Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption ...by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression.
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•Physiologic disruption of circadian rhythms accelerates lung cancer•Genetic loss of Per2 or Bmal1 promotes lung tumorigenesis•Cell-autonomous loss of circadian genes enhances transformation and growth•Circadian rhythm disruption leads to increased c-Myc levels and metabolic reprogramming
Papagiannakopoulos et al. demonstrate that both physiologic and genetic circadian rhythm disruption accelerates lung tumorigenesis in mice, pointing to a tumor cell-autonomous, tumor-suppressive role of the circadian machinery. Mechanistically, circadian rhythm disruption leads to increased c-Myc levels, enhanced proliferation, and metabolic reprogramming.
Proposals submitted to the FDA for MSC-based products are undergoing a rapid expansion that is characterized by increased variability in donor and tissue sources, manufacturing processes, proposed ...functional mechanisms, and characterization methods. Here we discuss the diversity in MSC-based clinical trial product proposals and highlight potential challenges for clinical translation.
Electrostatic interactions between small molecules and their respective receptors are essential for molecular recognition and are also key contributors to the binding free energy. Assessing the ...electrostatic match of protein–ligand complexes therefore provides important insights into why ligands bind and what can be changed to improve binding. Ideally, the ligand and protein electrostatic potentials at the protein–ligand interaction interface should maximize their complementarity while minimizing desolvation penalties. In this work, we present a fast and efficient tool to calculate and visualize the electrostatic complementarity (EC) of protein–ligand complexes. We compiled benchmark sets demonstrating electrostatically driven structure-activity relationships (SAR) from literature data, including kinase, protein−protein interaction, and GPCR targets, and used these to demonstrate that the EC method can visualize, rationalize, and predict electrostatically driven ligand affinity changes and help to predict compound selectivity. The methodology presented here for the analysis of EC is a powerful and versatile tool for drug design.
Given that an estimated 0.6% of the U.S. population is transgender (trans) and that large health disparities for this population have been documented, government and research organizations are ...increasingly expanding measures of sex/gender to be trans inclusive. Options suggested for trans community surveys, such as expansive check-all-that-apply gender identity lists and write-in options that offer maximum flexibility, are generally not appropriate for broad population surveys. These require limited questions and a small number of categories for analysis. Limited evaluation has been undertaken of trans-inclusive population survey measures for sex/gender, including those currently in use. Using an internet survey and follow-up of 311 participants, and cognitive interviews from a maximum-diversity sub-sample (n = 79), we conducted a mixed-methods evaluation of two existing measures: a two-step question developed in the United States and a multidimensional measure developed in Canada. We found very low levels of item missingness, and no indicators of confusion on the part of cisgender (non-trans) participants for both measures. However, a majority of interview participants indicated problems with each question item set. Agreement between the two measures in assessment of gender identity was very high (K = 0.9081), but gender identity was a poor proxy for other dimensions of sex or gender among trans participants. Issues to inform measure development or adaptation that emerged from analysis included dimensions of sex/gender measured, whether non-binary identities were trans, Indigenous and cultural identities, proxy reporting, temporality concerns, and the inability of a single item to provide a valid measure of sex/gender. Based on this evaluation, we recommend that population surveys meant for multi-purpose analysis consider a new Multidimensional Sex/Gender Measure for testing that includes three simple items (one asked only of a small sub-group) to assess gender identity and lived gender, with optional additions. We provide considerations for adaptation of this measure to different contexts.
Abstract Background Concerns have been raised about the risk of fractures with acid-suppressive medications, such as proton pump inhibitors and histamine2 -receptor antagonists. Methods This ...meta-analysis evaluated the association between proton pump inhibitor or histamine2 -receptor antagonist use and fractures. We performed a systematic search of published literature (1970 to October 10, 2010) in MEDLINE, EMBASE, and other sources. Ten publications reporting 11 studies were considered eligible for analysis. Results All studies were observational case-control or cohort studies and primarily evaluated older adults. The summary effect estimate for risk of hip fracture increased modestly among individuals taking proton pump inhibitors (relative risk RR 1.30, 95% confidence interval CI, 1.19-1.43). There also was an increase in spine (RR 1.56, 95% CI, 1.31-1.85) and any-site fractures (RR 1.16, 95% CI, 1.04-1.30) among proton pump inhibitor users. These findings were similar in both men and women and after stratification by duration of use. In contrast, histamine2 -receptor antagonist use was not significantly associated with increased risk of hip fracture (RR 1.12, 95% CI, 0.97-1.30). Conclusion In this meta-analysis of observational studies, proton pump inhibitors modestly increased the risk of hip, spine, and any-site fractures, whereas histamine2 -receptor antagonists were not associated with fracture risk. The possibility of residual confounding cannot be excluded. Further skeletal evaluation should be considered for patients who are taking proton pump inhibitors and also at risk for osteoporotic fracture.
