Frailty predicts knee pain trajectory over 9 years: results from the Osteoarthritis Initiative.

OBJECTIVE: Frailty is a multisystem syndrome and its relationship with symptomatic osteoarthritis has been reported. We aimed to identify trajectories of knee pain in a large prospective cohort and to describe the effect of frailty status at baseline on the pain trajectories over 9 years. METHODS: We included 4419 participants (mean age 61.3 years, 58% female) from the Osteoarthritis Initiative cohort. Participants were classified as "no frailty," "pre-frailty," or "frailty" at baseline, based on 5 characteristics (ie, unintentional weight loss, exhaustion, weak energy, slow gait speed, and low physical activity). Knee pain was evaluated annually using the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale (0-20) from baseline to 9 years. RESULTS: Of the participants included, 38.4%, 55.4%, and 6.3% were classified as "no frailty," "pre-frailty," and "frailty," respectively. Five pain trajectories were identified: "No pain" (n = 1010, 22.8%), "Mild pain" (n = 1656, 37.3%), "Moderate pain" (n = 1149, 26.0%), "Severe pain" (n = 477, 10.9%), and "Very Severe pain" (n = 127, 3.0%). Compared to participants with no frailty, those with pre-frailty and frailty were more likely to have more severe pain trajectories (pre-frailty: odds ratios [ORs] 1.5 to 2.1; frailty: ORs 1.5 to 5.0), after adjusting for potential confounders. Further analyses indicated that the associations between frailty and pain were mainly driven by exhaustion, slow gait speed, and weak energy. CONCLUSIONS: Approximately two-thirds of middle-aged and older adults were frail or pre-frail. The role of frailty in predicting pain trajectories suggests that frailty may be an important treatment target for knee pain.

Human embryonic stem cell-derived organoid retinoblastoma reveals a cancerous origin.

Retinoblastoma (Rb) is the most prevalent intraocular malignancy in children, with a worldwide survival rate <30%. We have developed a cancerous model of Rb in retinal organoids derived from genetically engineered human embryonic stem cells (hESCs) with a biallelic mutagenesis of the RB1 gene. These organoid Rbs exhibit properties highly consistent with Rb tumorigenesis, transcriptome, and genome-wide methylation. Single-cell sequencing analysis suggests that Rb originated from ARR3-positive maturing cone precursors during development, which was further validated by immunostaining. Notably, we found that the PI3K-Akt pathway was aberrantly deregulated and its activator spleen tyrosine kinase (SYK) was significantly up-regulated. In addition, SYK inhibitors led to remarkable cell apoptosis in cancerous organoids. In conclusion, we have established an organoid Rb model derived from genetically engineered hESCs in a dish that has enabled us to trace the cell of origin and to test novel candidate therapeutic agents for human Rb, shedding light on the development and therapeutics of other malignancies.

Integrative comparison of the genomic and transcriptomic landscape between prostate cancer patients of predominantly African or European genetic ancestry.

