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Aryl sulfones and aryl sulfonamides are of great importance in organic synthesis and medicinal chemistry. Although ortho‐C−H functionalization of aryl sulfonyl compounds has been extensively explored, the functionalization of remote meta‐ and para‐C−H bonds is very rare. Herein, we report a tunable meta‐ and para‐selective C−H borylation of aryl sulfonyl compounds enabled by computationally designed ligands and iridium catalyst. This method is capable of accommodating a broad range of substrates under mild reaction conditions. Gram‐scale preparation can be achieved with iridium catalyst loading as low as 0.1 mol%. As the introduced boronate group can be easily converted into many other groups, our method provides a general solution to installing functional groups at either meta‐ or para‐position of aryl sulfones and aryl sulfonamides with good to excellent selectivity. [ABSTRACT FROM AUTHOR]

Aryl sulfones and aryl sulfonamides are of great importance in organic synthesis and medicinal chemistry. Although ortho‐C−H functionalization of aryl sulfonyl compounds has been extensively explored, the functionalization of remote meta‐ and para‐C−H bonds is very rare. Herein, we report a tunable meta‐ and para‐selective C−H borylation of aryl sulfonyl compounds enabled by computationally designed ligands and iridium catalyst. This method is capable of accommodating a broad range of substrates under mild reaction conditions. Gram‐scale preparation can be achieved with iridium catalyst loading as low as 0.1 mol%. As the introduced boronate group can be easily converted into many other groups, our method provides a general solution to installing functional groups at either meta‐ or para‐position of aryl sulfones and aryl sulfonamides with good to excellent selectivity. [ABSTRACT FROM AUTHOR]

Background: Due to a limited patient sample size, substantial data on robotic rectal resection (RRR) is lacking. Here, we reported a large consecutive cases from the real word data to assess the safety and efficacy of RRR.Methods: From September 2010 to June 2017, a total of 1145 consecutive RRR procedures were performed in patients with stage I-IV disease. We conducted an analysis based on information from a prospectively designed database to evaluate surgical outcomes, urogenital function, and long-term oncological outcomes.Results: Of three types of RRR performed, 227 (24.2%) were abdominoperineal resections, 865 (75.5%) were anterior resections, and 3 (0.3%) were Hartmann. Conversion to an open procedure occurred in 5.9% of patients. The overall positive circumferential margin rate was 1.3%. Surgical complication rate and mortality were 16.2% and 0.8% within 30 days of surgery, respectively. Mean hospital stay after surgery and hospital cost were 6.3 ± 2.9 days and 10442.5 ± 3321.5 US dollars, respectively. Risk factors for surgical complications included male gender, tumor location (mid-low rectum), combined organ resection, and clinical T category (cT3-4). Urinary function and general sexual satisfaction decreased significantly 1 month after surgery for both sexes. Subsequently, both parameters increased progressively, and the values 1 year after surgery were comparable to those measured before surgery. At a median follow-up of 34.6 months, local recurrence and distant metastases occurred in 2.3% and 21.1% of patients, respectively.Conclusions: Robotic rectal resection was safe with preserved urogenital function and arrived equivalent oncological outcomes in a nonselected group of patients with rectal cancer. [ABSTRACT FROM AUTHOR]

• The syntheses of aliphatic and aromatic acyl fluorides are described. • The highly active CuF species generated from CuCF 3 is investigated. • Computational studies for copper fluoroalkyl intermediates are performed. Trifluoromethyl copper (CuCF 3), as a diverse fluorination reagent, has been widely used in trifluoromethylation, perfluoroalkylation, and difluorocarbene reactions. However, it has rarely been reported as a single fluorine source involved in nucleophilic fluorination reactions. This work describes a general strategy involving copper-mediated deoxyfluorination of redox-active esters to rapidly access various aliphatic and aromatic acyl fluorides. The highly active CuF species could be generated from either copper fluoride salts or CuCF 3. A plausible mechanism of CuCF 3 forming an [F-CuCF 2 F 5 ]- intermediate and NHBC ester forming acyl fluoride has been derived from DFT calculations. [Display omitted] [ABSTRACT FROM AUTHOR]

Gastrin was initially identified as the hormone primarily responsible for gastric acid secretion, but was subsequently shown to be a growth factor for the proximal stomach, acting through the gastrin receptor CCK2R. Studies in the past several decades have explored the role of gastrin, along with its incompletely processed precursors, in cancer development. The growth in long-term PPI use has frequently led to elevations in serum gastrin levels in patients with upper GI disease, including GERD, peptic ulcers, and chronic gastritis. However, while accumulated evidence has shown that gastrin likely does not promote — and may even suppress — distal antral gastric cancer, questions have now arisen regarding possible effects of gastrin on the development of gastric cardia cancer or esophageal adenocarcinoma at gastroesophageal junction. Here, we provide an overview of the possible roles of these gastrin peptides in upper GI cancer. [ABSTRACT FROM AUTHOR]

