Cyclin‐dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in ...driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti‐HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self‐renewal of breast CSCs and in vivo tumor‐initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab‐resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB‐PI3K‐AKT or WNT‐signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti‐HER2 therapies.
Synopsis
CDK12, a RNA polymerase II kinase, promotes breast cancer stem cell‐like properties mediated by WNT and ErbB‐PI3K signaling. Targeting CDK12 improves trastuzumab therapy in breast cancers characterised by HER2/CDK12 co‐amplification.
CDK12 amplification induces tumor initiation and progression, and mediates trastuzumab resistance.
CDK12 is required for transcriptional upregulation of genes involved in ErbB‐PI3K and WNT pathway activation.
CDK12 inhibition alone or in combination with trastuzumab therapy has anti‐tumor activity against HER2+ breast cancers.
CDK12, a RNA polymerase II kinase, promotes breast cancer stem cell‐like properties mediated by WNT and ErbB‐PI3K signaling. Targeting CDK12 improves trastuzumab therapy in breast cancers characterised by HER2/CDK12 co‐amplification.
The histone H3K27 demethylase, UTX, is a known component of the H3K4 methyltransferase MLL complex, but its functional association with H3K4 methylation in human cancers remains largely unknown. Here ...we demonstrate that UTX loss induces epithelial–mesenchymal transition (EMT)‐mediated breast cancer stem cell (CSC) properties by increasing the expression of the SNAIL, ZEB1 and ZEB2 EMT transcription factors (EMT‐TFs) and of the transcriptional repressor CDH1. UTX facilitates the epigenetic silencing of EMT‐TFs by inducing competition between MLL4 and the H3K4 demethylase LSD1. EMT‐TF promoters are occupied by c‐Myc and MLL4, and UTX recognizes these proteins, interrupting their transcriptional activation function. UTX decreases H3K4me2 and H3 acetylation at these promoters by forming a transcriptional repressive complex with LSD1, HDAC1 and DNMT1. Taken together, our findings indicate that UTX is a prominent tumour suppressor that functions as a negative regulator of EMT‐induced CSC‐like properties by epigenetically repressing EMT‐TFs.
Synopsis
UTX, a histone H3K27 demethylase, epigenetically silences EMT genes by facilitating LSD1‐dependent H3K4 demethylation and HDAC‐dependent histone deacetylation to inhibit EMT‐induced breast CSC properties.
UTX suppresses EMT and CSC properties in breast cancer.
UTX cooperates with LSD1 and HDAC1 to form a transcriptional repressive complex on EMT‐TF promoters.
UTX, a histone H3K27 demethylase, epigenetically silences EMT genes by facilitating LSD1‐dependent H3K4 demethylation and HDAC‐dependent histone deacetylation to inhibit EMT‐induced breast CSC properties.
Alzheimer's disease (AD) is accompanied by neural cell loss and memory deficit. Neural cell death, occurring via apoptosis and autophagy, is widely observed in the AD brain in addition to ...neuroinflammation mediated by necroptosis and the NLRP3 inflammasome. Neurotoxicity induced by amyloid-beta (Aβ) and tau aggregates leads to excessive neural cell death and neuroinflammation in the AD brain. During AD progression, uncontrolled neural cell death results in the dysregulation of cellular activity and synaptic function. Apoptosis mediated by pro-apoptotic caspases, autophagy regulated by autophagy-related proteins, and necroptosis controlled by the RIPK/MLKL axis are representative of neural cell death occurred during AD. Necroptosis causes the release of cellular components, contributing to the pro-inflammatory environment in the AD brain. Inordinately high levels of neural cell death and pro-inflammatory events lead to the production of pro-inflammatory cytokines and feed-forward hyper neuroinflammation. Thus, neural cell death and neuroinflammation cause synaptic dysfunction and memory deficits in the AD brain. In this review, we briefly introduce the mechanisms of neural cell death and neuroinflammation observed in the AD brain. Combined with a typical strategy for targeting Aβ and tau, regulation of neural cell death and neuroinflammation may be effective for the amelioration of AD pathologies.
