ABSTRACT
Developing highly-efficient electrocatalysts for the nitrate reduction reaction (NITRR) is a persistent challenge. Here, we present the successful synthesis of 14 amorphous/low crystallinity metal nanofilms on three-dimensional carbon fibers (M-NFs/CP), including Al, Ti, Mn, Fe, Co, Ni, Cu, Zn, Ag, In, Sn, Pb, Au, or Bi, using rapid thermal evaporation. Among these samples, our study identifies the amorphous Co nanofilm with fine agglomerated Co clusters as the optimal electrocatalyst for NITRR in a neutral medium. The resulting Co-NFs/CP exhibits a remarkable Faradaic efficiency (FENH3) of 91.15 % at - 0.9 V vs RHE, surpassing commercial Co foil (39 %) and Co powder (20 %), despite sharing the same metal composition. Furthermore, during the electrochemical NITRR, the key intermediates on the surface of the Co-NFs/CP catalyst were detected by in situ Fourier-transform infrared (FTIR) spectroscopy, and the possible reaction ways were probed by Density functional theory (DFT) calculations. Theoretical calculations illustrate that the abundant low-coordinate Co atoms of Co-NFs/CP could enhances the adsorption of *NO3 intermediates compared to crystalline Co. Additionally, the amorphous Co structure lowers the energy barrier for the rate-determining step (*NH2â*NH3). This work opens a new avenue for the controllable synthesis of amorphous/low crystallinity metal nano-catalysts for various electrocatalysis reaction applications.
ABSTRACT
The electrochemical reduction of CO2 into value-added chemicals has been explored as a promising solution to realize carbon neutrality and inhibit global warming. This involves utilizing the electrochemical CO2 reduction reaction (CO2RR) to produce a variety of single-carbon (C1) and multi-carbon (C2+) products. Additionally, the electrolyte solution in the CO2RR system can be enriched with nitrogen sources (such as NO3-, NO2-, N2, or NO) to enable the synthesis of organonitrogen compounds via C-N coupling reactions. However, the electrochemical conversion of CO2 into valuable chemicals still faces challenges in terms of low product yield, poor faradaic efficiency (FE), and unclear understanding of the reaction mechanism. This review summarizes the promising strategies aimed at achieving selective production of diverse carbon-containing products, including CO, formate, hydrocarbons, alcohols, and organonitrogen compounds. These approaches involve the rational design of electrocatalysts and the construction of coupled electrocatalytic reaction systems. Moreover, this review presents the underlying reaction mechanisms, identifies the existing challenges, and highlights the prospects of the electrosynthesis processes. The aim is to offer valuable insights and guidance for future research on the electrocatalytic conversion of CO2 into carbon-containing products of enhanced value-added potential.
ABSTRACT
The intricate web of cancer biology is governed by the active participation of long non-coding RNAs (lncRNAs), playing crucial roles in cancer cells' proliferation, migration, and drug resistance. Pioneering research driven by machine learning algorithms has unveiled the profound ability of specific combinations of lncRNAs to predict the prognosis of cancer patients. These findings highlight the transformative potential of lncRNAs as powerful therapeutic targets and prognostic markers. In this comprehensive review, we meticulously examined the landscape of lncRNAs in predicting the prognosis of the top five cancers and other malignancies, aiming to provide a compelling reference for future research endeavours. Leveraging the power of machine learning techniques, we explored the predictive capabilities of diverse lncRNA combinations, revealing their unprecedented potential to accurately determine patient outcomes.
lncRNAs play crucial roles in cancer biology, regulating proliferation, migration, and drug resistance.Emerging evidence suggests that machine learning can predict cancer prognosis using specific lncRNA combinations.Comprehensive information on the predictive abilities of lncRNA combinations in oncology concerning machine learning is lacking.This review offers up-to-date vital references on diverse lncRNA combinations pertinent to future research and clinical trials.
