Circadian rhythm of oestradiol: Impact on the bone metabolism of adult males

Background: Few studies have examined the variation in oestradiol with respect to age and circadian rhythm and the subsequent effects on BMD. Aim: Demonstrate the presence or absence of a circadian rhythm for oestrodial in older men and the integral role of concerted circadian rhythms of several factors including parathyroid hormone (PTH) in regulating biochemical markers of bone resorption and formation. Examine whether concentrations of both circulating total and bioavailable oestrogen in men differ with age and BMD. Design: Males were recruited: young men with normal BMD, older men with normal BMD and older men with osteoporosis. Methods: Subjects were hospitalized for a 25-hour period. Blood samples were obtained every 30 minutes. Hormone analysis results were plotted and reviewed. Results: Both total and bioavailable oestradiol concentrations were significantly lower in the older men than the young men (Total oestradiol: 34.5±4.4 pmol/L vs. 49.0±6.5 pmol/L, p<0.0001; Bioavailable oestradiol 16.7±2.2 pmol/L vs. 26.3±3.6 pmol/L, p<0.0001). Bioavailable oestrogen rhythm mirrored that of total estrogen. Conclusion: Both age groups with normal BMD display circadian rhythmicity with respect to circulating and bioavailable oestradiol. Younger men have increased mean total and bioavailable oestrogen concentrations and later acrophase compared to older counterparts. In older men with low BMD, total circulating oestrogen was not significantly different compared to age-matched older men with normal BMD; bioavailable oestrogen was significantly lower. Total oestrogen demonstrated a concerted circadian rhythm in all 3 groups, but bioavailable oestrogen did not demonstrate circadian rhythmicity in older men with decreased BMD

Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.

TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease

Global Retinoblastoma Presentation and Analysis by National Income Level

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4) were female. Most patients (n = 3685 84.7%) were from low-and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 62.8%), followed by strabismus (n = 429 10.2%) and proptosis (n = 309 7.4%). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 95% CI, 12.94-24.80, and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 95% CI, 4.30-7.68). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs. © 2020 American Medical Association. All rights reserved

Sidewall slopes of SU-8 HARMST using deep x-ray lithography

We describe a model that predicts sidewall slope in SU-8 high aspect ratio microstructures made using x-ray lithography. Our experimental results are in accordance with our model and we demonstrate that essentially zero sidewall taper can be obtained under certain conditions. We use our results to explore the feasibility of optimizing a structure simultaneously for slope and surface roughness

Sidewall slopes and roughness of SU-8 HARMST

In recent years we have investigated the feasibility of deep X-ray lithography in SU-8 as a means of fabricating very high aspect ratio and densely packed arrays of square channels. We have demonstrated how to overcome the problems in adhesion and stiction accompanying the fabrication of such high aspect ratio structures. We have also examined how to calculate the development time of these structures and how this can be used to optimize the dimensional fidelity of the resulting structures. More recently we have considered the effect of the non-uniform dose deposition and beam hardening as a function of depth in the resist on factors such as the surface roughness and the sidewall taper. In this paper we describe our experimental program, review these results and discuss their implications for the operation of our target device-the lobster-eye telescope