In the present study, equiatomic CoCrFeMnNi high entropy alloy (HEA) was subjected to thickness reductions of 20, 40, and 60% during cold rolling in order to thoroughly investigate the evolutions of ...both the microstructure and the deformation texture. Important aspects of deformed microstructures such as the activation of multiple twin variants and the formation of shear bands in the matrix were captured using electron backscatter diffraction (EBSD) and electron channeling contrast imaging (ECCI) techniques. Twin trace analysis (TTA) was performed in conjunction with resolved shear stress (RSS) analysis for the identification of active twin variants. The RSS ratio, which is a ratio of the maximum RSS values for corresponding twin and slip systems, was used to reveal the orientation dependence of deformation twinning. Visco-plastic self-consistent (VPSC) simulations were carried out to predict the evolution of the crystallographic texture, the transition routes of ideal orientations subjected to multiple deformation twinning, and the role that deformation modes play in the rotation of orientation. Experimental and simulation results substantiated the key finding of the deformation twinning of a Brass orientation, which established new perspectives concerning the evolution of microstructure and texture. One twin variant of the Copper orientation was moved to a Goss orientation by dislocation slip while the other two variants were rotated towards Brass and S orientations. Meanwhile, twin variants of the S and Brass orientations primarily transitioned to a Brass orientation. The Goss orientation showed great resistance to the twinning mode. Furthermore, dislocation slip and the formation of shear bands contributed to the evolution of a strong texture while deformation twinning had the opposite effect.
•The evolutions of both the microstructure and the deformation texture in HEA cold rolled up to 60% reduction in thickness were investigated.•RSS analysis was used with experimentally observed twin traces for the identification of active twin variants.•A preliminary analysis using the RSS ratio (max(RSSTwin)/max(RSSSlip)) predicted both the favorable (Copper and S) and unfavorable orientations (Brass and Goss) for twinning.•Twinning of the Brass orientation was found to delay the shifting of Copper-type texture to Brass-type texture leading to a stronger Goss component at 60% rolling reduction.•VPSC simulations predicted the twinning of the Brass orientation and role of multiple twin variants in the texture transitions.
Since a potential link between statins and the risk of adverse chronic periodontitis (CP) has been raised, we aimed to validate the association between statin use and the incidence of CP using ...nationwide cohort data. This longitudinal follow-up study included 169,381 patients prescribed statins who were matched with an equal number of controls using propensity scores from the Korean National Health Insurance Service-Health Screening Cohort database (2002-2015). A Cox proportional hazard model was used to assess the occurrence of CP following statin use after adjusting for multiple covariates. The occurrence of CP was significantly higher in patients who had long-term use (1-3 years, 3-5 years, or > 5 years) than with short-term use (≤ 1 year) of statins. After adjustment, statin users exhibited an occurrence of CP 1.32-fold higher (95% confidence interval 1.30-1.33) than that of the matched nonusers (incidence: 25.0 and 22.0 per 100 person-years, respectively). Subgroup analyses supported the adverse impact of statins on CP independent of age and gender. Statin user odds ratios for developing CP were higher compared to those of nonusers. This was consistent in individuals aged > 40 years in both genders, especially with long-term use.
Irisin is a newly identified myokine related to exercise and the browning of white fat. Recently, it was reported that irisin serum levels are associated with intrahepatic triglyceride content, ...suggesting that it might have an important role in the liver. The aim of this study was to determine the role of irisin in hepatocytes. Specifically, the effect of recombinant irisin on palmitic acid (PA)-induced lipogenesis and its related signal pathways were examined in AML12 cells and mouse primary hepatocytes. In the present study, we observed the presence of irisin inside the cells in response to the treatment of recombinant irisin by flow cytometry and cell imaging technique. Recombinant irisin significantly inhibited the PA-induced increase in lipogenic markers ACC and FAS at the mRNA and protein levels, and prevented the PA-induced lipid accumulation in hepatocytes. Additionally, irisin inhibited the PA-induced increase in the expression, nuclear localization, and transcriptional activities of the master regulators of lipogenesis (LXRα and SREBP-1c). Moreover, irisin attenuated PA-induced oxidative stress, which was confirmed by measuring the expression of inflammatory markers (NFκB, COX-2, p38 MAPK, TNF, IL-6) and superoxide indicator (dihydroethidium). The preventive effects of irisin against lipogenesis and oxidative stress were mediated by the inhibition of protein arginine methyltransferase-3 (PRMT3). These findings suggested that irisin might have a beneficial role in the prevention of hepatic steatosis by altering the expression of lipogenic genes and attenuating oxidative stress in a PRMT3 dependent manner.
•The anti-lipogenic role of irisin in palmitic acid-induced steatotic hepatocytes•Palmitic acid-induced oxidative stress lowering effect of irisin•The preventive roles of irisin are dependent on PRMT3.
Background
In tuberculosis (TB) treatment, adverse drug reactions (ADRs) can interrupt treatment and decrease the quality of life (QoL). We aimed to prospectively investigate the incidence of ADRs to ...first‐line anti‐TB drugs and related outcomes and QoL.
