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A combination of chiral Rh(iii) catalyst and chiral carboxamide allowed asymmetric C–H alkynylation of sulfoxides via desymmetrization, kinetic resolution, and parallel kinetic resolution.

For clinically low-risk stage III colorectal cancer, the decision on cycles of adjuvant chemotherapy after surgery is disputed. The present study investigates the use of additional biomarkers of ploidy and stroma-ratio(PS) to stratify patients with low-risk stage III colorectal cancer, providing a basis for individualized treatment in the future.This study retrospectively enrolled 198 patients with clinical-low-risk stage III colorectal cancer (T1-3N1M0) and analyzed the DNA ploidy and stroma ratio of FFPE tumor tissues. The patients were divided into PS-low-risk group (Diploidy or Low-stroma) and PS-high-risk group (Non-diploid and High-stroma). For survival analyses, Kaplan-Meier and Cox regression models were used.The results showed that the 5-year DFS of the PS-high-risk group was significantly lower than that in the PS-low-risk group (78.6 vs. 91.2%, HR = 2.606 [95% CI: 1.011-6.717], P = 0.039). Besides, in the PS-low-risk group, the 5 year OS (98.2 vs. 86.7%, P = 0.022; HR = 5.762 [95% CI: 1.281-25.920]) and DFS (95.6, vs 79.9%, P = 0.019; HR = 3.7 [95% CI: 1.24-11.04]) of patients received adjuvant chemotherapy for 3 months were significantly higher than those received adjuvant chemotherapy for 3 months. We also found that the PS could stratify the prognosis of patients with dMMR tumors. The 5-year OS (96.3 vs 71.4%, P = 0.037) and DFS (92.6 vs 57.1%, P = 0.015) were higher in the PS-low-risk dMMR patients than those in the PS-high-risk dMMR patients.In this study, we found that PS can predict the prognosis of patients with stage III low-risk CRC. Besides, it may guide the decision on postoperative adjuvant chemotherapy.

Rhodium-catalyzed regio- and stereoselective three-component carboamidation of 1,3-enynes has been realized using indoles and dioxazolones as the functionalizing reagents.

Doxorubicin (Dox), an anthracycline antibiotic with potent antitumor effects, has limited clinical applications due to cumulative cardiotoxicity. Ca

Control of regioselectivity that defies the intrinsic reactivity of arene C–H bonds remains a formidable challenge. In this work, dimeric Rh(II) complexes have been applied as an efficient catalyst...

PurposeUniversal germline testing in patients with colorectal cancer (CRC) with a multigene panel can detect various hereditary cancer syndromes. This study was performed to understand how to choose a testing panel and whether the result would affect clinical management.MethodsWe prospectively enrolled 486 eligible patients with CRC, including all patients with CRC diagnosed under age 70 years and patients with CRC diagnosed over 70 years with hereditary risk features between November 2017 and January 2018. All participants received germline testing for various hereditary cancer syndromes.ResultsThe prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes was 7.8% (38/486), including 25 PVs in genes with high-risk CRC susceptibility (the minimal testing set) and 13 PVs in genes with moderate-risk CRC susceptibility or increased cancer risk other than CRC (the additional testing set). All the clinically relevant PVs were found in patients diagnosed under age 70 years. Among them, 11 patients would not have been diagnosed if testing reserved to present guidelines. Most (36/38) of the patients with PVs benefited from enhanced surveillance and tailored treatment. PVs in genes from the minimal testing set were found in all age groups, while patients carried PVs in genes from the additional testing set were older than 40 years.ConclusionUniversal germline testing for cancer susceptibility genes should be recommended among all patients with CRC diagnosed under age 70 years. A broad panel including genes from the additional testing set might be considered for patients with CRC older than 40 years to clarify inheritance risks.Trial registration numberNCT03365986.

Chiral RhIII catalysts can catalyze the asymmetric [4+1] spiroannulation of O-pivaloyl oximes with α-diazo homophthalimides under redox-neutral and acid/base-neutral conditions, leading to formation of chiral spirocyclic imines as a result of C–H activation and N–O cleavage. The reaction proceeded with high efficiency and features broad substrate scope, mild reaction conditions, and high to excellent enantioselectivities.