Subject(s)
Neoplasms , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , Neoplasms/diagnosis , Neoplasms/genetics , Prognosis , Machine LearningABSTRACT
OBJECTIVES: The aim of this study was to investigate the relationship between body composition and leukocyte telomere length (LTL) in healthy Chinese children aged 6-11 years. METHODS: This cross-sectional study enrolled 406 healthy children (175 girls and 231 boys). The relative telomere length in their peripheral blood leukocytes was determined via quantitative polymerase chain reaction. Dual-energy X-ray absorptiometry was used to determine body fat content and regional fat distribution, appendicular skeletal muscle mass (ASM), bone mineral density (BMD) and bone mineral content (BMC) at the total body (TB) and total body less head (TBLH) levels, and total body lean mass (TBLM) was then determined. ASM/height2 (ASMI) was also calculated. RESULTS: After adjusting for potential covariates, multiple linear regression analyses revealed that neither body fat content nor regional body fat distribution were significantly associated with LTL (ß = -8.48 × 10-6-1.44 × 10-1, p = 0.227-0.959). However, ASM, ASMI, TB BMC/TB BMD, TBLH BMC/TBLH BMD and TBLM were positively associated with LTL (ß = 8.95 × 10-6-4.95 × 10-1, p = 0.005-0.035). Moreover, analysis of covariance revealed there was a statistically significant dose-dependent positive association between LTL and ASM, TB BMC/BMD, TBLH BMC/BMD, and TBLM (p-trend = 0.002-0.025). CONCLUSIONS: Skeletal muscle mass and bone mass but not body fat content or distribution were significantly associated with LTL in this pediatric population.
Subject(s)
Body Composition , Bone Density , Male , Female , Humans , Child , Cross-Sectional Studies , Body Composition/physiology , Bone Density/physiology , Absorptiometry, Photon , TelomereABSTRACT
Arrhythmia and cardiac hypertrophy are two very common cardiovascular diseases that can lead to heart failure and even sudden death, thus presenting a serious threat to human life and health. According to global statistics, nearly one million people per year die from arrhythmia, cardiac hypertrophy and other associated cardiovascular diseases. Hence, there is an urgent need to find new treatment targets and to develop new intervention measures. Recently, mitochondrial dysfunction has been examined in relation to heart disease with a view to lowering the incidence of arrhythmia and cardiac hypertrophy. The heart is the body's largest energy consuming organ, turning over about 20 kg of adenosine triphosphate (ATP) per day in the mitochondria. Mitochondrial oxidative phosphorylation (OXPHOS) produces up to 90% of the ATP needed by cardiac muscle cells for contraction and relaxation. Dysfunction of heart mitochondria can therefore induce arrhythmia, cardiac hypertrophy and other cardiovascular diseases. Mitochondrial DNA (mtDNA) mutations cause disorders in OXPHOS and defects in the synthesis of muscle contraction proteins. These lead to insufficient production of secondary ATP, increased metabolic requirements for ATP by the myocardium, and the accumulation of reactive oxygen species (ROS). The resulting damage to myocardial cells eventually induces arrhythmia and cardiac hypertrophy. Mitochondrial damage decreases the efficiency of energy production, which further increases the production of ROS. The accumulation of ROS causes mitochondrial damage and eventually leads to a vicious cycle of mitochondrial damage and low efficiency of mitochondrial energy production. In this review, the mechanism underlying the development of arrhythmia and cardiac hypertrophy is described in relation to mitochondrial energy supply, oxidative stress, mtDNA mutation and Mitochondrial dynamics. Targeted therapy for arrhythmia and cardiac hypertrophy induced by mitochondrial dysfunction is also discussed in terms of its potential clinical value. These strategies should improve our understanding of mitochondrial biology and the pathogenesis of arrhythmia and cardiac hypertrophy. They may also identify novel strategies for targeting mitochondria in the treatment of these diseases.