Aneffective Pd-catalyzed regiodivergent hydroesterification ofaryl olefins with phenyl formate is described. Either linear or branchedphenyl arylpropanoates can be obtained in good yields with high regioselectivitiesby the judicious choice of ligand without the use of toxic CO gas. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the role of HER2 positivity in prognosis and unresponsiveness to anti-EGFR therapy for colorectal cancer. Methods: Patients who underwent primary CRC tumor resection were included. HER2 status of CRC was confirmed by immunohistochemistry and fluorescence in situ hybridization tests. Comparison of survival analysis between HER2 positivity and negativity was evaluated by a stratified log-rank test and summarized with the use of Kaplan–Meier and Cox proportional hazards methods. The treatment effects of cetuximab were further compared in full subgroup analyses. Result: 1240 patients were enrolled, including 763 with stage I-III CRC and 477 with stage IV CRC. 57 (4.6%) CRC patients presented HER2 positivity in the entire cohort. The survival analysis showed that patients with HER2 positivity had significantly worse disease-free survival and overall survival in stage III and IV CRC. The multivariable analysis also confirmed that HER2 positivity was a significantly independent risk factor in stage III and IV CRC. Univariate and multivariable survival analysis showed no prognostic significance of HER2 positivity in stage I–II CRC patients. Prespecified subgroup analysis showed no favorable trends in progression-free survival and overall survival for cetuximab in the patients with HER2 positivity, KRAS/NRAS/BRAF wild-type metastatic CRC (interaction P values = 0.005 and 0.014). Conclusion: For stage III and IV CRC patients, HER2 positivity was confirmed as an independent prognostic risk factor. It could help predict the unresponsiveness to anti-EGFR therapy for metastatic CRC. [ABSTRACT FROM AUTHOR]

Background and Aim: Radical surgery is recommended for T1 colorectal cancer with non-curative endoscopic resection. However, there is still insufficient evidence about whether the non-curative endoscopic resection prior to surgical resection affects the short-term and long-term outcomes of patients. The purpose of this study was to investigate the effect of non-curative endoscopic resection before surgical resection on short-term and long-term outcomes in patients with T1 colorectal cancer.Patients and Methods: Patients with clinical T1N0M0 (cT1N0M0) colorectal cancer who underwent direct surgery or additional radical surgery after non-curative endoscopic resection were collected. We evaluated postoperative complications and long-term prognosis between the two groups.Results: From 2011 to 2017, 779 patients were clinically diagnosed with T1N0M0 colorectal cancer at Zhongshan Hospital. We assessed patients who underwent additional surgery following the prior non-curative endoscopic resection (n = 145) and patients who underwent radical surgery directly (n = 336). There was no significant difference in 5-year OS (99.3% vs. 99.4%, P = 0.866) and 5-year DFS (97.2% vs. 97.3%, P = 0.909) between the two groups. The total complication rate was slightly higher in prior endoscopic resection group (15.2% vs. 9.5%, P = 0.111). The 5-year OS and 5-year DFS of patients who refused additional surgery (n = 95) were significantly lower than ER prior to surgery group (For OS, 92.6% vs. 99.3%, P = 0.017; for DFS, 91.2% vs. 97.2%, P = 0.021).Conclusion: In patients who underwent additional surgery, non-curative endoscopic resection of cT1 colorectal carcinoma did not have adverse effect on short-term and long-term outcomes. Additional surgery should be recommended in patients who received non-curative ER. [ABSTRACT FROM AUTHOR]

A regioselective hydroesterification of 2-allylphenols with phenyl formate as CO source leads to benzo-fused ε-caprolactones in good yields under mild conditions. [ABSTRACT FROM AUTHOR]

A diagram is presented which explains the palladium-catalyzed enantioselective hydroesterification of phenyl formate and alkenylphenols.