Evidence suggests that transgender (trans) individuals in Canada are a medically underserved population; barriers range from lack of provider knowledge on trans issues to refusal of care. This paper ...provides the first formal estimation of health care inequalities between trans and cisgender individuals in Ontario, Canada.
Weighted statistics from the Ontario-wide Trans PULSE Project (n = 433) were compared with age-standardized Ontario data from the Canadian Community Health Survey (n = 39,980) to produce standardized prevalence differences (SPDs). Analysis was also conducted separately for trans men and trans women, each compared to the age-standardized Ontario population.
An estimated 33.2% (26.4,40.9) of trans Ontarians reported a past-year unmet health care need in excess of the 10.7% expected based on the age-standardized Ontario population. Inequality was greatest comparing trans with cisgender men (SPD = 34.4% (23.0, 46.1). While trans Ontarians evaluated health care availability in Ontario similarly to the broader population, they were significantly more likely to evaluate availability in their community as fair or poor.
Trans Ontarians experience inequalities in perception and reported experiences of health care access, with 43.9% reporting a past-year unmet health care need.
To achieve guide RNA (gRNA) multiplexing and an efficient delivery of tens of distinct gRNAs into single cells, we developed a molecular assembly strategy termed chimeric array of gRNA ...oligonucleotides (CARGO). We coupled CARGO with dCas9 (catalytically dead Cas9) imaging to quantitatively measure the movement of enhancers and promoters that undergo differentiation-associated activity changes in live embryonic stem cells. Whereas all examined functional elements exhibited subdiffusive behavior, their relative mobility increased concurrently with transcriptional activation. Furthermore, acute perturbation of RNA polymerase II activity can reverse these activity-linked increases in loci mobility. Through quantitative CARGO-dCas9 imaging, we provide direct measurements of cis-regulatory element dynamics in living cells and distinct cellular and activity states and uncover an intrinsic connection between cis-regulatory element mobility and transcription.
Chronic pain can be understood not only as an altered functional state, but also as a consequence of neuronal plasticity. Here we use in vivo structural MRI to compare global, local, and ...architectural changes in gray matter properties in patients suffering from chronic back pain (CBP), complex regional pain syndrome (CRPS) and knee osteoarthritis (OA), relative to healthy controls. We find that different chronic pain types exhibit unique anatomical 'brain signatures'. Only the CBP group showed altered whole-brain gray matter volume, while regional gray matter density was distinct for each group. Voxel-wise comparison of gray matter density showed that the impact on the extent of chronicity of pain was localized to a common set of regions across all conditions. When gray matter density was examined for large regions approximating Brodmann areas, it exhibited unique large-scale distributed networks for each group. We derived a barcode, summarized by a single index of within-subject co-variation of gray matter density, which enabled classification of individual brains to their conditions with high accuracy. This index also enabled calculating time constants and asymptotic amplitudes for an exponential increase in brain re-organization with pain chronicity, and showed that brain reorganization with pain chronicity was 6 times slower and twice as large in CBP in comparison to CRPS. The results show an exuberance of brain anatomical reorganization peculiar to each condition and as such reflecting the unique maladaptive physiology of different types of chronic pain.
Cultured cells convert glucose to lactate, and glutamine is the major source of tricarboxylic acid (TCA)-cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We ...infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was minimal, with lung tumors showing increased glucose contribution to the TCA cycle relative to normal lung tissue. Deletion of enzymes involved in glucose oxidation demonstrates that glucose carbon contribution to the TCA cycle is required for tumor formation. These data suggest that understanding nutrient utilization by tumors can predict metabolic dependencies of cancers in vivo. Furthermore, these data argue that the in vivo environment is an important determinant of the metabolic phenotype of cancer cells.
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•Metabolic phenotyping of tumors can identify essential metabolic pathways•Kras-driven lung tumors require pyruvate carboxylase and pyruvate dehydrogenase•Kras-driven lung tumors are less dependent on glutaminase than cultured cells•Tissue environment is an important determinant of tumor metabolic phenotypes
Davidson et al. find that lung cancer cells in culture use nutrients differently than lung tumors, especially regarding glutamine metabolism. This difference in metabolic phenotype reflects how the tumor environment determines nutrient dependency and highlights the importance of studying cancer metabolism in a physiological context.
In this study, we develop a complete microwave-induced thermoacoustic imaging (TAI) model for potential breast cancer imaging application. Acoustic pressures generated by different breast tissue ...targets are investigated by finite-difference time-domain simulations of the entire TAI process including the feeding antenna, matching mechanism, fluidic environment, 3-D breast model, and acoustic transducer. Simulation results achieve quantitative relationships between the input microwave peak power and the resulting specific absorption rate as well as the output acoustic pressure. Microwave frequency dependence of the acoustic signals due to different breast tissues is established across a broadband frequency range (2.3-12 GHz), suggesting key advantages of spectroscopic TAI compare to TAI at a single frequency. Reconstructed thermoacoustic images are consistent with the modeling results. This model will contribute to design, optimization, and safety evaluation of microwave-induced TAI and spectroscopy.
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