Developmental arsenic exposure impairs cognition, directly targets DNMT3A, and reduces DNA methylation.

Developmental arsenic exposure has been associated with cognitive deficits in epidemiological studies, but the underlying mechanisms remain poorly understood. Here, we establish a mouse model of developmental arsenic exposure exhibiting deficits of recognition and spatial memory in the offspring. These deficits are associated with genome-wide DNA hypomethylation and abnormal expression of cognition-related genes in the hippocampus. Arsenic atoms directly bind to the cysteine-rich ADD domain of DNA methyltransferase 3A (DNMT3A), triggering ubiquitin- and proteasome-mediated degradation of DNMT3A in different cellular contexts. DNMT3A degradation leads to genome-wide DNA hypomethylation in mouse embryonic fibroblasts but not in non-embryonic cell lines. Treatment with metformin, a first-line antidiabetic agent reported to increase DNA methylation, ameliorates the behavioral deficits and normalizes the aberrant expression of cognition-related genes and DNA methylation in the hippocampus of arsenic-exposed offspring. Our study establishes a DNA hypomethylation effect of developmental arsenic exposure and proposes a potential treatment against cognitive deficits in the offspring of pregnant women in arsenic-contaminated areas.

First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more (EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression. METHODS: EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03088540. FINDINGS: Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1-31·8; 149 [52%] of 284 died) versus 13·3 months (10·5-16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46-0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2-8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3-6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42-0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1-9·3) and overall survival of 15·1 months (11·3-18·7). The most common grade 3-4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals INTERPRETATION: At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer. FUNDING: Regeneron Pharmaceuticals and Sanofi.

Catalytic Dehydrogenative (3 + 2) Cycloaddition of Alkylbenzenes via π-Coordination.

Given the wide availability and low cost of alkylbenzenes, direct C-H functionalization of these aromatic hydrocarbons to afford structurally complex building blocks has long been of interest in organic synthesis. Herein we describe a method for rhodium-catalyzed dehydrogenative (3 + 2) cycloaddition reactions of alkylbenzenes with 1,1-bis(phenylsulfonyl)ethylene. The π-coordination with a rhodium catalyst facilitates the benzylic deprotonation, allowing for the subsequent (3 + 2) cycloaddition in which the metal-complexed carbanion serves as a unique all-carbon 1,3-dipole equivalent. We demonstrated the generality of this catalytic method by carrying out reactions of a large array of alkylbenzenes to generate dihydroindene derivatives bearing two synthetically versatile sulfonyl groups. Quantum-chemical calculations revealed details of the reaction process.

Prognostic implications of alpha-fetoprotein and C-reactive protein elevation in hepatocellular carcinoma following resection (PACE): a large cohort study of 2770 patients.

BACKGROUND: Routine clinical staging for hepatocellular carcinoma (HCC) incorporates liver function, general health, and tumor morphology. Further refinement of prognostic assessments and treatment decisions may benefit from the inclusion of tumor biological marker alpha-fetoprotein (AFP) and systemic inflammation indicator C-reactive protein (CRP). METHODS: Data from a multicenter cohort of 2770 HCC patients undergoing hepatectomy were analyzed. We developed the PACE risk score (Prognostic implications of AFP and CRP Elevation) after initially assessing preoperative AFP and CRP's prognostic value. Subgroup analyzes were performed in BCLC cohorts A and B using multivariable Cox analysis to evaluate the prognostic stratification ability of the PACE risk score and its complementary utility for BCLC staging. RESULTS: Preoperative AFP ≥ 400ng/mL and CRP ≥ 10 mg/L emerged as independent predictors of poorer prognosis in HCC patients who underwent hepatectomy, leading to the creation of the PACE risk score. PACE risk score stratified patients into low, intermediate, and high-risk groups with cumulative 5-year overall (OS) and recurrence-free survival (RFS) rates of 59.6%/44.9%, 43.9%/38.4%, and 20.6%/18.0% respectively (all P < 0.001). Increased PACE risk scores correlated significantly with early recurrence and extrahepatic metastases frequency (all P < 0.001). The multivariable analysis identified intermediate and high-risk PACE scores as independently correlating with poor postoperative OS and RFS. Furthermore, the PACE risk score proficiently stratified the prognosis of BCLC stages A and B patients, with multivariable analyses demonstrating it as an independent prognostic determinant for both stages. CONCLUSION: The PACE risk score serves as an effective tool for postoperative risk stratification, potentially supplementing the BCLC staging system.

N-Heterocyclic Carbene-Palladium Polymers Network: Recyclable Pre-catalyst for Effective Suzuki-Miyaura Coupling Reaction in Water.

