Targeting LYPLAL1-mediated cGAS depalmitoylation enhances the response to anti-tumor immunotherapy.

Cyclic GMP-AMP synthase (cGAS) binds pathogenic and other cytoplasmic double-stranded DNA (dsDNA) to catalyze the synthesis of cyclic GMP-AMP (cGAMP), which serves as the secondary messenger to activate the STING pathway and innate immune responses. Emerging evidence suggests that activation of the cGAS pathway is crucial for anti-tumor immunity; however, no effective intervention method targeting cGAS is currently available. Here we report that cGAS is palmitoylated by ZDHHC9 at cysteines 404/405, which promotes the dimerization and activation of cGAS. We further identified that lysophospholipase-like 1 (LYPLAL1) depalmitoylates cGAS to compromise its normal function. As such, inhibition of LYPLAL1 significantly enhances cGAS-mediated innate immune response, elevates PD-L1 expression, and enhances anti-tumor response to PD-1 blockade. Our results therefore reveal that targeting LYPLAL1-mediated cGAS depalmitoylation contributes to cGAS activation, providing a potential strategy to augment the efficacy of anti-tumor immunotherapy.

AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer.

The induction of type-I interferons (IFN-Is) is important for the efficacy of chemotherapy. By investigating the role of amino acids in regulation of IFN-I production under chemo-drug treatment in bladder cancer (BC) cells, we find an inherent AhR-dependent negative feedback to restrain STING signaling and IFN-I production. Mechanistically, in a ligand dependent manner, AhR bridges STING and CUL4B/RBX1 E3 ligase complex, facilitating STING degradation through ubiquitin-proteasome pathway. Inhibition of AhR increases STING levels and reduces tumor growth under cisplatin or STING agonist treatment. Endogenous AhR ligands are mainly consisted of tryptophan (Trp) metabolites; dietary Trp restriction, blocking the key Trp metabolism rate-limiting enzyme IDO1 or inhibition of cellular Trp importation also show similar effect as AhR inhibition. Clinically, BC patients with higher intratumoral expression of AhR or stronger intratumoral Trp metabolism (higher IDO1 or Kyn levels) that lead to higher AhR activation show worse response rate to neoadjuvant chemotherapy (NAC).

Differential Alterations in Topology Property of Resting State Networks Associated With Mental Health and Childhood Trauma.

Context: Childhood trauma can lead to greater vulnerability to psychopathology and can affect person's mental health throughout his or her life cycle. Research on the associations between childhood trauma and developmental outcomes is critical to creating effective interventions. Objective: The study intended to identify brain networks that are susceptible to childhood trauma by comparing differences in the networks of individuals with and without trauma, to investigate how changes in networks can mediate the effects childhood adversity on mental health. Design: The research team performed a prospective cross-sectional survey. Setting: The study took place at the Second Hospital of Hebei Medical University in Shijiazhuang, China. Participants: Participants were 80 individuals aged 18-30 years, with and without childhood trauma. Outcome Measures: Participants underwent resting-state functional magnetic resonance imaging (rs-fMRI). The research team: (1) assessed participants' depressive symptoms using the Beck Depression Inventory (BDI); anxiety levels using the State-Trait Anxiety Inventory (STAI); personality traits using the Three-Dimensional Personality Questionnaire (TPQ), and childhood traumatic experiences using the Childhood Trauma Questionnaire (CTQ); (2) analyzed the data using independent component analysis (ICA) and graph theory based on resting-state functional networks to assess the functional connectivity (FC) and global efficiency of participants' brains; (3) performed a correlation analysis between changes in the topological properties of participants' brains and neglect and abuse, (4) explored the mediating effects between childhood trauma and mental health, and (5) explored gender as a moderator of the relationship between neglect and changes in the global efficiency of within-network connectivity. Results: Childhood trauma was associated with altered global efficiency of the salience network (SAN) and the default mode network (DMN). Compared with the healthy control group, the childhood trauma group's global efficiency of the SAN for the left (P = .022) and right (P = .013) bilateral anterior insula were significantly higher and the global efficiency of the DMN for the right lateral precuneus was significantly lower (P = .022). Compared with males, neglect was significantly more likely to affect the global efficiency of the SAN for females (R2 = 0.473, t = -2.33, F(3,76) = 24.66, B = -0.005, and P = .022). The childhood trauma group's mean score for novelty seeking on the TPQ was significantly higher than that of the healthy control group (P = .029), showing that the global efficiency of the SAN and DMN had a significant role as a mediator between neglect and novelty seeking. Conclusions: These findings indicate that childhood trauma can alter resting-state functional networks in healthy youth. This abnormality in brain circuitry is especially relevant to the DMN and SAN networks.

