Cu2O-catalyzed cascade phosphinylation/cyclization of 2'-aminochalcones for the synthesis of hemi-indigo derivatives.

A Cu2O-catalyzed cascade phosphinylation/cyclization reaction of 2'-aminochalcones and diphenylphosphine oxides to produce hemi-indigo derivatives has been developed. This strategy facilitates the sequential formation of a C-P bonds and a C-N bond in a single reaction step. Notably, the approach features one-pot operation, an earth-abundant copper catalyst, readily available starting materials, a broad substrate scope and high compatibility with functional groups, providing 33 compounds in acceptable yields.

Tandem C-C/C-N Bond Formation via Rh(III)-Catalyzed α-Fluoroalkenylation and Sequential Annulation of 2-Arylquinazolinones and gem-Difluorostyrenes.

An efficient method of Rh(III)-catalyzed coupling reaction between 2-arylquinazolinones and gem-difluorostyrenes has been developed. In this work, two diverse structures of monofluoroalkenes and isoindolo[1,2-b]quinazolin-10(12H)-one derivatives were respectively synthesized by controlling the amount of additives (Ca(OH)2 and AgNTf2) to achieve controlled stepwise breaking of the C-F bonds of gem-difluorostyrenes. This reaction has the characteristics of a wide range of substrates and good functional group tolerance. Meanwhile, several control experiments were conducted and a plausible mechanism was proposed.

Synthesis of pyrazoles from sulfonyl hydrazone and benzyl acrylate under transition-metal-free conditions.

Pyrazoles as an important class of heterocyclic compounds, are widely found in pharmaceuticals and bioactive natural products. Herein we report a [3 + 2] cycloaddition reaction for the synthesis of a series of pyrazoles, with the yield up to 77%. This approach exhibits many notable features, such as convenient operating conditions, excellent functional group compatibility and readily accessible raw materials, providing an alternative route for the construction of pyrazole derivatives.

Rhodium(III)-catalyzed cascade C-H functionalization/annulation of sulfoximines with iodonium ylides for the synthesis of cyclohexanone-1,2-benzothiazines.

A highly efficient Rh(III)-catalyzed cascade C-H activation/annulation of sulfoximines with iodonium ylides under metal-oxidant-free conditions has been reported. The fused cyclohexanone-1,2-benzothiazine scaffold is readily achieved with a one-pot process in this reaction. This protocol exhibits good functional group tolerance and moderate to excellent yields. Additionally, the olefination of the target product illustrates the promising usefulness of this strategy.

Measurement of distal intramural spread and the optimal distal resection by naked eyes after neoadjuvant radiation for rectal cancers.

BACKGROUND: The safe distance between the intraoperative resection line and the visible margin of the distal rectal tumor after preoperative radiotherapy is unclear. We aimed to investigate the furthest tumor intramural spread distance in fresh tissue to determine a safe distal intraoperative resection margin length. METHODS: Twenty rectal cancer specimens were collected after preoperative radiotherapy. Tumor intramural spread distances were defined as the distance between the tumor's visible and microscopic margins. Visible tumor margins in fresh specimens were identified during the operation and were labeled with 5 - 0 sutures under the naked eye at the distal 5, 6, and 7 o'clock directions of visible margins immediately after removal of the tumor. After fixation with formalin, the sutures were injected with nanocarbon particles. Longitudinal tissues were collected along three labels and stained with hematoxylin and eosin. The spread distance after formalin fixation was measured between the furthest intramural spread of tumor cells and the nanocarbon under a microscope. A positive intramural spread distance indicated that the furthest tumor cell was distal to the nanocarbon, and a negative value indicated that the tumor cell was proximal to the nanocarbon. The tumor intramural spread distance in fresh tissue during the operation was 1.75 times the tumor intramural spread distance after formalin fixation according to the literature. RESULTS: At the distal 5, 6, and 7 o'clock direction, seven (35%), five (25%), and six (30%) patients, respectively, had distal tumor cell intramural spread distance > 0 mm. The mean and 95% confidence interval of tumor cell intramural spread distance in fresh tissue during operation was - 0.3 (95%CI - 4.0 ~ 3.4) mm, - 0.9 (95%CI - 3.4 ~ 1.7) mm, and - 0.4 (95%CI - 3.5 ~ 2.8) mm, respectively. The maximal intraoperative intramural spread distances in fresh tissue were 8.8, 7, and 7 mm, respectively. CONCLUSIONS: The intraoperative distance between the distal resection line and the visible margin of the rectal tumor after radiotherapy should not be less than 1 cm to ensure oncological safety.