ABSTRACT
Early bone accrual significantly influences adult bone health and osteoporosis incidence. We aimed to investigate the relationship between dietary patterns (DPs), bone mineral content (BMC) and bone mineral density (BMD) in school-age children in China. Children aged six-nine years (n = 465) were enrolled in this cross-sectional study. DPs were identified by principal component factor analysis. Total body (TB) and total body less head (TBLH) BMC and BMD were measured using dual-energy X-ray absorptiometry. Five DPs were identified. After adjustment for covariates, multiple linear regression analysis showed that the "fruit-milk-eggs" dietary pattern was positively associated with TB (ß = 10.480; 95% CI: 2.190, 18.770) and TBLH (ß = 5.577; 95% CI: 0.214, 10.941) BMC, the "animal organs-refined cereals" pattern was associated with low TB BMC (ß = -10.305; 95% CI: -18.433, -2.176), TBLH BMC (ß = -6.346; 95% CI: -11.596, -1.096), TB BMD (ß = -0.006; 95% CI: -0.011, -0.001) and TBLH BMD (ß = -0.004; 95% CI: -0.007, -0.001). In conclusion, our study recommends home or school meals should be rich in fruit, milk, eggs with a moderate amount of vegetables, coarse grains and meat to promote bone development for school-age children.
Subject(s)
Bone Density , Diet , Absorptiometry, Photon , Animals , Cross-Sectional Studies , Humans , VegetablesABSTRACT
Cadmium (Cd)-induced bone damage may be mediated through activating osteoclastogenesis. However, the underlying mechanism is unknown. The purpose of this study was to explore the effect and possible mechanism of CdCl2-induced osteoclastogenesis in RAW264.7 cells. We found that a low concentration of CdCl2 (0.025 and 0.050 µM) did not affect the viability of RAW264.7 cells, but promoted osteoclastogenesis. A low concentration of CdCl2 increased the mRNA and protein expression of osteoclastogenesis-related genes. TRAP staining and transmission electron microscopy (TEM) also demonstrated that CdCl2 promoted osteoclastogenesis. A low concentration of CdCl2 upregulated the levels of LC3-II and Beclin-1, and decreased p62 expression. TEM showed relatively abundant autophagic vacuoles (autophagosomes) after CdCl2 exposure. A low concentration of CdCl2 downregulated the expression levels of Mtor and p70S6K1, and the relative protein expression ratios of p-mTOR/mTOR and p-p70S6K1/p70S6K1. When cells were treated with the autophagy inhibitor chloroquine (CQ) or mTOR activator MHY1485 combined with CdCl2, the expressions of osteoclastogenesis related-genes were decreased and autophagy was attenuated compared with cells treated with CdCl2 alone. Deficiencies in autophagosomes and osteoclasts were also observed. Taken together, the results indicate that a low concentration of CdCl2 promotes osteoclastogenesis by enhancing autophagy via inhibiting the mTOR/p70S6K1 signaling pathway.
Subject(s)
Cadmium , Osteogenesis , Autophagy , Cadmium/toxicity , Ribosomal Protein S6 Kinases, 70-kDa , Signal Transduction , TOR Serine-Threonine Kinases/metabolismABSTRACT
BACKGROUND: Telomere length (TL) serves as a marker of cellular senescence and appears to plateau between the age of 4 y and young adulthood, after which the gut microbiota are supposed to be established. However, scarce data are available regarding the correlation between gut microbiota composition and TL in the pediatric population. OBJECTIVES: We aimed to investigate whether the gut microbiota and the concentrations of SCFAs in feces are associated with leukocyte TL in children. METHODS: In total, 401 children aged 6-9 y from Guangzhou were enrolled in this cross-sectional study. qPCR was used to determine relative TL in peripheral blood leukocytes. The gut microbiota was characterized by 16S ribosomal RNA amplicon sequencing and the fecal concentrations of total SCFAs and SCFA subtypes were determined using HPLC. The multivariate methods with an unbiased variable selection (MUVR) algorithm and partial least square models were used to select predictable operational taxonomic units (OTUs). Further correlation analyses were performed based on multiple linear regression models with adjustment for covariates and false discovery rate. RESULTS: With the use of MUVR, 35 relevant and minimal optimal OTUs were finally selected. Multiple linear regression analysis showed that the abundance of several OTUs, including OTU334 (belonging to the genus Family XIII AD3011 group), OTU726 (belonging to the species Lachnoclostridium phocaeense), OTU1441 (belonging to the genus Ruminococcus torques group), OTU2553 (belonging to the genus Lachnospiraceae UCG-010), and OTU3375 (belonging to the family Lachnospiraceae), was negatively associated with leukocyte TL (ß: -0.187 to -0.142; false discovery rate (FDR)-corrected P value (PFDR) = 0.009-0.035]. However, neither SCFA subtype nor total SCFA content in feces exhibited significant associations with TL (ß: -0.032 to 0.048; PFDR = 0.915-0.969). CONCLUSIONS: The gut microbiota, but not fecal SCFA concentration, was significantly associated with TL in this pediatric population.