Dependent on the choice of ligand, either linear or branched phenyl arylpropanoates are selectively obtained. [ABSTRACT FROM AUTHOR]

Objectives: Patients with colorectal liver metastases (CRLM) who underwent hepatic resection after conversion therapy had a high recurrence rate of nearly 90%. Preoperative DEB-TACE has the potential to prevent postoperative recurrence which has not been elucidated. The objective of this study was to evaluate the safety and efficacy of preoperative DEB-TACE. Materials and methods: Patients with CRLM who underwent liver resection from June 1, 2016, to June 30, 2021, were collected and those who received conversional hepatectomy were included in this study. Patients with preoperative DEB-TACE were propensity-score matched in a 1:1 ratio to patients without preoperative DEB-TACE. Short-term outcomes and recurrence-free survival (RFS) were compared between the two groups. Results: After PSM, 44 patients were included in each group. The toxicities of DEB-TACE were mild and could be managed by conservative treatment. Overall response rate (ORR) of conversion therapy (75.0% vs. 81.2%, p = 0.437) and postoperative complication of hepatic resection (27.3% vs. 20.5%, p = 0.453) were similar between the two groups. The median RFS of the DEB-TACE group (10.7 months, 95%CI: 6.6–14.8 months) was significantly longer than that of the control group (8.1 months, 95%CI: 3.4–12.8 months) (HR: 0.60, 95%CI: 0.37–0.95, p = 0.027). Conclusions: In patients who became resectable after conversion therapy, preoperative DEB-TACE might be a safe option to achieve longer RFS. Key Points: • This is a propensity-score matching study comparing patients who underwent conversional hepatectomy with or without preoperative DEB-TACE. • The preoperative DEB-TACE was safe and with mild toxicities (without toxicities more than CTCAE grade 3). • The preoperative DEB-TACE significantly prolonged the RFS of those patients who underwent conversional hepatectomy (10.7 vs. 8.1 months, p = 0.027). [ABSTRACT FROM AUTHOR]

Background: N6-methyladenosine (m6A) modification plays crucial roles in cancers. However, its alteration in colorectal cancer (CRC) is still poorly described. The purpose of this study is to explore the change of m6A modification and the function of m6A binding protein YTHDC2 in CRC. Methods: The global level of m6A modification was detected by mass spectrometry and dot blotting assay. The expression of YTHDC2 was investigated using The Cancer Genome Atlas and using real-time polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemistry based on CRC tissues. Kaplan–Meier analysis and Cox proportional hazards regression were performed to analyze the prognostic value of YTHDC2. RNA immunoprecipitation (RIP)-seq and m6A immunoprecipitation (MeRIP)-seq were used to explore the direct targets of YTHDC2. Gene oncology (GO) and Gene Set Enrichment Analysis (GSEA) were used to explore the pathways that could be influenced by YTHDC2. Results: No significant difference was observed in the global level of m6A modification on total RNA or mRNA between CRC and adjacent nontumor tissues. We further found a significant decreasing of YTHDC2 in CRC tissues. Kaplan–Meier analysis indicated that lower expression of YTHDC2 was related to the worse disease-free survival and overall survival. In addition, lower expression of YTHDC2 was an independent worse prognostic factor in univariate and multivariate Cox regression analysis. Using YTHDC2-RIP-seq and MeRIP-seq, we identified that YTHDC2 could participate in several important biological signal pathways. Conclusions: In summary, this study suggested that the global level of m6A did not change in CRC and identified that lower YTHDC2 as a prognostic marker for worse survival of CRC. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is one of the lethal cancers with a high mortality rate worldwide and understanding the mechanisms behind its progression is critical for improving patients' prognosis and developing therapeutics. MiR-500a-3p has been demonstrated to be involved in the progression of several human cancers but its role in CRC remains unclear. The aim of this study is to uncover the expression pattern and mechanisms of action of miR-500a-3p during the CRC progression. Methods: The expression of miR-500a-3p and Cyclin-dependent kinases 6 (CDK6) in 134 CRC tissues were tested by quantitative PCR (qPCR) and immunohistochemistry staining (IHC), respectively. The effect of miR-500a-3p on cell proliferation was explored in vitro and in vivo. The glycolysis of CRC cells was determined by Mass Spectrometry and Seahorse XF 96 Extracellular Flux Analyzer. A dual-luciferase reporter assay was performed to validate the relationship between miR-500a-3p and CDK6. Results: miR-500a-3p was abnormally downregulated in CRC tissues and cell lines and was negatively associated with a worse prognosis. miR-500a-3p mimics impeded CRC cell proliferation in vitro and in vivo. miR-500a-3p inhibited glucose consumption, lactate and ATP production, and down-regulated the expression of hexokinase2 (HK2). In silico prediction combined with western blot and luciferase assay confirmed that CDK6 is a direct target of miR-500a-3p. Overexpression of CDK6 phenotypically rescued the inhibitory effect of miR-500a-3p on the proliferation and glycolysis of CRC cells. Conclusions: Our study revealed a potential tumor-suppressive role of miR-500a-3p in CRC, specifically targeting CDK6 and inhibiting cancer cell proliferation and aerobic glycolysis, which may provide new insights into novel prognostic biomarkers and therapeutic targets for CRC. [ABSTRACT FROM AUTHOR]

