The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism

The steroid and xenobiotic receptor (SXR) (also known as pregnane X receptor or PXR) is a nuclear hormone receptor activated by a diverse array of endogenous hormones, dietary steroids, pharmaceutical agents, and xenobiotic compounds. SXR has an enlarged, flexible, hydrophobic ligand binding domain (LBD) which is remarkably divergent across mammalian species and SXR exhibits considerable differences in its pharmacology among mammals. The broad response profile of SXR has led to the development of "the steroid and xenobiotic sensor hypothesis". SXR has been established as a xenobiotic sensor that coordinately regulates xenobiotic clearance in the liver and intestine via induction of genes involved in drug and xenobiotic metabolism. In the past few years, research has revealed new and mostly unsuspected roles for SXR in modulating inflammation, bone homeostasis, vitamin D metabolism, lipid homeostasis, energy homeostasis and cancer. The identification of SXR as a xenobiotic sensor has provided an important tool for studying new mechanisms through which diet, chemical exposure, and environment ultimately impact health and disease. The discovery and pharmacological development of new PXR modulators might represent an interesting and innovative therapeutic approach to combat various diseases

Effect of the COVID-19 pandemic on surgery for indeterminate thyroid nodules (THYCOVID): a retrospective, international, multicentre, cross-sectional study

Background Since its outbreak in early 2020, the COVID-19 pandemic has diverted resources from non-urgent and elective procedures, leading to diagnosis and treatment delays, with an increased number of neoplasms at advanced stages worldwide. The aims of this study were to quantify the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic; and to evaluate whether delays in surgery led to an increased occurrence of aggressive tumours.Methods In this retrospective, international, cross-sectional study, centres were invited to participate in June 22, 2022; each centre joining the study was asked to provide data from medical records on all surgical thyroidectomies consecutively performed from Jan 1, 2019, to Dec 31, 2021. Patients with indeterminate thyroid nodules were divided into three groups according to when they underwent surgery: from Jan 1, 2019, to Feb 29, 2020 (global prepandemic phase), from March 1, 2020, to May 31, 2021 (pandemic escalation phase), and from June 1 to Dec 31, 2021 (pandemic decrease phase). The main outcomes were, for each phase, the number of surgeries for indeterminate thyroid nodules, and in patients with a postoperative diagnosis of thyroid cancers, the occurrence of tumours larger than 10 mm, extrathyroidal extension, lymph node metastases, vascular invasion, distant metastases, and tumours at high risk of structural disease recurrence. Univariate analysis was used to compare the probability of aggressive thyroid features between the first and third study phases. The study was registered on ClinicalTrials.gov, NCT05178186.Findings Data from 157 centres (n=49 countries) on 87 467 patients who underwent surgery for benign and malignant thyroid disease were collected, of whom 22 974 patients (18 052 [78 center dot 6%] female patients and 4922 [21 center dot 4%] male patients) received surgery for indeterminate thyroid nodules. We observed a significant reduction in surgery for indeterminate thyroid nodules during the pandemic escalation phase (median monthly surgeries per centre, 1 center dot 4 [IQR 0 center dot 6-3 center dot 4]) compared with the prepandemic phase (2 center dot 0 [0 center dot 9-3 center dot 7]; p<0 center dot 0001) and pandemic decrease phase (2 center dot 3 [1 center dot 0-5 center dot 0]; p<0 center dot 0001). Compared with the prepandemic phase, in the pandemic decrease phase we observed an increased occurrence of thyroid tumours larger than 10 mm (2554 [69 center dot 0%] of 3704 vs 1515 [71 center dot 5%] of 2119; OR 1 center dot 1 [95% CI 1 center dot 0-1 center dot 3]; p=0 center dot 042), lymph node metastases (343 [9 center dot 3%] vs 264 [12 center dot 5%]; OR 1 center dot 4 [1 center dot 2-1 center dot 7]; p=0 center dot 0001), and tumours at high risk of structural disease recurrence (203 [5 center dot 7%] of 3584 vs 155 [7 center dot 7%] of 2006; OR 1 center dot 4 [1 center dot 1-1 center dot 7]; p=0 center dot 0039).Interpretation Our study suggests that the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic period could have led to an increased occurrence of aggressive thyroid tumours. However, other compelling hypotheses, including increased selection of patients with aggressive malignancies during this period, should be considered. We suggest that surgery for indeterminate thyroid nodules should no longer be postponed even in future instances of pandemic escalation.Funding None.Copyright (c) 2023 Published by Elsevier Ltd. All rights reserved

The non-equilibrium landscape of the Sierra Nevada, California: Reply

We thank H.F. Garner for calling attention to an important factor governing fluvial erosion: the role of variable stream discharge caused by climatic fluctuations. We agree that climatic variations affect erosion rates and stream morphology by altering stream discharge, altering bed state such as armoring of channel bottoms and changing sedimentary flux, and can vary local base levels during glacial/interglacial cycles. These processes have most likely played a role in changing river profile form and erosion rates to some degree at various times throughout the Cenozoic in the Sierra Nevada. However, Garner argues that climatically driven changes in erosion rate led to elevation change through isostatic adjustment without any need to call on tectonic forces to explain the modern elevation of the range. This is where we disagree

The non-equilibrium landscape of the Sierra Nevada, California: Reply

We thank H.F. Garner for calling attention to an important factor governing fluvial erosion: the role of variable stream discharge caused by climatic fluctuations. We agree that climatic variations affect erosion rates and stream morphology by altering stream discharge, altering bed state such as armoring of channel bottoms and changing sedimentary flux, and can vary local base levels during glacial/interglacial cycles. These processes have most likely played a role in changing river profile form and erosion rates to some degree at various times throughout the Cenozoic in the Sierra Nevada. However, Garner argues that climatically driven changes in erosion rate led to elevation change through isostatic adjustment without any need to call on tectonic forces to explain the modern elevation of the range. This is where we disagree

The non-equilibrium landscape of the southern Sierra Nevada, California

The paleoelevation of the Sierra Nevada, California, is important to our understanding of the Cenozoic geodynamic evolution of the North America–Pacific plate boundary, and the current debate is fueled by data that argue for conflicting elevation histories. The non-equilibrium or transient landscape of the Sierra Nevada contains information about both past and present controls on the topography of the range. Using geomorphology and thermochronometry, two parts of the landscape of different geodynamic significance and age can be identified: (1) a long-lived, slowly eroding low-relief highland or relict landscape, which we relate to a period of lower relief and elevation from 80–32 Ma; and (2) younger, rapidly- incising river gorges created by at least two stages of elevation and relief increase since 32 Ma. Our data argue for moderate range elevation of ~1500 m at the cessation of arc magmatism in Late Cretaceous time, followed by two events at between 32 and 3.5 Ma and since 3.5 Ma that increased the range elevation to the 4000 m observed elevation today