Photoinduced Co/Ni-cocatalyzed Markovnikov hydroarylation of unactivated olefins with aryl bromides.

Transition-metal-catalyzed hydroarylation of unactivated alkenes via metal hydride hydrogen atom transfer (MHAT) is an attractive approach for the construction of C(sp2)-C(sp3) bonds. However, this kind of reaction focuses mainly on using reductive hydrosilane as a hydrogen donor. Here, a novel photoinduced Co/Ni-cocatalyzed Markovnikov hydroarylation of unactivated alkenes with aryl bromides using protons as a hydrogen source has been developed. This reaction represents the first example of photoinduced MHAT via a reductive route intercepting an organometallic coreactant. The key to this transformation was that the CoIII-H species was generated from the protonation of the CoI intermediate, and the formed CoIII-C(sp3) intermediate interacted with the organometallic coreactant rather than reacting with nucleophiles, a method which has been well developed in photoinduced Co-catalyzed MHAT reactions. This reaction is characterized by its high catalytic efficiency, construction of quaternary carbons, simple reaction conditions and expansion of the reactive mode of Co-catalyzed MHAT reactions via a reductive route. Moreover, this catalytic system could also be applied to complex substrates derived from glycosides.

Photoredox-Catalyzed Amino-Radical-Transfer-Mediated Three-Component Alkylarylation of Alkenes.

We herein reported a novel photoredox-catalyzed three-component alkylarylation of vinyl arenes with alkylboronic pinacol esters (APEs) and cyanoarenes via radical addition/cross-coupling to construct 1,1-diarylalkanes. In this transformation, alkyl radicals were easily available by visible-light-induced oxidative N-H cleavage of morpholine, which used APEs as a radical precursor. Furthermore, this protocol exhibited a broad substrate scope, enabling various styrenes, APEs, and cyanoarenes, as well as bioactive molecule derivatives.

Aryl-to-Vinyl 1,4-Nickel Migration/Reductive Cross-Coupling Reaction for the Stereoselective Synthesis of Multisubstituted Olefins.

The aryl-to-vinyl nickel 1,4-migration (1,4-Ni migration) reaction has been reported for the first time. The generated alkenyl Ni species undergo a reductive coupling reaction with unactivated brominated alkanes affording a series of trisubstituted olefins. This tandem reaction exhibits mild conditions, a broad substrate scope, high regioselectivity, and excellent Z/E stereoselectivity. A series of controlled experiments have shown that the critical 1,4-Ni migration process is reversible. In addition, the alkenyl nickel intermediates obtained after migration are highly Z/E stereoselective and do not undergo Z/E isomerization. The obtained trace isomerization products are caused by the instability of the product.

CHD1 deletion stabilizes HIF1α to promote angiogenesis and glycolysis in prostate cancer.

Chromodomain-helicase-DNA-binding protein 1 (CHD1) deletion is among the most common mutations in prostate cancer (PCa), but its role remains unclear. In this study, RNA sequencing was conducted in PCa cells after clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9)-based CHD1 knockout. Gene set enrichment analysis (GSEA) indicated upregulation of hypoxia-related pathways. A subsequent study confirmed that CHD1 deletion significantly upregulated hypoxia-inducible factor 1α (HIF1α) expression. Mechanistic investigation revealed that CHD1 deletion upregulated HIF1α by transcriptionally downregulating prolyl hydroxylase domain protein 2 (PHD2), a prolyl hydroxylase catalyzing the hydroxylation of HIF1α and thus promoting its degradation by the E3 ligase von Hippel-Lindau tumor suppressor (VHL). Functional analysis showed that CHD1 deletion promoted angiogenesis and glycolysis, possibly through HIF1α target genes. Taken together, these findings indicate that CHD1 deletion enhances HIF1α expression through PHD2 downregulation and therefore promotes angiogenesis and metabolic reprogramming in PCa.

Visible-Light-Driven [3 + 2]/[4 + 2] Annulation Reactions of Alkenes with N-Aminopyridinium Salts.

The annulation reactions of benzoamidyl radicals with alkenes were realized under visible light irradiation with fac-Ir(ppy)3 as catalyst and N-aminopyridinium salts as benzoamidyl radical precursors. The reaction can deliver two distinct types of products: in the case of vinyl arenes, [3 + 2] annulation product dihydrooxazoles were yielded exclusively; when alkyl-substituted alkenes were used, on the other hand, it afforded [4 + 2] annulation product dihydroisoquinolinones. Factors determining the reaction consequence were elucidated by DFT calculations.

Site-selective coupling of remote C(sp3)-H/meta-C(sp2)-H bonds enabled by Ru/photoredox dual catalysis and mechanistic studies.