Rhodium(III)-catalyzed C-H activation-based arylation of sterically hindered (hetero)arenes has been realized using diazo compounds and triazoles as arylating reagents for atroposelective synthesis of two classes of biaryls. The coupling of 3-substituted indoles and

Background It was reported that tumor-expressed dickkopf-related (DKK) proteins affect micro-environment. However, the influence of DKK1 on colorectal cancer (CRC) liver oligometastases (CRCLOM) remains unclear. Methods CRC cases after resection of liver oligometastases were enrolled in Sun Yat-Sen University Cancer Center with intact clinical data. Serum DKK1 was detected by ELISA assay. Immunofluorescent staining examination for CD3 and CD8 in slices were also conducted. Results Among 65 patients included, the recurrence-free survival (RFS) and overall survival (OS) were significantly better in the low serum DKK1 group (RFS: P = 0.021; OS: P = 0.043). DKK1 was overexpressed in stage IV CRC patients in TCGA data. The number of CD8+ tumor-infiltrating lymphocytes (TILs) in invasive margin of CRC liver oligometastases was significantly higher in low serum DKK1 group (P = 0.042). Conclusion Elevated serum DKK1 level was associated with poorer RFS and OS, and less CD8+ TILs in invasive margin in CRC liver oligometastases. DKK1 might serve as a supplementalprognostic factor for clinical risk score and a potential target for immunotherapy.

Inflammatory conditions are common complications in colorectal cancer (CRC) and play significant roles in tumor progression and immunosuppression. However, the influence of inflammatory conditions on the tumor response to immune checkpoint inhibitors (ICIs) remains unclear. We included a high microsatellite instability (MSI-H) CRC patient whose primary tumor progressed and liver metastasis regressed after Pembrolizumab treatment. An organoid-T cell coculture model demonstrated an inhibited local immune response instead of systemic immunosuppression. Single-cell RNA sequencing suggested that neutrophils suppress the immune microenvironment, mostly through CTLA-4-associated pathways. A cohort of 73 patients with MSI-H CRC who received ICIs were enrolled, among whom inflammatory conditions were correlated with a poor tumor response. We demonstrated that inflammatory conditions in MSI-H CRCs correlate with resistance to ICIs through neutrophil-associated immunosuppression. Additional CTLA-4 blockade may improve the sensitivity to PD-1 blockade. Clinically, inflammatory conditions could predict a poor response to ICIs in MSI-H CRCs.

Background: Genetic factors play an important role in colorectal cancer (CRC) risk, yet the prevalence and spectrum of germline cancer susceptibility gene mutations among unselected Chinese CRC patients is largely undetermined. Methods: We performed next-generation sequencing with a 73-genes panel and analyzed the prevalence and spectrum of germline mutations in 618 unselected Chinese CRC patients. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations. Clinical characteristics were assessed by age and mutation status. Protein expressions and interactions of MLH1 missense variants were evaluated by western blot and co- immunoprecipitation. Results: Overall, 112 (18.1%) of 618 unselected Chinese CRC patients were found to carry at least one pathogenic or likely pathogenic variant (totaling 97 variants), including 70 (11.3%) Lynch syndrome (LS) mutation carriers and 42 (6.8%) non-LS mutation carriers. LS mutation carriers were significantly younger at CRC diagnosis and were more likely to have right-sided, poorly differentiated, early stage, high-frequency microsatellite instability (MSI-H) or dMMR CRC and a family history of cancer compared with noncarriers. Non-LS mutation carriers were more likely to be proficient mismatch repair (pMMR) than noncarriers (p=0.039). We found four clinical variables (gender, tumor histological stage, cancer stage and mutation status) that showed significant differences between patients younger and older than 50 years old. Higher mutation rates were found in patients under 50 years old (p=0.017). Thirty-three novel variants were discovered and evaluated as pathogenic mutations by our study. Conclusion: Given the high frequency and wide spectrum of mutations, genetic testing with a multigene panel should be considered for all Chinese CRC patients under 50 years old and is also needed to determine whether a gene is associated with CRC susceptibility and to promote clinical translation.

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.

Cobalt(III)-catalyzed C–H amidation of arenes has been realized under assistance of weakly coordinating carbonyl groups with 1,4,2-dioxazol-5-ones as the amidating reagents. Both sulfoxonium ylides and α-benzoylketene dithioacetals are viable arene substrates. The coupling system features high yield, broad substrate scope, and functional group tolerance, providing a series of functionalized sulfur-containing compounds.

