Long non‐coding RNAs (LncRNAs) have been recently found to be pervasively transcribed in the genome and critical regulators of the epigenome. HOTAIR, as a well‐known LncRNA, has been found to play ...important roles in several tumors. Herein, the clinical application value and biological functions of HOTAIR were focused and explored in esophageal squamous cell carcinoma (ESCC). It was found that there was a great upregulation of HOTAIR in ESCC compared to their adjacent normal esophageal tissues. Meanwhile, patients with high HOTAIR expression have a significantly poorer prognosis than those with low expression. Moreover, HOTAIR was further validated to promote migration and invasion of ESCC cells in vitro. Then some specific molecules with great significance were investigated after HOTAIR overexpression using microarray and quantitative real time‐polymerase chain reaction (qPCR). WIF‐1 playing an important role in Wnt/β‐catenin signaling pathway was selected and further tested by immunehistochemistry. Generally, inverse correlation between HOTAIR and WIF‐1 expression was demonstrated both in ESCC cells and tissues. Mechanistically, HOTAIR directly decreased WIF‐1 expression by promoting its histone H3K27 methylation in the promoter region and then activated the Wnt/β‐catenin signaling pathway. This newly identified HOTAIR/WIF‐1 axis clarified the molecular mechanism of ESCC cell metastasis and represented a novel therapeutic target in patients with ESCC.
HOTAIR, a long non coding RNA, has been linked to the progression of several types of human cancer. In this study, we found that HOTAIR was not only significantly up‐regulated in tumor tissues, but also significantly associated with poor clinical outcome in patients with esophageal squamous cell carcinoma (ESCC). ESCC cells with HOTAIR overexpression displayed aberrant activated WNT signaling pathway by inhibiting the expression of WNT‐inhibitor factor 1, thereby promote the migration and invasion of ESCC cells. On the contrary, silencing of HOTAIR in ESCC cells led to decreased migration and invasion ability. Together, these results suggest that HOTAIR overexpression may serve as a novel prognostic biomarker and potential therapeutic target for the treatment of human ESCC.
Free radical mediated alkylation of alkenes is a challenging and largely unmet goal. Disclosed here is a conceptually novel “polarity umpolung” strategy for radical alkylation of alkenes using a ...portfolio of easily accessed, difunctional alkylating reagents. This strategy is achieved by substituting inherently nucleophilic alkyl radicals with electrophilic sulfone‐bearing surrogates, thus inverting the usual mode of reactivity. Along with alkylation, either an heteroaryl or oximino group is concurrently incorporated into the alkenes by a consecutive docking and migration process, leading to valuable products. The reaction displays a broad functional‐group tolerance under mild reaction conditions. The protocol opens new vistas for the late‐stage modification of complex natural products and drug molecules containing alkene moieties.
Polarity switch: A novel, mild, easy‐to‐execute protocol for radical alkylation of alkenes was developed using a polarity umpolung strategy. Both activated and challenging unactivated alkenes are suitable substrates. The protocol opens new vistas for the late‐stage modification of complex natural products and drug molecules containing alkene moieties.
Land use policies have turned southern China into one of the most intensively managed forest regions in the world, with actions maximizing forest cover on soils with marginal agricultural potential ...while concurrently increasing livelihoods and mitigating climate change. Based on satellite observations, here we show that diverse land use changes in southern China have increased standing aboveground carbon stocks by 0.11 ± 0.05 Pg C y
during 2002-2017. Most of this regional carbon sink was contributed by newly established forests (32%), while forests already existing contributed 24%. Forest growth in harvested forest areas contributed 16% and non-forest areas contributed 28% to the carbon sink, while timber harvest was tripled. Soil moisture declined significantly in 8% of the area. We demonstrate that land management in southern China has been removing an amount of carbon equivalent to 33% of regional fossil CO
emissions during the last 6 years, but forest growth saturation, land competition for food production and soil-water depletion challenge the longevity of this carbon sink service.
