Medium Effects on the 1,3-Dipolar Cycloaddition of Pyridazinium Dicyanomethanide with Ethyl Vinyl Ketone in Pure and Mixed Solvents from QM/MM Simulations

The 1,3-dipolar cycloaddition reaction between pyridazinium dicyanomethanide <b>1</b> and ethyl vinyl ketone (EVK) has been reported to be a concerted mechanism based on gas-phase ab initio calculations. Our current investigation of this 1,3-dipolar cycloaddition reaction in water, methanol, acetonitrile, H₂O–CH₃CN, and CH₃OH–CH₃CN mixtures using novel two-dimensional potentials of mean force (2-D PMF) calculations coupled to QM/MM simulations predicts an alternative free energy surface that supports a stepwise mechanism. The results for the kinetic effect are uniformly in close accord with experimental data and reflect a trigger point for the exponential rate rise in water–acetonitrile mixture. When methanol replaced water, the rate enhancements are more gradual, and there is no trigger point. Calculations in pure solvents and their mixtures at 25 °C and with pure water and acetonitrile at 37 °C indicate that the secondary bridging H-bonding from the first water molecules is necessary for the exponential rate enhancements, which is strong supported by the experimental results. This work provides new insight into solvent effects on 1,3-dipolar cycloaddition reaction

Computational Mechanism Study of Catalyst-Dependent Competitive 1,2-C→C, −O→C, and −N→C Migrations from β‑Methylene-β-silyloxy-β-amido-α-diazoacetate: Insight into the Origins of Chemoselectivity

Doyle et al. [J. Am. Chem. Soc. 2013, 135, 1244−1247] recently reported an efficient catalyst-controlled chemoselectivity of competitive 1,2-C→C, −O→C, and −N→C migrations from β-methylene-β-silyloxy-β-amido-α-diazoacetates using dirhodium or copper catalysts. With the aid of density functional theory calculations, the present study systematically probed the mechanism of the aforementioned reactions and the origins of the catalyst-controlled chemoselectivity. Similar to the method reported in the literature, simplified catalyst models Rh₂(O₂CH)₄ and Rh₂(<i>N</i>-methylformamide)₄ have been used in our initial calculations. However, using the Rh₂(O₂CH)₄ model could not describe the energies of all possible pathways, and high selectivity of three competitive migrations could not be achieved. In order to appropriately describe this 1,2-migration system, real catalyst models Rh₂(cap)₄, Rh₂(esp)₂, and CuPF₆ have been employed. It was found that the steric and electronic effects of ligands significantly influence the free energy barrier, which ultimately changes the chemoselectivity. In the CuPF₆ system, the electronic effects, coupled with the steric factor, give a qualitative explanation for the exclusive chemoselectivity of 1,2-N→C migration over 1,2-C→C or −O→C migration. On the other hand, the bulky ligands of dirhodium catalysts result in the significant steric hindrance around the dirhodium centers and withdrawal of the empty space around the bulky −OTBS group. By analyzing the divergence of three different migration transition states using the distortion/interaction and natural bond orbital analyses, it was found that the 1,2-N→C migration will suffer from a high free energy barrier because of the steric repulsion between the carbonyl group and the carbonyl oxygen of the pyrazolidinone ring. For 1,2-C→C and −O→C migrations, changing the ligands of dirhodium catalysts can change the electronic properties of carbenes, and that is the reason for controlling the major product by changing the dirhodium catalysts. The mechanistic proposal is supported by the calculated chemoselectivities, which are in good agreement with the experimental results

Image_1_Peripheral CD4+ T cells correlate with response and survival in patients with advanced non-small cell lung cancer receiving chemo-immunotherapy.jpeg

BackgroundThe aim of the present study was to explore the potential of peripheral immune cells in predicting the response and prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving anti-PD-1 immunotherapy and platinum-based chemotherapy.Participants and MethodsWe utilized flow cytometry to examine the levels and dynamics of blood immune cells in 79 advanced NSCLC patients treated with the chemoimmunotherapy between December 2019 and January 2022. The pre- and post-treatment blood samples were collected within 3 days prior to the initiation of the first and third cycle of combination treatment, respectively. Progression-free survival (PFS) and overall survival (OS) analyses were conducted using Kaplan-Meier method and Cox regression models.ResultsThe pre-treatment CD4+/Total T cells ratio was significantly higher in responders than non-responders (P +/Total T cells ratio was positively correlated with OS (P = 0.038). In multivariate analysis, post-treatment NK cells and post-treatment CD4+CD8+/Total T cells ratio were negatively associated with OS (hazard ratio [HR] = 10.30, P = 0.038) and PFS (HR = 1.95, P = 0.022), respectively. Notably, significantly positive correlations were observed between CD4+/Total T cells ratio and prognosis both before and after treatment (P ConclusionTo summarize, our finding reveals that high CD4+/total T cells ratio was associated with favorable response and prognosis, highlighting its potential as a predictive biomarker to guide the selection of likely responders to platinum and anti-PD-1 combination therapy.</p