Rational design of high-efficiency N-heterocyclic carbene (NHC) palladium catalyst is of great importance to modern organic synthesis, especially in chemical and pharmaceutical industries. Herein, we fabricate a polymer network containing N-heterocyclic carbene palladium (PNNHC-Pd) catalytic active sites via an immobilization process. The N-heterocyclic carbene palladium can serve as a promising linkage of polymer network as well as an effective catalytic active site owing to its structural preference and strong σ-donating ability with palladium species. The results display that N-heterocyclic carbene palladium disperses homogeneously in polymer network, thus rendering PNNHC-Pd excellent catalytic activity, high stability and superior reusability in palladium-catalyzed Suzuki-Miyaura coupling reaction in aqueous medium. This work provides a new insight into the development of heterogenization of homogeneous catalysts based on polymer network.

Catalytic Amination of Phenols with Amines.

Given the wide prevalence and ready availability of both phenols and amines, aniline synthesis through direct coupling between these starting materials would be extremely attractive. Herein, we describe a rhodium-catalyzed amination of phenols, which provides concise access to diverse anilines, with water as the sole byproduct. The arenophilic rhodium catalyst facilitates the inherently difficult keto-enol tautomerization of phenols by means of π-coordination, allowing for the subsequent dehydrative condensation with amines. We demonstrate the generality of this redox-neutral catalysis by carrying out reactions of a large array of phenols with various electronic properties and a wide variety of primary and secondary amines. Several examples of late-stage functionalization of structurally complex bioactive molecules, including pharmaceuticals, further illustrate the potential broad utility of the method.

iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition.

The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53-iASPP crystal structure reveals that iASPP displaces the p53 L1 loop-which mediates sequence-specific interactions with the signature-corresponding base-without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF-DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain-except the oncogenic E6 from human papillomaviruses (HPVs)-structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.

Rhodium-Catalyzed Stereoselective Deuteration of Benzylic C-H Bonds via Reversible η6 -Coordination.

We report a convenient method for benzylic H/D exchange of a wide variety of substrates bearing primary, secondary, or tertiary C-H bonds via a reversible η6 -coordination strategy. A doubly cationic [CpCF3 RhIII ]2+ catalyst that serves as an arenophile facilitates deprotonation of inert benzylic hydrogen atoms (pKa >40 in DMSO) without affecting other hydrogen atoms, such as those on aromatic rings or in α-positions of carboxylate groups. Notably, the H/D exchange reactions feature high stereoretention. We demonstrated the potential utility of this method by using it for deuterium labeling of ten pharmaceuticals and their analogues.

Rhodium-Catalyzed Benzylic Addition Reactions of Alkylarenes to Michael Acceptors.

The use of alkylarenes as nucleophile precursors in benzylic addition is challenging because the benzylic hydrogen atoms of these compounds are inert to deprotonation. Herein, we report Rh-catalyzed benzylic addition of alkylarenes to Michael acceptors for the formation of C(sp3 )-C(sp3 ) bonds. The catalyst is proposed to activate the aromatic ring via η6 -coordination, dramatically facilitating deprotonation of the unactivated benzylic C-H bond and addition of the resulting carbanion to the α,ß-unsaturated double bond in the absence of bases. Notably, this byproduct-free method provides an access to all-carbon quaternary centers through the development of ligands.

Amide-Functionalized Metal-Organic Frameworks Coupled with Open Fe/Sc Sites for Efficient Acetylene Purification.

Acetylene (C2H2) purification is of great importance for many chemical synthesis and processes. Metal-organic frameworks (MOFs) are widely used for gas adsorption and separation due to their variable structure and porosity. However, the exploitation of ideal MOF adsorbents for C2H2 keeps a challenging task. Herein, a combination of open metal sites (OMSs) and Lewis basic sites (LBSs) in robust MOFs is demonstrated to effectively promote the C2H2 purification performance. Accordingly, SNNU-37(Fe/Sc), two isostructural MOFs constituted by [Fe3O(COO)6] or [Sc3O(COO)6] trinuclear clusters and amide-functionalized tricarboxylate linkers, were designed with extra-stable 3,6-connected new architectures. Derived from the coexistence of high-density OMSs and LBSs, the C2H2 adsorption amounts of SNNU-37(Fe/Sc) are much higher than those values for C2H4 and CO2. Theoretical IAST selectivity values of SNNU-37(Fe) are 2.4 for C2H2/C2H4 (50/50, v/v) and 9.9 for C2H2/CO2 (50/50, v/v) at 298 K and 1 bar, indicating an excellent C2H2 separation ability. Experimental breakthrough curves also revealed that SNNU-37(Fe) could effectively separate C2H2/C2H4 and C2H2/CO2 under ambient conditions. GCMC simulations further indicate that open Fe or Sc sites and amide groups mainly contribute to stronger adsorption sites for C2H2 molecules.