Men of predominantly African Ancestry (AA) have higher prostate cancer (CaP) incidence and worse survival than men of predominantly European Ancestry (EA). While socioeconomic factors drive this disparity, genomic factors may also contribute to differences in the incidence and mortality rates. To compare the prevalence of prostate tumor genomic alterations and transcriptomic profiles by patient genetic ancestry, we evaluated genomic profiles from The Cancer Genome Atlas (TCGA) CaP cohort (n = 498). Patient global and local genetic ancestry were estimated by computational algorithms using genotyping data; 414 (83.1%) were EA, 61 (12.2%) were AA, 11 (2.2%) were East Asian Ancestry (EAA), 10 (2.0%) were Native American (NA), and 2 (0.4%) were other ancestry. Genetic ancestry was highly concordant with self-identified race/ethnicity. Subsequent analyses were limited to 61 AA and 414 EA cases. Significant differences were observed by ancestry in the frequency of SPOP mutations (20.3% AA vs. 10.0% EA; p = 5.6×10-03), TMPRSS2-ERG fusions (29.3% AA vs. 39.6% EA; p = 4.4×10-02), and PTEN deletions/losses (11.5% AA vs. 30.2% EA; p = 3.5×10-03). Differentially expressed genes (DEGs) between AAs and EAs showed significant enrichment for prostate eQTL target genes (p = 8.09×10-48). Enrichment of highly expressed DEGs for immune-related pathways was observed in AAs, and for PTEN/PI3K signaling in EAs. Nearly one-third of DEGs (31.3%) were long non-coding RNAs (DE-lncRNAs). The proportion of DE-lncRNAs with higher expression in AAs greatly exceeded that with lower expression in AAs (p = 1.2×10-125). Both ChIP-seq and RNA-seq data suggested a stronger regulatory role for AR signaling pathways in DE-lncRNAs vs. non-DE-lncRNAs. CaP-related oncogenic lncRNAs, such as PVT1, PCAT1 and PCAT10/CTBP1-AS, were found to be more highly expressed in AAs. We report substantial heterogeneity in the prostate tumor genome and transcriptome between EA and AA. These differences may be biological contributors to racial disparities in CaP incidence and outcomes.

PIAS3 suppresses damage in an Alzheimer's disease cell model by inducing the STAT3-associated STAT3/Nestin/Nrf2/HO-1 pathway.

BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, is caused by the degeneration of the central nervous system (CNS). A previous study reported that signal transducer and activator of transcription 3 (STAT3) is activated during AD development; nonetheless, the related mechanism remains unknown. Thus, this study used a cell model to explore whether and how the protein inhibitor of activated STAT3 (PIAS3) is involved in AD development. METHODS: Cerebrospinal fluid (CSF) specimens of 30 patients with AD and 10 normal participants were included in this study. SH-SY5Y cells were used to constructed AD model. Relevant indices were then detected and analyzed. RESULTS: The results showed that compared with the control group, PIAS3 expression was substantially decreased in patients with AD and amyloid beta (Aß)-treated SH-SY5Y cells. PIAS3 overexpression was able to reverse the detrimental effects of Aß treatment on cell survival and growth. Further, it could also ameliorate apoptosis and oxidative stress in Aß-treated SH-SY5Y cells. Additionally, PIAS3 was shown to reduce the activated form of STAT3 and increase the activity of the downstream Nestin/nuclear factor erythroid 2-related factor/heme oxygenase-1 pathway. CONCLUSIONS: STAT3 reactivation by colivelin treatment negated the influence of PIAS3 on the survival, growth, apoptosis, and oxidative stress of Aß-treated SH-SY5Y cells.

Effects of Prenatal Methamphetamine Exposure on Birth Outcomes, Brain Structure, and Neurodevelopmental Outcomes.

This study reviews the findings from previous research on the effects of prenatal methamphetamine (MA) exposure on birth outcomes, brain structure, and neurodevelopmental outcomes of the offspring. These findings indicate that prenatal MA exposure may lead to shorter gestational age, lower birth weight, lower head circumference, and shorter body length of neonatal, structural brain changes, and impairment in cognitive development, motor development, inhibitory control, and attention of children from 1 to 15 years. Based on these findings of the previous cohort studies on the effect of prenatal MA exposure on the birth outcomes and childhood outcomes of the offspring, we conclude by discussing the shortcomings and inconsistencies of previous studies in each section. A multicenter, large-scale population-based prospective cohort study is needed to establish and seek the differences and similarities of the pathological changes in different systems among offspring prenatally exposed to MA in different periods. And the pathophysiology mechanism underlying these changes should be studied by the method of omics technology in future. These efforts are of great significance to address the adverse health outcomes caused by prenatal MA exposure.

Supportive care needs and service use during palliative care in family caregivers of patients with advanced cancer: a prospective longitudinal study.