Efficient synthesis of 2-naphthols was realized by Ru(ii)-catalyzed C-H activation of aryl nitrones and intermolecular [3+3] annulation with α-diazo sulfonyl ketones under redox-neutral conditions. Easily available α-diazo sulfonyl ketones act as a three-carbon component in the reaction.

A straightforward and efficient protocol for dearomatizing indoles is described. The reaction, catalyzed by an inexpensive Co(III)/Zn(II) catalyst, starts from easily accessible N-pyrimidinyl indoles and ene-yne ketones. Mild reaction conditions, high diastereoselectivity, a broad substrate scope, effective functional group tolerance, and reasonable to remarkable yields were observed.

C-H bond activation has been established as an attractive strategy to access axially chiral biaryls, and the most straightforward method is direct C-H arylation of arenes. However, the arylating source has been limited to several classes of reactive and bulky reagents. Reported herein is rhodium-catalyzed 1:2 coupling of diarylphosphinic amides and diarylacetylenes for enantio- and diastereoselective construction of biaryls with both central and axial chirality. This twofold C-H activation reaction stays contrast to the previously explored Miura-Satoh type 1:2 coupling of arenes and alkynes in terms of chemoselectivity and proceeded under mild conditions with the alkyne acting as a rare arylating reagent. Both C-H activation events are stereo-determining and are under catalyst control, with the 2nd C-H activation being diastereo-determining in a remote fashion. Analysis of the stereochemistries of the major and side products suggests moderated enantioselectivity of the initial C-H activation-desymmetrization process. However, the minor stereoisomeric (R) intermediate is consumed more readily in undesired protonolysis, eventually resulting in high enantio- and diastereoselectivity of the major product.

Reported herein is the rhodium(III)-catalyzed C-H activation of anilines bearing an N-isoquinolyl directing group for oxidative [3+2] annulation with four classes of internal alkynes, leading to atroposelective indole synthesis via dynamic kinetic annulation with C-N reductive elimination constituting the stereo-determining step. This reaction proceeds under mild conditions with high regio- and enantioselectivity and functional group compatibility.

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Rhodium(iii)-catalyzed C-C coupling of heteroarenes and fluorinated α-diazo diketones has been realized for the facile synthesis of 3-arylchromones. The reaction proceeds via chelation-assisted C-H activation, carbene insertion, and uncatalyzed intramolecular nucleophilic aromatic substitution, with C-F cleavage being accommodated in the nucleophilic aromatic substitution step. Three classes of heteroarenes have been defined with decent functional group tolerance.

OBJECTIVE: To investigate the protective effect of melatonin against myocardial ischemia reperfusion (IR) injury in isolated rat hearts and explore the underlying mechanisms. METHODS: The isolated hearts from 40 male SD rats were randomly divided into 4 groups (n=10): the control group, where the hearts were perfused with KH solution for 175 min; IR group, where the hearts were subjected to global ischemia for 45 min followed by reperfusion for 120 min; IR+melatonin (Mel+IR) group, where melatonin (5 μmol/L) was administered to the hearts 1 min before ischemia and during the first 5 min of reperfusion, followed by 115 min of reperfusion; and IR+2, 3-butanedione monoxime (IR+BDM) group, where the hearts were treated with BDM (20 mmol/L) in the same manner as melatonin treatment. Myocardial injury in the isolated hearts was assessed based on myocardial injury area, caspase-3 activity, and expressions of cytochrome C and cleaved caspase-3 proteins. Cardiac contracture was assessed using HE staining and by detecting lactate dehydrogenase (LDH) activity and the content of cardiac troponin I (cTnI) in the coronary outflow, measurement of left ventricular end-diastolic pressure (LVEDP) and electron microscopy. The content of ATP in the cardiac tissue was also determined. RESULTS: Compared with those in the control group, the isolated hearts in IR group showed significantly larger myocardial injury area and higher caspase-3 activity and the protein expressions of cytochrome C and cleaved caspase-3 with significantly increased LDH activity and cTnI content in the coronary outflow and elevated LVEDP at the end of reperfusion; HE staining showed obvious fractures of the myocardial fibers and the content of ATP was significantly decreased in the cardiac tissue; electron microscopy revealed the development of contraction bands. In the isolated hearts with IR, treatment with Mel or BDM significantly reduced the myocardial injury area, caspase-3 activity, and protein expressions of cytochrome C and cleaved caspase-3, obviously inhibited LDH activity, lowered the content of cTnI and LVEDP, reduced myocardial fiber fracture, and increased ATP content in the cardiac tissue. Both Mel and BDM inhibited the formation of contraction bands in the isolated hearts with IR injury. CONCLUSION: Mel can alleviate myocardial IR injury in isolated rat hearts by inhibiting cardiac contracture, the mechanism of which may involve the upregulation of ATP in the cardiac myocytes to lessen the tear of membrane and reduce cell content leakage.