Association of early immune-related adverse events with treatment efficacy of neoadjuvant Toripalimab in resectable advanced non-small cell lung cancer.

Background: Neoadjuvant immunotherapy with anti-PD-1 was proved promising in resectable non-small cell lung cancer (NSCLC). Immune-related adverse events (irAEs) have been preliminarily implicated their association with treatment efficacy. Here we elucidated the early onset of irAEs associated with better clinical outcomes in a prospective study (Renaissance study). Methods: We conducted the prospective study of NSCLC patients treated by neoadjuvant Toripalimab (240mg, every 3 weeks) plus double platinum-based chemotherapy from December 2020 to March 2022 at Peking University Cancer Hospital. Patients were enrolled if they have resectable IIB-IIIB NSCLC without EGFR/ALK mutation. Data were analyzed to explore the relationship between clinical outcome and irAEs after neoadjuvant treatment. A multidisciplinary team including physicians, surgeons, and radiologists, confirmed the irAEs according to the clinical manifestation. The relationship between irAEs and pathological outcomes was analyzed. The Renaissance study was approved by the Peking University Ethic board (2020YJZ58) and registered at https://clinicaltrials.gov/ as NCT04606303. Results: Fifty-five consecutive patients were enrolled with a male-to-female ratio of 10:1, the median age was 62 years old (IQR: 45-76), of which 44 patients (80%) were diagnosed with squamous cell carcinoma. Forty-eight of 55 patients finally received thoracic surgery with a median preoperative waiting time of 67 days (IQR 39-113 days). Pathological results demonstrated that 31 (64.6%) patients achieved major pathological response (MPR) and 24 (50.0%) achieved complete pathological response (pCR). Among 48 patients who received R0 resection, immunotherapy-related thyroid dysfunction, rash/pruritus and enteritis occurred in 11 patients (22.9%), 7 patients (14.6%), and 1 patient (2.1%), respectively. Six patients (54.5%) with thyroid dysfunction achieved MPR with 5 (45.5%) achieved pCR, and a median time to onset was 45 days (IQR 21-91 days). Six patients (85.7%) with rash or pruritus achieved MPR and 5 patients (71.4%) achieved pCR, with median time to onset being 8 days (IQR 6-29 days). Furthermore, irAEs had no significant influence on operation time (170.6 min vs 165.7 min, P=0.775), intraoperative blood loss (67.4 mL vs 64.3 mL, P=0.831) and preoperative waiting time (93 days vs 97 days, P=0.630) when comparing with patients without irAEs (Figure 1).Figure 1Comparison of operation time (A), intraoperative blood loss (B), and preoperative waiting time (C) between "with irAEs" and "without irAEs". Conclusion: The immunotherapy-related rash is potentially associated with pathological outcomes in NSCLC patients after neoadjuvant chemo-immunotherapy, suggesting easy-to-find irAEs, such as rash, can be used as indicators to predict response to neoadjuvant chemo-immunotherapy.Clinical trial registration: clinicaltrials.gov/, identifier NCT04606303.

Aryl-to-Vinyl 1,4-Nickel Migration/Reductive Cross-Coupling Reaction for the Stereoselective Synthesis of Multisubstituted Olefins.