LncRNA LBX2-AS1 promotes colorectal cancer progression and 5-fluorouracil resistance.

BACKGROUND: Recent reports suggest that the long non-coding RNA LBX2 antisense RNA 1 (LBX2-AS1) acts as an important regulator in cancer progression, but its significance in colorectal cancer (CRC) remains undetermined. METHODS: LBX2-AS1 expression levels in CRC were determined from the GEPIA database and CRC tissues to investigate clinical relevance. meRIP-PCR assays investigated the molecular mechanisms underlying the function of m6A in LBX2-AS1. Loss of function experiments was used to define the role of LBX2-AS1 in the progression of CRC. The ceRNA function of LBX2-AS1 was evaluated by RNA immunoprecipitation. In vitro and PDX models were used to determine if LBX2-AS1 promotes 5-fluorouracil resistance. RESULTS: Data from the TCGA and our institutional patient cohorts established that LBX2-AS1 levels were significantly upregulated in most CRC tissues relative to normal adjacent colon tissues. Moreover, LBX2-AS1 levels were positively correlated with aggressive disease characteristics, constituting an independent prognostic indicator of overall patient survival. Mechanistic investigations suggested that the increased LBX2-AS1 in CRC was mediated by METTL3-dependent m6A methylation. In vitro experiments indicated that knockdown of LBX2-AS1 inhibited CRC proliferation, migration and invasion with this phenotype linked to LBX2-AS1-mediated regulation of AKT1, acting as a ceRNA to sponge miR-422a. Ex vivo analysis of patient-derived CRC xenografts showed that low LBX2-AS1 expression cases exhibited 5-FU responsiveness and clinical investigations confirmed that low LBX2-AS1 expression was associated with improved clinical benefits from 5-FU therapy. CONCLUSIONS: Together these results suggest that LBX2-AS1 may serve as a therapeutic target and predictor of 5-FU benefit in CRC patients.

Tropomodulin 3 modulates EGFR-PI3K-AKT signaling to drive hepatocellular carcinoma metastasis.

The mechanism of hepatocellular carcinoma (HCC) metastasis remains poorly understood. Tropomodulin 3 (TMOD3) is a member of the pointed end capping protein family that contributes to invasion and metastasis in several types of malignancies. It has been found to be crucial for the membranous skeleton and embryonic development, although, its role in HCC progression remains largely unclear. We observed increased levels of Tmod3 in HCCs, especially in extrahepatic metastasis. High Tmod3 expression correlated with aggressive carcinoma and poor patient with HCC survival. Loss-of-function studies conducted by us determined Tmod3 as an oncogene that promoted HCC growth and metastasis. Mechanistically, Tmod3 increases transcription of matrix metalloproteinase-2, -7, and -9 which required PI3K-AKT. Interaction between Tmod3 and epidermal growth factor receptor (EGFR) that supports the activation of EGFR phosphorylation, is essential for signaling activation of PI3K-AKT viral oncogene homolog. These findings reveal that Tmod3 enhances aggressive behavior of HCC both in vitro and in vivo by interacting with EFGR and by activating the PI3K-AKT signaling pathway.

Transition-metal- and oxidant-free three-component reaction of quinoline N-oxides, sodium metabisulfite and aryldiazonium tetrafluoroborates via a dual radical coupling process.

A convenient and straightforward three-component transformation of quinoline N-oxides, sodium metabisulfite and aryldiazonium tetrafluoroborates has been developed, providing the target products in moderate to good yields. Compared with previous studies, the present methodology avoids the use of transition-metal catalysts and excess oxidants, providing a simple and practical alternative approach for the construction of 2-sulfonylquinolines. Control experiments indicate that a dual radical coupling process is responsible for this reaction.