Construction of C(sp2)-C(sp3) bonds via regioselective coupling of C(sp2)-H/C(sp3)-H bonds is challenging due to the low reactivity and regioselectivity of C-H bonds. Here, a novel photoinduced Ru/photocatalyst-cocatalyzed regioselective cross-dehydrogenative coupling of dual remote C-H bonds, including inert γ-C(sp3)-H bonds in amides and meta-C(sp2)-H bonds in arenes, to construct meta-alkylated arenes has been accomplished. This metallaphotoredox-enabled site-selective coupling between remote inert C(sp3)-H bonds and meta-C(sp2)-H bonds is characterized by its unique site-selectivity, redox-neutral conditions, broad substrate scope and wide use of late-stage functionalization of bioactive molecules. Moreover, this reaction represents a novel case of regioselective cross-dehydrogenative coupling of unactivated alkanes and arenes via a new catalytic process and provides a new strategy for meta-functionalized arenes under mild reaction conditions. Density functional theory (DFT) calculations and control experiments explained the site-selectivity and the detailed mechanism of this reaction.

Three-Component Ru-Catalyzed Regioselective Alkylarylation of Vinylarenes via Meta-Selective C(sp2)-H Bond Functionalization.

We report a novel Ru-catalyzed regioselective alkylarylation of vinylarenes with alkyl halides and arenes via meta-C(sp2)-H bond functionalization to construct 1,1-diarylalkanes that generally show bioactivity. In this transformation, a wide spectrum of primary, secondary, and tertiary alkyl halides and electronically varied arenes was well-tolerated. This reaction is characterized by its exquisite regioselectivity of vinylarenes, unique meta-C(sp2)-H selectivity, and redox-neutral conditions. The mechanism presented was supported by radical probes and kinetic isotope effect studies.

Photoredox-catalyzed redox-neutral difluoroalkylation to construct perfluoroketones with difluoroenoxysilanes.

A mild and facile approach to construct various perfluoroketones via photo-catalyzed difluoroalkylation of difluoroenoxysilanes is developed. The reaction includes a strategy of combination of two fluorine-containing functional groups, which confers the reaction with characteristics like high efficiency, mild conditions, and broad scope. A variety of fluoroalkyl halides including perfluoroalkyl iodides, bromo difluoro esters and amides can be employed as radical precursors. Control experiments indicate that a single-electron transfer pathway may be involved in the reaction.

Cu-Catalyzed Direct C-H Alkylation of Polyfluoroarenes via Remote C(sp3)-H Functionalization in Carboxamides.

A novel dehydrogenative coupling reaction of N-fluorocarboxamides with polyfluoroarenes forming C(sp2)-C(sp3) bonds enabled by copper catalysis has been accomplished. N-Fluorocarboxamides are postulated to undergo copper-mediated dehydrogenative cross-coupling reaction with electron-deficient polyfluoroarenes via a radical pathway. Benzylic C-H bonds and aliphatic C-H bonds in N-fluorocarboxamides could proceed smoothly and demonstrated excellent regioselectivity. The detailed mechanism presented is supported by control experiments and density functional theory calculations.

Copper-Catalyzed Radical Aryl Migration Approach for the Preparation of Cyanoalkylsulfonylated Oxindoles/Cyanoalkyl Amides.

A copper-catalyzed radical cross-coupling of oxime esters and activated alkenes is accomplished for the synthesis of cyanoalkylsulfonylated oxindoles and cyanoalkyl amides via an aryl migration strategy. Specifically, the subsequent mechanism research indicates that the unique desulfonylation and sulfone addition processes were involved in the transformation. This transformation is identified as having good functional group applicability with two different quaternary stereocenter in a regioselective manner, which is controlled by the substituent group of the nitrogen.

Visible-Light-Mediated Decarboxylative Radical Addition Bifunctionalization Cascade for the Production of 1,4-Amino Alcohols.

A photocatalytic decarboxylative radical addition bifunctionalization cascade for the synthesis of functionalized alcohols is described. The catalytic cycle is completed through single-electron transfer. The advantages of this reaction are the commercially available materials, wide functional group compatibility, and mild conditions. Notably, some amino acids and bioactive carboxylic acids can provide corresponding products in moderate to good yields, reflecting the potential value in drug development.

Visible-Light-Mediated Trifluoromethylation/Benzylation of Styrenes Catalyzed by 4-CzIPN.

Difunctionalization of alkenes is a valuable tool for the synthesis of complicated compounds from simple precursors. Herein, a feasible method for the construction of ß-trifluoromethyl-α-substituted alcohols under visible-light-induced metal-free conditions is described. This catalytic system exhibits mild reaction conditions and good compatibility of functional groups. Trifluoromethyl and alcohols are valuable structural motifs due to their unique biological properties, and this work shows the potential application in the realm of pharmacy and organic synthesis.

