Toxoflavin analog D43 exerts antiproliferative effects on breast cancer by inducing ROS-mediated apoptosis and DNA damage.

Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.

Pd-Catalyzed Regiodivergent Hydrocarboxylation of Olefins with Oxalic Acid: A Remarkable Effect of the Counteranion on Regioselectivity.

A regioselective Pd-catalyzed hydrocarboxylation of vinyl arenes with oxalic acid is described. A wide variety of either linear or branched carboxylic acids can be readily obtained with high regioselectivities under mild reaction conditions. The reaction process is operationally simple and requires no handling of toxic CO. Besides the ligand, the counteranion of the Pd catalyst system plays an important role in the regioselectivity.

Integrin ß4 promotes DNA damage-related drug resistance in triple-negative breast cancer via TNFAIP2/IQGAP1/RAC1.

Anti-tumor drug resistance is a challenge for human triple-negative breast cancer (TNBC) treatment. Our previous work demonstrated that TNFAIP2 activates RAC1 to promote TNBC cell proliferation and migration. However, the mechanism by which TNFAIP2 activates RAC1 is unknown. In this study, we found that TNFAIP2 interacts with IQGAP1 and Integrin ß4. Integrin ß4 activates RAC1 through TNFAIP2 and IQGAP1 and confers DNA damage-related drug resistance in TNBC. These results indicate that the Integrin ß4/TNFAIP2/IQGAP1/RAC1 axis provides potential therapeutic targets to overcome DNA damage-related drug resistance in TNBC.

Pd-Catalyzed Regioselective Hydroformylation of Olefins with HCO2H and Its Derivatives.

An effective Pd-catalyzed regioselective hydroformylation process with N-formylsaccharin or 2,4,6-trichlorophenyl formate along with formic acid is described. Linear aldehydes can be obtained in up to 83% yield and >20:1 l/b ratio. The reaction is operationally simple without the need for external CO and H2.

Histone Deacetylase Inhibitors (HDACi) Promote KLF5 Ubiquitination and Degradation in Basal-like Breast Cancer.

Basal-like breast cancer (BLBC) accounts for approximately 15% of all breast cancer cases, and patients with BLBC have a low survival rate. Our previous study demonstrated that the KLF5 transcription factor promotes BLBC cell proliferation and tumor growth. In this study, we demonstrated that the histone deacetylase inhibitors (HDACi), suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA), increased KLF5 acetylation at lysine 369 (K369), downregulated KLF5 protein expression levels, and decreased cell viability in BLBC cell lines. HDACi target KLF5 for proteasomal degradation by promoting KLF5 protein ubiquitination. K369 acetylation of KLF5 decreases the binding between KLF5 and its deubiquitinase, BAP1. These findings revealed a novel mechanism by which HDACi suppress BLBC, and a novel crosstalk between KLF5 protein acetylation and ubiquitination.

YB-1 is a positive regulator of KLF5 transcription factor in basal-like breast cancer.

Y-box binding protein 1 (YB-1) is a well-known oncogene highly expressed in various cancers, including basal-like breast cancer (BLBC). Beyond its role as a transcription factor, YB-1 is newly defined as an epigenetic regulator involving RNA 5-methylcytosine. However, its specific targets and pro-cancer functions are poorly defined. Here, based on clinical database, we demonstrate a positive correlation between Kruppel-like factor 5 (KLF5) and YB-1 expression in breast cancer patients, but a negative correlation with that of Dachshund homolog 1 (DACH1). Mechanistically, YB-1 enhances KLF5 expression not only through transcriptional activation that can be inhibited by DACH1, but also by stabilizing KLF5 mRNA in a RNA 5-methylcytosine modification-dependent manner. Additionally, ribosomal S6 kinase 2 (RSK2) mediated YB-1 phosphorylation at Ser102 promotes YB-1/KLF5 transcriptional complex formation, which co-regulates the expression of BLBC specific genes, Keratin 16 (KRT16) and lymphocyte antigen 6 family member D (Ly6D), to promote cancer cell proliferation. The RSK inhibitor, LJH685, suppressed BLBC cell tumourigenesis in vivo by disturbing YB-1-KLF5 axis. Our data suggest that YB-1 positively regulates KLF5 at multiple levels to promote BLBC progression. The novel RSK2-YB-1-KLF5-KRT16/Ly6D axis provides candidate diagnostic markers and therapeutic targets for BLBC.

Pd-Catalyzed Regioselective Branched Hydrocarboxylation of Terminal Olefins with Formic Acid.

