Epithelial Cell Lineage and Signaling in Murine Salivary Glands.

Maintaining salivary gland function is critical for oral health. Loss of saliva is a common side effect of therapeutic irradiation for head and neck cancer or autoimmune diseases such as Sjögren's syndrome. There is no curative treatment, and current strategies proposed for functional regeneration include gene therapy to reengineer surviving salivary gland tissue, cell-based transplant therapy, use of bioengineered glands, and development of drugs/biologics to stimulate in vivo regeneration or increase secretion. Understanding the genetic and cellular mechanisms required for development and homeostasis of adult glands is essential to the success of these proposed treatments. Recent advances in genetic lineage tracing provide insight into epithelial lineage relationships during murine salivary gland development. During early fetal gland development, epithelial cells expressing keratin 14 (K14) Sox2, Sox9, Sox10, and Trp63 give rise to all adult epithelium, but as development proceeds, lineage restriction occurs, resulting in separate lineages of myoepithelial, ductal, and acinar cells in postnatal glands. Several niche signals have been identified that regulate epithelial development and lineage restriction. Fibroblast growth factor signaling is essential for gland development, and other important factors that influence epithelial patterning and maturation include the Wnt, Hedgehog, retinoic acid, and Hippo signaling pathways. In addition, other cell types in the local microenvironment, such as endothelial and neuronal cells, can influence epithelial development. Emerging evidence also suggests that specific epithelial cells will respond to different types of salivary gland damage, depending on the cause and severity of damage and the resulting damaged microenvironment. Understanding how regeneration occurs and which cell types are affected, as well as which signaling factors drive cell lineage decisions, provides specific targets to manipulate cell fate and improve regeneration. Taken together, these recent advances in understanding cell lineages and the signaling factors that drive cell fate changes provide a guide to develop novel regenerative treatments.

Salivary Glands: Stem Cells, Self-duplication, or Both?

Understanding the intrinsic potential for renewal and regeneration within a tissue is critical for the rational design of reparative strategies. Maintenance of the salivary glands is widely thought to depend on the differentiation of stem cells. However, there is also new evidence that homeostasis of the salivary glands, like that of the liver and pancreas, relies on self-renewal of differentiated cells rather than a stem cell pool. Here, we review the evidence for both modes of turnover and consider the implications for the process of regeneration. We propose that the view of salivary glands as postmitotic and dependent on stem cells for renewal be revised to reflect the proliferative activity of acinar cells and their role in salivary gland homeostasis.

Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo.

BACKGROUND: Optimal expression and proper function of key mitotic proteins facilitate control and repair processes that aim to prevent loss or gain of chromosomes, a hallmark of cancer. Altered expression of small regulatory microRNAs is associated with tumourigenesis and metastasis but the impact on mitotic signalling has remained unclear. METHODS: Cell-based high-throughput screen identified miR-378a-5p as a mitosis perturbing microRNA. Transient transfections, immunofluorescence, western blotting, time-lapse microscopy, FISH and reporter assays were used to characterise the mitotic anomalies by excess miR-378a-5p. Analysis of microRNA profiles in breast tumours was performed. RESULTS: Overexpression of miR-378a-5p induced numerical chromosome changes in cells and abrogated taxol-induced mitotic block via premature inactivation of the spindle assembly checkpoint. Moreover, excess miR-378a-5p triggered receptor tyrosine kinase-MAP kinase pathway signalling, and was associated with suppression of Aurora B kinase. In breast cancer in vivo, we found that high miR-378a-5p levels correlate with the most aggressive, poorly differentiated forms of cancer. INTERPRETATION: Downregulation of Aurora B by excess miR-378a-5p can explain the observed microtubule drug resistance and increased chromosomal imbalance in the microRNA-overexpressing cells. The results suggest that breast tumours may deploy high miR-378a-5p levels to gain growth advantage and antagonise taxane therapy.

Identifying microRNAs regulating B7-H3 in breast cancer: the clinical impact of microRNA-29c.

BACKGROUND: B7-H3, an immunoregulatory protein, is overexpressed in several cancers and is often associated with metastasis and poor prognosis. Here, our aim was to identify microRNAs (miRNAs) regulating B7-H3 and assess their potential prognostic implications in breast cancer. METHODS: MicroRNAs targeting B7-H3 were identified by transfecting two breast cancer cell lines with a library of 810 miRNA mimics and quantifying changes of B7-H3 protein levels using protein lysate microarrays. For validations we used western immunoblotting and 3'-UTR luciferase assays. Clinical significance of the miRNAs was assayed by analysing whether their expression levels correlated with outcome in two cohorts of breast cancer patients (142 and 81 patients). RESULTS: We identified nearly 50 miRNAs that downregulated B7-H3 protein levels. Western immunoblotting validated the impact of the 20 most effective miRNAs. Thirteen miRNAs (miR-214, miR-363*, miR-326, miR-940, miR-29c, miR-665, miR-34b*, miR-708, miR-601, miR-124a, miR-380-5p, miR-885-3p, and miR-593) targeted B7-H3 directly by binding to its 3'-UTR region. Finally, high expression of miR-29c was associated with a significant reduced risk of dying from breast cancer in both cohorts. CONCLUSIONS: We identified miRNAs efficiently downregulating B7-H3 expression. The expression of miR-29c correlated with survival in breast cancer patients, suggesting a tumour suppressive role for this miRNA.

Incidence of Candida parapsilosis colonization in an intensive care nursery population and its association with invasive fungal disease.

We have studied 82 consecutive intensive care nursery admissions to determine rates of colonization and incidence of fungal sepsis. Cultures were obtained from stool, gastric aspirate and skin at three different times. Infants studied ranged in gestational age from 23 to 38 weeks (mean +/- SEM 29 +/- 0.4 weeks). Nineteen percent of all infants were colonized with Candida sp.; stools were more frequently culture-positive than skin or gastric aspirates. Colonized infants began enteral feeds at a later time compared with noncolonized neonates. Five of the study infants developed fungal sepsis. One had congenital Candida albicans sepsis and died at 10 days of age; the other four had Candida parapsilosis sepsis and survived. The development of C. parapsilosis sepsis was significantly associated with gastrointestinal colonization. Our results suggest that early initiation of enteral feeds decreases gastrointestinal colonization with C. parapsilosis. Gastrointestinal colonization was strongly associated with the subsequent development of C. parapsilosis sepsis in this group of high risk neonates.

Laparoscopia en un servicio de fertilidad. / Laparoscopy in a Service of Fertility

Se revisan 269 estudios laparoscopicos realizados sobre igual numero de mujeres en el Servicio de Fertilidad de la Maternidad "Concepcion Palacios". Se encontro patologia en 91,8%. En orden decreciente de frecuencia, la patologia encontrada fue tubaria, tubaria asociada a otra patologia, ovarica y el factor peritoneal. Se enfatiza la importancia de esta exploracion en la paciente esteril

Comparacion entre histerosalpingografia y laparoscopia en pacientes esteriles. / Comparison between hysterosalpingography and laparoscopy in sterile patients

Se comparan los hallazgos histerosalpingograficos en 269 mujeres infertiles. Se encuentra una coincidencia entre la exploracion radiologica con la endoscopica en el 62% de los casos estudiados. Se concluye que la H.S.G. debe ser considerada como la exploracion inicial en el estudio preliminar de la mujer infertil pero ningun estudio de estas pacientes es completo sin la exploracion endoscopica