BackgroundTo date, there are no highly sensitive and specific minimally invasive biomarkers for detection of breast cancer at an early stage. The occurrence of circulating microRNAs (miRNAs) in blood components (including serum and plasma) has been repeatedly observed in cancer patients as well as healthy controls. Because of the significance of miRNA in carcinogenesis, circulating miRNAs in blood may be unique biomarkers for early and minimally invasive diagnosis of human cancers. The objective of this pilot study was to discover a panel of circulating miRNAs as potential novel breast cancer biomarkers.Methodology/Principal FindingsUsing microarray-based expression profiling followed by Real-Time quantitative Polymerase Cycle Reaction (RT-qPCR) validation, we compared the levels of circulating miRNAs in plasma samples from 20 women with early stage breast cancer (10 Caucasian American (CA) and 10 African American (AA)) and 20 matched healthy controls (10 CAs and 10 AAs). Using the significance level of p<0.05 constrained by at least two-fold expression change as selection criteria, we found that 31 miRNAs were differentially expressed in CA study subjects (17 up and 14 down) and 18 miRNAs were differentially expressed in AA study subjects (9 up and 9 down). Interestingly, only 2 differentially expressed miRNAs overlapped between CA and AA study subjects. Using receiver operational curve (ROC) analysis, we show that not only up-regulated but also down-regulated miRNAs can discriminate patients with breast cancer from healthy controls with reasonable sensitivity and specificity. To further explore the potential roles of these circulating miRNAs in breast carcinogenesis, we applied pathway-based bioinformatics exploratory analysis and predicted a number of significantly enriched pathways which are predicted to be regulated by these circulating miRNAs, most of which are involved in critical cell functions, cancer development and progression.ConclusionsOur observations from this pilot study suggest that the altered levels of circulating miRNAs might have great potential to serve as novel, noninvasive biomarkers for early detection of breast cancer.

In cancer-immunity cycle, the immune checkpoint PD1 and its ligand PDL1 act as accomplices to help tumors resist to immunity-induced apoptosis and promote tumor progression. Immunotherapy targeting PD1/PDL1 axis can effectively block its pro-tumor activity. Anti-PD1/PDL1 therapy has achieved great success in the past decade. However, only a subset of patients showed clinical responses. Most of the patients can not benefit from anti-PD1/PDL1 therapy. Furthermore, a large group of responders would develop acquired resistance after initial responses. Therefore, understanding the mechanisms of resistance is necessary for improving anti-PD1/PDL1 efficacy. Currently, researchers have identified primary resistance mechanisms which include insufficient tumor immunogenicity, disfunction of MHCs, irreversible T cell exhaustion, primary resistance to IFN-γ signaling, and immunosuppressive microenvironment. Some oncogenic signaling pathways also contribute to the primary resistance. Under the pressure applied by anti-PD1/PDL1 therapy, tumors experience immunoediting and preserve beneficial mutations, upregulate the compensatory inhibitory signaling and induce re-exhaustion of T cells, all of which may attenuate the durability of the therapy. Here we explore the underlying mechanisms in detail, review biomarkers that help identifying responders among patients and discuss the strategies that may relieve the anti-PD1/PDL1 resistance.

EDR in resistance vessels from patients with ADPKD is impaired even in the absence of hypertension or CRI, but becomes more marked as hypertension develops. Patients with ADPKD have defective nitric oxide generation from diminished cNOS activity. Endothelial dysfunction and impaired cNOS activity in ADPKD may predispose to hypertension whose occurrence is accompanied by a further sharp deterioration in EDR.

Ethanol alters the distribution and abundance of PKC␦ in neural cell lines. Here we investigated whether PKC␦ also regulates behavioral responses to ethanol. PKC␦ Ϫ/Ϫ mice showed reduced intoxication when administered ethanol and reduced ataxia when administered the nonselective GABA A receptor agonists pentobarbital and pregnanolone. However, their response to flunitrazepam was not altered, suggesting that PKC␦ regulates benzodiazepine-insensitive GABA A receptors, most of which contain ␦ subunits and mediate tonic inhibitory currents in neurons. Indeed, the distribution of PKC␦ overlapped with GABA A ␦ subunits in thalamus and hippocampus, and ethanol failed to enhance tonic GABA currents in PKC␦ Ϫ/Ϫ thalamic and hippocampal neurons. Moreover, using an ATP analog-sensitive PKC␦ mutant in mouse L(tk Ϫ ) fibroblasts that express ␣4␤3␦ GABA A receptors, we found that ethanol enhancement of GABA currents was PKC␦-dependent. Thus, PKC␦ enhances ethanol intoxication partly through regulation of GABA A receptors that contain ␦ subunits and mediate tonic inhibitory currents. These findings indicate that PKC␦ contributes to a high level of behavioral response to ethanol, which is negatively associated with risk of developing an alcohol use disorder in humans.

Do some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL)effect