Impact of VDR and RXR expression in non-melanoma skin cancer pathogenesis.

1,25(OH)2 D3 , the active form of vitamin D, has been extensively studied for its putative protective activities against tumors. It does biological work by connecting to a nuclear receptor called VDR, which heterodimerizes itself to another nuclear receptor, RXR. The study observed differences in VDR and RXR expression in non-melanoma skin cancer a actinic keratosis and compared it with normal skin. We performed VDR and RXR immunohistochemistry of 76 controls (normal skin), 49 actinic keratosis, 99 basal cell carcinomas and 96 squamous cell carcinomas from formalin-fixed paraffin-embedded, resulting from surgical procedures. There was a clear pattern in the control group (p < 0.001), with the positivity of both receptors, VDR and RXR. Actinic keratosis differed from the basal cell carcinoma and control groups concerning RXR expression (p < 0.001). SCC was negative for both receptors, differing in all groups (p < 0.001). The site of positivity (nuclear, cytoplasmatic or both) of VDR differed between all groups (p < 0.001). To date, our series is the largest of VDR and RXR immunohistochemistry concerning non-melanoma skin cancer. Our findings reinforce the need to understand the pathways involving VDR and RXR to direct therapies and prevention manoeuvres.

Toll-Like Receptor-2 and -4 Expression by Maternal Neutrophils in Preterm Labor.

BACKGROUND AND AIMS: The inflammatory response in preterm parturition is regulated by the innate immune system. Toll-like receptors (TLR)-2 and TLR-4 are innate immune receptors that recognize the microorganisms most frequently involved in amniotic cavity infections, which are associated with activating the inflammatory response at the maternal-fetal interface during preterm labor. This study aimed to evaluate the expression of TLR-2 and TLR-4 in maternal neutrophils in preterm labor. METHODS: A cross-sectional study was conducted in the Obstetrics Care Unit of Botucatu Medical School, UNESP, Brazil. The preterm group was composed of 20 pregnant women who presented preterm labor and preterm delivery. The control group was composed of 20 nonlaboring pregnant women matched to the preterm group by gestational age. Neutrophils were isolated from peripheral blood and TLR expressions were performed by real-time polymerase chain reaction and flow cytometry. RESULTS: Gene expressions of TLR-2 and TLR-4 in neutrophils from the preterm group were statistically higher than expressions in neutrophils from the matched control group. The percentage of TLR-4+ neutrophils was higher in the preterm group than the matched control group, while the percentage of TLR-2+ neutrophils did not differ between groups. CONCLUSION: TLR-4 expression in maternal neutrophils is associated with spontaneous preterm labor.

Amniotic Fluid-Soluble Form of Triggering Receptors Expressed on Myeloid Cells: A Physiologic Constituent at Term.

BACKGROUND: Triggering receptors expressed on myeloid cells-1 (TREM-1) are innate immune receptors that mediate inflammatory response. In recent times, the role of these receptors has become the focus of several studies in the gestational context. Evaluation of soluble TREM-1 concentration in normal pregnancy is scarce, and no data are available on the levels of this receptor in the last weeks of normal pregnancy. METHOD: Amniotic fluid (AF) samples were obtained from 77 patients in the last weeks of normal pregnancy during cesarean section, and the soluble form of TREM-1 (sTREM-1) levels determined using specific sandwich enzyme-linked immunosorbent assay kit. RESULTS: sTREM-1 was detectable in all AF samples, and its levels did not vary in the last weeks of third trimester pregnancy. There was no correlation between sTREM-1 levels in AF and advancing gestational age. CONCLUSION: sTREM-1 is a physiologic constituent of AF and its levels are not temporally regulated in pregnancies at term.

Feto-Maternal Interface Organ-on-Chip: A New Technology to Study Ascending Infection.

Modeling human pregnancy is challenging as two subjects, the mother and fetus, must be evaluated in tandem. To understand pregnancy, parturition, and adverse pregnancy outcomes, the two feto-maternal interfaces (FMi) that form during gestation (i.e., the placenta and fetal membrane) need to be investigated to understand their biological roles, and organ dysfunction can lead to adverse outcomes. Adverse pregnancy outcomes such as preterm rupture of the membranes, spontaneous preterm birth, preeclampsia, intra-uterine growth restriction, and gestational diabetes rates are on the rise worldwide, highlighting the need for future studies and a better understanding of molecular and cellular pathways that contribute to disease onset. Current in vivo animal models nor in vitro cell culture systems can answer these questions as they do not model the function or structure of human FMis. Utilizing microfabrication and soft-lithography techniques, microfluidic organ-on-chip (OOC) devices have been adapted by many fields to model the anatomy and biological function of complex organs and organ systems within small in vitro platforms.These techniques have been adapted to recreate the fetal membrane FMi (FMi-OOC) using immortalized cells and collagen derived from patient samples. The FMi-OOC is a four-cell culture chamber, concentric circle system, that contains both fetal (amniochorion) and maternal (decidua) cellular layers and has been validated to model physiological and pathological states of pregnancy (i.e., ascending infection, systemic oxidative stress, and maternal toxicant exposure). This platform is fully compatible with various analytical methods such as microscopy and biochemical analysis. This protocol will outline this device's fabrication, cell loading, and utility to model ascending infection-related adverse pregnancy outcomes.

Influence of single nucleotide polymorphisms (SNPs) in immunoregulatory genes in the morbidity of preterm newborns.

BACKGROUND: Prematurity is the main cause of perinatal and neonatal morbidity and mortality worldwide. Single nucleotide polymorphisms (SNPs) have been associated with the pathogenesis of morbidities in preterm neonates. We aimed to investigate the association between SNPs in regulatory genes of innate immune response IL1B, IL6, IL6R, IL10, TNFA, TNFRII, TLR2 and TLR4 and neonatal/infant morbidities in preterm newborns. METHODS: Oral swabs were collected from 272 newborns (91 preterm and 181 at term) seen at Botucatu Medical School, Unesp, between 2013 and 2014 and SNPs were identified using Taqman® Genotyping Assays. Medical records were examined to obtain data regarding neonatal/infant morbidity. Stepwise binomial logistic regression models were used to explain the morbidities. RESULTS: Minor neonatal morbidity was influenced by the clinical parameters of maternal age and newborn weight at birth and by the presence of the allele IL6R2 C (rs2228145) while major neonatal morbidity was only influenced by gestational age. Minor infant morbidity was associated with the allele TLR2 T (rs4696480) and major infant morbidity was associated with gestational age and presence of IL6R2 C. CONCLUSION: The presence of SNPs that exacerbate the inflammatory response increases the susceptibility to neonatal and infant morbidity.