BRAF and MLH1 promoter methylation testings have been proven effective prescreens for Lynch Syndrome. We aimed to compare different screening strategies for Lynch Syndrome in patients with MLH1(-) CRC. Patients with MLH1(-) CRC who had been tested for BRAF mutation and germline variants of DNA mismatch repair genes were included. We compared the sensitivities and specificities for identifying Lynch Syndrome and the cost-effectiveness of four screening approaches that used the following tests as prescreens: BRAF testing, MLH1 methylation testing, MLH1 methylation & BRAF testing, and MLH1 methylation testing & Revised Bethesda Criteria. Of 109 patients included, 23 (21.1%) were Lynch Syndrome patients. BRAF mutation and MLH1 methylation occurred in 6 (5.5%) and 40 (36.7%) patients, respectively. The sensitivity for identifying Lynch syndrome of BRAF testing was 100%, but the specificity was only 7%. MLH1 methylation testing had a lower sensitivity than BRAF testing (97.5% vs 100%), but had a markedly higher specificity (45.3% vs 7%). The combination of the two testings had a slightly higher specificity than MLH1 methylation testing alone (47.7% vs 45.3%). The MLH1 methylation testing approach had a 10% lower cost of identifying MLH1(-) Lynch syndrome carriers per case than universal genetic testing, but it missed 4.5% of patients. BRAF and MLH1 promoter methylation testings as prescreens for Lynch syndrome are less effective in Chinese patients with MLH1(-) CRC than in their Western counterparts. Universal genetic testing could be considered an up-front option for this population.

Rhodium(III)-catalyzed mild and oxidative [4+1] spiroannulation has been realized via C–H activation of oximes and benzoic acids with 1-diazonaphthelen-2(1H)-ones as coupling reagents. This transformation integrates C–H activation and dearomatization and provides a direct approach to spirocyclic isoindole N-oxides and isobenzofuranones with functional group tolerance.

Axial-to-central chirality transfer is an important strategy to construct chiral centers, where the axially chiral reagents are mostly limited to atropomerically stable ones. Reported herein is a RhIII -catalyzed enantioselective spiroannulative synthesis of nitrones. The coupling proceeds via C-H arylation to give an atropomerically metastable biaryl, followed by intramolecular dearomative trapping under oxidative conditions with high degree of chirality transfer.

Background: The clinical manifestation of metastatic colorectal cancer (mCRC) varies from patient to patient, with the underlying genetic alterations and expression profiles deceptive. We aim to investigate the phylogenetic relationships of the multi-organ mCRC and the possible biomarkers of disease progression. Methods: Whole Extron Sequencing (WES) was performed in CRC and their matched multi-organ metastases from three patients with different clinical manifestations. Sciclone calculation between individual lesions illustrated the evolutionary origins of each metastatic sites. Genomic divergence between primary and metastatic sites were identified and their potential role in the metastatic process were annotated. Following the WES results, the significantly correlated genes were validated by immunohistochemistry. Findings: The evolutionary tree showed that the distant metastasis could originated from either the primary colon cancer or the other metastatic site. Organotropism exists in both mCRC and protein levels in terms of APOB and FLNC, and a number of driver mutations potentially decide the disease progression. Moreover, the expressive change of APOB between primary CRC and CRC liver metastasis indicates worse long-term outcomes. Interpetation: Metastatic routes of multi-organ mCRC are highly heterogeneous. We identified previously unreported gene alterations might facilitate metastatic and organotropic progression, providing potential biomarkers for diagnosis and treatment. Funding Statement: This work was funded by the National Science and Technology Major Project of China (2018ZX10723204, 2018ZX10302205), the National Natural Science Foundation of China (81874070, 81871991, 81772595), Guangzhou Science and Technology Plan Projects (Health Medical Collaborative Innovation Program of Guangzhou) (201803040019, 201400000001-4). Declaration of Interests: The authors have no conflict of interest to declare. Ethics Approval Statement: This study was approved by the ethical committee of our institute (GZR2019-014).