PURPOSE: This study aimed to investigate the supportive care needs of family caregivers (FCs) of advanced cancer patients and their support service use at the beginning of specialist inpatient palliative care (SIPC), near the patient's death, and during bereavement. METHODS: FCs reported their needs using the Family Inventory of Needs (FIN), along with their utilization of psychosocial and bereavement support services at the beginning (N = 232) and 6-9 months after SIPC (N = 160). RESULTS: At the beginning of SIPC, mean of 16.9 of 20 needs were reported to be highly important, and 12.2 were reported to be met. At the time of the patient's death, 16.8 needs were highly important, and 13.8 were met. At both time points, the highest ranked need was related to information about changes in the patient's condition (100% vs. 99%), and the most frequently unmet need was related to feeling hope (73% vs. 71%). Multivariate linear regression analysis revealed a low education level to be consistently related to a greater number of highly important needs. Higher satisfaction with care and better social support was related to a greater number of met needs. Twenty-five percent of FCs had accessed at least one psychosocial support service prior to SIPC, and 30% had done so during bereavement. Among non-users of support services, > 75% indicated sufficient informal support as a barrier to service use. CONCLUSIONS: The findings offer a useful guide for adequately addressing FCs' needs in an effort to optimize FC support. However, only a subgroup of the FCs used support services. Better information and provision of tailored services might improve FCs' situations in the future.

RNA-sequencing-based transcriptome analysis of cantharidin-induced myocardial injury.

The cardiotoxicity of cantharidin has been well characterized, but the understanding of the underlying mechanism(s) is incomplete. To more fully understand the differentially expressed genes (DEGs) in cantharidin-induced myocardial injury, Sprague-Dawley rats were exposed to cantharidin (1.34 mg/kg or 2.67 mg/kg) for 24 h and then the heart was sampled for pathologic changes analysis and RNA-sequencing-based transcriptomic profiling. In addition, serum troponin T (TN-T) levels were also tested using the enzyme-linked immunosorbent assay method. The results showed that cantharidin could cause myocardial damage and elevated serum TN-T levels. The genes with a fold change ≥2 were considered as DEGs and we found 38 DEGs that were mainly enriched in eight pathways revealed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The cellular component of gene ontology analysis showed that the DEGs were mostly enriched in the extracellular matrix. In conclusion, our present study demonstrated that cantharidin induces myocardial injury by multiple modulatory mechanisms, which provide new insights for further study of the pathophysiologic mechanism of cantharidin-induced myocardial injury.

Cantharidin-induced acute hepatotoxicity: the role of TNF-α, IKK-α, Bcl-2, Bax and caspase3.

Cantharidin is of high medicinal value but has strong toxicity. Nowadays, multiple research has focused on the mechanism of its antitumor activity while research on toxicological profiles associated with cantharidin poisoning is still limited. Its hepatotoxicity has attracted attention recently for the crucial role of the liver in detoxification. Here, we aim to find a potential mechanism for cantharidin-induced acute hepatotoxicity with a view to assisting subsequent research or clinical use or detoxification. Twenty-one male Sprague-Dawley rats were randomly divided into control, low-dose (1.34 mg/kg) and high-dose (2.67 mg/kg) cantharidin exposure groups. We used hematoxylin-eosin to observe pathological changes and used immunofluorescent staining, western blotting and real-time quantitative polymerase chain reaction to detect the expression of the markers. The main pathological changes in livers of cantharidin-treated rats were necrosis, inflammatory infiltration and hemorrhage. We found coexpression of tumor necrosis factor alpha (TNF-α), IkappaB kinase-alpha (IKK-α) and caspase3 by immunofluorescent staining in livers of cantharidin-treated rats. Compared with the control, the levels of TNF-α, IKK-α and caspase3 increased significantly in the experimental groups (P < .05). The ratio of B-cell lymphoma-2 (Bcl-2)/Bax increased in the low-dose group but decreased in the high-dose group (P < .05). Cantharidin exposure raised IKK-α mRNA and caspase3 mRNA levels (P < .05). In conclusion, the participation of TNF-α, IKK-α, Bcl-2, Bax and caspase3 uncovered a novel mechanism underlying cantharidin-induced acute hepatotoxicity, and the mechanism needs to be studied further.