Subject(s)
Gastrointestinal Microbiome , Adult , Child , Cross-Sectional Studies , Fatty Acids, Volatile/analysis , Feces/chemistry , Gastrointestinal Microbiome/genetics , Humans , Leukocytes/chemistry , RNA, Ribosomal, 16S/analysis , RNA, Ribosomal, 16S/genetics , Telomere , Young AdultABSTRACT
Metabolic syndrome (MetS) in patients with schizophrenia occurs 2-3 times more frequently than in the general population. Antipsychotic medication is a primary risk factor for patients with MetS. In particular, the widely used second-generation antipsychotics can affect glucose and lipid metabolism and can induce insulin resistance and other metabolic abnormalities through various receptors. Notably, the metabolic risks of various antipsychotics may differ because of their different pharmacological affinity to MetS-related receptors. Several previous studies have shown that switching from high to low metabolic risk antipsychotics may improve patients' metabolic parameters. The current review aims to discuss the strategies for switching antipsychotic medications and the impact on metabolic abnormalities in patients with schizophrenia.
ABSTRACT
CDK4/6 has been identified as an attractive therapeutic target for treatment of cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for cancer therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Mice , Mice, Inbred BALB C , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tissue DistributionSubject(s)
Antidepressive Agents/therapeutic use , Anxiety/drug therapy , Anxiety/physiopathology , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/physiopathology , Selective Serotonin Reuptake Inhibitors/therapeutic use , Citalopram/therapeutic use , Fluoxetine/therapeutic use , Fluvoxamine/therapeutic use , Follow-Up Studies , Humans , Least-Squares Analysis , Paroxetine/therapeutic use , Sertraline/therapeutic use , Treatment OutcomeABSTRACT
The cyclin-dependent kinase (CDK)4/6-cyclin D1-Rb-p16/ink4a pathway is responsible for regulating cell progression past the G1 restriction point during the cell cycle. The development of a majority of human tumors is associated with dysregulation of this pathway, resulting in increased cancer cell proliferation. Both CDK4 and CDK6, well-validated cancer drug targets, function primarily as catalytic enzymes that mediate the phosphorylation of retinoblastoma protein (Rb). Here, we determined that SPH3643 is a novel potent antiproliferative agent that inhibits CDK4/6 kinase activity. In biochemical assays, SPH3643 showed more potent inhibition of both CDK4 and CDK6 than did 2 published CDK4/6 inhibitors, LY2835219 and palbociclib, and had better selectivity than LY2835219. Further in vitro study revealed that SPH3643 blocked Cdk/Rb signaling by inhibiting the phosphorylation of RbSer780 and arrested the MCF-7 cancer cells at G0 /G1 phase, resulting in marked inhibition of the proliferation of Rb-positive cancer cell lines. In vivo SPH3643 treatment in mice bearing xenograft tumor models of breast cancer, colon cancer, acute myelocytic leukemia, and glioblastoma resulted in significant decreases in tumor growth. SPH3643 was able to particularly strongly inhibit glioblastoma (U87-MG) cell growth in the brains of orthotopic carcinoma xenograft mice due to its high degree of intracerebral penetration and significant persistence in this setting. Together these results revealed that SPH3643 is a potent, orally active small-molecule inhibitor of CDK4/6 with robust anticancer efficacy and a high degree of blood-brain barrier permeability.
