Exosomal microRNAs in breast cancer: towards theranostic applications

Breast cancer is one of the top two reproductive cancers responsible for high rates of morbidity and mortality among women globally. Despite the advancements in the treatment of breast cancer, its early diagnosis remains a challenge. Recent evidence indicates that despite the adroit use of numerous strategies to facilitate rapid and precision-oriented screening of breast cancer at the community level through the use of mammograms, Fine-needle aspiration cytology (FNAC) and biomarker tracking, no strategy has been unequivocally accepted as a gold standard for facilitating rapid screening for disease. This necessitates the need to identify novel strategies for the detection and triage of breast cancer lesions at higher rates of specificity, and sensitivity, whilst taking into account the epidemiologic and social-demographic features of the patients. Recent shreds of evidence indicate that exosomes could be a robust source of biomaterial for the rapid screening of breast cancer due to their high stability and their presence in body fluids. Increasing evidence indicates that the Exosomal microRNAs- play a significant role in modifying the tumour microenvironment of breast cancers, thereby potentially aiding in the proliferation, invasion and metastasis of breast cancer. In this review, we summarize the role of ExomiRs in the tumour microenvironment in breast cancer. These ExomiRs can also be used as candidate biomarkers for facilitating rapid screening and triaging of breast cancer patients for clinical intervention

Lymphocytic Choriomeningitis Virus Infection Demonstrates Higher Replicative Capacity and Decreased Antiviral Response in the First-Trimester Placenta

Lymphocytic choriomeningitis virus (LCMV) is a rodent disease that can be transmitted to humans. A majority of persons infected with LCMV have only minor symptoms; however, it can cross the placental barrier during pregnancy and cause congenital defects in the fetus. Some viral infections early in gestation are hypothesized to lead to worse outcomes compared to those acquired during late gestation; however, LCMV has not been studied in this context. In the present study, differences in immunomodulation between the first- and third-trimester placental explants infected with LCMV were measured. LCMV replication was observed in the first-trimester chorionic villi, but not in term. The term placenta exhibited a robust innate immune response to infection by LCMV, marked by induction of ifn-α, il-6, and tnf-α gene expression which was not seen in the first-trimester explants. Cytokine secretion was also only seen in term explants. The results indicate that the first-trimester and term placentas differ in their permissiveness for LCMV infection, inversely correlating with the innate antiviral responses. This has implications for developing effective mechanisms that protect the fetus from infection based on stage of development

Placental Immune Responses to Viruses: Molecular and Histo-Pathologic Perspectives

As most recently demonstrated by the SARS-CoV-2 pandemic, congenital and perinatal infections are of significant concern to the pregnant population as compared to the general population. These outcomes can range from no apparent impact all the way to spontaneous abortion or fetal infection with long term developmental consequences. While some pathogens have developed mechanisms to cross the placenta and directly infect the fetus, other pathogens lead to an upregulation in maternal or placental inflammation that can indirectly cause harm. The placenta is a temporary, yet critical organ that serves multiple important functions during gestation including facilitation of fetal nutrition, oxygenation, and prevention of fetal infection in utero. Here, we review trophoblast cell immunology and the molecular mechanisms utilized to protect the fetus from infection. Lastly, we discuss consequences in the placenta when these protections fail and the histopathologic result following infection

Efficacy of Rubella Vaccination after Co-Inoculation with Rhogam

Congenital rubella syndrome is a constellation of birth defects that can have devastating consequences, impacting approximately 100,000 births worldwide each year. The incidence is much lower in countries that routinely vaccinate their population. In the US, postnatal immunization of susceptible women is an important epidemiological strategy for the prevention of rubella as the Center for Disease Control (CDC) does not recommend administering this vaccine during pregnancy due to its nature as a live attenuated virus vaccine. However, concerns that the co-administration of rubella vaccine with other immunoglobins (i.e., Rhogam) could compromise vaccine efficacy has produced warnings that can delay the administration of rubella vaccination postpartum, leaving women susceptible to the disease in subsequent pregnancies. We aimed to address whether the co-administration of the measles, mumps, and rubella (MMR) vaccine and Rhogam decreased antibody responses compared to those receiving only MMR vaccination. This retrospective cohort study utilized clinical data from 78 subjects who received the MMR vaccine and Rhogam after delivery and 45 subjects who received the MMR vaccine alone. Maternal demographics, pregnancy complications and rubella status at the start of a subsequent pregnancy were recorded for analysis. Overall, the two cohorts had similar baseline characteristics; however, lower parity was noted in the participants that received both MMR vaccination and Rhogam. Making assessments based on maternal antibody IgG index for rubella during the next pregnancy, we observed that 88% of the Rhogam + MMR vaccine group had positive serology scores, which was not significantly different from the 80% rate in the MMR-vaccine-only cohort (p = 0.2). In conclusion, no differences were observed in rubella immunity status in subsequent pregnancies in those mothers given both the MMR vaccine and Rhogam concurrently. Given these findings, warnings against co-administration of vaccines in combination with Rhogam appear unwarranted

Growth Modeling of the Maternal Cytokine Milieu throughout Normal Pregnancy: Macrophage-Derived Chemokine Decreases as Inflammation/Counterregulation Increases