Abstract: A novel and efficient chemoselective tandem Friedel–Crafts alkylation/cyclization reaction of glycidic esters with 2-naphthol derivatives initiated by stable radical cation salt (0.5 mol %) has been developed. [Copyright &y& Elsevier]

We aimed to identify potential differentially expressed proteins that play roles in the spinal cord injury. The mouse model of spinal cord injury was firstly built, followed by grip strength evaluation. Then, isobaric tags for relative and absolute quantization (iTRAQ) analysis was used to identify differentially expressed proteins at 1, 2, 3 and 8 weeks after spinal cord injury. Finally, analysis of spinal cord injury repair related differentially expressed proteins in the early and middle-late stage of injury was performed followed by the functional analysis. The result of grip strength evaluation showed that the motor function of the forelimbs of the mouse was significantly impaired after spinal cord injury. In the iTRAQ analysis, a total of 29 common differentially expressed proteins (such as Hbb-bs, Hba, S100a6, Ca1, Apoa4, Hspb1, Hist1h1c, Hist1h1e, Hbb-b1, Apoa1 and S100a10) were obtained at 1, 2, 3 and 8 weeks after spinal cord injury. A total of 70 and 180 common differentially expressed proteins were identified in the early and middle-late stage of injury, respectively. PPAR signaling pathway (involved Apoa1) and VEGF signaling pathway (involved Hspb1) were identified in the middle-late stage of spinal cord injury repair. Identified differentially expressed proteins and related signaling pathways may be associated with spinal cord injury. [ABSTRACT FROM AUTHOR]

Backgrounds: Cancer-related mortality in patients with colorectal cancer (CRC) is predominantly caused by development of colorectal liver metastases (CLMs). How to screen the sensitive chemotherapy and targeted therapy is the key element to improve the prognosis of CLMs patients. The study aims to develop patient-derived organoids-based xenografted liver metastases (PDOX-LM) model of CRC, to recapitulate the clinical drug response.Methods: We transplanted human CRC primary tumor derived organoids in murine spleen to obtain xenografted liver metastases in murine liver. Immunohistochemistry (IHC) staining, whole-exome and RNA sequencing, and drug response testing were utilized to identify the homogeneity in biological and genetic characteristics, and drug response between the PDOX-LM models and donor liver metastases.Results: We successfully established PDOX-LM models from patients with CLMs. IHC staining showed that positive expression of CEA, Ki67, VEGF, FGFR2 in donor liver metastases were also well preserved in matched xenografted liver metastases. Whole-exon sequencing and transcriptome analysis showed that both xenografted and donor liver metastases were highly concordant in somatic variants (≥ 0.90 frequency of concordance) and co-expression of driver genes (Pearson's correlation coefficient reach up to 0.99, P = 0.001). Furthermore, drug response testing showed that the PDOX-LM models can closely recapitulated the clinical response to mFOLFOX6 regiments.Conclusions: This PDOX-LM model provides a more convenient and informative platform for preclinical testing of individual tumors by retaining the histologic and genetic features of donor liver metastases. This technology holds great promise to predict treatment sensitivity for patients with CLMs undergoing chemotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Major histocompatibility complex (MHC) plays an important role in colorectal cancer (CRC) immunity. However, the function of MHC class I chain-related B (MICB) molecule is not very clear. In this study, we explored the prognostic effect of MICB in colorectal cancer. Material and methods: From 2008-05 to 2012-11, consecutive CRC patients of Zhongshan Hospital, Fudan University were retrospectively enrolled as primary cohort. The inclusion criteria were as follows: receiving primary radical resection, pathologically confirmed colorectal adenocarcinoma, no treatment before surgery, clinicopathological data available. Another cohort of CRC patients were collected from a public dataset GSE39582 of GEO database from 1987 to 2007 in the same criteria for validation. MICB was detected using immunochemistry and evaluated as prognostic biomarker. The cut-off value of MICB expression was calculated using X-tile software. Results: Finally, 863 patients were enrolled in the primary cohort, and 556 patients were enrolled in the validation cohort. MICB expression was significantly associated with tumor size and primary histological type in primary cohort, and with primary tumor location and distant metastases in validation cohort. The survival analysis showed that patients with high MICB expression had significantly better overall survival in both primary (P = 0.002) and validation (P = 0.001) cohorts. The multivariate analysis also confirmed that high MICB expression was a significantly independent protective factor for overall survival in both primary (hazard ratio HR = 0.741, 95% CI 0.594–0.924) and validation (HR = 0.699, 95% CI 0.508–0.961) cohorts. Conclusion: For stage I–IV CRC patients, MICB was confirmed a novel independent prognostic factor. It could help better stratification of CRC prognosis. [ABSTRACT FROM AUTHOR]

