Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells

Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner. Mechanistic investigations using phosphorylation-defective mutants revealed that KAP1 Ser473 phosphorylation limited mitochondrial hyperfusion in glucose-starved breast cancer cells, as driven by downregulation of the mitofusin protein MFN2, leading to reduced oxidative phosphorylation and ROS production. In clinical specimens of breast cancer, reduced expression of MFN2 corresponded to poor prognosis in patients. In a mouse xenograft model of human breast cancer, there was an association in the core region of tumors between MFN2 downregulation and the presence of highly fragmented mitochondria. Collectively, our results suggest that KAP1 Ser473 phosphorylation acts through MFN2 reduction to restrict mitochondrial hyperfusion, thereby contributing to cancer cell survival under conditions of sustained metabolic stress

Joint relationship between renal function and proteinuria on mortality of patients with type 2 diabetes: The Taichung Diabetes Study

Abstract Background Estimated glomerular filtration rate (eGFR) is a powerful predictor of mortality in diabetic patients with limited proteinuria data. In this study, we tested whether concomitant proteinuria increases the risk of mortality among patients with type 2 diabetes. Methods Participants included 6523 patients > 30 years with type 2 diabetes who were enrolled in a management program of a medical center before 2007. Renal function was assessed by eGFR according to the Modification of Diet in Renal Disease Study equation for Chinese. Proteinuria was assessed by urine dipstick. Results A total of 573 patients (8.8%) died over a median follow-up time of 4.91 years (ranging from 0.01 year to 6.42 years). The adjusted expanded cardiovascular disease (CVD)-related mortality rates among patients with proteinuria were more than three folds higher for those with an eGFR of 60 mL/min/1.73 m2 or less compared with those with an eGFR of 90 mL/min/1.73 m2 or greater [hazard ratio, HR, 3.15 (95% confidence interval, CI, 2.0–5.1)]. The magnitude of adjusted HR was smaller in patients without proteinuria [1.98 (95% CI, 1.1–3.7)]. An eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 significantly affected all-cause mortality and mortality from expanded CVD-related causes only in patients with proteinuria. Similarly, proteinuria affected all outcomes only in patients with an eGFR of <60 mL/min/1.73 m2. Conclusion The risks of all-cause mortality, as well as expanded and non-expanded mortality from CVD-related causes associated with proteinuria or an eGFR of 90 mL/min/1.73 m2 or greater are independently increased. Therefore, the use of proteinuria measurements with eGFR increases the precision of risk stratification for mortality.http://deepblue.lib.umich.edu/bitstream/2027.42/112804/1/12933_2012_Article_558.pd

Association of maternal levothyroxine use during pregnancy with offspring birth and neurodevelopmental outcomes: a population-based cohort study

BACKGROUND: The influence of maternal levothyroxine treatment during pregnancy remains unclear. This study aimed to evaluate the associations of maternal levothyroxine treatment during pregnancy with the birth and neurodevelopmental outcomes in offspring. METHODS: This population-based cohort study was conducted among pregnant women using the Hong Kong Clinical Data Analysis and Reporting System. Mother-child pairs in Hong Kong from 2001 to 2015 were included and children were followed up till 2020. We defined the exposure group as mothers who were exposed to levothyroxine during pregnancy. Preterm birth and small for gestational age (SGA) were included as birth outcomes. Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) were included as neurodevelopmental outcomes. Odds ratios (OR) or hazard ratios (HRs) with a 95% confidence interval (CI) were evaluated to assess the association of gestational levothyroxine use with offspring birth and neurodevelopmental outcomes respectively, using propensity score fine-stratification weighting and a Cox proportional hazards regression model. RESULTS: Among 422,156 mother-child pairs, 2125 children were born from mothers exposed to levothyroxine during pregnancy. A significantly increased risk of preterm birth was observed in children with maternal levothyroxine exposure during pregnancy, when compared to mothers who had no history of thyroid-related diagnoses or prescriptions (weighted OR [wOR]: 1.22, 95% CI: 1.07, 1.39). Similarly, an increased risk of preterm birth was found among children of gestational levothyroxine users, when compared to children of mothers who had used levothyroxine before but stopped during pregnancy (wOR: 2.16, 95% CI: 1.09, 4.25). Sensitivity analysis, by excluding mothers exposed to psychotropic or antiepileptic medications before or during pregnancy, also indicated a similar increased risk of preterm birth regarding the gestational use of levothyroxine (wOR: 1.26, 95% CI: 1.10, 1.45). No significant association was observed for the risk of SGA, ADHD, and ASD. CONCLUSIONS: There is no evidence that gestational use of levothyroxine is associated with SGA, ADHD, or ASD in offspring. Gestational levothyroxine treatment is associated with a higher risk of preterm birth. Such risk might be confounded by the underlying maternal thyroid disease itself, however, we cannot completely exclude the possible effect of gestational L-T4 treatment on offspring preterm birth. Our findings provided support to the current guidelines on the cautious use of levothyroxine treatment during pregnancy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02586-9

Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells

Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner. Mechanistic investigations using phosphorylation-defective mutants revealed that KAP1 Ser473 phosphorylation limited mitochondrial hyperfusion in glucose-starved breast cancer cells, as driven by downregulation of the mitofusin protein MFN2, leading to reduced oxidative phosphorylation and ROS production. In clinical specimens of breast cancer, reduced expression of MFN2 corresponded to poor prognosis in patients. In a mouse xenograft model of human breast cancer, there was an association in the core region of tumors between MFN2 downregulation and the presence of highly fragmented mitochondria. Collectively, our results suggest that KAP1 Ser473 phosphorylation acts through MFN2 reduction to restrict mitochondrial hyperfusion, thereby contributing to cancer cell survival under conditions of sustained metabolic stress

Efficacy of multidomain interventions to improve physical frailty, depression and cognition: data from cluster- randomized controlled trials

BackgroundFrailty is the pre- eminent exigency of aging. Although frailty- related impairments are preventable, and multidomain interventions appear more effective than unimodal ones, the optimal components remain uncertain.MethodsWe devised multidomain interventions against physical and cognitive decline among prefrail/frail community- dwelling - ¥65- year- olds and evaluated these in complementary cluster- randomized trials of efficacy and participant empowerment. The Efficacy Study compared ~3- monthly telephone consultations vs. 16, 2 h sessions/year comprising communally partaken physical and cognitive training plus nutrition and disease education; the Empowerment Study compared the standard Efficacy Study multidomain intervention (Sessions 1- 10) vs. an enhanced version redesigned to empower and motivate individual participants. Changes from baseline in physical, functional, and cognitive performance were measured after 6 and 12 months in the Efficacy Study and after 6 months in the Empowerment Study, with post- intervention follow- up at 9 months. Primary outcomes are as follows: Cardiovascular Health Study frailty score; gait speed; handgrip strength; and Montreal Cognitive Assessment (MoCA). Secondary outcomes are as follows: instrumental activities of daily living; metabolic equivalent of task (MET); depressed mood (Geriatric Depression Scale- 5 - ¥2); and malnutrition (Mini- Nutritional Assessment short- form - ¤11). Intervention effects were analyzed using a generalized linear mixed model.ResultsEfficacy Study participants (n = 1082, 40 clusters) were 75.1 ± 6.3 years old, 68.7% women, and 64.7% prefrail/frail; analytic clusters: 19 intervention (410/549 completed) vs. 21 control (375/533 completed). Empowerment Study participants (n = 440, 14 clusters) were 75.9 ± 7.1 years old, 83.6% women, and 56.7% prefrail/frail; analytic clusters: seven intervention (209/230 completed) vs. seven control (189/210 completed). The standard and enhanced multidomain interventions both reduced frailty and significantly improved aspects of physical, functional, and cognitive performance, especially among - ¥75- year- olds. Standard multidomain intervention decreased depression [odds ratio 0.56, 95% confidence interval (CI) 0.32, 0.99] and malnutrition (odds ratio 0.45, 95% CI 0.26, 0.78) by 12 months and improved concentration at Months 6 (0.23, 95% CI 0.04, 0.42) and 12 (0.46, 95% CI 0.22, 0.70). Participant empowerment augmented activity (4.67 MET/h, 95% CI 1.64, 7.69) and gait speed (0.06 m/s, 95% CI 0.00, 0.11) at 6 months, with sustained improvements in delayed recall (0.63, 95% CI 0.20, 1.06) and MoCA performance (1.29, 95% CI 0.54, 2.03), and less prevalent malnutrition (odds ratio 0.39, 95% CI 0.18, 0.84), 3 months after the intervention ceased.ConclusionsPragmatic multidomain intervention can diminish physical frailty, malnutrition, and depression and enhance cognitive performance among community- dwelling elders, especially - ¥75- year- olds; this might supplement healthy aging policies, probably more effectively if participants are empowered.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/156002/1/jcsm12534.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156002/2/10.1002_jcsm.12534_Fig_S4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156002/3/jcsm12534_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156002/4/10.1002_jcsm.12534_Fig_S2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156002/5/10.1002_jcsm.12534_Table_S3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156002/6/10.1002_jcsm.12534_Fig_S3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156002/7/10.1002_jcsm.12534_Appendix_S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156002/8/10.1002_jcsm.12534_Table_S2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156002/9/10.1002_jcsm.12534_Table_S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/156002/10/10.1002_jcsm.12534_Fig_S1.pd