Subject(s)
Antineoplastic Agents/pharmacology , Blood-Brain Barrier/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/therapeutic use , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/metabolism , Female , Humans , MCF-7 Cells , Mice , Mice, Nude , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Phosphorylation/drug effects , Protein Kinase Inhibitors/therapeutic use , Retinoblastoma Protein/metabolism , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
MYCN-amplified neuroblastoma (NB) is characterized by poor prognosis, and directly targeting MYCN has proven challenging. Here, we showed that aldehyde dehydrogenase family 18 member A1 (ALDH18A1) exerts profound impacts on the proliferation, self-renewal, and tumorigenicity of NB cells and is a potential risk factor in patients with NB, especially those with MYCN amplification. Mechanistic studies revealed that ALDH18A1 could both transcriptionally and posttranscriptionally regulate MYCN expression, with MYCN reciprocally transactivating ALDH18A1 and thus forming a positive feedback loop. Using molecular docking and screening, we identified an ALDH18A1-specific inhibitor, YG1702, and demonstrated that pharmacological inhibition of ALDH18A1 was sufficient to induce a less proliferative phenotype and confer tumor regression and prolonged survival in NB xenograft models, providing therapeutic insights into the disruption of this reciprocal regulatory loop in MYCN-amplified NB.
Subject(s)
Aldehyde Dehydrogenase/genetics , N-Myc Proto-Oncogene Protein , Neural Stem Cells , Neuroblastoma , Cell Line, Tumor , Feedback , Humans , Molecular Docking Simulation , N-Myc Proto-Oncogene Protein/genetics , Neuroblastoma/geneticsABSTRACT
Targeting CDK4/6 has been identified as an effective therapeutics for treatment of cancer. We herein reported the discovery of a series of 6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine derivatives as CDK4/6 inhibitors against cancer. Compound 3c, which displayed high potency and selectivity on CDK4/6 (IC50â¯=â¯0.710/1.10â¯nM) over a variety of other kinases, possessed desirable antiproliferative activities, excellent metabolic properties, and favorable pharmacokinetic characters. In MCF-7, Colo-205, and A549 xenograft models, compound 3c exhibited significant tumor growth inhibitions with low toxicities, which could be a promising drug candidate for further development.
Subject(s)
Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Drug Discovery , Protein Kinase Inhibitors/pharmacology , A549 Cells , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Mice , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
The original and corrected figures are shown in the accompanying Author Correction.
ABSTRACT
Early invasive growth along specific anatomical structures, especially the white matter tract, is regarded as one of the main causes of poor therapeutic outcome of people with gliomas. We show that some glioma stem cells (GSCs) are preferentially located along white matter tracts, which exhibit a demyelinated phenotype, at the invasive frontier of glioma tissues. These GSCs are CD133+Notch1+, whereas the nerve fibers express the Notch ligand Jagged1. The Notch-induced transcription factor Sox9 promotes the transcription of SOX2 and the methylation level of the NOTCH1 promoter is attenuated by the upregulation of SOX2 to reinforce NOTCH1 expression in GSCs. This positive-feedback loop in a cohort of glioma subjects is correlated with a poor prognosis. Inhibition of Notch signaling attenuates the white-matter-tract tropism of GSCs. These findings provide evidence indicating that the NOTCH1-SOX2 positive-feedback loop controls GSC invasion along white matter tracts.
Subject(s)
Brain Neoplasms/metabolism , Feedback, Physiological/physiology , Glioma/metabolism , Neoplastic Stem Cells/metabolism , Receptor, Notch1/metabolism , SOXB1 Transcription Factors/metabolism , White Matter/metabolism , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , Cell Line, Tumor , Diffusion Tensor Imaging , Glioma/diagnostic imaging , Glioma/pathology , Humans , Jagged-1 Protein/metabolism , Neoplasm Invasiveness/pathology , Neoplastic Stem Cells/pathology , White Matter/pathologyABSTRACT
Calbindin modulates intracellular Ca2+ dynamics and synaptic plasticity. Reduction of hippocampal calbindin levels has been implicated in early-life stress-related cognitive disorders, but it remains unclear how calbindin in distinct populations of hippocampal neurons contributes to stress-induced memory loss. Here we report that early-life stress suppressed calbindin levels in CA1 and dentate gyrus (DG) neurons, and calbindin knockdown in adult CA1 or DG excitatory neurons mimicked early-life stress-induced memory loss. In contrast, calbindin knockdown in CA1 interneurons preserved long-term memory even after an acute stress challenge. These results indicate that the dysregulation of calbindin in hippocampal excitatory, but not inhibitory, neurons conveys susceptibility to stress-induced memory deficits. Moreover, calbindin levels were downregulated by early-life stress through the corticotropin-releasing hormone receptor 1-nectin3 pathway, which in turn reduced inositol monophosphatase levels. Our findings highlight calbindin as a molecular target of early-life stress and an essential substrate for memory.