A regioselective Pd-catalyzed hydrocarboxylation of terminal olefins with HCOOH is described. A wide variety of branched carboxylic acids can readily be obtained with high regioselectivities under mild reaction conditions. The reaction is operationally simple and requires no handling of toxic CO. The ligand and LiCl are important factors for reaction reactivity and selectivity.

Copper-Catalyzed Bisannulations of Malonate-Tethered O-Acyl Oximes with Pyridine, Pyrazine, Pyridazine, and Quinoline Derivatives for the Construction of Dihydroindolizine-Fused Pyrrolidinones and Analogues.

A copper-catalyzed bisannulation reaction of malonate-tethered O-acyl oximes with pyridine, pyrazine, pyridazine, and quinoline derivatives has been developed for the concise synthesis of structurally novel dihydroindolizine-fused pyrrolidinones and their analogues. The present reaction shows excellent regioselectivity and stereoselectivity. Theoretical calculations reveal that the coordination effect of the carbonyl group in the nucleophilic substrate determines the excellent regioselectivity. Further functionalization of the generated dihydroindolizine-fused pyrrolidinone could be easily realized through substitution, Michael addition, selective aminolysis, and hydrolysis reactions.

An Efficient Score Test Integrated with Empirical Bayes for Genome-Wide Association Studies.

Many methods used in multi-locus genome-wide association studies (GWAS) have been developed to improve statistical power. However, most existing multi-locus methods are not quicker than single-locus methods. To address this concern, we proposed a fast score test integrated with Empirical Bayes (ScoreEB) for multi-locus GWAS. Firstly, a score test was conducted for each single nucleotide polymorphism (SNP) under a linear mixed model (LMM) framework, taking into account the genetic relatedness and population structure. Then, all of the potentially associated SNPs were selected with a less stringent criterion. Finally, Empirical Bayes in a multi-locus model was performed for all of the selected SNPs to identify the true quantitative trait nucleotide (QTN). Our new method ScoreEB adopts the similar strategy of multi-locus random-SNP-effect mixed linear model (mrMLM) and fast multi-locus random-SNP-effect EMMA (FASTmrEMMA), and the only difference is that we use the score test to select all the potentially associated markers. Monte Carlo simulation studies demonstrate that ScoreEB significantly improved the computational efficiency compared with the popular methods mrMLM, FASTmrEMMA, iterative modified-sure independence screening EM-Bayesian lasso (ISIS EM-BLASSO), hybrid of restricted and penalized maximum likelihood (HRePML) and genome-wide efficient mixed model association (GEMMA). In addition, ScoreEB remained accurate in QTN effect estimation and effectively controlled false positive rate. Subsequently, ScoreEB was applied to re-analyze quantitative traits in plants and animals. The results show that ScoreEB not only can detect previously reported genes, but also can mine new genes.

Copper-Catalyzed Cascade Annulation of Malonate-Tethered O-Acyl Oximes with Cyclic 1,3-Dicarbonyl Compounds for the Synthesis of Spiro-Pentacyclic Derivatives.

A copper-catalyzed cascade annulation of malonate-tethered O-acyl oximes with cyclic 1,3-dicarbonyl compounds has been developed for the rapid synthesis of spiro-pentacyclic derivatives. This reaction allows the one-step formation of five C-C/N/O bonds and an angular tricyclic core under very mild conditions and shows excellent regioselectivity and stereoselectivity.

mrMLM v4.0.2: An R Platform for Multi-locus Genome-wide Association Studies.

Previous studies have reported that some important loci are missed in single-locus genome-wide association studies (GWAS), especially because of the large phenotypic error in field experiments. To solve this issue, multi-locus GWAS methods have been recommended. However, only a few software packages for multi-locus GWAS are available. Therefore, we developed an R software named mrMLM v4.0.2. This software integrates mrMLM, FASTmrMLM, FASTmrEMMA, pLARmEB, pKWmEB, and ISIS EM-BLASSO methods developed by our lab. There are four components in mrMLM v4.0.2, including dataset input, parameter setting, software running, and result output. The fread function in data.table is used to quickly read datasets, especially big datasets, and the doParallel package is used to conduct parallel computation using multiple CPUs. In addition, the graphical user interface software mrMLM.GUI v4.0.2, built upon Shiny, is also available. To confirm the correctness of the aforementioned programs, all the methods in mrMLM v4.0.2 and three widely-used methods were used to analyze real and simulated datasets. The results confirm the superior performance of mrMLM v4.0.2 to other methods currently available. False positive rates are effectively controlled, albeit with a less stringent significance threshold. mrMLM v4.0.2 is publicly available at BioCode (https://bigd.big.ac.cn/biocode/tools/BT007077) or R (https://cran.r-project.org/web/packages/mrMLM.GUI/index.html) as an open-source software.

