shRNA-mediated PPARα knockdown in human glioma stem cells reduces in vitro proliferation and inhibits orthotopic xenograft tumour growth.

The overall survival for patients with primary glioblastoma is very poor. Glioblastoma contains a subpopulation of glioma stem cells (GSC) that are responsible for tumour initiation, treatment resistance and recurrence. PPARα is a transcription factor involved in the control of lipid, carbohydrate and amino acid metabolism. We have recently shown that PPARα gene and protein expression is increased in glioblastoma and has independent clinical prognostic significance in multivariate analyses. In this work, we report that PPARα is overexpressed in GSC compared to foetal neural stem cells. To investigate the role of PPARα in GSC, we knocked down its expression using lentiviral transduction with short hairpin RNA (shRNA). Transduced GSC were tagged with luciferase and stereotactically xenografted into the striatum of NOD-SCID mice. Bioluminescent and magnetic resonance imaging showed that knockdown (KD) of PPARα reduced the tumourigenicity of GSC in vivo. PPARα-expressing control GSC xenografts formed invasive histological phenocopies of human glioblastoma, whereas PPARα KD GSC xenografts failed to establish viable intracranial tumours. PPARα KD GSC showed significantly reduced proliferative capacity and clonogenic potential in vitro with an increase in cellular senescence. In addition, PPARα KD resulted in significant downregulation of the stem cell factors c-Myc, nestin and SOX2. This was accompanied by downregulation of the PPARα-target genes and key regulators of fatty acid oxygenation ACOX1 and CPT1A, with no compensatory increase in glycolytic flux. These data establish the aberrant overexpression of PPARα in GSC and demonstrate that this expression functions as an important regulator of tumourigenesis, linking self-renewal and the malignant phenotype in this aggressive cancer stem cell subpopulation. We conclude that targeting GSC PPARα expression may be a therapeutically beneficial strategy with translational potential as an adjuvant treatment. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

False-positive pregnancy test after transfusion of solvent/detergent-treated plasma.

BACKGROUND: The transmission of pathogens, antibodies, and proteins is a possible consequence of blood product transfusion. A female patient had an unexpected positive serum ß-human chorionic gonadotropin result, indicative of pregnancy, after she had received a transfusion with 1 unit of platelet concentrate, 4 units of red blood cells, and 4 units of pooled solvent/detergent-treated plasma (Octaplas). STUDY DESIGN AND METHODS: To investigate the possibility of passive transfusion of ß-human chorionic gonadotropin from the plasma transfusion, one additional unit from the same batch was thawed and analyzed. To validate the ß-human chorionic gonadotropin assay for use in solvent/detergent-treated plasma and to investigate any interference in the assay, dilution experiments were performed using the implicated plasma batch diluted with male and non-pregnant female sera. Also, plasma from a known pregnant woman was diluted with Octaplas (tested negative for ß-human chorionic gonadotropin) and with a male serum to validate the assay for use in solvent/detergent-treated plasma. RESULTS: The implicated solvent/detergent-treated plasma had a mean ß-human chorionic gonadotropin level of 91.5 mIU/mL. Results from the dilution experiments revealed an excellent correlation (r > 0.99) between ß-human chorionic gonadotropin measurement in solvent/detergent-treated plasma and male serum and no over or under recovery of the expected results. Further measurements of ß-human chorionic gonadotropin levels in the female recipient revealed an estimated half-life of 6 hours. CONCLUSION: This case demonstrates the importance of considering the possibility of passive transmission of analytes to a patient from the transfusion of blood products. Furthermore, the measurement of ß-human chorionic gonadotropin is valid in solvent/detergent-treated plasma using a Roche Cobas analyzer.

Contemporary and historical evidence to suggest that women's preference for age at birth of first child remains consistent across time.

Women's ability to reproduce is restricted by menarche and menopause. First children are, however, not typically born until some years after the onset of puberty. Other factors therefore contribute towards this delay. In this context, women's hips do not reach full adult form until they are in their mid-20s. Therefore, physiological and morphological factors appear to determine an optimum age-range for reproduction. The following studies were conducted in order to investigate this hypothesis. Study 1 asked nulliparous women questions about ages at which particular life events related to reproduction should ideally occur. This revealed their preferred age at birth of first child to be approximately 27 years old. Study 2 replicated these findings and further showed that women with children actually had their first child at a very similar age (27.93 [±0.79]). Findings from Study 3 were also remarkably consistent (28.15 [±0.39]). Study 4 examined the 1901 U.K. Census record and incorporated an analysis of the influence of wealth. Middle class women were on average 24.88 (±0.22) years old at the birth of their first child. Poor women were on average 23.50 (±0.20) years old. These figures at least approximate to findings from Studies 1-3, which is noteworthy given that modern contraceptive methods were not widely available at the time. It is concluded that female strategies to delay giving birth to their first child until they are of an age that approaches or coincides with their full hip maturation are enduring across time.

An immunoglobulin G complexed form of thyroid-stimulating hormone (macro thyroid-stimulating hormone) is a cause of elevated serum thyroid-stimulating hormone concentration.

BACKGROUND: Macrocomplexes can be the cause of elevated serum hormone concentrations and may cause diagnostic confusion. This is well recognized for prolactin and commonly screened for using polyethylene glycol (PEG) precipitation. The phenomenon and a suitable screening method is less familiar with respect to thyroid-stimulating hormone (TSH). METHOD: Samples sent to the laboratory for routine analysis of thyroid function and found to have a TSH >10 mU/L were evaluated to determine the prevalence of macro-TSH in the Roche Elecsys assay, using PEG precipitation with confirmation by gel filtration chromatography. RESULTS: Of 495 samples tested, 3 (0.6%) were found to have macro-TSH. From the distribution of recoveries, a cut-off <25% was determined for identifying samples requiring further investigation for the presence of macro-TSH. CONCLUSION: The prevalence of elevated TSH due to macro-TSH was found to be 0.6%. Laboratories should be aware of this cause of assay interference.