Subject(s)
CA1 Region, Hippocampal/metabolism , Calbindins/metabolism , Interneurons/metabolism , Memory Disorders/metabolism , Stress, Psychological/metabolism , Animals , CA1 Region, Hippocampal/cytology , CA1 Region, Hippocampal/physiology , Calbindins/genetics , Dentate Gyrus/cytology , Dentate Gyrus/metabolism , Dentate Gyrus/physiology , Interneurons/physiology , Male , Memory Disorders/etiology , Memory, Long-Term , Mice , Mice, Inbred C57BL , Nectins/metabolism , Receptors, Corticotropin-Releasing Hormone/metabolism , Spatial Memory , Stress, Psychological/complicationsABSTRACT
A novel strategy for the fabrication of hollow Co and N-codoped carbon nanopolyhedra (H-CoNC) from metal-organic framework (MOF) using in situ evaporation of ZnO nanosphere templates is proposed. The excess Zn supply during the pyrolysis process is found beneficial in terms of high nitrogen (≈9.75 at%), relatively homogenous CoN bonding, and the electrochemically accessible hierarchical porous system. Compared with other reported "solid" CoNC of identical surface areas, the newly developed H-CoNC shows enhanced kinetic current in 0.1 m KOH electrolyte and elevated oxygen reduction reaction (ORR) performance in 6 m KOH. The latter exceeds results obtained with the benchmark 20 wt% Pt/C, which is related to the strong confinement of O2 molecules in the H-CoNC hierarchical porous system. Furthermore, the H-CoNC displays great tolerance toward the methanol crossover and KSCN poisoning. Finally, the assembled Zn-air batteries with H-CoNC yield a record open circuit potential (1.59 V vs Zn, stabilized at 1.52 V), high power density (331.0 mW cm-2 ), and promising rate performance. This work provides a new guideline for the design of MOF-derived carbon materials, as well as novel insights into spatial confinement effect toward the ORR activity.
ABSTRACT
Over half of patients with BRCA1-deficient cancers do not respond to treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we report that a combination of 53BP1 and BRCA1 may serve as a biomarker of PARP inhibitor sensitivity. Based on the mRNA levels of four homologous recombination repair (HR) genes and PARP inhibitor sensitivity, we selected BRCA1-deficient MDA-MB-436 cells to conduct RNA interference. Reducing expression of 53BP1, but not the other three HR genes, was found to lower simmiparib sensitivity. Additionally, we generated 53BP1-/-/BRCA1-/- clonal variants by the transcription activator-like effector nuclease (TALEN) technique and found that depleting 53BP1 impaired PARP inhibitor sensitivity with a 36.7-fold increase in their IC50 values. Consistent with its effect on PARP inhibitor sensitivity, 53BP1 loss alleviated cell cycle arrest and apoptosis and partially restored HR function. Importantly, 53BP1 depletion dramatically reduced the ability of PARP inhibitors to suppress tumor growth in vivo. The inhibition rate of simmiparib was 74.16% for BRCA1-deficient MDA-MB-436 xenografts, but only 7.79% for 53BP1/BRCA1-deficient xenografts. Re-expressing 53BP1 in the dual-deficient cells restored PARP inhibitor sensitivity and the levels of HR regulators. Considering that at least 10% of BRCA1-deficient breast and ovarian cancers have reduced expression of 53BP1, using a combination of 53BP1 with BRCA1 as a biomarker for patient selection should reduce the number of patients undergoing futile treatment with PARP inhibitors.