A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury

Glucocorticoids are used for treating preterm neonatal infants suffering from life-threatening lung, airway, and cardiovascular conditions. However, several studies have raised concerns about detrimental effects of postnatal glucocorticoid administration on the developing brain leading to cognitive impairment, cerebral palsy, and hypoplasia of the cerebellum, a brain region critical for coordination of movement and higher-order neurological functions. Previously, we showed that glucocorticoids inhibit Sonic hedgehog-Smoothened (Shh-Smo) signaling, the major mitogenic pathway for cerebellar granule neuron precursors. Conversely, activation of Shh-Smo in transgenic mice protects against glucocorticoid-induced neurotoxic effects through induction of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) pathway. Here, we show that systemic administration of a small-molecule agonist of the Shh-Smo pathway (SAG) prevented the neurotoxic effects of glucocorticoids. SAG did not interfere with the beneficial effects of glucocorticoids on lung maturation, and despite the known associations of the Shh pathway with neoplasia, we found that transient (1-week-long) SAG treatment of neonatal animals was well tolerated and did not promote tumor formation. These findings suggest that a small-molecule agonist of Smo has potential as a neuroprotective agent in neonates at risk for glucocorticoid-induced neonatal cerebellar injury.     

Death receptor expression is associated with poor response to chemotherapy and shorter survival in metastatic ovarian carcinoma

BACKGROUND: Death receptors mediate both apoptosis and survival in cancer cells. The authors analyzed death receptor expression in metastatic ovarian carcinoma. METHODS: Viable tumor cells in ovarian carcinoma effusions (n = 95) were analyzed for DR4, DR5, Fas, TNFR1, and TNFR2 expression using flow cytometry. Results were analyzed for association with clinicopathologic parameters, chemotherapy response, and survival. RESULTS: DR4, DR5, and Fas were expressed by the majority of specimens, with less frequent expression of TNFR1 and TNFR2. DR4 (P = .005) and TNFR2 (P = .041) expression was higher in FIGO stage IV compared with stage III tumors. Effusions from patients who responded poorly to chemotherapy administered at disease recurrence had significantly higher DR4 (P = .006), DR5 (P = .01), and Fas (P = .001) expression. In univariate survival analysis, higher DR4 expression in viable cells correlated with poor overall (P = .0352) and progression-free (P = .0411) survival. DR4 expression was found to be an independent predictor of overall (P = .008) and progression-free (P = .003) survival. CONCLUSIONS: The authors have presented the first evidence of death receptor coexpression in ovarian carcinoma effusions. The association of death receptor expression in effusions with advanced stage, poor response to chemotherapy, and shorter survival suggests that these molecules are linked to an aggressive clinical course in metastatic ovarian carcinoma.     

Expression of HLA-G in malignant mesothelioma and clinically aggressive breast carcinoma

The aim of the present study was to evaluate HLA-G expression in breast carcinoma and malignant mesothelioma (MM). Malignant breast carcinoma effusions (46) and corresponding solid tumors (39) and 104 MM (26 effusions, 78 solid tumors) were analyzed using immunohistochemistry (IHC). HLA-G protein and mRNA expression were further studied using immunoblotting (IB) and RT-PCR. HLA-ABC expression was analyzed using flow cytometry (FCM). IHC showed predominantly focal HLA-G expression in 12 of 46 (26%) breast carcinoma effusions and 16 of 39 (41%) solid lesions. In MM, 20 of 78 (26%) solid lesions and 14 of 26 (54%) effusions were focally HLA-G positive. Expression in MM was higher in effusions (p=0.008). IB showed more frequent HLA-G expression in MM compared with breast carcinoma effusions, while RT-PCR showed HLA-G mRNA expression in both tumors. FCM showed conserved HLA-ABC expression in 15 of 15 effusions. Breast cancer patients with HLA-G-positive tumor cells had shorter disease-free survival (mean 37 vs 85, median 25 vs 31 months), though not significantly (p=0.14). In conclusion, HLA-G is focally expressed in MM and breast carcinoma, while HLA-ABC expression is conserved. However, the up-regulated expression of HLA-G in MM effusions and its possible association with shorter disease-free survival in advanced stage of breast carcinoma suggest a possible role in immune response evasion in some tumors.     

Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma

Whether the brain tumor medulloblastoma originates from stem cells or restricted progenitor cells is unclear. To investigate this, we activated oncogenic Hedgehog (Hh) signaling in multipotent and lineage-restricted central nervous system (CNS) progenitors. We observed that normal unipotent cerebellar granule neuron precursors (CGNPs) derive from hGFAP(+) and Olig2(+) rhombic lip progenitors. Hh activation in a spectrum of early- and late-stage CNS progenitors generated similar medulloblastomas, but not other brain cancers, indicating that acquisition of CGNP identity is essential for tumorigenesis. We show in human and mouse medulloblastoma that cells expressing the glia-associated markers Gfap and Olig2 are neoplastic and retain features of embryonic-type granule lineage progenitors. Thus, oncogenic Hh signaling promotes medulloblastoma from lineage-restricted granule cell progenitors.     