Multicenter analysis of risk factors for anastomotic leakage after middle and low rectal cancer resection without diverting stoma: a retrospective study of 319 consecutive patients.

PURPOSE: The purpose of this study was to evaluate the risk factors for anastomotic leakage (AL) after anterior resection for middle and low rectal cancer in order to help surgeons to decide which patients could benefit from a diverting stoma. METHODS: Data on 319 patients having a middle and low rectal cancer resection with anastomosis between May 2011 and October 2015 from two hospitals were included in the study. The analysis included the following variables: patient-related variables (gender, age, diabetes mellitus, ASA score, preoperative radiochemotherapy, body mass index, blood hemoglobin, and serum albumin level), tumor-related variables (K-ras status, distance of tumor from the anal verge, histopathologic grade, pathological T stage, pathological N stage, pathological M stage, TNM stage, and tumor size), and surgery-related variables (laparoscopic or open surgery, blood loss, and operative time). Univariate and multivariate regression analysis were carried out to identify risk factors for AL. RESULTS: The AL rate was 11.91% (38/319). Male (OR 2.898, 95% CI 1.265-6.637, p = 0.012), diabetes mellitus (OR 2.482, 95% CI 1.004-6.134, p = 0.049), K-ras mutation (OR 2.544, 95% CI 1.210-5.348, p = 0.014), distance of tumor from the anal verge (OR 3.445, 95% CI 1.631-7.279, p = 0.001), and preoperative radiochemotherapy (OR 2.790, 95% CI 1.056-7.372, p = 0.039) were independent risk factors of AL. One (2.63%) in 38 patients with AL presented with no risk factor of AL, 6 (15.8%) in 38 patients with 1 risk factor, 16 (42.1%) in 38 patients with 2 risk factors, 9 (23.7%) in 38 patients with 3 risk factors, and 6 (15.7%) in 38 patients with 4 risk factors. No patient with 5 risk factors in our study. AL rate increased with the elevated number of risk factors clustering in individuals. CONCLUSIONS: K-ras mutation is first reported to be an independent risk factor for AL after sphincter-preserving surgery without diverting stoma. A diverting stoma should be performed in sphincter-preserving surgery for middle and low rectal cancer patients with 2 or more risk factors identified in this analysis.

Influence of neoadjuvant chemoradiotherapy on the anal sphincter: ultrastructural damage may be critical.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) in addition to the curative surgery has been the first of treatment for local advanced rectal cancer because of its benefits in local recurrence and sphincter-saving. However, its side effects on anorectal function have been recognized. The histopathological changes on internal anal sphincter (IAS) have been reported, but ultrastructure changes of external anal sphincter (EAS) are unknown. The aim of this study is to detect the alterations on the gross morphology of IAS and ultrastructure of EAS after nCRT. METHODS: We collected 34 anal canal specimens of patients undergoing abdominoperineal resection (APR) prospectively. The length and thickness of IAS were measured with vernier caliper. The EAS was dissected for observation with transmission electron microscope (TEM). RESULTS: Ten patients received nCRT (nCRT group) before surgery and 24 underwent APR directly (control group). The length and thickness of IAS in nCRT group were 22.68 ± 3.56 and 5.39 ± 0.74 mm, respectively. These parameters were 21.28 ± 3.62 and 5.35 ± 1.12 mm in control group, respectively. There were no significant differences in the length and thickness of IAS between the two groups (P>0.05). In nCRT group, the sarcomere and myofibril were arranged disorderly and parts of them that were filled with collagenous fiber, triads, and mitochondria were destroyed severely and the glycogenosome also distributed disorderly. Such alterations of EAS did not occur in control group. CONCLUSIONS: The nCRT cannot change the gross morphology of IAS, while it induces serious damages to the ultrastructures of EAS which may adversely affect the anorectal function.

Lower rate of colonoscopic perforation: 110,785 patients of colonoscopy performed by colorectal surgeons in a large teaching hospital in China.

