Water-mediated radical C-H tosylation of alkenes with tosyl cyanide.

The water-mediated tosylation of alkenes with tosyl cyanide was discovered. Experimental investigations revealed that the reaction was initiated by the in situ formation of sulfinyl sulfone in the presence of water. The sulfinyl sulfone species decomposed to a sulfonyl radical and a sulfinyl radical through homolytic fission. The vinyl sulfone was afforded via sequential addition of the alkene to the sulfonyl radical and the sulfinyl radical, followed by ß-elimination of a sulfinyl moiety.

Synthesis, biological evaluation and preliminary mechanisms of 6-amino substituted harmine derivatives as potential antitumor agents.

To explore the effect of the introduction of the amino and substituted amino groups on the antitumor activity of harmine, twenty-five novel 6-amino substituted harmine derivatives (3a-3j and 5a-5o) were synthesized and evaluated for anti-proliferative activity on a panel of cancer cell lines. Compounds 3i and 5n exhibited the most potent antiproliferative activity with IC50 values lower than 2.2 µM. Especially, compound 5n possessed extremely potent antitumor activity with IC50 values of 0.34 µM and 0.65 µM against HL-60 and A549 cell lines, respectively. Further, the preliminary studies of mechanisms showed that compound 5n could significantly induce cell apoptosis in a dose-dependent manner, cause cell cycle arrest at the G2/M phase and intercalate into ct-DNA via the competition with EB, while displaying very weak topoisomerase I (Topo I) inhibition activity. More importantly, 5n showed mild cytotoxicity against human normal lung epithelial cells BEAS-2B. Based on these considerations, 5n may be a good antitumor candidate compound for further exploration.

Photochemical Synthesis of Indolocarbazoles through Tandem Indolization/Dimerization/Mannich Cyclization from Allenes.

Indolocarbazole alkaloids and their derivatives were discovered to have potent protein kinase and topoisomerase I inhibitory activities. Disclosed herein is the photochemical synthesis of the indolocarbazole ring system from N-allenyl-2-iodoanilines. The tandem protocol included visible-light-mediated 5-exo-trig radical cyclization and subsequent radical dimerization, followed by acid-promoted deprotection and intramolecular Mannich cyclization. This strategy showed exceptional functional group tolerance and was successfully applied in the concise synthesis of natural products tjipanazoles B and D.

A Matrigel-based 3D construct of SH-SY5Y cells models the α-synuclein pathologies of Parkinson's disease.

Parkinson's disease (PD) is associated with α-synuclein-based Lewy body pathology, which has been difficult to observe in conventional two-dimensional (2D) cell culture and even in animal models. We herein aimed to develop a three-dimensional (3D) cellular model of PD to recapitulate the α-synuclein pathologies. All-trans-retinoic acid-differentiated human SH-SY5Y cells and Matrigel were optimized for 3D construction. The 3D cultured cells displayed higher tyrosine hydroxylase expression than 2D cells and improved dopaminergic-like phenotypes, as suggested by RNA-sequencing analyses. Multiple forms of α-synuclein, including monomer, and low- and high-molecular mass oligomers, were differentially present in the 2D and 3D cells, but mostly remained unchanged upon N-methyl-4-phenyl pyridine or rotenone treatment. Phosphorylated α-synuclein was accumulated, and detergent-insoluble α-synuclein fraction was observed, in the neurotoxin-treated 3D cells. Importantly, Lewy body-like inclusions were captured in the 3D system, including proteinase K-resistant α-synuclein aggregates, ubiquitin aggregation, and ß-amyloid and ß-sheet protein deposition. The study provides a unique and convenient 3D model of PD that recapitulates critical α-synuclein pathologies and should be useful in multiple PD-associated applications.

Acylation of Arenes with Aldehydes through Dual C-H Activations by Merging Photocatalysis and Palladium Catalysis.

An acylation of arenes with aldehydes through dual C-H activations at room temperature is reported. The acylation was initiated by phenanthraquinone-catalyzed hydrogen atom transfer from aldehyde under visible light irradiation. The aldehyde-derived acyl radical merged with palladium-catalyzed activation of arenes to afford the cross coupling products.

Three-Component Minisci Reaction with 1,3-Dicarbonyl Compounds Induced by Visible Light.

A three-component Minisci reaction coupling of 1,3-dicarbonyl compounds with vinyl ethers and quinolines or isoquinolines under visible light is developed. The 1,3-dicarbonyl compound undergoes single-electron oxidation to afford an electrophilic 1,3-dicarbonyl radical under visible light irradiation. Due to the polarity of the free radical, the electrophilic radical adds to the electron-rich olefin to afford the nucleophilic radical. It coupled with the heteroarene to afford the three-component coupling products.

Neoadjuvant chemotherapy brings more survival benefits than postoperative chemotherapy for resectable gastric cancer: a Meta-analysis of randomized controlled trials.