Psychological burden in family caregivers of patients with advanced cancer at initiation of specialist inpatient palliative care.

BACKGROUND: This study prospectively evaluated distress, depressive and anxiety symptoms as well as associated factors in family caregivers (FC) of advanced cancer patients at initiation of specialist inpatient palliative care. METHODS: Within 72 h after the patient's first admission, FCs were asked to complete German versions of the Distress Thermometer, Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire depression module 9-item scale (PHQ-9) for outcome measure. Multivariate logistic regression analyses were used to identify associated factors. RESULTS: In 232 FCs (62% spouses/partners), mean level of distress was 7.9 (SD 1.8; range, 2-10) with 95% presenting clinically relevant distress levels. Most frequent problems were sadness (91%), sorrows (90%), anxiety (78%), exhaustion (77%) and sleep disturbances (73%). Prevalence rates of moderate to severe anxiety and depressive symptoms were 47 and 39%, respectively. Only 25% of FCs had used at least one source of support previously. In multivariate regression analysis, being female (OR 2.525), spouse/partner (OR 2.714), exhaustion (OR 10.267), and worse palliative care outcome ratings (OR 1.084) increased the likelihood for moderate to severe anxiety symptom levels. Being female (OR 3.302), low socio-economic status (OR 6.772), prior patient care other than home-based care (OR 0.399), exhaustion (OR 3.068), sleep disturbances (OR 4.183), and worse palliative care outcome ratings (OR 1.100) were associated with moderate to severe depressive symptom levels. CONCLUSIONS: FCs of patients presenting with indication for specialist palliative care suffer from high distress and relevant depressive and anxiety symptoms, indicating the high need of psychological support not only for patients, but also their FCs. Several socio-demographic and care-related risk-factors influence mental burden of FCs and should be in professional caregivers' focus in daily clinical practice.

Cantharides poisoning: A retrospective analysis from 1996 to 2016 in China.

Cantharides poisoning may cause serious adverse reactions or even death.We attempt to retrieval articles automatically and manually with the key words of "cantharides" and " poisoning " or " side effects ", then summarized and analyzed the cases of cantharides poisoning from 1996 to 2016 in China, to provide some reference for clinical drug use and forensic identification. Finally, 91 cases were conformance to require; general data, clinical data, prognosis, autopsy results were analyzed.We found that the health education of cantharides in primary doctors and people is lackable, the case fatality rate was 18.68% . The death patients of cantharides poisoning had cardiomyocyte necrosis and neuronal apoptosis in the histopathological examination of autopsy , but the toxicological mechanism was unclear. There may be redistribution of cantharidin in vivo after death. Collectively, we hope that an anthropological database for cantharides poisoning established by multicenter cooperation, include medical institutions and forensic identified centers, and conduct more further studies on its cardiotoxicity and neurotoxicity.

BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis.

Expression of bone morphogenetic protein 4 (BMP4) in adipocytes of white adipose tissue (WAT) produces "white adipocytes" with characteristics of brown fat and leads to a reduction of adiposity and its metabolic complications. Although BMP4 is known to induce commitment of pluripotent stem cells to the adipocyte lineage by producing cells that possess the characteristics of preadipocytes, its effects on the mature white adipocyte phenotype and function were unknown. Forced expression of a BMP4 transgene in white adipocytes of mice gives rise to reduced WAT mass and white adipocyte size along with an increased number of a white adipocyte cell types with brown adipocyte characteristics comparable to those of beige or brite adipocytes. These changes correlate closely with increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. Conversely, BMP4-deficient mice exhibit enlarged white adipocyte morphology and impaired insulin sensitivity. We identify peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as the target of BMP signaling required for these brown fat-like changes in WAT. This effect of BMP4 on WAT appears to extend to human adipose tissue, because the level of expression of BMP4 in WAT correlates inversely with body mass index. These findings provide a genetic and metabolic basis for BMP4's role in altering insulin sensitivity by affecting WAT development.