The aryl-to-vinyl nickel 1,4-migration (1,4-Ni migration) reaction has been reported for the first time. The generated alkenyl Ni species undergo a reductive coupling reaction with unactivated brominated alkanes affording a series of trisubstituted olefins. This tandem reaction exhibits mild conditions, a broad substrate scope, high regioselectivity, and excellent Z/E stereoselectivity. A series of controlled experiments have shown that the critical 1,4-Ni migration process is reversible. In addition, the alkenyl nickel intermediates obtained after migration are highly Z/E stereoselective and do not undergo Z/E isomerization. The obtained trace isomerization products are caused by the instability of the product.

Osimertinib as neoadjuvant therapy in patients with EGFR-mutant resectable stage II-IIIB lung adenocarcinoma (NEOS): A multicenter, single-arm, open-label phase 2b trial.

OBJECTIVES: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been approved for EGFR-mutant non-small-cell lung cancer (NSCLC). We aimed to evaluate the efficacy and safety of neoadjuvant osimertinib in patients with EGFR-mutant resectable locally advanced NSCLC. MATERIALS AND METHODS: This single-arm, phase 2b trial (ChiCTR1800016948) was conducted at six centers in mainland China. Patients with a measurable stage IIA-IIIB (T3-4 N2) lung adenocarcinoma and EGFR exon 19 and/or 21 mutations were enrolled. The patients were treated with osimertinib 80 mg orally once per day for six weeks, followed by surgical resection. The primary endpoint was the objective response rate (ORR) assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. RESULTS: Between October 17, 2018, and June 08, 2021, 88 patients were screened for eligibility. Forty patients were enrolled and treated with neoadjuvant osimertinib therapy. The ORR was 71.1 % (27/38) (95 % confidence interval: 55.2-83.0) in 38 patients who completed the 6-week osimertinib treatment. Thirty-two patients underwent surgery, and 30 (93.8 %) underwent successful R0 resection. Thirty (75.0 %) of 40 patients had treatment-related adverse events during neoadjuvant treatment, and three (7.5 %) had treatment-related adverse events of grade 3. The most common treatment-related adverse events were rash (n = 20 [50 %]), diarrhea (n = 12 [30 %]), and oral ulceration (n = 12 [30 %]). CONCLUSIONS: The third-generation EGFR TKI osimertinib, with satisfying efficacy and acceptable safety profile, could be a promising neoadjuvant therapy in patients with resectable EGFR-mutant NSCLC.

ß-Ionone represses renal cell carcinoma progression through activating LKB1/AMPK-triggered autophagy.

ß-Ionone, the end ring analog of ß-carotenoids, has been proven to have an antitumor effect in a variety of cancers. In this study, we investigated the impact of ß-ionone on renal cell carcinoma (RCC) cell lines (786-O and ACHN) using colony formation assays, flow cytometry analysis, and western blot analysis. We found that ß-ionone effectively inhibited the proliferation of RCC cells in vitro, which was also confirmed in a xenograft model. Moreover, we found that ß-ionone could induce autophagy, as indicated by LC3 puncta in 786-O and ACHN cell lines and the expression of LC3 in ß-ionone-treated RCC cells. To further explore the underlying mechanism, we assessed liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) signaling pathway activity, and the results showed that ß-ionone inhibited the proliferation of RCC cells by inducing autophagy via the LKB1/AMPK signaling pathway. In summary, our findings provide a new therapeutic strategy of ß-ionone-induced autophagy in RCC.

CHD1 deletion stabilizes HIF1α to promote angiogenesis and glycolysis in prostate cancer.

