Immunomodulatory Effects of Sex Hormones: Requirements for Pregnancy and Relevance in Melanoma

Similarities between the pathologic progression of cancer and the physiologic process of placentation (eg, proliferation, invasion, and local/systemic tolerance) have been recognized for many years. Sex hormones such as human chorionic gonadotropin, estrogens, progesterone, and others contribute to induction of immunologic tolerance at the beginning of gestation. Sex hormones have been shown to play contributory roles in the growth of cancers such as breast cancer, prostrate cancer, endometrial cancer, and ovarian cancer, but their involvement as putative mediators of the immunologic escape of cancer is still being elucidated. Herein, we compare the emerging mechanism by which sex hormones modulate systemic immunity in pregnancy and their potentially similar role in cancer. To do this, we conducted a PubMed search using combinations of the following keywords: “immune regulation,” “sex hormones,” “pregnancy,” “melanoma,” and “cancer.” We did not limit our search to specific publication dates. Mimicking the maternal immune response to pregnancy, especially in late gestation, might aid in design of better therapies to reconstitute endogenous antitumor immunity and improve survival.     

Percutaneous penetration of octyl salicylate from representative sunscreen formulations through human skin in vitro

The human skin penetration of [¹⁴C]octyl salicylate from two representative sunscreen vehicles was determined in vitro. ³H-sucrose was incorporated into all formulations and provided a marker for membrane integrity. When applied as a finite dose in an oil-in-water emulsion vehicle containing 5% (w/w) octyl salicylate, the average total absorption of ¹⁴C over 48 hr was 0.65 ± 0.16% of the applied dose (representing a total amount permeated of 1.58 ± 0.36 μg/cm²). When applied as an infinite dose in the oil-in-water emulsion vehicle the average total absorption of ¹⁴C over 48 hr was 0.47 ± 0.22% of the applied dose (representing a total amount permeated of 27.54 ± 13.91 μg/cm²). When applied as a finite dose in a representative hydroalcoholic formulation containing 5% (w/w) octyl salicylate, the average total absorption of ¹⁴C over 48 hr was 0.59 ± 0.09% of the applied dose (representing a total amount permeated of 1.58 ± 0.25 μg/cm²). When applied as an infinite dose in the hydroalcoholic formulation the average total absorption of ¹⁴C over 48 hr was 0.23 ± 0.05% of the applied dose (representing a total amount permeated of 11.28 ± 2.55 μg/cm²). The penetration of [¹⁴C]salicylic acid [applied at a concentration of 2.7% (w/w), in the oil-in-water emulsion] was also determined. When applied as a finite dose the average total absorption of ¹⁴C over 48 hr was 1.14 ± 0.23% of the applied dose (representing a total amount permeated of 1.65 ± 0.39 μg/cm²). These results suggest that the in vitro human skin permeation of octyl salicylate is relatively low. The amounts of octyl salicylate and salicylic acid permeated when applied in similar vehicles were remarkably similar over 48 hr (1.58 μg/cm² and 1.65 μg/cm², respectively). This suggests the possibility that the ¹⁴C label appearing in the receptor fluid may, in both cases, represent salicylic acid. If this is the case, then it is possible that the amount of octyl salicylate permeating through the skin is much less than that suggested by the data obtained here. This supposition is, however, entirely speculative and has yet to be confirmed experimentally.     

Early identification of the risk for free radical-related diseases in preterm newborns

Background

Despite recent advances in preterm newborns healthcare, perinatal pathologies and disabilities are increasing. Oxidative stress (OS) is determinant for the onset of an unbalance between free radicals (FRs) production and antioxidant systems which plays a key role in pathogenesis of pathologies such as retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), grouped as ‘free radical-related diseases’ (FRD).

Aim

This study tests the hypothesis that OS markers levels in cord blood may predict the onset of FRD pathologies.

Patients and methods

168 preterm newborns of GA: 24-32 weeks (28.09 ± 1.99); and BW: 470-2480 gr (1358.11 ± 454.09) were consecutively recruited. Markers of potential OS risk (non-protein bound iron, NPBI; basal superoxide anion, BSA; under stimulation superoxide anion, USSA) and markers of OS-related damage (total hydroperoxides, TH; advanced oxidation protein products, AOPP) were assessed in cord blood. Associations between FRD onset and OS markers were checked through inferential analysis (univariate logistic regression).

Results

The development of FRD was significantly associated to high cord blood levels of TH, AOPP and NPBI (respectively p = 0.000, OR = 1.025, 95%CI = 1.013-1.038; p = 0.014, OR = 1.092, 95%CI = 1.018-1.172; p = 0.007, OR = 1.26995%CI = 1.066-1.511).