Cp*RhIII /IrIII complexes are known to play important roles in both C-H activation and transfer hydrogenation (TH). However, these two areas evolved separately. They have been integrated in redox- and chemodivergent coupling reactions of N-pyridylanilines with enones. The iridium-catalyzed coupling with enones leads to the efficient synthesis of tetrahydroquinolines through TH from i PrOH. Counterintuitively, i PrOH does not serve as the sole hydride source, and the major reaction pathway involves disproportionation of a dihydroquinoline intermediate, followed by the convergent and iterative reduction of quinolinium species.

Purpose: This study aimed at investigating the long-term outcomes of oxaliplatin and capecitabine (XELOX) administered concurrently with preoperative radiation and extended to the resting period in patients with high-risk locally advanced rectal cancer (LARC). Methods: From January 2010 to December 2013, 45 patients were recruited. Study treatment consisted two cycles of XELOX regimen concomitant with preoperative radiation and then followed by an additional cycle of XELOX regimen between completion of neoadjuvant radiotherapy and surgery. Disease-free survival (DFS) time and overall survival (OS) time were analyzed. Results: The median follow-up was 51 months. Twelve (26.7%) patients developed local recurrence or distant metastasis, including 10 (22.2%) patients developing distant metastasis only, 1 (2.2%) patient local recurrence only, and 1 (2.2%) patient both local recurrence and distant metastasis. The estimated 3-year DFS and OS was 75.5% (95% CI, 63.0%-88.0%) and 88.6% (95% CI, 98.0%-79.2%), respectively. Receiving adjuvant chemotherapy was a significant predictor for DFS, with hazard ratio 0.24 (95% CI: 0.08-0.74). Conclusion: This intensified strategy with oxaliplatin and capecitabine (XELOX) administered concomitantly with neoadjuvant radiotherapy and then extended to the resting period in high-risk LARC patients is efficient. The long-term outcome is promising. Further study of this strategy is warranted.

Ru(II)-Catalyzed efficient α-fluoroalkenylation of arenes has been realized with gem-difluorostyrene as an olefinating reagent. This coupling system is efficient with a broad substrate scope, providing 1,2-diaryl-substituted monofluoroalkenes with good to excellent regio- and stereoselectivities under silver-free conditions.

A rhodium-catalyzed C-H amination of benzamides and isoquinolones with anthranils has been realized under assistance of a weakly coordinating tertiary amide, leading to a bifunctional amination product bearing a proximal carbonyl group. N-benzoylpyrrolidine and N-substituted isoquinolones are two classes of amides that are applicable. The aminated products can further cyclize to acridine under in situ or ex situ conditions.

An efficient, atom-economical, and regioselective insertion of indoles into terminal alkynes has been realized via cobalt(III)-catalyzed C–H activation under mild conditions, leading to efficient synthesis of α-gem-vinylindoles. The insertion of the alkynes follows a rare 1,2-selectivity, and silyl alkynes, alkyl alkynes, propargyl alcohols, and protected propargyl amines are all applicable. The mechanism of this hydroarylation system has been studied in detail by a combination of experimental and computational approaches. In the reaction of silyl terminal alkynes, the regioselectivity is dictated by the steric effects of the alkyne substituent, especially in the protonolysis stage. However, for protected propargyl amines, the selectivity results from electronic effects during the insertion step, with protonolysis being insignificant in the determination of selectivity. An internal alkyne also coupled in high efficiency but with low regioselectivity. Comparisons of cobalt, rhodium, and iridium catalysts h...

Rh(III)-catalyzed activation and acylation of sp3 C–H bonds has been realized with diarylcyclopropenone as an acylating reagent. Both benzylic C–H in 8-methylquinolines and unactivated C–H in 2-alkylpyridines are applicable in this C–H acylation reaction, providing enones in good yields under redox-neutral conditions.

Cobalt(III) and rhodium(III) catalysts exhibited complementary scope in C-H amidation of aryl enaminones. The amidation reactions proceeded with broad scope under the assistance of a weakly coordinating and bifunctional enaminone directing group. The electrophilicity of the enaminone group can be further utilized in subsequent hydrolysis-cyclization reactions to afford NH 4-quinolones in telescoping reactions.

An efficient synthesis of 2-substituted quinolines from readily available cyclopropanols and imidamides has been developed, where the cyclopropanol acts as a C3 synthon. With the assistance of a bifunctional imidamide directing group, the reaction occurred via sequential C–H/C–C cleavage and C–C/C–N bond formation.