Effects of and satisfaction with short message service reminders for patient medication adherence: a randomized controlled study

BACKGROUND: Medication adherence is critical for patient treatment. This study involved evaluating how implementing Short Message Service (SMS) reminders affected patient medication adherence and related factors. METHODS: We used a structured questionnaire to survey outpatients at three medical centers. Patients aged 20 years and older who were prescribed more than 7 days of a prescription medication were randomized into SMS intervention or control groups. The intervention group received daily messages reminding them of aspects regarding taking their medication; the control group received no messages. A phone follow-up was performed to assess outcomes after 8 days. Data were collected from 763 participants in the intervention group and 435 participants in the control group. RESULTS: After participants in the intervention group received SMS reminders to take medication or those in the control group received no messages, incidences of delayed doses were decreased by 46.4 and 78.8% for those in the control and intervention groups, respectively. The rate of missed doses was decreased by 90.1% for participants in the intervention group and 61.1% for those in the control group. We applied logistic regression analysis and determined that participants in the intervention group had a 3.2-fold higher probability of having a decrease in delayed doses compared with participants in the control group. Participants in the intervention group also showed a 2.2-fold higher probability of having a decrease in missed doses compared with participants in the control group. CONCLUSIONS: Use of SMS significantly affected the rates of taking medicine on schedule. Therefore, daily SMS could be useful for reminding patients to take their medicine on schedule

The core domain as the force sensor of the yeast mechanosensitive TRP channel

Stretch-activated conductances are commonly encountered in careful electric recordings. Those of known proteins (TRP, MscL, MscS, K2p, Kv, etc.) all share a core, which houses the ion pathway and the gate, but no recognizable force-sensing domain. Like animal TRPs, the yeast TRPY1 is polymodal, activated by stretch force, Ca2+, etc. To test whether its S5–S6 core senses the stretch force, we tried to uncouple it from the peripheral domains by strategic peptide insertions to block the covalent core–periphery interactions. Insertion of long unstructured peptides should distort, if not disrupt, protein structures that transmit force. Such insertions between S6 and the C-terminal tail largely removed Ca2+ activation, showing their effectiveness. However, such insertions as well as those between S5 and the N-terminal region, which includes S1–S4, did not significantly alter mechanosensitivity. Even insertions at both locations flanking the S5–S6 core did not much alter mechanosensitivity. Tryptophan scanning mutations in S5 were also constructed to perturb possible noncovalent core–periphery contacts. The testable tryptophan mutations also have little or no effects on mechanosensitivity. Boltzmann fits of the wild-type force–response curves agree with a structural homology model for a stretch-induced core expansion of ∼2 nm2 upon opening. We hypothesize that membrane tension pulls on S5–S6, expanding the core and opening the TRPY1 gate. The core being the major force sensor offers the simplest, though not the only, explanation of why so many channels of disparate designs are mechanically sensitive. Compared with the bacterial MscL, TRPY1 is much less sensitive to force, befitting a polymodal channel that relies on multiple stimuli