Several recent studies have shown differences in the maternal immune milieu at different phases of pregnancy, but most studies have been cross-sectional or of relatively few time points. Levels of 42 cytokines were determined using a multiplex bead-based assay on archived serum from a cohort of pregnant women N=16 at median of 18 time points tested, from the first trimester through to parturition, per woman. Unconditional growth modeling was then used to determine time-dependent changes in levels of these cytokines. Macrophage-derived chemokine (MDC, aka CCL22) decreases as pregnancy progresses. IL-1β, IL-6, IL-8, IL-12p70, IL-13, IL-15, IP-10, and FLT3-ligand increase as a function of gestational weeks, and IFNα2, IL-1ra, IL-3, IL-9, IL-12p40, and soluble CD40 ligand increase as a function of trimester. As pregnancy normally progresses, a maternal shift away from a type 2-biased immune response and toward an inflammatory/counterregulatory response is observed

Endocrine disrupting chemicals: gestational diabetes and beyond

Abstract Gestational Diabetes Mellitus (GDM) has been on the rise for the last two decades along with the growing incidence of obesity. The ubiquitous use of Endocrine-Disrupting Chemicals (EDCs) worldwide has been associated with this increase in GDM incidence. Epigenetic modifications such as DNA methylation, histone acetylation, and methylation have been associated with prenatal exposure to EDCs. EDC exposure can also drive a sustained disruption of the hypothalamus-pituitary-thyroid axis and various other signaling pathways such as thyroid signaling, PPARγ signaling, PI3K-AKT signaling. This disruption leads to impaired glucose metabolism, insulin resistance as well as β-cell dysfunction, which culminate into GDM. Persistent EDC exposure in pregnant women also increases adipogenesis, which results in gestational weight gain. Importantly, pregnant mothers transfer these EDCs to the fetus via the placenta, thus leading to other pregnancy-associated complications such as intrauterine growth restriction (IUGR), and large for gestational age neonates. Furthermore, this early EDC exposure of the fetus increases the susceptibility of the infant to metabolic diseases in early life. The transgenerational impact of EDCs is also associated with higher vascular tone, cognitive aberrations, and enhanced susceptibility to lifestyle disorders including reproductive health anomalies. The review focuses on the impact of environmental toxins in inducing epigenetic alterations and increasing the susceptibility to metabolic diseases during pregnancy needs to be extensively studied such that interventions can be developed to break this vicious cycle. Furthermore, the use of EDC-associated ExomiRs from the serum of patients can help in the early diagnosis of GDM, thereby leading to triaging of patients based on increasing risk factor of the clinicopathological condition

Evaluating Markers of Immune Tolerance and Angiogenesis in Maternal Blood for an Association with Risk of Pregnancy Loss

Pregnancy loss affects approximately 20% of couples. The lack of a clear cause complicates half of all miscarriages. Early evidence indicates the maternal immune system and angiogenesis regulation are both key players in implantation success or failure. Therefore, this prospective study recruited women in the first trimester with known viable intrauterine pregnancy and measured blood levels of immune tolerance proteins galectin-9 (Gal-9) and interleukin (IL)-4, and angiogenesis proteins (vascular endothelial growth factors (VEGF) A, C, and D) between 5 and 9 weeks gestation. Plasma concentrations were compared between groups defined based on (a) pregnancy outcome and (b) maternal history of miscarriage, respectively. In total, 56 women were recruited with 10 experiencing a miscarriage or pregnancy loss in the 2nd or 3rd trimester and 11 having a maternal history or miscarriage. VEGF-C was significantly lower among women with a miscarriage or pregnancy loss. Gal-9 and VEGF-A concentrations were decreased in women with a prior miscarriage. Identification of early changes in maternal immune and angiogenic factors during pregnancy may be a tool to improve patient counseling on pregnancy loss risk and future interventions to reduce miscarriage in a subset of women

T-Cell Homeostatic Imbalance in Placentas From Women With Human Immunodeficiency Virus in the Absence of Vertical Transmission

BackgroundImplementation of universal antiretroviral therapy (ART) has significantly lowered vertical transmission rates but has also increased numbers of human immunodeficiency virus (HIV)-exposed uninfected children, who remain vulnerable to morbid effects. In the current study, we investigated whether T-cell alterations in the placenta contribute to altered immune status in HIV-exposed uninfected.MethodsWe analyzed T cells from term placenta decidua and villous tissue and paired cord blood from pregnant women living with HIV (PWH) who initiated ART late in pregnancy (n = 21) with pregnant women not living with HIV (PWNH) (n = 9).ResultsPlacentas from PWH showed inverted CD4/CD8 ratios and higher proportions of tissue resident CD8+ T cells in villous tissue relative to control placentas. CD8+ T cells in the fetal capillaries, which were of fetal origin, were positively correlated with maternal plasma viremia before ART initiation, implying that imbalanced T cells persisted throughout pregnancy. In addition, the expanded memory differentiation of CD8+ T cells was confined to the fetal placental compartment and cord blood but was not observed in the maternal decidua.ConclusionsT-cell homeostatic imbalance in the blood circulation of PWH is reflected in the placenta. The placenta may be a causal link between HIV-induced maternal immune changes during gestation and altered immunity in newborn infants in the absence of vertical transmission