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Circadian rhythms are important for maintaining homeostasis, from regulating physiological activities (e.g., sleep–wake cycle and cognitive performance) to cellular processes (e.g., cell cycle and DNA damage repair). Melatonin is a key regulator of circadian rhythms and exerts control by binding to melatonin receptor 1 (MT1), decreasing neuronal firing in the suprachiasmatic nucleus (SCN). Previous work studying effects of melatonin on circadian rhythms utilized in vivo models. Since MT1 is also expressed outside of the brain, it is important to study impacts of melatonin on circadian gene oscillations in vitro. We evaluated the effects of melatonin and an MT1 inverse agonist, UCSF7447, in U2OS circadian reporter cell lines, which facilitate detailed assessments of oscillatory changes. We report that cellular circadian rhythms are responsive to treatment with MT1-targeting molecules; their activities are not dependent upon the SCN. Corroborating in vivo data, both melatonin and UCSF7447 lengthened the periods of BMAL1 and PER2, and while melatonin delayed circadian phases, UCSF7447 advanced them. Compounds were also dosed at two different times, however this did not yield changes. Our findings indicate the importance of utilizing in vitro models and that the direct effects of melatonin likely go beyond the SCN and should be explored further. [ABSTRACT FROM AUTHOR]

Background: This study aimed to measure fear of thyroid cancer in the general U.S. population and identify factors associated with a high level of thyroid cancer-specific fear that may contribute to overtreatment. Methods: We conducted a cross-sectional survey using Prolific Academic Ltd.®, an online survey platform. The survey was administered in August 2020 to English speaking adults (>17 years) in the United States who were registered with Prolific. The target sample was stratified to represent the demographics of the U.S. population. A validated, eight-item breast cancer fear scale was adapted to measure thyroid cancer-specific fear. Multivariate logistic regression identified factors significantly associated with high levels of thyroid cancer-specific fear. Results: Of the 1136 respondents (94.3% eligibility), 50.4% were female, 74.1% White, and the mean age was 45 years (SD = 16 years). Overall, 47.5% of respondents had high levels of thyroid cancer-specific fear. Multivariate regression demonstrated that age <40 years (OR = 2.46 vs. 65+ [95% confidence interval {CI} = 1.60–3.80]) and female gender (OR = 1.48 vs. male [CI = 1.13–1.93]) were associated with high levels of thyroid cancer fear. Believing thyroid cancer (OR = 2.71 [CI = 1.99–3.69]) and cancer in general are serious (OR = 1.53 [CI = 1.13–2.08]) were also associated with high levels of thyroid cancer fear. Respondents who overestimated thyroid cancer incidence (OR = 1.64 [CI = 1.25–2.13]) and believed they had a high chance of developing cancer (OR = 1.70 [CI = 1.19–2.42]) were also more likely to have high fear of thyroid cancer. Conclusion: Thyroid cancer-specific fear is prevalent in U.S. adults particularly in females and those younger than 40 years. Because disease-specific fear is associated with overtreatment, targeted education about the seriousness, incidence, and risk factors for developing thyroid cancer may decrease public fear and possibly overtreatment related to "scared decision-making." [ABSTRACT FROM AUTHOR]

Macrophages are white blood cells that play disparate roles in homeostasis and immune responses. They can reprogram their phenotypes to pro-inflammatory (M1) or anti-inflammatory (M2) states in response to their environment. About 8–15% of the macrophage transcriptome has circadian oscillations, including genes closely related to their functioning. As circadian rhythms are associated with cellular phenotypes, we hypothesized that polarization of macrophages to opposing subtypes might differently affect their circadian rhythms. We tracked circadian rhythms in RAW 264.7 macrophages using luminescent reporters. Cells were stably transfected with Bmal1:luc and Per2:luc reporters, representing positive and negative components of the molecular clock. Strength of rhythmicity, periods and amplitudes of time series were assessed using multiple approaches. M1 polarization decreased amplitudes and rhythmicities of Bmal1:luc and Per2:luc , but did not significantly affect periods, while M2 polarization increased periods but caused no substantial alterations to amplitudes or rhythmicity. As macrophage phenotypes are also altered in the presence of cancer cells, we tested circadian effects of conditioned media from mouse breast cancer cells. Media from highly aggressive 4T1 cells caused loss of rhythmicity, while media from less aggressive EMT6 cells yielded no changes. As macrophages play roles in tumors, and oncogenic features are associated with circadian rhythms, we tested whether conditioned media from macrophages could alter circadian rhythms of cancer cells. Conditioned media from RAW 264.7 cells resulted in lower rhythmicities and periods, but higher amplitudes in human osteosarcoma, U2OS- Per2:luc cells. We show that phenotypic changes in macrophages result in altered circadian characteristics and suggest that there is an association between circadian rhythms and macrophage polarization state. Additionally, our data demonstrate that macrophages treated with breast cancer-conditioned media have circadian phenotypes similar to those of the M1 subtype, and cancer cells treated with macrophage-conditioned media have circadian alterations, providing insight to another level of cross-talk between macrophages and cancer. [ABSTRACT FROM AUTHOR]