Hybrid of Restricted and Penalized Maximum Likelihood Method for Efficient Genome-Wide Association Study.

In genome-wide association studies, linear mixed models (LMMs) have been widely used to explore the molecular mechanism of complex traits. However, typical association approaches suffer from several important drawbacks: estimation of variance components in LMMs with large scale individuals is computationally slow; single-locus model is unsatisfactory to handle complex confounding and causes loss of statistical power. To address these issues, we propose an efficient two-stage method based on hybrid of restricted and penalized maximum likelihood, named HRePML. Firstly, we performed restricted maximum likelihood (REML) on single-locus LMM to remove unrelated markers, where spectral decomposition on covariance matrix was used to fast estimate variance components. Secondly, we carried out penalized maximum likelihood (PML) on multi-locus LMM for markers with reasonably large effects. To validate the effectiveness of HRePML, we conducted a series of simulation studies and real data analyses. As a result, our method always had the highest average statistical power compared with multi-locus mixed-model (MLMM), fixed and random model circulating probability unification (FarmCPU), and genome-wide efficient mixed model association (GEMMA). More importantly, HRePML can provide higher accuracy estimation of marker effects. HRePML also identifies 41 previous reported genes associated with development traits in Arabidopsis, which is more than was detected by the other methods.

Effectiveness of Lifestyle and Drug Intervention on Hypertensive Patients: a Randomized Community Intervention Trial in Rural China.

BACKGROUND: Strict medication guidance and lifestyle interventions to manage blood pressure (BP) in hypertensive patients are typically difficult to follow. OBJECTIVE: To evaluate the 1-year effectiveness of lifestyle and drug intervention in the management of rural hypertensive patients. DESIGN: Randomized community intervention trial. PARTICIPANTS: The control group comprised 967 patients who received standard antihypertensive drug intervention therapy from two communities, whereas the intervention group comprised 1945 patients who received antihypertensive drug and lifestyle intervention therapies from four communities in rural China. MAIN MEASURES: Data on lifestyle behaviors and BP measurements at baseline and 1-year follow-up were collected. A difference-in-difference logistic regression model was used to assess the effect of the intervention. KEY RESULTS: BP control after the 1-year intervention was better than that at baseline in both groups. The within-group change in BP control of 59.3% in the intervention group was much higher than the 25.2% change in the control group (P < 0.001). Along with the duration of the follow-up period, systolic and diastolic BP decreased rapidly in the early stages and then gradually after 6 months in the intervention group (P < 0.001). In the intervention group, drug therapy adherence was increased by 39.5% (from 48.1% at 1 month to 87.6% at 1 year) (P < 0.001), more in women (45.6%) than in men (31.2%; P < 0.001). The net effect of the lifestyle intervention improved the rate of BP control by 56.1% (70.8% for men and 44.7% for women). For all physiological and biochemical factors, such as body mass index, waist circumference, lipid metabolism, and glucose control, improvements were more significant in the behavioral intervention group than those in the control group (all P < 0.001). CONCLUSION: The addition of lifestyle intervention by physicians or nurses helps control BP effectively and lowers BP better than usual care with antihypertensive drug therapy alone.

A Pd-Catalyzed Site-Controlled Isomerization of Terminal Olefins.

An effective Pd-catalyzed isomerization of olefins with 2-PyPPh2 as the ligand is described. A wide variety of trans-2-olefins bearing various functional groups can be obtained with high regio- and stereoselectivity under mild reaction conditions. The ligand is crucial for the reaction.

Pd-Catalyzed Highly Chemo- and Regioselective Hydrocarboxylation of Terminal Alkyl Olefins with Formic Acid.

An efficient Pd-catalyzed hydrocarboxylation of alkenes with HCOOH is described. A wide variety of linear carboxylic acids bearing various functional groups can be obtained with excellent chemo- and regioselectivities under mild reaction conditions. The reaction process is operationally simple and requires no handling of toxic CO.

RAGE may act as a tumour suppressor to regulate lung cancer development.

Although the correlation of the RAGE rs2070600 polymorphism and cancer risk has been confirmed, detailed studies with functional and experimental evaluations are lacking. In this study, we first aimed to examine whether this polymorphism is associated with cancer risk based on the latest published data, and consistent with previous meta-analyses, a significant association between the rs2070600 polymorphism and cancer risk was observed (A versus G: OR = 1.25; 95% CI = 1.12-1.40). In additional stratified analyses based on cancer type, rs2070600 was significantly associated with an increased risk of lung cancer (A versus G: OR = 1.20; 95% CI = 1.09-1.33). Moreover, TCGA database showed that the expression level of RAGE was significantly lower in lung cancer tumour tissues than in adjacent non-tumour tissues, which was validated in the GEO database. Additionally, eQTL analysis indicated that the rs2070600 polymorphism may modify the expression level of RAGE in lung squamous cell carcinoma tissues (P = 0.09). Finally, we performed functional experiments in lung cancer cells and preliminarily demonstrated that RAGE may act as a tumour suppressor in lung cancer development. These findings provide evidence that the variant A allele of rs2070600 may decrease the expression of the tumour suppressor gene RAGE, thereby increasing lung cancer risk.

