A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance.

Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance.

Disease-associated astrocyte epigenetic memory promotes CNS pathology.

Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis. However, little is known about the stability of these astrocyte subsets and their ability to integrate past stimulation events. Here we report the identification of an epigenetically controlled memory astrocyte subset that exhibits exacerbated pro-inflammatory responses upon rechallenge.

Disease-associated astrocyte epigenetic memory promotes CNS pathology.

Astrocytes play important roles in the central nervous system (CNS) physiology and pathology. Indeed, astrocyte subsets defined by specific transcriptional activation states contribute to the pathology of neurologic diseases, including multiple sclerosis (MS) and its pre-clinical model experimental autoimmune encephalomyelitis (EAE) . However, little is known about the stability of these disease-associated astrocyte subsets, their regulation, and whether they integrate past stimulation events to respond to subsequent challenges.

Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function.

Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells.

Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are considered attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology.

Identification of astrocyte regulators by nucleic acid cytometry.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system. Astrocytes are heterogeneous glial cells that are resident in the central nervous system and participate in the pathogenesis of multiple sclerosis and its model experimental autoimmune encephalomyelitis. However, few unique surface markers are available for the isolation of astrocyte subsets, preventing their analysis and the identification of candidate therapeutic targets; these limitations are further amplified by the rarity of pathogenic astrocytes.

Identification of environmental factors that promote intestinal inflammation.

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation.

Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity.

Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here, we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the antimicrobial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence in situ mRNA hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18.

Positive STAT5 Protein and Locus Amplification Status Predicts Recurrence after Radical Prostatectomy to Assist Clinical Precision Management of Prostate Cancer.

Background: A significant fraction of prostate cancer patients experience post-radical prostatectomy (RP) biochemical recurrence (BCR). New predictive markers are needed for optimizing postoperative prostate cancer management. is an oncogene in prostate cancer that undergoes amplification in 30% of prostate cancers during progression.

Alterations in Cell Motility, Proliferation, and Metabolism in Novel Models of Acquired Temozolomide Resistant Glioblastoma.

Glioblastoma (GBM) is an aggressive and incurable tumor of the brain with limited treatment options. Current first-line standard of care is the DNA alkylating agent temozolomide (TMZ), but this treatment strategy adds only ~4 months to median survival due to the rapid development of resistance. While some mechanisms of TMZ resistance have been identified, they are not fully understood.

Metabolomic profiling of breast tumors using ductal fluid.

Identification of new biomarkers for breast cancer remains critical in order to enhance early detection of the disease and improve its prognosis. Towards this end, we performed an untargeted metabolomic analysis of breast ductal fluid using an ultra-performance liquid chromatography coupled with a quadrupole time-of-light (UPLC-QTOF) mass spectrometer. We investigated the metabolomic profiles of breast tumors using ductal fluid samples collected by ductal lavage (DL).

MicroRNA analysis of breast ductal fluid in breast cancer patients.

Recent studies suggest that microRNAs show promise as excellent biomarkers for breast cancer; however there is still a high degree of variability between studies making the findings difficult to interpret. In addition to blood, ductal lavage (DL) and nipple aspirate fluids represent an excellent opportunity for biomarker detection because they can be obtained in a less invasive manner than biopsies and circumvent the limitations of evaluating blood biomarkers with regards to tissue of origin specificity. In this study, we have investigated for the first time, through a real-time PCR array, the expression of 742 miRNAs in the ductal lavage fluid collected from 22 women with unilateral breast tumors.

Frequent loss of the BLID gene in early-onset breast cancer.

The BH3-like motif-containing inducer of cell death (BLID) is an intronless gene localized on 11q24.1. Loss of that region has frequently been reported in early-onset breast cancer and is significantly associated with poor prognosis and reduced survival.

Pluripotent stem cells derived from adult human testes.

Recent reports have demonstrated that adult tissue cells can be induced to pluripotency, the iPS cells, mostly with the addition of genes delivered using viruses. Also, several publications both in mouse and in human have demonstrated that spermatogonial stem cells (SSCs) from testes can convert back to embryonic stem (ES)-like cells without the addition of genes. Furthermore, these pluripotent ES-like cells can differentiate into all three germ layers and organ lineages.

Amplification of the BP1 homeobox gene in breast cancer.

The homeobox gene BP1 is expressed in over 80% of breast cancers and is associated with tumor progression and invasion. However, the mechanism of BP1 activation in these tumors remains unknown. Therefore our aim in this study is to assess the amplification status of the BP1 gene in breast cancer and to determine whether BP1 protein expression is caused by gene amplification in these tumors.

Subcutaneous scalp emphysema, pneumo-orbitis and pneumocephalus in a neonate on high humidity high flow nasal cannula.

High humidity high flow nasal cannula has become a widely used alternative for nasal continuous positive airway pressure for the treatment of apnea of prematurity. We describe our experience of one incident of subcutaneous scalp emphysema, pneumo-orbitis and pneumocephalus with concomitant use of the high-flow nasal cannula.

Patterns of DNA copy number changes in sentinel lymph node breast cancer metastases.

The sentinel lymph node (SLN) is considered to be the first axillary node that contains malignant cells in metastatic breast tumors, and its positivity is currently used in clinical practice as an indication for axillary lymph node dissection. Therefore, accurate evaluation of the SLN for the presence of breast metastatic cells is essential. The main aim of our study is to characterize the genomic changes present in the SLN metastatic samples with the ultimate goal of improving the predictive value of SLN evaluation.

Immortalization and transformation of human mammary epithelial cells by a tumor-derived Myc mutant.

The Myc transcription factor is commonly dysregulated in many human cancers, including breast carcinomas. However, the precise role of Myc in the initiation and maintenance of malignancy is unclear. In this study we compared the ability of wild-type Myc (wt Myc) or Myc phosphorylation deficient mutants (T58A, S62A or T58A/S62A) to immortalize and transform human mammary epithelial cells (HMECs).