Kinetics control over the Schiff base formation reaction for fabrication of hierarchical porous carbon materials with tunable morphology for high-performance supercapacitors.

Schiff base formation reaction is highly dynamic, and the microstructure of Schiff base polymers is greatly affected by reaction kinetics. Herein, a series of Schiff base cross-linked polymers (SPs) with different morphologies are synthesized through adjusting the species and amount of catalysts. Nitrogen/oxygen co-doped hierarchical porous carbon nanoparticles (HPCNs), with tunable morphology, specific surface area (SSA) and porosity, are obtained after one-step carbonization. The optimal sample (HPCN-3) possesses a coral reef-like microstructure, high SSA up to 1003 m2g-1, and a hierarchical porous structure, exhibiting a remarkable specific capacitance of 359.5 F g-1(at 0.5 A g-1), outstanding rate capability and cycle stability in a 1 M H2SO4electrolyte. Additionally, the normalized electric double layer capacitance (EDLC) and faradaic capacitance of HPCN-3 are 0.239 F m-2and 10.24 F g-1respectively, certifying its superior electrochemical performance deriving from coral reef-like structure, high external surface area and efficient utilization of heteroatoms. The semi-solid-state symmetrical supercapacitor based on HPCN-3 delivers a capacitance of 55 F g-1at 0.5 A g-1, good cycle stability of 86.7% after 5000 GCD cycles at 10 A g-1, and the energy density ranges from 7.64 to 4.86 Wh kg-1.

Catalytic SN Ar Hydroxylation and Alkoxylation of Aryl Fluorides.

Nucleophilic aromatic substitution (SN Ar) is a powerful strategy for incorporating a heteroatom into an aromatic ring by displacement of a leaving group with a nucleophile, but this method is limited to electron-deficient arenes. We have now established a reliable method for accessing phenols and phenyl alkyl ethers via catalytic SN Ar reactions. The method is applicable to a broad array of electron-rich and neutral aryl fluorides, which are inert under classical SN Ar conditions. Although the mechanism of SN Ar reactions involving metal arene complexes is hypothesized to involve a stepwise pathway (addition followed by elimination), experimental data that support this hypothesis is still under exploration. Mechanistic studies and DFT calculations suggest either a stepwise or stepwise-like energy profile. Notably, we isolated a rhodium η5 -cyclohexadienyl complex intermediate with an sp3 -hybridized carbon bearing both a nucleophile and a leaving group.

Ru(II)-Catalyzed Amination of Aryl Fluorides via η6-Coordination.

We developed a Ru/hemilabile-ligand-catalyzed nucleophilic aromatic substitution (SNAr) of aryl fluorides as the limiting reagents. Significant ligand enhancement was demonstrated by the engagement of both electron-rich and neutral arenes in the SNAr amination without using excess arenes. Preliminary mechanistic studies revealed that the nucleophilic substitution proceeds on a η6-complex of the Ru catalyst and the substrate, and the hemilabile ligand facilitates dissociation of products from the metal center.

Application of Pyridinium 1,4-Zwitterionic Thiolates: Synthesis of Benzopyridothiazepines and Benzothiophenes.

Pyridinium 1,4-zwitterionic thiolates, as a novel kind of sulfur-containing synthon, have been applied to the synthesis of 12aH-benzo[f]pyrido[1,2-d][1,4]thiazepines and benzo[b]thiophenes. Benzopyridothiazepines were produced through a 1,5-dipolar cycloaddition reaction from pyridinium 1,4-zwitterionic thiolates with arynes, whereas benzothiophenes as side products were generated via a [3 + 2] cascade cyclization reaction. The [5 + 2] reaction mode of pyridinium 1,4-zwitterionic thiolates is disclosed for the first time.

Switchable Ring-Contractive Extrusion Reactions of 2,5-Dihydro-1,4,5-thiadiazepine S-Oxides: Entries to Pyridazines or Pyrazoles.

Switchable ring-contractive extrusion reactions of 2,5-dihydro-1,4,5-thiadiazepine S-oxides are described, which allow expedient access to pyridazines under thermal conditions or pyrazoles under Lewis acid-mediated conditions.

Tailoring the Pore Environment of a Robust Ga-MOF by Deformed [Ga3O(COO)6] Cluster for Boosting C2H2 Uptake and Separation.