Methods
Adult patients with TB who had been treated with first‐line anti‐TB drugs in five Korean hospitals were enrolled. ADR questionnaire surveys and blood tests were performed four times serially, and QoL was assessed on the fourth TB treatment week (±2 weeks).
Results
Of 410 enrolled patients with TB (males, 62%; mean age, 52.1 ± 18.1 years those aged ≥65 years, 26.6%), 67.8% experienced any ADRs (≥ grade 2) to TB drugs. The most common ADR was fatigue (53.2%), followed by itching (42.7%) and anorexia (41.7%). Older adult patients experienced relatively more ADRs, including anorexia, dyspepsia, rash, dizziness, anemia, abnormal hepatic/renal function tests, and increased uric acid levels (p < 0.05). Treatment regimens changed for 9.5% of patients owing to ADRs to anti‐TB drugs. Patients with any ADRs and older adult patients had significantly lower QoL than their counterparts (p < 0.05). Old age (odds ratio OR, 1.02) and being male (OR 2.65) were independently associated with ADRs, whereas active smoking (OR 4.73) and a relatively long treatment phase (OR 5.13) were independently associated with hepatotoxicity.
Conclusion
ADRs to first‐line anti‐TB drugs were common and related to relatively low QoL, especially among older adults. Although 9.5% of patients had ADR‐related regimen changes, most patients with ADRs completed treatments successfully.
This study tested the effectiveness of moxibustion on pain and function in chronic knee osteoarthritis (KOA) and evaluated safety.
A multi-centre, non-blinded, parallel-group, randomised controlled ...trial compared moxibustion with usual care (UC) in KOA. 212 South Korean patients aged 40-70 were recruited from 2011-12, stratified by mild (Kellgren/Lawrence scale grades 0/1) and moderate-severe KOA (grades 2/3/4), and randomly allocated to moxibustion or UC for four weeks. Moxibustion involved burning mugwort devices over acupuncture and Ashi points in affected knee(s). UC was allowed. Korean Western Ontario and McMaster Universities Questionnaire (K-WOMAC), Short Form 36 Health Survey (SF-36v2), Beck Depression Inventory (BDI), physical performance test, pain numeric rating scale (NRS) and adverse events were evaluated at 5 and 13 weeks. K-WOMAC global score at 5 weeks was the primary outcome.
102 patients (73 mild, 29 moderate-severe) were allocated to moxibustion, 110 (77 mild, 33 moderate-severe) to UC. K-WOMAC global score (moxibustion 25.42+/-SD 19.26, UC 33.60+/-17.91, p<0.01, effect size = 0.0477), NRS (moxibustion 44.77+/-22.73, UC 56.23+/-17.71, p<0.01, effect size = 0.0073) and timed-stand test (moxibustion 24.79+/-9.76, UC 25.24+/-8.84, p = 0.0486, effect size = 0.0021) were improved by moxibustion at 5 weeks. The primary outcome improved for mild but not moderate-severe KOA. At 13 weeks, moxibustion significantly improved the K-WOMAC global score and NRS. Moxibustion improved SF-36 physical component summary (p = 0.0299), bodily pain (p = 0.0003), physical functioning (p = 0.0025) and social functioning (p = 0.0418) at 5 weeks, with no difference in mental component summary at 5 and 13 weeks. BDI showed no difference (p = 0.34) at 5 weeks. After 1158 moxibustion treatments, 121 adverse events included first (n = 6) and second degree (n = 113) burns, pruritus and fatigue (n = 2).
Moxibustion may improve pain, function and quality of life in KOA patients, but adverse events are common. Limitations included no sham control or blinding.
Clinical Research Information Service (CRIS) KCT0000130.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by severe brain damage and dementia. There are currently few therapeutics to treat this disease, and they can only temporarily ...alleviate some of the symptoms. The pathogenesis of AD is mainly preceded by accumulation of abnormal amyloid beta (Aβ) aggregates, which are toxic to neurons. Therefore, modulation of the formation of these abnormal aggregates is strongly suggested as the most effective approach to treat AD. In particular, numerous studies on natural products associated with AD, aiming to downregulate Aβ peptides and suppress the formation of abnormal Aβ aggregates, thus reducing neural cell death, are being conducted. Generation of Aβ peptides can be prevented by targeting the secretases involved in Aβ-peptide formation (secretase-dependent). Additionally, blocking the intra- and intermolecular interactions of Aβ peptides can induce conformational changes in abnormal Aβ aggregates, whereby the toxicity can be ameliorated (structure-dependent). In this review, AD-associated natural products which can reduce the accumulation of Aβ peptides via secretase- or structure-dependent pathways, and the current clinical trial states of these products are discussed.
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