Table_1_Peripheral CD4+ T cells correlate with response and survival in patients with advanced non-small cell lung cancer receiving chemo-immunotherapy.docx

BackgroundThe aim of the present study was to explore the potential of peripheral immune cells in predicting the response and prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving anti-PD-1 immunotherapy and platinum-based chemotherapy.Participants and MethodsWe utilized flow cytometry to examine the levels and dynamics of blood immune cells in 79 advanced NSCLC patients treated with the chemoimmunotherapy between December 2019 and January 2022. The pre- and post-treatment blood samples were collected within 3 days prior to the initiation of the first and third cycle of combination treatment, respectively. Progression-free survival (PFS) and overall survival (OS) analyses were conducted using Kaplan-Meier method and Cox regression models.ResultsThe pre-treatment CD4+/Total T cells ratio was significantly higher in responders than non-responders (P +/Total T cells ratio was positively correlated with OS (P = 0.038). In multivariate analysis, post-treatment NK cells and post-treatment CD4+CD8+/Total T cells ratio were negatively associated with OS (hazard ratio [HR] = 10.30, P = 0.038) and PFS (HR = 1.95, P = 0.022), respectively. Notably, significantly positive correlations were observed between CD4+/Total T cells ratio and prognosis both before and after treatment (P ConclusionTo summarize, our finding reveals that high CD4+/total T cells ratio was associated with favorable response and prognosis, highlighting its potential as a predictive biomarker to guide the selection of likely responders to platinum and anti-PD-1 combination therapy.</p

Image_3_Peripheral CD4+ T cells correlate with response and survival in patients with advanced non-small cell lung cancer receiving chemo-immunotherapy.jpeg

BackgroundThe aim of the present study was to explore the potential of peripheral immune cells in predicting the response and prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving anti-PD-1 immunotherapy and platinum-based chemotherapy.Participants and MethodsWe utilized flow cytometry to examine the levels and dynamics of blood immune cells in 79 advanced NSCLC patients treated with the chemoimmunotherapy between December 2019 and January 2022. The pre- and post-treatment blood samples were collected within 3 days prior to the initiation of the first and third cycle of combination treatment, respectively. Progression-free survival (PFS) and overall survival (OS) analyses were conducted using Kaplan-Meier method and Cox regression models.ResultsThe pre-treatment CD4+/Total T cells ratio was significantly higher in responders than non-responders (P +/Total T cells ratio was positively correlated with OS (P = 0.038). In multivariate analysis, post-treatment NK cells and post-treatment CD4+CD8+/Total T cells ratio were negatively associated with OS (hazard ratio [HR] = 10.30, P = 0.038) and PFS (HR = 1.95, P = 0.022), respectively. Notably, significantly positive correlations were observed between CD4+/Total T cells ratio and prognosis both before and after treatment (P ConclusionTo summarize, our finding reveals that high CD4+/total T cells ratio was associated with favorable response and prognosis, highlighting its potential as a predictive biomarker to guide the selection of likely responders to platinum and anti-PD-1 combination therapy.</p

Image_4_Peripheral CD4+ T cells correlate with response and survival in patients with advanced non-small cell lung cancer receiving chemo-immunotherapy.jpeg

BackgroundThe aim of the present study was to explore the potential of peripheral immune cells in predicting the response and prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving anti-PD-1 immunotherapy and platinum-based chemotherapy.Participants and MethodsWe utilized flow cytometry to examine the levels and dynamics of blood immune cells in 79 advanced NSCLC patients treated with the chemoimmunotherapy between December 2019 and January 2022. The pre- and post-treatment blood samples were collected within 3 days prior to the initiation of the first and third cycle of combination treatment, respectively. Progression-free survival (PFS) and overall survival (OS) analyses were conducted using Kaplan-Meier method and Cox regression models.ResultsThe pre-treatment CD4+/Total T cells ratio was significantly higher in responders than non-responders (P +/Total T cells ratio was positively correlated with OS (P = 0.038). In multivariate analysis, post-treatment NK cells and post-treatment CD4+CD8+/Total T cells ratio were negatively associated with OS (hazard ratio [HR] = 10.30, P = 0.038) and PFS (HR = 1.95, P = 0.022), respectively. Notably, significantly positive correlations were observed between CD4+/Total T cells ratio and prognosis both before and after treatment (P ConclusionTo summarize, our finding reveals that high CD4+/total T cells ratio was associated with favorable response and prognosis, highlighting its potential as a predictive biomarker to guide the selection of likely responders to platinum and anti-PD-1 combination therapy.</p

