Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance

Women with late-stage ovarian cancer usually develop chemotherapeutic-resistant recurrence. It has been theorized that a rare cancer stem cell, which is responsible for the growth and maintenance of the tumor, is also resistant to conventional chemotherapeutics. We have isolated from multiple ovarian cancer cell lines an ovarian cancer stem cell-enriched population marked by CD44, CD24, and Epcam (3+) and by negative selection for Ecadherin (Ecad-) that comprises less than 1% of cancer cells and has increased colony formation and shorter tumor-free intervals in vivo after limiting dilution. Surprisingly, these cells are not only resistant to chemotherapeutics such as doxorubicin, but also are stimulated by it, as evidenced by the significantly increased number of colonies in treated 3+Ecad- cells. Similarly, proliferation of the 3+Ecad- cells in monolayer increased with treatment, by either doxorubicin or cisplatin, compared with the unseparated or cancer stem cell-depleted 3-Ecad+ cells. However, these cells are sensitive to Mullerian inhibiting substance (MIS), which decreased colony formation. MIS inhibits ovarian cancer cells by inducing G1 arrest of the 3+Ecad- subpopulation through the induction of cyclin-dependent kinase inhibitors. 3+Ecad- cells selectively expressed LIN28, which colocalized by immunofluorescence with the 3+ cancer stem cell markers in the human ovarian carcinoma cell line, OVCAR-5, and is also highly expressed in transgenic murine models of ovarian cancer and in other human ovarian cancer cell lines. These results suggest that chemotherapeutics may be stimulative to cancer stem cells and that selective inhibition of these cells by treating with MIS or targeting LIN28 should be considered in the development of therapeutics.     

Autophagy is required for CSF-1-induced macrophagic differentiation and acquisition of phagocytic functions

Autophagy is the process by which superfluous or damaged macromolecules or organelles are degraded by the lysosome. Pharmacologic and genetic evidence indicates that autophagy plays pleiotropic functions in cellular homeostasis, development, survival, and differentiation. The differentiation of human blood monocytes into macrophages is a caspase-dependent process when triggered ex vivo by colony stimulating factor-1. We show here, using pharmacologic inhibitors, siRNA approaches, and Atg7-/- mice, that autophagy initiated by ULK1 is required for proper colony stimulating factor-1-driven differentiation of human and murine monocytes. We also unravel a role for autophagy in macrophage acquisition of phagocytic functions. Collectively, these findings highlight an unexpected and essential role of autophagy during monocyte differentiation and acquisition of macrophage functions.     

Board Certification in Clinical Neuropsychology: A Response to Rohling et al.

Board certification is intended to protect the public by identifying practitioners that have met minimum standards for education and training in their specialty or discipline. For varied reasons, clinical neuropsychology, like professional psychology as a whole, has struggled to achieve levels of board certification comparable to the medical profession. Rohling, Lees-Haley, Langhinrichsen-Rohling, & Williamson (2003) Rohling, M. L., Lees-Haley, P. R., Langhinrichsen-Rohling, J. and Williamson, D. J. 2003. A statistical analysis of board certification in clinical neuropsychology. Archives of Clinical Neuropsychology, 18: 331–352.  [Google Scholar] have recently published a critique of the board certification process in clinical neuropsychology as it is conducted by American Board of Clinical Neuropsychology (ABCN), arguing that one reason for this failure is the overly restrictive nature of the process. In their paper, Rohling et al. provide a signal detection analysis that makes several assumptions about the process and conclude with recommendations for improving the process to better identify “competent” neuropsychologists in practice. While we agree in principle with many of their recommendations, and ABCN had, in fact, implemented several prior to publication of their article, the article contains many faulty assumptions and logical inconsistencies that we believe are harmful to constructive review of the certification process. In this article, we provide a critical review of their analysis and present new and additional data that demonstrate the procedure is not overly restrictive. A primary consideration is the low incidence of seeking board certification among professionals who identify themselves as neuropsychologists (i.e., a low application rate), rather than an overly restrictive process. We describe steps taken to improve the process and conclude that there are numerous areas of agreement with Rohling et al., including the need for ongoing review and continued improvement in the board certification process in all psychological specialties.     

Outcome of Poor-Grade Subarachnoid Hemorrhage as Determined by Biomarkers of Glucose Cerebral Metabolism

Purpose

The aim of this study was to determine if the measurement of blood biomarkers of glucose cerebral metabolism, performed with retrograde jugular catheter, could predict the outcome of poor-grade aneurysmal subarachnoid hemorrhage (aSAH) patients.

Methods

This study was conducted in 68 poor-grade aSAH patients. A total of 4,024 blood samples obtained from jugular and radial catheters were analyzed for glucose, lactate, and oxygen content every 8 h for 10 ± 0.5 days. Metabolic ratio (MR) and lactate–oxygen index (LOI) were obtained by ratios using arterio-jugular differences. Functional outcome was evaluated at 12 months with the Glasgow Outcome Scale.

Results

Outcome was unfavorable in 40 patients. In this group of patients, the MR was significantly lower (p < 0.0001) and the LOI was significantly higher (p = 0.0001) than in the group with favorable outcome. The MR cutoff value, below which the patients are likely to have an unfavorable outcome, was determined to be 3.35. More interestingly, the data obtained in this study demonstrated that the patients achieving an unfavorable outcome were distinguished from those with a favorable outcome by having at least three events of MR inferior to 3.35 (sensitivity = 90 %, specificity = 82.1 %). Moreover, in patients who developed cerebral vasospasm, we observed a significant decrease in the MR.

Conclusion

Our data provide additional support to the view that the MR is a reliable marker for predicting the outcome of poor-grade aSAH patients. Prospective studies are needed to confirm its value in multimodal monitoring.