PURPOSE: To find out which treatment, neoadjuvant chemotherapy (NAC) or postoperative chemotherapy (PAC), can bring greater survival benefits to gastric cancer patients. METHODS: Pubmed, Embase and Cochrane Library databases were searched for randomized controlled trials （RCTs）about multidisciplinary treatment of resectable gastric cancer (NAC vs PAC, NAC + surgery vs surgery alone, and surgery alone vs surgery + PAC). Quality was assessed by collaboration recommendation in Cochrane. All outcomes were evaluated by odds ratio (OR) and 95% confidence interval (CI). Pairwise comparisons were conducted by R3.12 software. Aggregate Data Drug Information System (ADDIS software 1.16.5) was used to perform network meta-analysis. RESULTS: Simple meta-analysis showed NAC could bring more survival benefits than PAC for resectable gastric cancer. NAC was significantly better than PAC in 1-year (I2=0, p=0.4085, fixed effects model, OR=2.28, 95%CI: 1.27-4.04), 3-year (I2=0,p=0.6979，fixed effects model, OR=2.10, 95%CI: 1.09-4.03), and 5-year survival (I2=37.8%, p=0.2048，fixed effects model, OR=2.04, 95%CI: 1.03-4.06). Network meta-analysis showed NAC + surgery was better compared with surgery + PAC and surgery alone. NAC + surgery were significantly better than surgery + PAC and surgery alone in 1-year or 3-year survival. For 5-year survival, NAC + surgery were significantly better than surgery alone, but no significant difference was observed when compared with surgery + PAC. NAC + surgery ranked first in 1-year, 3-year and 5-year probability sequence diagram. CONCLUSION: NAC brings greater survival benefits than PAC for patients with resectable gastric cancer.

Late onset warfarin-induced skin necrosis.

The incidence of warfarin-induced skin necrosis (WISN) is rare. The majority of WISN cases usually appear between 3 and 6 days after the initiation of warfarin therapy. Here we report a late-onset case of WISN that occurred in a 52-year-old man 4 years after the initiation of therapy. The skin lesions in the patient were associated with acquired deficiency of protein C and protein S and abnormal liver function.

Organocatalyzed Intermolecular Asymmetric Allylic Dearomatization of Both α- and ß-Naphthols.

The first highly stereoselective intermolecular catalytic asymmetric dearomatization (CADA) of α-naphthols through C-C formation and the first asymmetric allylic dearomatization of naphthols by chiral organocatalysis have been achieved. These new and complete atom-economic reactions provide enantioriched α- and ß-naphthalenones bearing an all-carbon quaternary center.

Symptomatic treatment of brain metastases in renal cell carcinoma with sorafenib.

Brain metastasis is synchronous to the diagnosis of renal cell carcinoma (RCC). The prognosis of brain metastasis in RCC with the current treatment options is dismissal. Therefore, we present a case of an elderly female patient with RCC showing a partial response of brain metastasis after 18 months of 600 mg once daily sorafenib treatment who underwent right-sided nephrectomy. Further, withdrawal of sorafenib resulted in psychiatric changes along with increased metastasis lesions, which were recovered upon resuming the treatment, proposing that oral sorafenib can be used safely and efficiently for treatment of brain metastasis in advanced RCC.

Tumor-targeting templated silica nanoparticles as a dual-drug delivery system for anti-angiogenic ovarian cancer therapy.

The present study indicated the successful construction of a silica nanoparticle (SLN)-based drug delivery system (DDS) for the tumor-targeted co-delivery of two anti-angiogenic drugs, candesartan (CD) and trastuzumab (Tra), for ovarian cancer therapy via different anti-angiogenic mechanisms using hyaluronic acid (HA)/Tra/CD/SLNs. In vitro and in vivo anti-angiogenic assays indicated that CD and Tra exert beneficial functions on suppressing cancer angiogenesis, and exhibited significantly enhanced effects compared with the angiotensin stimulated group (P<0.01). CD and Tra co-delivery also significantly increased the anti-angiogenic effect compared with applying either drug alone (P<0.01). Furthermore, HA on the surface of the DDS was demonstrated to reduce the cytotoxicity of the DDS and also endowed the particles with an advanced tumor-homing property in vitro and in vivo. The present results revealed that HA/Tra/CD/SLNs may be a preferable formulation for anti-angiogenic ovarian cancer therapy.

Molecular mechanisms of breast cancer metastasis by gene expression profile analysis.