Visible-Light-Induced Pd-Catalyzed Radical Strategy for Constructing C-Vinyl Glycosides.

A novel visible-light-induced palladium-catalyzed Heck reaction for bromine sugars and aryl olefins with high regio- and stereochemistry selectivity for the preparation of C-glycosyl styrene is described. This reaction takes place in one step at room temperature by using a simple and readily available starting material. This protocol can be scaled up to a wide range of glycosyl bromide donors and aryl olefin substrates. Mechanistic studies indicate that a radical addition pathway is involved.

Thermal ablation versus hepatic resection for the treatment of liver metastases from gastrointestinal stromal tumors: a retrospective study.

Objective: The study aimed to compare effectiveness and safety of thermal ablation and hepatic resection in patients with liver metastases of gastrointestinal stromal tumors (GISTs).Method: A total of 55 patients (27 in the ablation group and 28 in the surgery group) with liver metastases were included. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier's survival estimate curves. Univariate and multivariate regression analyses were carried out to identify potential prognostic factors.Results: The median OS was 102.0 months in the ablation group and 117.0 months in the surgery group (p = .875). The 1-, 3- and 5-year OS rates were 100%, 88.9% and 74.1% in the ablation group and 92.8%, 82.1% and 78.6% in the surgery group, respectively. The 1-, 3- and 5-year PFS rates were 48.1%, 25.9% and 18.5% in the ablation group and 67.8%, 64.3% and 64.3% in the surgery group, respectively. Multivariate analysis showed that preoperative tyrosine kinase inhibitor (TKI) treatment (progressive disease, PD) (HR, 13.985; 95% CI, 1.791-109.187; p = .012) was the only significant independent prognostic factor for OS. Tumor number (HR, 1.318; 95% CI, 1.021-1.702; p = .034) was identified as an independent predictor for PFS in multivariate analysis. There were fewer postoperative complications (18.5% vs. 78.6%, p = .001) and shorter lengths of hospital stay (8.0 vs. 16.5 days, p = .001) in the ablation group.Conclusion: Compared with resection, thermal ablation offered comparable OS for liver metastases of GISTs. Furthermore, thermal ablation had the advantages of fewer complications and shorter lengths of hospital stay.

[Evaluation on the Impacts of Different Background Determination Methods on CO2 Sources and Sinks Estimation and Seasonal Variations].

To accurately determine background conditions or extract sources and sinks information from the observed atmospheric carbon dioxide (CO2) concentration is crucial for quantitative estimation of regional and global carbon budget and future trends of atmospheric CO2. In this study, the synchronized observed surface winds and carbon monoxide (CO) concentration have been examined to test their effectiveness as filter factors to determine CO2 background conditions at Waliguan site. The results show that the surface winds and CO concentrations can be used as filter factor in winter, but they are not very effective in summer. Three statistical methods, robust estimation of background signal (REBS), Fourier transform algorithm (FTA) and a new developed moving average filtering (MAF), are applied to atmospheric CO2 background selection. The result suggested that our new developed MAF method, which can well estimate the elevated and sequestered CO2 concentrations due to using changing and adjusting filter criteria at every two-week fitting window, is thus better than the other two statistical methods. A good consistency is indicated by the three methods for estimating the elevated CO2 caused by local or regional emissions, but it showed large discrepancies when determining the sequestered CO2. The result suggested that the three methods can reasonable extract those anthropogenic influenced episodes, but only MAF method would well identify those episodes due to terrestrial CO2 fluxes. Mean seasonal amplitude of atmospheric CO2 at Waliguan during 1995-2008 is 10. 3 x 10(-6) estimated by MAF method, which is in good agreement with previous studies. Whereas, the seasonal amplitudes derived by REBS method are much lower, only with a value of ~9. 1 x 10(-6) during 1995-2008, which will result in an underestimation of regional or global CO2 fluxes.

A long noncoding RNA activated by TGF-ß promotes the invasion-metastasis cascade in hepatocellular carcinoma.

The role of TGF-ß-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination is well established, but the involvement of lncRNAs in TGF-ß signaling is still unknown. In this study, we observed that the lncRNA-activated by TGF-ß (lncRNA-ATB) was upregulated in hepatocellular carcinoma (HCC) metastases and associated with poor prognosis. lncRNA-ATB upregulated ZEB1 and ZEB2 by competitively binding the miR-200 family and then induced EMT and invasion. In addition, lncRNA-ATB promoted organ colonization of disseminated tumor cells by binding IL-11 mRNA, autocrine induction of IL-11, and triggering STAT3 signaling. Globally, lncRNA-ATB promotes the invasion-metastasis cascade. Thus, these findings suggest that lncRNA-ATB, a mediator of TGF-ß signaling, could predispose HCC patients to metastases and may serve as a potential target for antimetastatic therapies.

