Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of glioma stem cells (GSC). Pan-cancer analyses have revealed that stemness of cancer cells correlates positively with immunosuppressive pathways in many solid tumors, including GBM, prompting us to conduct a gain-of-function screen of epigenetic regulators that may infl uence GSC self-renewal and tumor immunity. The circadian regulator CLOCK emerged as a top hit in enhancing stem-cell self-renewal, which was amplifi ed in about 5% of human GBM cases. CLOCK and its heterodimeric partner BMAL1 enhanced GSC self-renewal and triggered protumor immunity via transcriptional upregulation of OLFML3, a novel chemokine recruiting immune-suppressive microglia into the tumor microenvironment. In GBM models, CLOCK or OLFML3 depletion reduced intratumoral microglia density and extended overall survival. We conclude that the CLOCK-BMAL1 complex contributes to key GBM hallmarks of GSC maintenance and immunosuppression and, together with its downstream target OLFML3, represents new therapeutic targets for this disease. SIGNIFICANCE: Circadian regulator CLOCK drives GSC self-renewal and metabolism and promotes microglia infi ltration through direct regulation of a novel microglia-attracting chemokine, OLFML3. CLOCK and/or OLFML3 may represent novel therapeutic targets for GBM.

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OBJECTIVE. Our purposewas to depict the characteristics of the global vasculatureof cervical lymphadenopathies and to clarify the efficiency of Doppler spectral analysis and power Doppler sonography in the differential diagnosis.SUBJECTS AND METHODS. Prospectively, 289 lymph nodelesionsunderwentDop pier flow studiesand were groupedas metastasis, lymphoma,tuberculosis, and benignlym phadenopathies. Sonographic assessmentsincluded vascular pattern and vascular density (presentedas vascularityindex) asrevealedby power Doppler sonography. Vascularresistive index and pulsatility index were assessed by at least three flow samplings. Values of both the highest and the lowest resistancewere analyzed. Vascularity index, resistive index, pulsatility index, nodal size, and age were correlated. RESULTS. Most benign lymphadenopathies (87%), tuberculous lymphadenopathies (72%),and lymphomas (7 1%) revealed an avascular or hilar vascular pattern. Vascular patterns of most metastaticlymphadenopathies(90%) were of spotted(26%). peripheral (I 1%). or mixed (53%) type. The vascularity indexes of metastatic lymphadenopathy (mean, 0. 176) and lymphoma (mean, 0.122) were significantly higher than those of tuberculous and benign lymphadenopathy (mean, 0.054 and 0.042, respectively). In vascular resistance studies, the highest pulsatility index andresistiveindex in metastaticlymphadenopathystatisticallyexceededthoseofbenign lymphad enopathy,whereasno difference was found in the lowest values.Negativecorrelation was found between the vascularity index of meta.static lesions and their lowest vascular resistance, and posi tive correlation wasfound betweenvascularityindex andnodal sizein benign lymphadenopathies. CONCLUSION.In additionto vascularresistanceassessed traditionallywith Doppler spectral analysis, vascular pattern and vascular density assessedwith power Doppler sonogra phy can better differentiate the nature of lymphadenopathies. Our study investigatedthe usefulnessof color Doppler spectral analysis and power Doppler sonography for differentiation of vim ous cervical lymphadenopathies (metastasis, lymphoma, tuberculosis, and other benign lymphadenopathies)in terms of vascularresis tance, vascular pattern, and vascular density.The clinical and biologic implications of these vascularparameterswere also investigated.

The Taiwan orogenic belt is often treated as a steady, southward-propagating orogenic system with an essentially constant erosion rate of 4–6 mm/yr over the past 5 m.y. We present 4 new age-elevation transects from the Central Range based on 19 new and 86 previously published fission track and (U-Th)/He dates of completely reset detrital zircon and apatite grains. The age-elevation curves and thermal models imply slow cooling prior to ca. 2–1.5 Ma (at exhumation rates of ∼0.1 mm/yr), an increase in exhumation rates from ca. 2–1.5 Ma to ca. 0.5 Ma (2–4 mm/yr), and possibly a further acceleration in exhumation from ca. 0.5 Ma to present (4–8 mm/yr). Three transects from three different latitudes in the eastern Central Range yield similar results, each showing punctuated exhumation with progressively faster rates.