during pregnancy could induce the synthesis of VEGF and by this means stimulate the development and metastatic potential of breast cancer cells in the pregnancy period. Thus, research involving hCG and VEGF would help us understand the physiopathology of breast cancer during pregnancy, as well as provide us with probable prognostic tools.     

Anti-inflammatory activity of cacalol and cacalone sesquiterpenes isolated from Psacalium decompositum

The hexane extract and two sesquiterpenic compounds, cacalol and cacalone, were isolated from the roots and rhizomes of Psacalium decompositum. Then, their anti-inflammatory activity was evaluated in carrageenan-induced rat paw edema and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema. Indomethacin was used as the anti-inflammatory agent of reference. In the rat paw model of inflammation, both the hexane extract and the sesquiterpenes isolated from Psacalium decompositum showed a clear dose-dependent inhibition of the carrageenan-induced edema (P < 0.05), with important differences among them during the temporal course of the inhibition. In the TPA-induced mouse ear edema all tested compounds showed anti-inflammatory activity in dose-dependent manner (P < 0.05). In both models, cacalone showed the most prominent anti-inflammatory activity. We conclude that some of the beneficial effects attributed to Psacalium decompositum in traditional medicine can be related with the anti-inflammatory activity of cacalol and cacalone.     

Mechanisms of relaxant action of a crude hexane extract of Gnaphalium liebmannii in guinea pig tracheal smooth muscle

We investigated the mechanisms of action of Gnaphalium liebmannii which is used as a folk medicine in México for treating various respiratory diseases such as gripe, fever, asthma, cough, cold, bronchitis, expectorating, and bronchial affections. The tension changes of guinea pig tracheal segments were isometrically recorder on a polygraph. Hexane extract of Gnaphalium liebmannii was the most active relaxant extract (IC(30)=54.23+/-19.79 microg/mL with 99.5+/-3.2 % of relaxation), followed by dichloromethane extract (IC(30)=120.22+/-5.27 microg/mL) and methanol extract (IC(30)=190.25+/-30.02 microg/mL). Hexane extract produced a parallel rightward shift of the concentration-response curve of carbachol in a competitive manner (pA(2)=-2.4), but did not modify the concentration-response curves for histamine. The relaxant effect of hexane extract of Gnaphalium liebmannii was unaffected by the presence of propranolol (3x10(-6)M) or glibenclamide (10 microM). However hexane extract produced a leftward shifts of the concentration-response curve of forskolin (10(-8) to 10(-3)M), nitroprusside (10(-10) to 10(-6)M), isoproterenol (3x10(-10) to 3x10(-5)M) and aminophylline (10(-11) to 10(-2)M). The above results suggest that Gnaphalium liebmannii induce relaxation of the tracheal muscle, probably via phosphodiesterase inhibition. The bronchodilator effect of Gnaphalium liebmannii might explain in part their traditional use as anti-asthmatic remedy.     

Prognosis of breast cancer diagnosed during pregnancy and early postpartum according to immunohistochemical subtype: A matched case–control study

Purpose

Pregnancy-associated breast cancer (PABC) poses a clinical challenge and its prognosis remains controversial. During the pregnancy and postpartum periods, the breast undergoes biological events that may uniquely influence disease behavior and treatment response. This study aimed to assess if a PABC diagnosis influences survival compared to non-PABC.

Methods

A single-center record review was performed to identify PABC patients diagnosed from January 2007 through June 2018. Two controls were matched to each PABC case by stage, immunohistochemical (IHC) subtype, age (±?3) and year of diagnosis (±?2). Disease-free survival (DFS) and overall survival (OS) were estimated with the Kaplan–Meier method and compared with the log-rank test. Multivariate analysis was used to assess the impact of PABC on outcomes.

Results

125 PABC patients (pregnant: 62; postpartum: 63) and 250 controls were included. Median follow-up was 67.7 and 73.4 months, respectively. 4-year DFS was 62% in pregnant vs 78% in controls (p?=?0.010), and 63% in postpartum vs 83% in controls (p?=?0.034). Subanalysis by IHC subtype revealed a significantly inferior DFS in PABC with hormone receptor-positive/HER2-negative (p?=?0.032) and HER2-positive disease (p?=?0.005) compared to corresponding non-PABC patients. 4-year OS was similar between case groups and controls. Multivariate analysis supported the independent impact of pregnant and postpartum status on DFS (p?<?0.05).