The construction of superstable metal-organic frameworks (MOFs) for selective gas uptake is urgently demanded but remains a great challenge. Herein, a unique bifunctional deformed [Ga3O(COO)6] inorganic secondary building unit (SBU) generated from the desymmetrical evolution of typical triangular prismatic trinuclear cluster was first introduced, which was extended by an isosceles triangular organic linker to produce a robust Ga-MOF (SNNU-63). Remarkably, SNNU-63 can stabilize in water at 25 °C for 96 h and at 80 °C for more than 24 h, which surpasses nearly all other Ga-MOFs. The combined effects of open metal sites and hydrophobic pore environment provided by deformed [Ga3O] SBUs render SNNU-63 with high C2H2 storage capacity and efficient C2H2 and natural gas purification performance. The ideal adsorbed solution theory calculation, column breakthrough tests, and grand canonical Monte Carlo simulations demonstrate that SNNU-63 is a potential material for addressing the challenge of C2H2/CO2 and C2H2/CH4 mixture separation under ambient conditions.

Synthesis of fully substituted pyrazoles from pyridinium 1,4-zwitterionic thiolates and hydrazonoyl chlorides via a [[3 + 3] - 1] pathway.

A novel and practical protocol for the synthesis of fully substituted pyrazoles from pyridinium 1,4-zwitterionic thiolates and hydrazonoyl chlorides in excellent yields under mild conditions is described. The transformation proceeds via an unusual [[3 + 3] - 1] pathway, which involves a formal [3 + 3] cascade cyclization followed by a spontaneous ring-contraction/sulfur extrusion reaction from 4H-1,3,4-thiadiazine intermediates.

Synthesis of indolizines from pyridinium 1,4-zwitterionic thiolates and propiolic acid derivatives via a formal [4 + 1] pathway.

A novel cyclization reaction of pyridinium 1,4-zwitterionic thiolates and propiolic acid derivatives mediated by triethylamine is described, which allows the facile synthesis of indolizines under mild reaction conditions. The net transformation involves an acetylide-driven formal [5 + 1] annulation reaction followed by a spontaneous ring-contraction/sulfur extrusion process of transient pyridothiazine intermediates.

SDA: a semi-parametric differential abundance analysis method for metabolomics and proteomics data.

BACKGROUND: Identifying differentially abundant features between different experimental groups is a common goal for many metabolomics and proteomics studies. However, analyzing data from mass spectrometry (MS) is difficult because the data may not be normally distributed and there is often a large fraction of zero values. Although several statistical methods have been proposed, they either require the data normality assumption or are inefficient. RESULTS: We propose a new semi-parametric differential abundance analysis (SDA) method for metabolomics and proteomics data from MS. The method considers a two-part model, a logistic regression for the zero proportion and a semi-parametric log-linear model for the possibly non-normally distributed non-zero values, to characterize data from each feature. A kernel-smoothed likelihood method is developed to estimate model coefficients and a likelihood ratio test is constructed for differential abundant analysis. The method has been implemented into an R package, SDAMS, which is available at https://www.bioconductor.org/packages/release/bioc/html/SDAMS.html . CONCLUSION: By introducing the two-part semi-parametric model, SDA is able to handle both non-normally distributed data and large fraction of zero values in a MS dataset. It also allows for adjustment of covariates. Simulations and real data analyses demonstrate that SDA outperforms existing methods.

Competing endogenous RNA network and prognostic nomograms for hepatocellular carcinoma patients who underwent R0 resection.

The prognosis of hepatocellular carcinoma (HCC) after R0 resection is unsatisfactory due to the high rate of recurrence. In this study, we investigated the recurrence-related RNAs and the underlying mechanism. The long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) expression data and clinical information of 247 patients who underwent R0 resection patients with HCC were obtained from The Cancer Genome Atlas. Comparing the 1-year recurrence group (n = 56) with the nonrecurrence group (n = 60), we detected 34 differentially expressed lncRNAs (DElncRNAs), five DEmiRNAs, and 216 DEmRNAs. Of these, three DElncRNAs, hsa-mir-150-5p, and 11 DEmRNAs were selected for constructing the competing endogenous RNA (ceRNA) network. Next, two nomogram models were constructed based separately on the lncRNAs and mRNAs that were further selected by Cox and least absolute shrinkage and selection operator regression analysis. The two nomogram models that showed a high prediction accuracy for disease-free survival with the concordance indexes at 0.725 and 0.639. Further functional enrichment analysis of DEmRNAs showed that the mRNAs in the ceRNA network and nomogram models were associated with immune pathways. Hence, we constructed a hsa-mir-150-5p-centric ceRNA network and two effective nomogram prognostic models, and the related RNAs may be useful as potential biomarkers for predicting recurrence in patients with HCC.