Proteome profiling of mitotic clonal expansion during 3T3-L1 adipocyte differentiation using iTRAQ-2DLC-MS/MS.

Mitotic clonal expansion (MCE) is one of the important events taking place at the early stage during 3T3-L1 adipocyte differentiation. To investigate the mechanism underlying this process, we carried out a temporal proteomic analysis to profile the dynamic changes in MCE. Using 8-plex-iTRAQ-2DLC-MS/MS analysis, 3152 proteins were quantified during the initial 28 h of 3T3-L1 adipogenesis. Functional analysis was performed on 595 proteins with maximum or minimum quantities at 20 h of adipogenic induction that were potentially involved in MCE, which identified PI3K/AKT/mTOR as the most relevant pathway. Among the 595 proteins, PKM2 (Pyruvate kinase M2), a patterned protein identified as a potential target gene of C/EBPß in our previous work, was selected for further investigation. Network analysis suggested positive correlations among C/EBPß, PIN1, and PKM2, which may be related with the PI3K-AKT pathway. Knockdown of PKM2 with siRNA inhibited both MCE and adipocyte differentiation of 3T3-L1 cells. Moreover, PKM2 was down-regulated at both the mRNA level and the protein level upon the knockdown of C/EBPß. And overexpressed PKM2 can partially restore MCE, although it did not restore terminal adipocyte differentiation, which was inhibited by siC/EBPß. Thus, PKM2, potentially regulated by C/EBPß, is involved in MCE during adipocyte differentiation. The dynamic proteome changes quantified here provide a promising basis for revealing molecular mechanism regulating adipogenesis.

MicroRNA-140 promotes adipocyte lineage commitment of C3H10T1/2 pluripotent stem cells via targeting osteopetrosis-associated transmembrane protein 1.

BMP4 has been shown to induce C3H10T1/2 pluripotent stem cells to commit to adipocyte lineage. In addition to several proteins identified, microRNAs also play a critical role in the process. In this study, we identified microRNA-140 (miR-140) as a direct downstream component of the BMP4 signaling pathway during the commitment of C3H10T1/2 cells to adipocyte lineage. Overexpression of miR-140 in C3H10T1/2 cells promoted commitment, whereas knockdown of its expression led to impairment. Additional studies indicated that Ostm1 is a bona fide target of miR-140, which is significantly decreased during commitment, and Ostm1 was also demonstrated to function as an anti-adipogenic factor.

Serum ferritin is associated with the presence of ischemic stroke among individuals with type 2 diabetes.

Background: Epidemiological evidence regarding the possible link between serum ferritin (SF) level and ischemic stroke risk among individuals with type 2 diabetes mellitus (T2DM) is sparse. Aim: To evaluate the association between SF level in plasma and ischemic stroke risk among individuals with T2DM. Methods: SF levels were measured in 210 T2DM patients with (n = 165) or without ischemic stroke (n = 45). Multivariate logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: The SF level of T2DM patients with ischemic stroke was significantly higher than that of patients without ischemic stroke (P = 0.003). The multivariate logistic regression analyses revealed that each 1-SD increase in SF (OR: 1.92; 95%CI: 1.22, 3.03) was significantly associated with increased ischemic stroke risk among T2DM patients. In addition, interaction effect of SF and BMI on ischemic stroke risk were also observed (Pfor interaction = 0.037). Conclusions: Higher levels of SF were independently associated with increased risk of ischemic stroke among individuals with T2DM.

Molecular biomarkers of diffuse axonal injury: recent advances and future perspectives.