Conclusion

Patients diagnosed during pregnancy and early postpartum are at high risk of recurrence. Further research is warranted to better characterize PABC tumor biology and enable the identification of novel therapeutic interventions to improve treatment outcomes.

     

Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism is heterogeneously distributed worldwide, with the highest and lowest frequencies of the T allele in Mexico and Africa, respectively, and a south-to-north gradient in Europe. Distribution of MTHFR 1298A-->C is less well known. It has been hypothesized that 677T frequency could result in part from gene-nutrient interactions. OBJECTIVE: The objective was to compare the association of 677T and 1298C alleles with plasma concentrations of homocysteine, folate, and vitamin B-12 in geographical areas with contrasting 677T allele frequencies. DESIGN: Healthy young adults (n = 1277) were recruited in Mexico City, the West African countries of Bénin and Togo, France, and Sicily (Italy). Homocysteine, folate, and vitamin B-12 were measured in plasma, and MTHFR polymorphisms were measured in genomic DNA. RESULTS: Mexico City and Sicily reported the highest and Bénin and Togo reported the lowest plasma concentrations of folate. Mexico City had the highest 677T allele prevalence and the lowest influence of 677TT genotype on homocysteine, whereas the opposite was observed in Africa. The prevalence of the 1298C allele was lowest in the Mexicans and Africans and highest in the French. The percentage of the 677T genotype was significantly associated with the folate concentrations in 677CC carriers in a univariate analysis (R = 0.976; 95% CI: 0.797, 0.996; P < 0.0002) and in a multiple regression model that included homocysteine, vitamin B-12, and age (P = 0.0002). CONCLUSION: Our data agree with the hypothesis of a gene-nutrient interaction between MTHFR 677C-->T polymorphism and folate status that may confer a selective advantage of TT-homozygous genotype when dietary intake of folate is adequate, at least in the areas studied.     

Serum human chorionic gonadotropin is associated with angiogenesis in germ cell testicular tumors

Background

Germ cell testicular tumors have survival rate that diminishes with high tumor marker levels, such as human chorionic gonadotropin (hCG). hCG may regulate vascular neoformation through vascular endothelial growth factor (VEGF). Our purpose was to determine the relationship between hCG serum levels, angiogenesis, and VEGF expression in germ cell testicular tumors.

Methods

We conducted a retrospective study of 101 patients. Serum levels of hCG, alpha-fetoprotein (AFP), and lactate dehydrogenase were measured prior to surgery. Vascular density (VD) and VEGF tissue expression were determined by immunohistochemistry and underwent double-blind analysis.

Results

Histologically, 46% were seminomas and 54%, non-seminomas. Median follow-up was 43 ± 27 months. Relapse was present in 7.5% and mortality in 11.5%. Factors associated with high VD included non-seminoma type (p = 0.016), AFP ≥ 14.7 ng/mL (p = 0.0001), and hCG ≥ 25 mIU/mL (p = 0.0001). In multivariate analysis, the only significant VD-associated factor was hCG level (p = 0.04). When hCG levels were stratified, concentrations ≥ 25 mIU/mL were related with increased neovascularization (p < 0.0001). VEGF expression was not associated with VD or hCG serum levels.

Conclusion

This is the first study that relates increased serum hCG levels with vascularization in testicular germ cell tumors. Hence, its expression might play a role in tumor angiogenesis, independent of VEGF expression, and may explain its association with poor prognosis. hCG might represent a molecular target for therapy.     