BACKGROUND: Colonoscopic perforation (CP) has a low incidence rate. However, with the extensive use of colonoscopy, even low incidence rates should be evaluated to identify and address risks. Information on CP is quite limited in China. OBJECTIVE: Our study aimed to determine the frequency of CP in colonoscopies performed by surgeons at a large teaching hospital in China over a 12-year period. METHODS: A retrospective review of medical records was performed for all patients who had CPs from 1 January 2000 to 31 December 2012. Iatrogenic perforations were identified mainly by abdominal X-ray or computed tomography scan. Follow-up information of adverse events post-colonoscopy was identified from the colorectal surgery database of our hospital. Patients' demographic data, colonoscopy procedure information, location of perforation, treatment, and outcome were recorded. RESULTS: A total of 110,785 diagnostic and therapeutic colonoscopy procedures were performed (86,800 diagnostic cases and 23,985 therapeutic cases) within the 12-year study period. A total of 14 incidents (0.012%) of CP were reported (seven males and seven females), of which nine cases occurred during diagnostic colonoscopy (0.01%) and five after therapeutic colonoscopy (three polypectomy cases, one endoscopic mucosal resection, and one endoscopic mucosal dissection). Mean patient age was 67.14 years. One case of CP (7.14%) after colonoscopy polypectomy was treated using curative colonoscopy endoclips. Other patients underwent operations: six cases (46.15%) of primary repair, four cases (28.57%) of resection with anastomosis, and two cases (15.38%) of resection without anastomosis. No obvious perforation was found in one patient (7.69%). Surgeons attempted to treat one case laparoscopically but eventually resorted to open surgery. The postoperative course was uncomplicated in eight cases (57.14%) and complicated in six cases (42.86%) but without mortality. CONCLUSION: CP is a serious but rare complication of colonoscopy. A perforation risk of 0.012% was found in our study. The optimal management of CP remains controversial. Treatment for CP should be individualized according to the patient's condition, related devices, and surgical skills of endoscopists or surgeons. Selective measures such as colonoscopy without intravenous sedation and decrease of loop formation can effectively reduce rates of perforation.

Synthesis of ß-Hydroxysulfides via Multi-Component Cascade Hydroxysulfenylation of Styrenes with NH4 SCN and Water under Transition-metal-free Conditions.

Transition-mental-free multi-component hydroxysulfenylation of styrenes with NH4 SCN and water to from ß-hydroxysulfides is established. The reaction mechanism proceeded via a domino reaction after a radical addition to 2-phenylimidazo[1,2-a]pyridines. This approach features a wide substrate scope and functional group compatibility, providing 34 compounds in acceptable yields.

Palladium-Catalyzed (3 + 2) Annulation of Aromatic Acids by C(sp3)-H Olefination and Decarboxylative Cross-Coupling Reaction.

A palladium-catalyzed (3 + 2) annulation of 2-methylbenzoic acid with maleimide using Ac-Leu-OH as a powerful ligand has been reported. Through a site-selective γ-C(sp3)-H olefination reaction and a sequential decarboxylative cross-coupling reaction, a five-membered cyclic ring was obtained as the final product. This novel reaction features great site selectivity and reactivity to generate various cyclic products in moderate to good yields.

C-H Borylation of Benzophenones Using Hydrazone as the Traceless Directing Group.

C-H borylation is one of the powerful C-H bond functionalization reactions. In this context, a metal-free C-H borylation of benzophenones using hydrazone as the traceless directing group has been reported. The dibromoboron intermediates can be obtained in excellent yields, and the corresponding arylboronic esters are generated in moderate to excellent yields. Furthermore, the borylated compounds can be transformed in a one-pot method, avoiding the loss of overall yield caused by the separation of the arylboronic esters.

Palladium-Catalyzed Tandem Diolefination Reaction of Benzaldehyde Enabled by a Remote Directing Group.

A tandem diolefination reaction of benzaldehyde has been developed via Pd-catalyzed ß-C(sp2)-H olefination of the benzene ring and tandem C(sp2)-H olefination of acrylate. 2-((Aminooxy)methyl)benzonitrile was involved with the benzaldehyde substrate as a remote directing group to realize the C-H bond activation. The control experiments proved that the presence of a remote cyano group is essential for this novel diolefination reaction.