Primary tumour resection (PTR) is still a selection for patients with low tumour burden and good condition, especially with conversion therapy purpose for colorectal liver-limited metastases (CRLMs). The objective was to evaluate whether pre-PTR chemotherapy could improve progression-free survival (PFS) for patients with asymptomatic synchronous unresectable CRLMs. Patients with asymptomatic synchronous unresectable CRLMs were randomly assigned to receive pre-PTR chemotherapy (arm A) or upfront PTR (arm B). Chemotherapy regimens of mFOLFOX6 plus cetuximab, mFOLFOX6 plus bevacizumab or mFOLFOX6 alone were chosen according to the RAS genotype. The primary end-point was PFS; secondary end-points included overall survival (OS), tumour response, disease control rate (DCR), liver metastases resection rate, surgical complications and chemotherapy toxicity. Three hundred and twenty patients were randomly assigned to arm A (160 patients) and arm B (160 patients). Patients in arm A had significantly improved the median PFS compared with arm B (10.5 versus 9.1 months; P = 0.013). Patients in arm A also had significantly better DCR (84.4% versus 75.0%; P = 0.037). The median OS (29.4 versus 27.2 months; P = 0.058), objective response rate (ORR) (53.1% versus 45.0%; P = 0.146) and liver metastases resection rate (21.9% versus 18.1%; P = 0.402) were not significantly different. The Clavien–Dindo 3–4 complications post PTR (4.5% versus 3.8%, P = 0.759) and the incidence of grade 3/4 chemotherapy events (42.2% versus 40.4%, P = 0.744) reached no statistical significance. For asymptomatic synchronous unresectable CRLMs, Pre-PTR chemotherapy improved the PFS compared with upfront PTR. • It was the first RCT to evaluate the PFS of pre-PTR chemotherapy for CRLMs. • Pre-PTR chemotherapy improved the PFS compared with upfront PTR. • This trial provided evidence to confirm the advantages of pre-PTR chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose. We aimed to identify new predictive biomarkers for cetuximab in first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). Methods. The study included patients with KRAS wild-type unresectable liver-limited mCRC treated with chemotherapy with or without cetuximab. Next-generation sequencing was done for single nucleotide polymorphism according to custom panel. Potential predictive biomarkers were identified and integrated into a predictive model within a training cohort. The model was validated in a validation cohort. Results. Thirty-one of 247(12.6%) patients harbored RAS mutations. In training cohort (N=93), six potential predictive genes, namely, ATP6V1B1, CUL9, ERBB2, LY6G6D, PTCH1, and RBMXL3, were identified. According to predictive model, patients were divided into responsive group (n=66) or refractory group (n=27). In responsive group, efficacy outcomes were significantly improved by addition of cetuximab to chemotherapy. In refractory group, no benefit was observed. Interaction test was significant across all endpoints. In validation cohort (N=123), similar results were also observed. Conclusions. In the first-line treatment of mCRC, the predictive model integrating six new predictive mutations divided patients well, indicating a promising approach to further refine patient selection for cetuximab on the basis of RAS mutations. [ABSTRACT FROM AUTHOR]

The tandem Friedel-Crafts alkylation/cyclization reactions of glycidic esters with 2-naphthols or 2-naphthyl ethers are catalyzed by a stable aminium cation to give dihydronaphthofuran derivatives. [ABSTRACT FROM AUTHOR]

A novel and efficient stable radical cation triarylaminium salt-catalyzed aerobic double Friedel-Crafts alkylation reaction of glycine derivatives with indoles has been developed. The reaction was performed in the absence of any other additives under mild conditions and only requires an air atmosphere (or oxygen, 1 atm) as co-oxidant. [ABSTRACT FROM AUTHOR]

An aminium radical catalyzed reaction of N-tosylglycine derivatives with indoles is developed to yield products (III), (VI), and (VIII) via a double Friedel-Crafts reaction. [ABSTRACT FROM AUTHOR]