Circadian rhythm disruption can elicit the development of various diseases, including breast cancer. While studies have used cell lines to study correlations between altered circadian rhythms and cancer, these models have different genetic backgrounds and do not mirror the changes that occur with disease development. Isogenic cell models can recapitulate changes across cancer progression. Hence, in this study, a patient-derived breast cancer model, the 21T series, was used to evaluate changes to circadian oscillations of core clock protein transcription as cells progress from normal to malignant states. Three cell lines were used: H16N2 (normal breast epithelium), 21PT (atypical ductal hyperplasia), and 21MT-1 (invasive metastatic carcinoma). The cancerous cells are both HER2+. We assessed the transcriptional profiles of two core clock proteins, BMAL1 and PER2, which represent a positive and negative component of the molecular oscillator. In the normal H16N2 cells, both genes possessed rhythmic mRNA oscillations with close to standard periods and phases. However, in the cancerous cells, consistent changes were observed: both genes had periods that deviated farther from normal and did not have an anti-phase relationship. In the future, mechanistic studies should be undertaken to determine the oncogenic changes responsible for the circadian alterations found. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Thyroid hormone is one of the most commonly prescribed medications in the United States. Misuse of and overtreatment with thyroid hormone is common in older adults and can lead to cardiovascular and skeletal adverse events. Even though deprescribing can reduce inappropriate care, no studies have yet explored specific barriers and facilitators to guide thyroid hormone deprescribing in older adults (defined as discontinuation of thyroid hormone when initiated without an appropriate indication or dose reduction in those overtreated).We conducted semi‐structured interviews with 19 endocrinologists, geriatricians, and primary care physicians who prescribe thyroid hormone. Interviews were completed between July 2020 and December 2021 via two‐way video conferencing. We used both an inductive and deductive content analysis guided by the Theoretical Domains Framework to evaluate transcribed and coded participant responses. Thematic analysis characterized themes related to barriers and facilitators to thyroid hormone deprescribing practices in older adults.The most commonly reported barriers to thyroid hormone deprescribing were related to patient‐level factors, followed by physician‐ and system‐level factors. Patient factors included patients' perceived need for thyroid hormone use and patient anxiety/concerns about potential side effects related to thyroid hormone dose reduction, patient lack of knowledge, and misinformation regarding deprescribing. Physician‐ and system‐level barriers included clinic visit time constraints, physician inertia, physician lack of knowledge about deprescribing, perceived lack of sufficient patient follow‐up, and electronic health record limitations. The most prominent physician‐reported facilitators to thyroid hormone deprescribing were effective physician‐to‐patient communication, and positive physician–patient relationship, including patients' trust in their treating physician.Barriers and facilitators to thyroid hormone deprescribing in older adults were reported at multiple levels including patient‐, physician‐, and system‐level factors. Interventions to improve thyroid hormone deprescribing in older adults should aim to improve patient education and expectations, increase multidisciplinary physician awareness, and overcome physician inertia. [ABSTRACT FROM AUTHOR]

Although the suprachiasmatic nucleus (SCN) has long been considered the master circadian clock in mammals, the topology of the connections that synchronize daily rhythms among SCN cells is not well understood. We combined experimental and computational methods to infer the directed interactions that mediate circadian synchrony between regions of the SCN. We analyzed PERIOD2 (PER2) expression from SCN slices during and after treatment with tetrodotoxin, allowing us to map connections as cells resynchronized their daily cycling following blockade and restoration of cell-cell communication. Using automated analyses, we found that cells in the dorsal SCN stabilized their periods slower than those in the ventral SCN. A phaseamplitude computational model of the SCN revealed that, to reproduce the experimental results: (1) the ventral SCN had to be more densely connected than the dorsal SCN and (2) the ventral SCN needed strong connections to the dorsal SCN. Taken together, these results provide direct evidence that the ventral SCN entrains the dorsal SCN in constant conditions. [ABSTRACT FROM AUTHOR]

The article presents a legal issue facing record labels today concerning termination of copyright transfers, as to whether sound recordings created under exclusive recording agreements on or after 1978 constitute works made for hire under the U.S. Copyright Act of 1976. The copyright law, termination of transfer and work for hire provisions, and authorship and ownership of copyright in sound recordings are explained. It notes that the courts are due to make a decision as early as 2013, and cites the impact it will have to record labels and artists.