Metastasis is the main cause of breast cancer­related mortalities. The present study aimed to uncover the relevant molecular mechanisms of breast cancer metastasis and to explore potential biomarkers that may be used for prognosis. Expression profile microarray data GSE8977, which contained 22 stroma samples (15 were from normal breast and 7 were from invasive ductal carcinoma tumor samples), were obtained from the Gene Expression Omnibus database. Following data preprocessing, differentially expressed genes (DEGs) were selected based on analyses conducted using the linear models for microarray analysis package from R and Bioconductor software. The resulting data were used in subsequent function and pathway enrichment analyses, as well as protein­protein interaction (PPI) network and subnetwork analyses. Transcription factors (TFs) and tumor­associated genes were also identified among the DEGs. A total of 234 DEGs were identified, which were enriched in immune response, cell differentiation and cell adhesion­related functions and pathways. Downregulated DEGs included TFs, such as the proto­oncogene SPI1, pre­B­cell leukemia homeobox 3 (PBX3) and lymphoid enhancer­binding factor 1 (LEF1), as well as tumor suppressors (TSs), such as capping actin protein, gelsolin like (CAPG) and tumor protein p53­inducible nuclear protein 1 (TP53INP1). Upregulated DEGs also included TFs and tumor suppressors, consisting of transcription factor 7­like 2 (TCF7L2) and pleiomorphic adenoma gene­like 1 (PLAGL1). DEGs that were identified at the hub nodes in the PPI network and the subnetwork were epidermal growth factor receptor (EGFR) and spleen­associated tyrosine kinase (SYK), respectively. Several genes crucial in the metastasis of breast cancer were identified, which may serve as potential biomarkers, many of which were associated with cell adhesion, proliferation or immune response, and may influence breast cancer metastasis by regulating these function or pathways.

Retrospective analysis of results of treatment for nasopharyngeal carcinoma in Macao.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common malignancy in Southeast Asia, however, a full consensus has not yet been reached as to the value of comprehensive treatment for NPC. This study was designed to evaluate the epidemiological characteristics of NPC and their prognostic value, as well as the long-term efficacy of NPC treatment. PATIENTS AND METHODS: A total of 248 patients, with different stages of NPC, were included in this study. RESULTS: The 5-year overall survival (OS) rates for patients in stages I, II, III and IV were 90.48%, 76.71%, 76.89% and 33.87%, respectively (P=0.000), while the respective 5-year progression-free survival (PFS) rates were 85.15%, 72.36%, 63.88% and 26.26% (P=0.000). The respective 5-year OS rates, according to stage, for the group that received radiotherapy combined with chemotherapy and for the group that received radiotherapy only were as follows: stages I and II, 81.67% and 79.59% (P=0.753); stage III, 79.91% and 70.38% (P=0.143); stage IV, 35.22% and 0% (P=0.000). The respective 5-year PFS rates in these groups were as follows: stages I and II, 75.83% and 74.98% (P=0.814); stage III, 74.08% and 42.25% (P=0.027); stage IV, 27.31% and 0% (P=0.000). CONCLUSIONS: Clinical staging appears to be the most important prognostic factor for NPC. As the stage number increases, both the 5-year OS and PFS significantly decrease. Adding chemotherapy to radiotherapy was not advantageous for patients with stage I or II NPC, however the addition of chemotherapy to radiotherapy significantly improved OS and PFS in patients with stage IV NPC. The addition of chemotherapy improved PFS, but not OS in patients with stage III NPC.

Paclitaxel-octreotide conjugates in tumor growth inhibition of A549 human non-small cell lung cancer xenografted into nude mice.

Targeted chemotherapy is a novel approach to cancer therapies. This study evaluated the anti-tumor effects of conjugates made by coupling cytotoxic paclitaxel to the somatostatin analog octreotide in A549 human non-small-cell lung cancer (NSCLC) cells xenografted into nude mice. Two cytotoxic somatostatin analogs, paclitaxel-octreotide and 2paclitaxel-octreotide, were prepared by the coupling of one or two paclitaxel molecules with an octreotide molecule. A549 xenografts expressed mRNAs for type 1, 2, 4, and 5 somatostatin receptors. Immunohistology revealed that type 2 somatostatin receptors were mainly located in tumor cell membrane but type 5 somatostatin receptors were found in tumor cell membrane and cytoplasm. Significant tumor growth inhibition was achieved by 2paclitaxel-octreotide at 150 nM/kg and 300 nM/kg. 2paclitaxel-octreotide also significantly extended the tumor doubling time and significantly reduced tumor microvessel density at these doses. Moreover, there was more fragmented DNA in the 2paclitaxel-octreotide single and double dose groups than in the controls. Paclitaxel was ineffective and more toxic than the conjugate as shown by the significant decline of body weight in Paclitaxel group on Days 6, 12, and 26 compared to those treated with 2paclitaxel-octreotide (P<0.05). White blood cell counts in the paclitaxel single and double dose groups were also significantly less than in the controls (P<0.05). In conclusion, the targeting conjugate 2paclitaxel-octreotide made by coupling two molecules of cytotoxic paclitaxel to one somatostatin analog octreotide could enhance tumor growth inhibition and reduce toxicity in comparison to using the cytotoxic paclitaxel alone.