Hepatocyte growth factor in cerebrospinal fluid is associated with mortality and recurrence of glioblastoma,and could be of prognostic value

Malignant gliomas—glioblastoma multiforme and anaplastic astrocytoma—are among the most fatal forms of cancer in humans. It has been suggested that hepatocyte growth factor (HGF) is a reliable predictor of glioma malignancy; amounts of HGF are directly related to cellular proliferation, angiogenesis, low apoptotic rate, and poor prognosis (WHO III and IV). We measured the HGF content of cerebrospinal fluid (CSF) from patients with malignant glioma glioblastoma multiforme (WHO IV; n = 14), anaplastic astrocytoma (WHO III; n = 4), and meningioma (WHO I; n = 9), and from control subjects (n = 25), and found a high concentration of HGF in patients with malignant glioma. However, CSF concentrations from glioblastoma multiforme and anaplastic astrocytoma patients were not statistically significantly different (893 ± 157 vs. 728 ± 61, respectively; P > 0.01). A negative correlation between HGF and survival was found at five years of follow-up (R = −0.922, R ² = 0.850, P < 0.001). Also, the HGF concentration in CSF was a reliable means of explaining the highly variable survival of patients with malignant glioma. CSF concentrations of HGF higher than 500 pg/ml were associated with increased mortality whereas values higher than 850 pg/ml were associated with a brief tumor-free period after surgery (9 ± 0.6 vs. 6 ± 0.6 months, respectively, P < 0.001). Our findings support the idea that measurement of HGF in CSF could be a useful tool for monitoring the biological activity of malignant glioma. The findings will ultimately need to be confirmed in a much larger study.     

Micafungin in pediatrics: when one size does not fit all

Micafungin is one of three FDA-approved echinocandins, a novel class of antifungal agents that target 1,3-beta-D-glucan in the fungal cell wall. Its spectrum of activity and favorable safety profile have made it an attractive option in the treatment of invasive Candida and Aspergillus infections. Since its approval in 2005 in the US, a variety of studies describing micafungin's use in the pediatric population have been published. As with many drugs, the pharmacokinetic profiles observed in the pediatric population differ from those seen in adult studies. A thorough understanding of the unique characteristics of this drug in the pediatric population is essential in order to optimize treatment outcomes for this diverse population of patients.     

The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study

BACKGROUND: Lifelong adherence to a strict gluten-free diet is the cornerstone of coeliac disease treatment. Elucidation of disease pathogenesis has created opportunities for novel therapeutic approaches to coeliac disease. AT-1001 is an inhibitor of paracellular permeability whose structure is derived from a protein secreted by Vibrio cholerae. AIM: To determine the safety and tolerability of 12 mg doses of AT-1001 in coeliac disease subjects challenged with gluten. METHODS: An in-patient, double-blind, randomized placebo-controlled safety study utilizing intestinal permeability, measured via fractional excretions of lactulose and mannitol, as an exploratory measure of drug efficacy. RESULTS: Compared to placebo, no increase in adverse events occurred in patients exposed to AT-1001. Following acute gluten exposure, a 70% increase in intestinal permeability was detected in the placebo group, while none was seen in the AT-1001 group. Interferon-gamma levels increased in four of seven patients (57%) of the placebo group, but only in four of 14 patients (29%) of the AT-1001 group. Gastrointestinal symptoms were more frequently detected in the placebo group when compared to the AT-1001 group (P = 0.018). CONCLUSIONS: AT-1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure.     

Recommendations for the Diagnosis and Therapeutic Management of Hyperammonaemia in Paediatric and Adult Patients

Hyperammonaemia is a metabolic derangement that may cause severe neurological damage and even death due to cerebral oedema, further complicating the prognosis of its triggering disease. In small children it is a rare condition usually associated to inborn errors of the metabolism. As age rises, and especially in adults, it may be precipitated by heterogeneous causes such as liver disease, drugs, urinary infections, shock, or dehydration. In older patients, it is often overlooked, or its danger minimized. This protocol was drafted to provide an outline of the clinical measures required to normalise ammonia levels in patients of all ages, aiming to assist clinicians with no previous experience in its treatment. It is an updated protocol developed by a panel of experts after a review of recent publications. We point out the importance of frequent monitoring to assess the response to treatment, the nutritional measures that ensure not only protein restriction but adequate caloric intake and the need to avoid delays in the use of specific pharmacological therapies and, especially, extrarenal clearance measures. In this regard, we propose initiating haemodialysis when ammonia levels are >200–350 µmol/L in children up to 18 months of age and >150–200 µmol/L after that age.