UGT1A1 genotype-guided irinotecan dosing during neoadjuvant chemoradiotherapy for locally advanced rectal cancer: A prospective analysis of SN-38 concentration.

Irinotecan plays a crucial role in the neoadjuvant chemoradiotherapy (nCRT) of rectal cancer, but its optimal dosing is still unclear. In this study, we included 101 eligible patients with the UGT1A1*28 genotype of UGT1A1*1*1 (74.3%) and UGT1A1*1*28 (25.7%) and UGT1A1*6 genotypes of GG (63.4%), GA (32.7%), and AA (3.9%). All patients received preoperative radiotherapy (50 Gy/25 fractions) with concurrent irinotecan (UGT1A1*1*1: 80 mg/m2 ; UGT1A1*1*28: 65 mg/m2 ) and capecitabine (CapIri). SN-38 concentrations were measured at 1.5, 24, and 49 h post-administration. Patients were divided into four groups (Q1-Q4) based on the SN-38 concentration. The complete-response (CR) rate was the primary endpoint. The analysis demonstrated that the 49 h SN-38 concentration was relatively optimal for predicting efficacy and toxicity. The Q4 group had a significantly higher CR rate than the Q1 group (p = .019), but also higher rates of adverse events (p = .009). We screened the recommended 49 h SN-38, with a 0.5-1.0 ng/mL concentration range. We also validated the correlation between UGT1A1*6 polymorphism and SN-38 concentration, along with the clinical efficacy of irinotecan. In conclusion, our study identified the relatively optimal timepoint and concentration range for monitoring SN38 concentrations and revealed the clinical significance of UGT1A1*6 and UGT1A1*28 polymorphisms in guiding irinotecan administration, offering meaningful insights for personalised irinotecan dosing.

Prediction of response and adverse drug reaction of pemetrexed plus platinum-based chemotherapy in lung adenocarcinoma by serum metabolomic profiling.

BACKGROUND: Pemetrexed plus platinum doublet chemotherapy regimen remains to be the standard first-line treatment for lung adenocarcinoma patients. However, few biomarkers can be used to identify potential beneficiaries with maximal efficacy and minimal toxicity. This study aimed to explore potential biomarker models predictive of efficacy and toxicity after pemetrexed plus platinum chemotherapy based on metabolomics profiling. METHODS: A total of 144 patients who received at least two cycles of pemetrexed plus platinum chemotherapy were enroled in the study. Serum samples were collected before initial treatment to perform metabolomics profiling analysis. Logistic regression analysis was performed to establish prediction models. RESULTS: 157 metabolites were found to be differentially expressed between the response group and the nonresponse group. A panel of Phosphatidylserine 20:4/20:1, Sphingomyelin d18:1/18:0, and Phosphatidic Acid 18:1/20:0 could predict pemetrexed and platinum chemotherapy response with an Area Under the Receiver Operating Characteristic curve (AUROC) of 0.7968. 76 metabolites were associated with hematological toxicity of pemetrexed plus platinum chemotherapy. A panel incorporating triglyceride 14:0/22:3/22:5, 3-(3-Hydroxyphenyl) Propionate Acid, and Carnitine C18:0 was the best predictive ability of hematological toxicity with an AUROC of 0.7954. 54 differential expressed metabolites were found to be associated with hepatotoxicity of pemetrexed plus platinum chemotherapy. A model incorporating stearidonic acid, Thromboxane B3, l-Homocitrulline, and phosphoinositide 20:3/18:0 showed the best predictive ability of hepatotoxicity with an AUROC of 0.8186. CONCLUSIONS: This study established effective and convenient models that can predict the efficacy and toxicity of pemetrexed plus platinum chemotherapy in lung adenocarcinoma patients before treatment delivery.

Radical 1,4-Aryl Migration Enabled Remote Cross-Electrophile Coupling of α-Amino-ß-Bromo Acid Esters with Aryl Bromides.

We report an unprecedented, efficient nickel-catalysed radical relay for the remote cross-electrophile coupling of ß-bromo-α-benzylamino acid esters with aryl bromides via 1,4-aryl migration/arylation cascades. ß-Bromo-α-benzylamino acid esters are considered as unique molecular scaffolds allowing for aryl migration reactions, which are conceptually novel variants for the radical Truce-Smiles rearrangement. This reaction enables the formation of two new C(sp3 )-C(sp2 ) bonds using a bench-stable Ni/bipyridine/Zn system featuring a broad substrate scope and excellent diastereoselectivity, which provides an effective platform for the remote aryl group migration and arylation of amino acid esters via redox-neutral C(sp3 )-C(sp2 ) bond cleavage. Mechanistically, this cascade reaction is accomplished by combining two powerful catalytic cycles consisting of a cross-electrophile coupling and radical 1,4-aryl migration through the generation of C(sp3 )-centred radical intermediates from the homolysis of C(sp3 )-Br bonds and the switching of the transient alkyl radical into a robust α-aminoalkyl radical.

Hybrid ZIF-8-90 for Selective Solid-Phase Microextraction of Exhaled Breath from Gastric Cancer Patients.

Metal-organic frameworks (MOFs) are a new kind of microporous materials whose unique properties make them promising as coatings for solid phase microextraction (SPME). However, previous MOF coatings for SPME exclusively focus on single-linker MOFs, and the selective enrichment of polar or nonpolar targets depends on the polarity of linker on the surface of MOFs, which greatly limits the application of MOF coating for SPME in real samples. Here, we report a hybrid MOF-coated stainless steel fiber for SPME of biomarkers in exhaled breath from gastric cancer patients. Zeolitic imidazolate framework-8-90 (ZIF-8-90) possesses the aldehyde groups and methyl groups in the framework as a model MOF, and eight biomarkers (ethanol, acetone, hexanal, hexanol, nonane, isoprene, heptane, and decane) were used as the target analytes. The ZIF-8-90-coated fiber shows high enrichment efficiency for hydrophilic targets and hydrophobic targets, wide linearity (three orders of magnitude), and low detection limits (0.82-2.64 µg L-1). The ZIF-8-90-coated fiber exhibited higher enrichment performance for all the investigated analytes as a result of the synergy of methyl and aldehyde groups, the porous structure, and the suitable pore size of ZIF-8-90 (4-5 Å). The relative standard deviation (RSD) of six repetitions for extractions using the same ZIF-8-90-coated fiber ranged from 2.5 to 7.3%. The reproducibility between the three fibers prepared in parallel varied in the range of 4.8-12% (RSD). The fabricated ZIF-8-90-coated fiber lasted for at least 120 cycles of extraction/desorption/conditioning without an obvious reduction in extraction efficiency and precision. Finally, the developed ZIF-8-90-coated SPME fiber has been successfully used for the analysis of exhaled breath samples from gastric patients with satisfied recoveries (88-106%).

Copper-catalyzed radical cascades of para-quinone methides with AIBN and H2O via α-cyanoalkylation by C-C bond cleavage: new access to benzofuran-2(3H)-ones.

We describe the first one-pot construction of a benzofuran-2(3H)-one scaffold via a radical cascade reaction of para-quinone methides with azodiisobutyronitrile and water. In the presence of CuI (20 mol%), this cascade proceeds smoothly through 1,6-conjugate addition/aromatization, α-cyanoalkylation by unstrained and non-polar C(aryl)-C(t-butyl) bond cleavage, and downstream cyano-insertion/cyclization/hydrolysis, which leads to cyano-containing benzofuran-2(3H)-ones with an excellent functional-group compatibility.