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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.

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

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.

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.

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.

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.

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.

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.

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.

Rh-catalyzed redox-neutral coupling between N-aryl nitrones and alkynes has been achieved under relatively mild conditions. The reaction proceeded via C–H activation at the N-aryl ring with subsequent O-atom transfer, affording trisubstituted indolines in good chemoselectivity and moderate to good diasteroselectivity.

Rh(III)-catalyzed synthesis of mesoionic heterocycles has been achieved via C–H activation of sydnones and oxidative coupling with internal alkynes. This reaction occurred under mild conditions with high efficiency, broad substrate scope, and low catalyst loading. Moreover, synthetic applications of a coupled product have been demonstrated in the late-stage derivatization into a variety of highly functionalized scaffolds.

Background: Local or distant recurrence may develop beyond 5 years after radical resection for colorectal cancer (CRC). There is little evidence of a pattern of recurrence after the routinely recommended 5 years of follow-up. We aimed to investigate the efficacy of the prolonged follow-up beyond 5 years. Methods: We retrospectively analyzed clinical and survival data of 1,054 CRC patients who underwent radical resections from 1980 to 1996 in our center. The prolonged surveillance was recommended for each patient with a duration of over 20 years. Results: The follow-up rates of 5, 10, 15, and 20 years were 92.6%, 86.9%, 82.3% and 76.8%, respectively. Overall survival (OS) rates of 5, 10, 15, and 20 years were 68.4%, 57.7%, 52.6% and 45.0%, respectively. Totally, 112 (10.6%) patients developed local recurrences and 174 (16.5%) patients developed distant metastases. The 99.2% postoperative local recurrences and distant metastases occurred within the first 15 years of surveillance. Survival differed between four age groups. Local recurrence was mainly diagnosed among rectal cancer patients, especially in those with lower-third rectal cancer. Metastases were commonly found in the liver and lungs. Patients with colon cancer and stage I/II manifested significantly longer OS than patients with rectal cancer and stage III/IV (both P Conclusions: In this study, postoperative local recurrences and distant metastases was rarely found after 15 years of enhanced surveillance, which indicated a “true cure” if the patient did not develop recurrences and metastases after 15 years.

The rhodium(III)-catalyzed regioselective alkylation of (hetero)arenes using cyclopropanols as a reactive and efficient coupling partner under oxidative conditions has been developed. This coupling occurred at room temperature via C–H activation of arenes and C–C cleavage of cyclopropanols. Various types of (hetero)arenes (indolines, carbazole, tetrahydrocarbazole, pyrrole, thiophene, etc.) were all successfully reacted under the present conditions. This protocol provides the facile and efficient construction of C7-alkylated indoline scaffolds.

To investigate the role of ventrolateral periaqueductal gray (VL-PAG) metabotropic glutamate receptors subtype 7 and 8 (mGluR 7/8) in descending modulation of cardiosomatic motor reflex (CMR) in rats.AMN082 (agonist of mGluR 7) and DCPG (agonist of mGluR 8) were injected into the VL-PAG of a rat model of CMR to observe their effects in modulating CMR. The raphe magnus nucleus (NRM) or the gigantocellular reticular nucleus (Gi) was then damaged, and the changes in VL-PAG descending modulation were observed.Selective activation of mGluR 7 of the VL-PAG by AMN082 obviously facilitated capsaicin (CAP)-induced CMR (P0.05), which was suppressed by DCPG-induced mGluR 8 activation (P0.05). These facilitatory or inhibitory effects were completely reversed by group III mGluR antagonist MSOP. Damaging the NRM of VL-PAG main relay nucleus did not significantly affect the facilitatory effect produced by AMN082 microinjection (P0.05), but partially attenuated the inhibitory effect of DCPG microinjection (P0.05). Both the facilitatory effect of AMN082 and the inhibitory effect of DCPG were reduced obviously after bilateral Gi damage (P0.05).VL-PAG mGluR 7 and mGluR 8 mediate biphasic regulation of CMR in rats probably through activation of different sub-nuclei and different neurons in the rostroventral medulla.

To observe the descending modulation of cardiac nociception by the rostral ventromedial medulla (RVM) in rats.A rat model of cardiosomatic motor reflex (CMR) was established by injecting capsaicin into the pericardial sac to induce cardiac nociception, and the electromyogram (EMG) response of the dorsal spinotrapezius muscle was studied. The RVM was electrically stimulated (25, 75 and 100 µA) or destroyed to examine whether RVM exerted descending modulation on cardiac nociception.Electrical stimulation of the RVM at 8 sites produced intensity-dependent inhibition of EMG responses to noxious cardiac stimulus (F[2,21]=43.188, P=0.001). Electrical stimulation at 3 sites caused facilitated EMG responses, but the increased magnitude of the EMG was not dependent on stimulation intensity (F[2,6]=0.884, P=0.461). Stimulation at 11 sites produced biphasic effects: at a low intensity (25 µA), the elicited EMG magnitude was significantly larger than baseline (P0.05), and at greater intensities (75/100 µA), the stimulation caused suppression of the EMG magnitude to a level significantly lower than the baseline (P0.05). Electrolytic lesion of the RVM resulted in significantly increased EMG responses compared with the baseline and sham lesion group.Cardiac nociception evoked by capsaicin stimulation is subjected to descending biphasic modulation by the RVM, which produces predominantly descending inhibition on heart pain.

Objective To explore uterine arterial impedance and endometrial-subendometrial vascularity determined by two-dimensional Doppler ultrasonography (2D-DU) and three-dimensional ultrasonography and power Doppler angiography (3D-PDA) between patients with antiphospholipid antibodies–associated recurrent miscarriage (aPL-RM) and normal fertile women, and to further investigate the relationship between these parameters and endometrial microvessel density (MVD). Design Prospective observational study. Setting Tertiary-care fertility center. Patient(s) A total of 109 aPL-RM patients (aPL-RM group) and 49 normal fertile women (control group). Intervention(s) Uterine measurement by transvaginal ultrasonography and endometrial MVD in the midluteal phase was assessed for both groups. Main Outcome Measure(s) Endometrial thickness, volume, and MVD, uterine arterial pulsatility index (PI) and resistance index (RI), and the vascularization index (VI), flow index (FI), and vascularization flow index (VFI) of endometrial and subendometrial regions were measured on day 7 of a natural cycle after ovulation. Result(s) Both groups had similar endometrial thickness, volume, and MVD and uterine arterial PI and RI. Endometrial VI, FI, VFI, and subendometrial FI were significantly reduced in the aPL-RM group compared with the control group. None of the uterine arterial 2D-DU and endometrial-subendometrial 3D-PDA parameters correlated with the endometrial MVD in both groups. Conclusion(s) Endometrial and subendometrial vascularity was significantly impaired in aPL-RM patients during natural midluteal phase compared with normal fertile women, and endometrial MVD did not correlate with any of the acquired vascularity parameters.