Clinical and cell line specific expression profiles of a human gene identified in experimental central nervous system metastases

Some cancers, particularly malignant melanomas and carcinomas of the breast and lung, metastasize to the central nervous system (CNS) in advanced stages. In order to develop into clinically manifest metastases, hematogenously disseminated tumor cells must respond to trophic factors within the CNS microenvironment. We have previously identified a nuclearfactor, com1, expressed in human breast carcinoma cells upon formation of experimental metastatic tumors in the CNS. In the present study distinct com1 mRNA expression was detected in cerebral metastases from patients with lung carcinomas, whereas the expression level was generally much lower in glioblastomas (primary brain tumors). In tissue specimens from normal brain and lung, as well as in glioma and lung carcinoma cell lines, com1 expression was barely detectable. One potential mechanism involved in the induction of com1 expression was indicated in the metastatic MCF7/LCC2 breast carcinoma cells. Significant increases in the level of com1 mRNA were observed upon activation of receptor tyrosine kinase signaling, which is known to operate during metastatic tumor cell proliferation within the CNS. The observations in this study strengthen the assumption that com1 may be involved in the tumor cell response to regulatory signals upon metastasis formation.     

Measuring the Year Consumption of Alcohol: The Development of a Questionnaire

Most general alcohol consumption population surveys are meant to represent the year consumption, although they actually ask only for habitual drinking and/or frequencies and quantities of binge drinking in the past months. These surveys typically cover about half of the alcohol sales figures. In order to enhance sales coverage and to reduce seasonal bias, we developed a year consumption questionnaire on the basis of daily and weekly drinking adding 13 categories of less-than-weekly drinking occasions over the year. As a first test we offered the new questionnaire together with a traditional typical week questionnaire, in different modes to various groups adding up to a purposive high diversity sample of 101 drinking persons (56 women, 44 men, 16–69 years old, mean age 34 years). After correction for overlaps between weekly habits and less-than-weekly occasions, the new questionnaire produces considerably higher reports of annual consumption, compared with the typical-week-based estimates of year consumption. Limitations of the study are discussed.     

Triassic–Jurassic climate in continental high-latitude Asia was dominated by obliquity-paced variations (Junggar Basin, ürümqi,China)

Empirical constraints on orbital gravitational solutions for the Solar System can be derived from the Earth’s geological record of past climates. Lithologically based paleoclimate data from the thick, coal-bearing, fluvial-lacustrine sequences of the Junggar Basin of Northwestern China (paleolatitude ∼60°) show that climate variability of the warm and glacier-free high latitudes of the latest Triassic–Early Jurassic (∼198–202 Ma) Pangea was strongly paced by obliquity-dominated (∼40 ky) orbital cyclicity, based on an age model using the 405-ky cycle of eccentricity. In contrast, coeval low-latitude continental climate was much more strongly paced by climatic precession, with virtually no hint of obliquity. Although this previously unknown obliquity dominance at high latitude is not necessarily unexpected in a high CO₂ world, these data deviate substantially from published orbital solutions in period and amplitude for eccentricity cycles greater than 405 ky, consistent with chaotic diffusion of the Solar System. In contrast, there are indications that the Earth–Mars orbital resonance was in today’s 2-to-1 ratio of eccentricity to inclination. These empirical data underscore the need for temporally comprehensive, highly reliable data, as well as new gravitational solutions fitting those data.Our understanding of Triassic and Early Jurassic high-latitude climate, biotic evolution, mass extinction, and geochronology is very poor in contrast to that of the contemporaneous tropics (1, 2). This poor resolution impairs an elucidation of the basic patterns of Earth system function during the early Mesozoic, notably the high-latitude climatic response to orbital forcing, as well as the effects of the eruption of the Triassic–Jurassic Central Atlantic Igneous Province (CAMP) (3). The former issue bears on the stability of the Solar System, in which determining variations in orbital eccentricity (via climatic precession) and inclination (via obliquity) figure as crucial (4–6), and the latter bears on the causes, effects, and recovery from the end-Triassic mass extinction (ETE) (e.g., ref. 2). Here, we describe results of a cyclostratigraphic investigation of lithologic variations in the paleo-high latitude, lacustrine, Late Triassic–Early Jurassic Haojiagou and Badaowan formations of the Junggar Basin, China representing, to our knowledge, the first analysis of orbital cyclicity from a high-latitude, early Mesozoic continental sequence, and a step toward development of an empirical basis for evaluating numerical solutions of Solar System chaotic behavior.