Relationship of "weekend warrior" and regular physical activity patterns with metabolic syndrome and its associated diseases among Chinese rural adults.

Little is known about the "weekend warrior" pattern of physical activity (PA) where people perform all their PA in 1 or 2 sessions per week. We investigated the relationship of weekend warrior and other PA patterns with metabolic syndrome (MS) and its associated diseases. Data on sociodemographic and lifestyle characteristics were collected from the Nantong Metabolic Syndrome Study that included 13,505 women and 6,997 men between 2007 and 2008. Compared with inactive participants, weekend warriors were at lower risk of MS, diabetes, and hypertension; respective odds ratios (95% confidence intervals) for men and women were 0.58 (0.43-0.79) and 0.67 (0.52-0.86), 0.52 (0.34-0.79) and 0.52 (0.33-0.83), and 0.79 (0.63-0.99) and 0.71 (0.57-0.89). Similar results were observed with regular activity, at a frequency of >3 sessions per week. Both weekend warrior and regular PA patterns showed a 10-60% decrease in abnormal triglycerides, glucose, and blood pressure in both sexes; abnormal waist circumference in men only; and abnormal high-density lipoprotein in women only. Our observed cross-sectional relationships reflect that >150 min/week of moderate PA or 75 min/week vigorous-intensity PA is needed to prevent MS and its component diseases, even if in a short-bout, intermittent PA pattern. ABBREVIATIONS: MS: Metabolic syndrome; WC: Waist circumference; TG: Triglycerides; HDL-c: High-density lipoprotein cholesterol; BP: Blood pressure; SBP: Systolic blood pressure, DBP: Diastolic blood pressure; PA: Physical activity; JIS: Joint Interim Statement; CVD: Cardiovascular disease; ATP III: US Third Report of the National Cholesterol Education Program, the Adult Treatment Panel; IDF: International Diabetes Federation; IPAQ: International Physical Activity Questionnaire; BMI: Body mass index; CDC: the Nantong Centers for Disease Control; OR: Odds ratio; CI: Confidence interval; SD: Standard deviation; IQR: Interquartile range.

pKWmEB: integration of Kruskal-Wallis test with empirical Bayes under polygenic background control for multi-locus genome-wide association study.

Although nonparametric methods in genome-wide association studies (GWAS) are robust in quantitative trait nucleotide (QTN) detection, the absence of polygenic background control in single-marker association in genome-wide scans results in a high false positive rate. To overcome this issue, we proposed an integrated nonparametric method for multi-locus GWAS. First, a new model transformation was used to whiten the covariance matrix of polygenic matrix K and environmental noise. Using the transferred model, Kruskal-Wallis test along with least angle regression was then used to select all the markers that were potentially associated with the trait. Finally, all the selected markers were placed into multi-locus model, these effects were estimated by empirical Bayes, and all the nonzero effects were further identified by a likelihood ratio test for true QTN detection. This method, named pKWmEB, was validated by a series of Monte Carlo simulation studies. As a result, pKWmEB effectively controlled false positive rate, although a less stringent significance criterion was adopted. More importantly, pKWmEB retained the high power of Kruskal-Wallis test, and provided QTN effect estimates. To further validate pKWmEB, we re-analyzed four flowering time related traits in Arabidopsis thaliana, and detected some previously reported genes that were not identified by the other methods.

A Ligand-Directed Catalytic Regioselective Hydrocarboxylation of Aryl Olefins with Pd and Formic Acid.

An effective Pd-catalyzed hydrocarboxylation of aryl olefins with Ac2O and formic acid is described. A variety of 2- and 3-arylpropanoic acids can be regioselectively formed by the judicious choice of ligand without the use of toxic CO gas.

Palladium-Catalyzed Highly Regio- and Enantioselective Hydroesterification of Aryl Olefins with Phenyl Formate.

An effective Pd-catalyzed regio- and enantioselective hydroesterification of aryl olefins with phenyl formate is described. A variety of phenyl 2-arylpropanoates can be obtained in good yields with high b/l ratios and ee's without using toxic CO gas.