Herein, an electroreductive carboxylation of organic carbon‐halogen bonds (X=Br and Cl) promoted by catalytic amounts of naphthalene as an organic mediator is reported. This transformation proceeds ...smoothly under mild conditions with a broad substrate scope of 59 examples, affording the valuable and versatile carboxylic acids in moderate to excellent yields without the need of costly transition metal, wasted stoichiometric metal reductants, or sacrificial anodes. Further late‐stage carboxylations of natural product and drug derivatives demonstrate its synthetic utility. Mechanistic studies confirmed the activation of carbon‐halogen bonds via single‐electron transfer and the key role of naphthalene in this reaction.
A general and metal‐free method for the electroreductive carboxylation of carbon‐halogen bonds has been developed to obtain carboxylated compounds in the presence of catalytic amounts of naphthalene as a mediator. This reaction exhibits a broad substrate scope, and is shown to be a powerful approach for the late‐stage carboxylation of natural product and drug derivatives.
Over 17 and 160 types of chemical modifications have been identified in DNA and RNA, respectively. The interest in understanding the various biological functions of DNA and RNA modifications has lead ...to the cutting-edged fields of epigenomics and epitranscriptomics. Developing chemical and biological tools to detect specific modifications in the genome or transcriptome has greatly facilitated their study. Here, we review the recent technological advances in this rapidly evolving field. We focus on high-throughput detection methods and biological findings for these modifications, and discuss questions to be addressed as well. We also summarize third-generation sequencing methods, which enable long-read and single-molecule sequencing of DNA and RNA modification.
Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and ...select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients.
We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes.
CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival.
This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments.
ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.
A nickel‐catalyzed highly γ‐regioselective arylation and carbonylative arylation of 3‐bromo‐3,3‐difluoropropene has been developed. The reaction proceeds under mild reaction conditions, providing the ...gem‐difluoroalkenes with high efficiency and good functional group tolerance. The resulting gem‐difluoroalkenes can serve as versatile building blocks for diversified synthesis. Preliminary mechanistic studies and density functional theory calculations reveal that both non‐radical and radical pathways are possible for the reaction, and the radical pathway is more likely. The high γ‐regioselectivity results from the β‐bromide elimination of alkylnickel(II) species or from the reductive elimination of nickel(III) species (aryl)(CF2=CHCH2)NiIII(Ln)X. The γ‐selective carbonylation of 3‐bromo‐3,3‐difluoropropene under 1 atm CO gas also provides a new way for nickel‐catalyzed carbonylation.
A nickel‐catalyzed highly γ‐regioselective arylation and carbonylation of 3‐bromo‐3,3‐difluoropropene has been developed. The reaction provides a variety of gem‐difluoroalkenes with good functional group tolerance and high efficiency. Preliminary mechanistic studies and DFT calculations revealed that both non‐radical and radical pathways are possible for the reaction.
β‐fluorocarbanions have garnered considerable attention for their dual reactivity in nucleophilic processes and β‐fluorine elimination. In this study, a thorough computational analysis was conducted ...to explore the reactions of α‐(trifluoromethyl)styrenes with 2‐pyridones to delineate the factors determining protonation or defluorination pathways for the in situ generated β‐fluorocarbanions under varied basic conditions. Our findings illuminate the critical role of organobase basicity in steering the direction of the competitive protonation and β‐fluorine elimination reactions. We propose the use of pKaH values of organobases as a quantitative indicator for discerning the predominant reaction pathways. This provides an efficient approach to predict and control the reaction outcome, facilitating the deliberate design of reactions to leverage the unique reactivity of β‐fluorocarbanions in the realm of fluorine chemistry.
Dual reactivity of key intermediates β‐fluorocarbanions leads to hydroamination versus defluoroamination in reactions between α‐(trifluoromethyl)styrenes and 2‐pyridones. The competition between defluorination and protonation is mainly influenced by the sources of protons. Consequently, the pKaH values may serve as reliable indicators for predicting the most favorable reaction pathway.
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