Phosphonium ylide acts as an efficient bifunctional directing group in Rh(III)-catalyzed C–H activation of arenes and oxidative coupling with activated olefins, leading to facile construction of indanones via a sequence of oxidative olefination and carboannulation. The phosphonium moiety functions as an oxophilic group, and dephosphination triggers a nucleophilic cyclization.

Background: We launched a screening program for colorectal cancer (CRC) in Yuexiu District, Guangzhou, China, in 2014. Here we aimed to report the early results of the program and evaluate the benefits of a screening questionnaire. Methods: Residents aged between 50 and 74 were eligible for the screening. A questionnaire and two consecutive fecal immunological tests (FITs) were used as primary screening methods. Subjects who were positive for any of the two tests were referred for further examination with colonoscopy. Neoplasms were removed either colonoscopically or by colectomy. Atypical adenoma and CRC were defined as advanced neoplasms. Results: A total of 6,971 residents in Dadong Street, Yuexiu District were screened with a questionnaire, and among them, 5,343 underwent at least one FIT. Four thousand and two hundred eleven (60.4%) were female, and 2,760 (39.6%) were male, with a median age of 62.0 years. Questionnaire and FITs identified 1,219 candidates for further examination with colonoscopy, among whom only 647 (53.1%) comply. As of this writing, 623 colonoscopy results were obtained, among which 270 (43.3%) had positive findings. The adenoma detection rate (ADR) was 43.3% (270/623). The ADR was 43.3% (270/623). Of the 270 patients, 10 (3.07%) had CRC, 81 (30.0%) had advanced adenoma, 178 had low-grade adenoma or other benign polyps, one had carcinoid. Except for three advanced CRC, all neoplasms detected were benign or in an early stage. Conclusions: Our screening program help identified patients with colonic neoplasms at an early stage, precluding them from developing into the malignant disease. The addition of the questionnaire significantly increased the sensitivity of primary screening, while also decreasing the specificity. Long-term results should evaluate the social and economic benefits of this program.

Additional file 1: Table S1. Univariate and multivariate Cox proportional hazards regression models for OS.

Silver-catalyzed nucleophilic addition and intramolecular Friedel–Crafts alkylation between α-oxoketene dithioacetals and tertiary propargylic carbonates have been realized. The reactions proceeded in moderate to good yields with broad substrate scope, providing a straightforward method for the synthesis of substituted indenes.

BackgroundDickkopf 1 (DKK1) is associated with tumor progression. However, whether DKK1 influences the tumor response to programmed cell death protein 1 (PD-1) blockade in colorectal cancers (CRCs) with deficient mismatch repair (dMMR) or microsatellite instability (MSI) has never been clarified.MethodsTumor tissues from 80 patients with dMMR CRC were evaluated for DKK1 expression and immune status via immunohistochemistry. Serum DKK1 was measured in another set of 43 patients who received PD-1 blockade therapy. CT26 cells and dMMR CRC organoids were cocultured with T cells, and CT26-grafted BALB/c mice were also constructed. T-cell cytotoxicity was assessed by apoptosis assays and flow cytometry. The pathway through which DKK1 regulates CD8+ T cells was investigated using RNA sequencing, and chromatin immunoprecipitation and luciferase reporter assays were conducted to determine the downstream transcription factors of DKK1.ResultsElevated DKK1 expression was associated with recurrence and decreased CD8+ T-cell infiltration in dMMR CRCs, and patients with high-serum DKK1 had a poor response to PD-1 blockade. RNA interference or neutralization of DKK1 in CRC cells enhanced CD8+ T-cell cytotoxicity, while DKK1 decreased T-bet expression and activated GSK3β in CD8+ T cells. In addition, E2F1, a downstream transcription factor of GSK3β, directly upregulated T-bet expression. In organoid models, the proportion of apoptotic cells was elevated after individual neutralization of PD-1 or DKK1 and was further increased on combined neutralization of PD-1 and DKK1.ConclusionsDKK1 suppressed the antitumor immune reaction through the GSK3β/E2F1/T-bet axis in CD8+ T cells. Elevated serum DKK1 predicted poor tumor response to PD-1 blockade in dMMR/MSI CRCs, and DKK1 neutralization may restore sensitivity to PD-1 blockade.