Conclusions

Elevated levels of TH, AOPP and, above all, NPBI, in cord blood are associated with increased risk for FRD. OS markers allow the early identification of infants at risk for FRD because of perinatal oxidant exposure. This can be useful in devising strategies to prevent or ameliorate perinatal outcome.     

The predictive value of serum soluble E-cadherin levels in breast cancer patients undergoing preoperative systemic chemotherapy

Objectives

To date, no reliable markers are available to predict response to or to assess prognosis after preoperative systemic chemotherapy (PST) in patients with locally advanced breast cancer. Previous studies demonstrated that elevated levels of soluble E-cadherin (sE-cadherin), a product of proteolytic cleavage of cell surface E-cadherin, are associated with higher risk for metastatic disease and poor prognosis in various tumor types. We, therefore, hypothesized that serum sE-cadherin levels measured before PST may correlate with pathological response.

Design and methods

In a retrospective analysis, sE-cadherin levels were measured in sera of 108 female patients with histologically proven breast cancer before initiation of PST by using a commercially available quantitative sandwich enzyme immunoassay technique. Patients received a median number of 4 (range 3–6) cycles of anthracyline-based chemotherapy. The median patient age was 51.5 (range 21–71) years. Tumor size was measured clinically and translated into the tumor–node–metastasis (TNM)-system before the start of chemotherapy. Histopathological response in surgically removed specimens was evaluated using a modified Sinn regression score. In univariate analyses the correlations between levels of sE-cadherin and pathological response to PST were calculated.

Results

The histopathological regression scores correlated significantly with tumor grading (p = 0.045), clinical lymph node status before PST (p = 0.031) and sE-cadherin levels (p = 0.039). No correlation was seen between histopathological regression scores and hormone receptor and menopausal status as well as Her2-neu status.

Conclusion

sE-cadherin may be a marker predicting response to PST for patients with breast cancer. Our findings warrant further evaluation of sE-cadherin in a prospective trial.     

Effect of β-Blockers and Other Antihypertensive Drugs On the Risk of Melanoma Recurrence and Death

ObjectiveTo verify preliminary studies on patients with melanoma exposed to β-blockers that suggested a reduced risk of disease recurrence and death.Patients and MethodsData were obtained from all consecutive patients diagnosed as having melanoma between January 1, 1993, and December 31, 2009, at the Department of Dermatology of the University of Florence, Azienda Sanitaria di Firenze. Participants were excluded if at baseline they reported a previous diagnosis of cutaneous malignant melanoma or another malignant disease. We also excluded participants with evidence of visceral, lymph nodal, and in-transit metastasis at the time of the diagnosis.ResultsOf 741 consecutive patients with melanoma, 79 (11%) were prescribed β-blockers (for hypertension in most cases) for 1 or more years (treated) and 662 (89%) were not (untreated). The multivariate Cox model indicated that the treated group had improved overall survival after a median follow-up of 4 years (P=.005). For each year of β-blocker use, the risk of death was reduced by 38%. The presence of hypertension, the use of antihypertensive agents for 1 or more years, or the use of other commonly used medicines were not associated with a better outcome for patients with melanoma.ConclusionThe results confirm and strengthen previous findings that β-blocker use is associated with a reduced risk of melanoma recurrence and death. The results also indicate the strong need for a randomized clinical trial to conclusively assess whether β-blockers afford protection against melanoma recurrence and death.     

Protective role of vitamins E and C against oxidative stress caused by intermittent cold exposure in aging rat's frontoparietal cortex

This study examined the role of vitamins E and C in combating oxidative stress (OS) caused by intermittent cold exposure (ICE) in the frontoparietal cortex (FPC) of adult (3 months), late-adult (12 months), middle-aged (18 months) and old (24 months) male Wistar rats. Each age group was divided into sub-groups, control (CON), cold-exposed at 5 °C (C5), control supplementees (CON + S) and cold-exposed supplementees (C5 + S). The supplement was a daily dose of 400 mg vitamin C and 50 I.U. of vitamin E/kg body weight. Cold exposure lasted 2 h/day for 4 weeks. All age groups except the old showed an increase in the final body mass in the cold-exposed. The feeding efficiency was higher in the cold-exposed irrespective of age. OS as reflected in age-related increased levels of hydrogen peroxide, protein carbonyl, advanced oxidation protein products and malondialdehyde showed further increase with ICE in the FPC. However, vitamins E and C supplementation attenuated the ICE-induced OS. ICE depleted the levels of tissue vitamins E and C while supplementation resulted in increased levels. Further age emerged as a significant factor in ICE-induced stress and also the response to vitamins E and C supplementation. Behavioral studies are underway to examine the findings on ICE-induced oxidative injury in the FPC, and the prospects for using vitamins E and C in cold exposures in the aged.