DataSheet_1_Efficacy and acceptability of psilocybin for primary or secondary depression: A systematic review and meta-analysis of randomized controlled trials.docx

IntroductionPsilocybin is a classic psychedelics, which has been shown to have antidepressant effects by many studies in recent years. In this study, we aim to evaluate the efficacy, acceptability and tolerability of psilocybin in the treatment of primary (major depressive disorder) or secondary (experiencing distress related to life-threatening diagnoses and terminal illness) depression.MethodsWe searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov for clinical trials of psilocybin for depression (updated to 4 October, 2023). Effect size Hedges’ g was used as an indicator of efficacy, and other outcomes included response rate, drop-out rate, and adverse events.ResultsA total of 10 studies were finally included in systematic review. 8 studies were included in the meta-analysis, involving a total of 524 adult patients, and produced a large effect size in favor of psilocybin (Hedge’s g =-0.89, 95% CI -1.25~-0.53, I² = 70.19%, PDiscussionOur study shows that psilocybin has both short-term and long-term antidepressant effects and holds promise as a potential complementary or alternative therapy for depression, probably. Further research may reveal more about its therapeutic potential.</p

DataSheet_1_Peripheral CD4+ T cells correlate with response and survival in patients with advanced non-small cell lung cancer receiving chemo-immunotherapy.pdf

BackgroundThe aim of the present study was to explore the potential of peripheral immune cells in predicting the response and prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving anti-PD-1 immunotherapy and platinum-based chemotherapy.Participants and MethodsWe utilized flow cytometry to examine the levels and dynamics of blood immune cells in 79 advanced NSCLC patients treated with the chemoimmunotherapy between December 2019 and January 2022. The pre- and post-treatment blood samples were collected within 3 days prior to the initiation of the first and third cycle of combination treatment, respectively. Progression-free survival (PFS) and overall survival (OS) analyses were conducted using Kaplan-Meier method and Cox regression models.ResultsThe pre-treatment CD4+/Total T cells ratio was significantly higher in responders than non-responders (P +/Total T cells ratio was positively correlated with OS (P = 0.038). In multivariate analysis, post-treatment NK cells and post-treatment CD4+CD8+/Total T cells ratio were negatively associated with OS (hazard ratio [HR] = 10.30, P = 0.038) and PFS (HR = 1.95, P = 0.022), respectively. Notably, significantly positive correlations were observed between CD4+/Total T cells ratio and prognosis both before and after treatment (P ConclusionTo summarize, our finding reveals that high CD4+/total T cells ratio was associated with favorable response and prognosis, highlighting its potential as a predictive biomarker to guide the selection of likely responders to platinum and anti-PD-1 combination therapy.</p

Image_2_Peripheral CD4+ T cells correlate with response and survival in patients with advanced non-small cell lung cancer receiving chemo-immunotherapy.jpeg

BackgroundThe aim of the present study was to explore the potential of peripheral immune cells in predicting the response and prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving anti-PD-1 immunotherapy and platinum-based chemotherapy.Participants and MethodsWe utilized flow cytometry to examine the levels and dynamics of blood immune cells in 79 advanced NSCLC patients treated with the chemoimmunotherapy between December 2019 and January 2022. The pre- and post-treatment blood samples were collected within 3 days prior to the initiation of the first and third cycle of combination treatment, respectively. Progression-free survival (PFS) and overall survival (OS) analyses were conducted using Kaplan-Meier method and Cox regression models.ResultsThe pre-treatment CD4+/Total T cells ratio was significantly higher in responders than non-responders (P +/Total T cells ratio was positively correlated with OS (P = 0.038). In multivariate analysis, post-treatment NK cells and post-treatment CD4+CD8+/Total T cells ratio were negatively associated with OS (hazard ratio [HR] = 10.30, P = 0.038) and PFS (HR = 1.95, P = 0.022), respectively. Notably, significantly positive correlations were observed between CD4+/Total T cells ratio and prognosis both before and after treatment (P ConclusionTo summarize, our finding reveals that high CD4+/total T cells ratio was associated with favorable response and prognosis, highlighting its potential as a predictive biomarker to guide the selection of likely responders to platinum and anti-PD-1 combination therapy.</p

Synthesis, Solid-State Structures, and Molecular Recognition of Chiral Molecular Tweezer and Related Structures Based on a Rigid Bis-Naphthalene Cleft

The rigid and nonchiral bis-naphthalene cleft was used for the first time as a scaffold to build a chiral molecular tweezer. The molecular tweezer and its related compounds have been synthesized and carefully characterized by X-ray crystallography and NMR spectroscopy. Their solid-state structures and molecular recognition properties have also been studied