The [3 + 2] Cycloaddition Reaction of N-Substituted Pyrrole-2-carboxaldehydes with Arylalkenes under Copper Catalysis: Access to Dihydropyrrolizine Skeletons.

Herein, we found that treating N-substituted pyrrole-2-carboxaldehydes with arylalkenes in DMF in N2 at 120 °C could afford pyrrolidine scaffolds with an up to 85% yield. This approach has several remarkable features, such as atom and step economy, readily accessible raw materials, and easy-to-operate manner, providing a simple and efficient method for constructing complicated bicyclic pyrroles. Additionally, we have successfully synthesized 28 target compounds, which further demonstrates its practicality and wide applicability.

Erratum: miR-365a-3p regulates ADAM10-JAK-STAT signaling to suppress the growth and metastasis of colorectal cancer cells: Erratum.

[This corrects the article DOI: 10.7150/jca.42731.].

Single-cell sequencing technology in colorectal cancer: a new technology to disclose the tumor heterogeneity and target precise treatment.

Colorectal Cancer (CRC) is one of the most common gastrointestinal tumors, and its high tumor heterogeneity makes traditional sequencing methods incapable of obtaining information about the heterogeneity of individual cancer cells in CRC. Therefore, single-cell sequencing technology can be applied to better analyze the differences in genetic and protein information between cells, to obtain genomic sequence information of single cells, and to more thoroughly analyze the cellular characteristics and interactions in the CRC microenvironment. This will provide a more comprehensive understanding of colorectal cancer development and metastasis and indicate the treatment plan and prognosis. In this study, we review the application of single-cell sequencing to analyze the tumor microenvironment of CRC, explore the mechanisms involved in CRC metastasis and progression, and provide a reference for potential treatment options.

DSTN Hypomethylation Promotes Radiotherapy Resistance of Rectal Cancer by Activating the Wnt/ß-Catenin Signaling Pathway.

PURPOSE: Although surgical resection combined with neoadjuvant radiation therapy can reduce the local recurrence rate of rectal cancer, not all patients benefit from neoadjuvant radiation therapy. Therefore, screening for patients with rectal cancer who are sensitive or resistant to radiation therapy has great clinical significance. METHODS AND MATERIALS: Patients with rectal cancer were selected according to postoperative tumor regression grade, and tumor samples were taken for detection. Differential genes between radiation-resistant and radiation-sensitive tissues were screened and validated by Illumina Infinium MethylationEPIC BeadChip, proteomics, Agena MassARRAY methylation, reverse transcription quantitative real-time polymerase chain reaction, and immunohistochemistry. In vitro and in vivo functional experiments verified the role of DSTN. Protein coimmunoprecipitation, western blot, and immunofluorescence were used to investigate the mechanisms of DSTN-related radiation resistance. RESULTS: DSTN was found to be highly expressed (P < .05) and hypomethylated (P < .01) in rectal cancer tissues resistant to neoadjuvant radiation therapy. Follow-up data confirmed that patients with high expression of DSTN in neoadjuvant radiation therapy-resistant rectal cancer tissues had shorter disease-free survival (P < .05). DSTN expression increased after methyltransferase inhibitor inhibition of DNA methylation in colorectal cancer cells (P < .05). In vitro and in vivo experiments showed that knockdown of DSTN promoted the sensitivity of colorectal cancer cells to radiation therapy, and overexpression of DSTN promoted the resistance of colorectal cancer cells to radiation (P < .05). The Wnt/ß-catenin signaling pathway was activated in colorectal cancer cells overexpressing DSTN. ß-catenin was highly expressed in radiation therapy-resistant tissues, and there was a linear correlation between the expression of DSTN and ß-catenin (P < .0001). Further studies showed that DSTN can bind to ß-catenin and increase its stability. CONCLUSIONS: The degree of DNA methylation and the expression level of DSTN can be used as biomarkers to predict the sensitivity of neoadjuvant radiation therapy for rectal cancer. DSTN and ß-catenin are also expected to become a reference for the selection of neoadjuvant radiation therapy.