[Diagnostic accuracy research of needle puncture biopsy during operation for pulmonary single nodules].

OBJECTIVE: To investigate the diagnostic accuracy of needle puncture biopsy and pathological examination of frozen during operation for pulmonary nodules, and whether this diagnostic method can replace tumor resection examination. METHODS: Totally 50 patients (28 males and 22 females, average age was 59 years) who had the single nodule after imaging examination without any pathological diagnostic from January to October 2010 were selected in this research work. During open operation or video assisted thoracic surgery, needle (14 G model) was used to puncture biopsy for pathological examination of frozen. All the adverse events during puncture biopsy would be recorded. The resection specimens would be accepted paraffin pathological examination. The relationship between puncture frozen pathological and paraffin pathological examination was analyzed. RESULTS: All tumor sizes were ranged from 1.0 cm × 0.6 cm to 5.6 cm × 9.0 cm. The paraffin pathological examination after operation as the golden standard, there were 7 cases of benign tumor and 43 cases of malignant tumor. The diagnostic sensitivity of puncture biopsy was 90.7%, the specificity was 100%, the positive predictive value was 100% and the negative predictive value was 63.6%. There were 11 cases of benign tumor diagnosed by needle puncture biopsy, among which 4 cases were proved as malignant tumor by paraffin pathology, and the false negative rate was 9.3%. The main risk of puncture biopsy was bleeding after puncture immediately, and the rate was 4.0% (2/50). CONCLUSIONS: The puncture biopsy during operation had a high specificity for malignant lung tumor, and there was a certain false negative rate for benign tumor. Puncture biopsy and pathological examination of frozen tissue can replace tumor section biopsy in a way.

[Diagnostic value of enhanced computed tomography plus vascular endothelial growth factor C expression in hilar and mediastinal lymph node metastasis of non-small cell lung cancer].

OBJECTIVE: To explore the diagnostic value of preoperative enhanced computed tomography (CT) plus vascular endothelial growth factor C (VEGF-C) expression in hilar and mediastinal lymph nodes metastasis of non-small cell lung cancer. METHODS: A total of 87 patients with non-small cell lung cancer (NSCLC) received preoperative chest enhanced CT scans and underwent standard radical operation and systematic lymph node dissection. Pathologic examination was selected as the gold standard to determine lymph node metastasis. The immunohistochemical method was used to detect the expression of VEGF-C. The predicting values of chest enhanced CT, VEGF-C expression and their combination for the diagnosis of hilar and mediastinal lymph nodes metastasis were evaluated through comparing the sensitivity, specificity and accuracy. RESULTS: The sensitivity of CT scan was 75.0%, specificity 59.6% and accuracy 66.7%. The positive expression rate of VEGF-C was 78.2% (68/87) and strong positive rate 13.8% (12/87). The sensitivity of VEGF-C was 97.5%, specificity 38.3% and accuracy 65.5%. The combination of CT and VEGF-C had a better accuracy (74.7%) and the sensitivity and specificity were 80.0% and 70.2% respectively. CONCLUSION: Compared with CT scan or VEGF-C expression alone, the combination of CT and VEGF-C improves the specificity and accuracy of diagnosing lymph nodes metastasis in NSCLC. If this combination method is employed before therapy, the accuracy of clinical nodal staging may be enhanced.

Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans.

UNLABELLED: In recent years, long noncoding RNAs (lncRNAs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of lncRNAs to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain largely unknown. Differentially expressed lncRNAs between HBV-related HCC and paired peritumoral tissues were identified by microarray and validated using quantitative real-time polymerase chain reaction. Liver samples from patients with HBV-related HCC were analyzed for levels of a specific differentially expressed lncRNA High Expression In HCC (termed lncRNA-HEIH); data were compared with survival data using the Kaplan-Meier method and compared between groups by the log-rank test. The effects of lncRNA-HEIH were assessed by silencing and overexpressing the lncRNA in vitro and in vivo. The expression level of lncRNA-HEIH in HBV-related HCC is significantly associated with recurrence and is an independent prognostic factor for survival. We also found that lncRNA-HEIH plays a key role in G(0) /G(1) arrest, and further demonstrated that lncRNA-HEIH was associated with enhancer of zeste homolog 2 (EZH2) and that this association was required for the repression of EZH2 target genes. CONCLUSIONS: Together, these results indicate that lncRNA-HEIH is an oncogenic lncRNA that promotes tumor progression and leads us to propose that lncRNAs may serve as key regulatory hubs in HCC progression.