INTRODUCTION: Diffuse axonal injury (DAI), with high mortality and morbidity both in children and adults, is one of the most severe pathological consequences of traumatic brain injury. Currently, clinical diagnosis, disease assessment, disability identification, and postmortem diagnosis of DAI is mainly limited by the absent of specific molecular biomarkers. AREAS COVERED: In this review, we first introduce the pathophysiology of DAI, summarized the reported biomarkers in previous animal and human studies, and then the molecular biomarkers such as ß-Amyloid precursor protein, neurofilaments, S-100ß, myelin basic protein, tau protein, neuron-specific enolase, Peripherin and Hemopexin for DAI diagnosis is summarized. Finally, we put forward valuable views on the future research direction of diagnostic biomarkers of DAI. EXPERT OPINION: In recent years, the advanced technology has ultimately changed the research of DAI, and the numbers of potential molecular biomarkers was introduced in related studies. We summarized the latest updated information in such studies to provide references for future research and explore the potential pathophysiological mechanism on diffuse axonal injury.

New approach for near-infrared wavelength selection using a combination of MIC and firefly evolution.

Full-length spectral data analysis has a big problem that the variables are highly in collinearity and correlation. Spectral wavelength selection is a continuing hot topic in quantitative or qualitative analysis. In this paper, we propose a new approach for near-infrared (NIR) wavelength selection. The novel strategy mainly refers to the modification of maximum information coefficient (MIC) method and an improvement of firefly evolutionary algorithm. We introduce the orthogonal decomposition to modify the MIC method, so as to search the informative signals conceived in projection vectors. We also raise the common firefly algorithm (FA) as in the discretized mode, and design a novel adaptive mapping function to improve its intelligent computing effect. In experiment, the modified MIC (MICm) method and the adaptive discrete FA algorithm (DFAadp) are joint together for combined optimization of the NIR calibration model. The proposed combined modeling strategy is applied for quantitative analysis of the fishmeal samples, in the concern to select their informative variables/wavelengths. Experimental results indicate that the combination of MICm and DFAadp perform better than traditional MIC method and common DFA. We conclude that the proposed combined optimization strategy is beneficial for wavelength selection in NIR spectral analysis. It is anticipated to be validated for further applications in a wide range.

Association of handgrip strength asymmetry and weakness with cognitive function: a nationally representative cohort study.

OBJECTIVE: To describe the association of handgrip strength asymmetry and weakness with cognitive function among Chinese middle-aged and older adults. STUDY DESIGN: We used data from four waves (2011, 2013, 2015, and 2018) of the China Health and Retirement Longitudinal Study. Handgrip strength was measured at baseline. Handgrip strength asymmetry was defined on the basis of the ratio of handgrip strength of the non-dominant hand to that of the dominant hand (i.e. non-dominant/dominant): a ratio of <0.9 defined as dominant handgrip strength asymmetry and >1.1 as non-dominant handgrip strength asymmetry. Weakness was defined as a handgrip strength of <28 kg for males or <18 kg for females. MAIN OUTCOME MEASURES: Cognitive function with its two core dimensions (episodic memory and mental status) at each wave was assessed and standardized. RESULTS: 9333 participants (48.3 % female, age 58.2 ± 9.0 years) were included. Non-dominant but not dominant handgrip strength asymmetry was significantly associated with poorer cognitive function at baseline (ß = -0.121, -0.092, and -0.132 for mental status, episodic memory, and global cognition, respectively). In longitudinal analyses over 2 years, dominant handgrip strength asymmetry significantly slowed cognitive decline (ß = -0.078 and -0.069 for mental status and global cognition, respectively), and non-dominant handgrip strength asymmetry accelerated cognitive decline (ß = 0.053 and 0.043 for episodic memory and global cognition, respectively). Weakness was associated with poorer cognitive function at baseline and cognitive decline over 2, 4, and 7 years (all P < 0.05). CONCLUSIONS: In middle-aged and older adults, non-dominant handgrip strength asymmetry and weakness were associated with poorer cognitive function and predicted accelerated cognitive decline. Dominant handgrip strength asymmetry may be beneficial for maintaining cognitive function.

Research on the dynamic tensile characteristics and surface crack evolution of coal under impact loading.

The tensile properties of coal under dynamic loading are important mechanical characteristics of coal and are highly important for controlling coal rock stability under impact loading conditions, selecting blasting engineering parameters, and studying the mechanism of rockburst disasters. To investigate the dynamic tensile failure process of coal subjected to impact loading, this study used high-speed photography and digital image correlation technology to capture the dynamic tensile failure of coal under impact loading. The dynamic tensile evolution was quantitatively analyzed from the beginning of coal sample being loaded to failure. The captured images of the coal were processed, and the fractal dimension was used to quantitatively describe the evolution of the coal surface cracks under impact loading. The following conclusions were drawn from the experimental results: (1) An empirical formula was established to describe the dynamic tensile strength characteristics of coal under different loading rates. (2) Under impact loading, the maximum strain of a Brazilian disc coal sample first appeared at the contact end between the sample and the incident rod. (3) Under impact loading, a Brazilian disc coal sample cracked from the center of the sample outward, and the crack subsequently extended toward both ends. The fractal dimension of the crack exhibited a power function relationship with time, and the variation range of the fractal dimension of the crack was 1.05-1.39.

Repression of PRMT activities sensitize homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment.

An "induced PARP inhibitor (PARPi) sensitivity by epigenetic modulation" strategy is being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARPi treatments. To expand its clinical applications and identify more efficient combinations, we performed a drug screen by combining PARPi with 74 well-characterized epigenetic modulators that target five major classes of epigenetic enzymes. Both type I PRMT inhibitor and PRMT5 inhibitor exhibit high combination and clinical priority scores in our screen. PRMT inhibition significantly enhances PARPi treatment-induced DNA damage in HR-proficient ovarian and breast cancer cells. Mechanistically, PRMTs maintain the expression of genes associated with DNA damage repair and BRCAness and regulate intrinsic innate immune pathways in cancer cells. Analyzing large-scale genomic and functional profiles from TCGA and DepMap further confirms that PRMT1, PRMT4, and PRMT5 are potential therapeutic targets in oncology. Finally, PRMT1 and PRMT5 inhibition act synergistically to enhance PARPi sensitivity. Our studies provide a strong rationale for the clinical application of a combination of PRMT and PARP inhibitors in patients with HR-proficient ovarian or breast cancer.

G9a is transactivated by C/EBPß to facilitate mitotic clonal expansion during 3T3-L1 preadipocyte differentiation.

In 3T3-L1 preadipocyte differentiation, the CCAAT/enhancer-binding protein-ß (C/EBPß) is an important early transcription factor that activates cell cycle genes during mitotic clonal expansion (MCE), sequentially activating peroxisome proliferator-activated receptor-γ (PPARγ) and C/EBPα during terminal differentiation. Although C/EBPß acquires its DNA binding activity via dual phosphorylation at about 12-16 h postinduction, the expression of PPARγ and C/EBPα is not induced until 36-72 h. The delayed expression of PPARγ and C/EBPα ensures the progression of MCE, but the mechanism responsible for the delay remains elusive. We provide evidence that G9a, a major euchromatic methyltransferase, is transactivated by C/EBPß and represses PPARγ and C/EBPα through H3K9 dimethylation of their promoters during MCE. Inhibitor- or siRNA-mediated G9a downregulation modestly enhances PPARγ and C/EBPα expression and adipogenesis in 3T3-L1 preadipocytes. Conversely, forced expression of G9a impairs the accumulation of triglycerides. Thus, this study elucidates an epigenetic mechanism for the delayed expression of PPARγ and C/EBPα.