Chromodomain-helicase-DNA-binding protein 1 (CHD1) deletion is among the most common mutations in prostate cancer (PCa), but its role remains unclear. In this study, RNA sequencing was conducted in PCa cells after clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9)-based CHD1 knockout. Gene set enrichment analysis (GSEA) indicated upregulation of hypoxia-related pathways. A subsequent study confirmed that CHD1 deletion significantly upregulated hypoxia-inducible factor 1α (HIF1α) expression. Mechanistic investigation revealed that CHD1 deletion upregulated HIF1α by transcriptionally downregulating prolyl hydroxylase domain protein 2 (PHD2), a prolyl hydroxylase catalyzing the hydroxylation of HIF1α and thus promoting its degradation by the E3 ligase von Hippel-Lindau tumor suppressor (VHL). Functional analysis showed that CHD1 deletion promoted angiogenesis and glycolysis, possibly through HIF1α target genes. Taken together, these findings indicate that CHD1 deletion enhances HIF1α expression through PHD2 downregulation and therefore promotes angiogenesis and metabolic reprogramming in PCa.

Visible-Light-Driven [3 + 2]/[4 + 2] Annulation Reactions of Alkenes with N-Aminopyridinium Salts.

The annulation reactions of benzoamidyl radicals with alkenes were realized under visible light irradiation with fac-Ir(ppy)3 as catalyst and N-aminopyridinium salts as benzoamidyl radical precursors. The reaction can deliver two distinct types of products: in the case of vinyl arenes, [3 + 2] annulation product dihydrooxazoles were yielded exclusively; when alkyl-substituted alkenes were used, on the other hand, it afforded [4 + 2] annulation product dihydroisoquinolinones. Factors determining the reaction consequence were elucidated by DFT calculations.

Site-selective coupling of remote C(sp3)-H/meta-C(sp2)-H bonds enabled by Ru/photoredox dual catalysis and mechanistic studies.

Construction of C(sp2)-C(sp3) bonds via regioselective coupling of C(sp2)-H/C(sp3)-H bonds is challenging due to the low reactivity and regioselectivity of C-H bonds. Here, a novel photoinduced Ru/photocatalyst-cocatalyzed regioselective cross-dehydrogenative coupling of dual remote C-H bonds, including inert γ-C(sp3)-H bonds in amides and meta-C(sp2)-H bonds in arenes, to construct meta-alkylated arenes has been accomplished. This metallaphotoredox-enabled site-selective coupling between remote inert C(sp3)-H bonds and meta-C(sp2)-H bonds is characterized by its unique site-selectivity, redox-neutral conditions, broad substrate scope and wide use of late-stage functionalization of bioactive molecules. Moreover, this reaction represents a novel case of regioselective cross-dehydrogenative coupling of unactivated alkanes and arenes via a new catalytic process and provides a new strategy for meta-functionalized arenes under mild reaction conditions. Density functional theory (DFT) calculations and control experiments explained the site-selectivity and the detailed mechanism of this reaction.

Multi-input adaptive neural network for automatic detection of cervical vertebral landmarks on X-rays.

Cervical vertebral landmark detection is a significant pre-task for vertebral relative motion parameter measurement, which is helpful for doctors to diagnose cervical spine diseases. Accurate cervical vertebral landmark detection could provide reliable motion parameter measurement results. However, different cervical spines in X-rays with various poses and angles have imposed quite challenges. It is observed that there are similar appearances of vertebral bones in different cervical spine X-rays. For this, to fully use these similar features, a multi-input adaptive U-Net (MultiIA-UNet) focusing on the similar local features between different cervical spine X-rays is put forward to do cervical vertebral landmark detection accurately and effectively. MultiIA-UNet used an improved U-Net structure as backbone network combining with the novel adaptive convolution module to better extract changing global features. At training, MultiIA-UNet applied a multi-input strategy to extract features from random pairs of training data at the same time, and then learned their similar local features through a subspace alignment module. We collected a dataset including 688 cervical spine X-rays to evaluate MultiIA-UNet. The results exhibited that our method demonstrated the state-of-the-art performance (the minimum average point to point error of 12.988 pixels). In addition, we further evaluated the effect of these landmark detection results on cervical motion angle parameter measurement. It showed that our method was capable to obtain more accurate cervical spine motion angle parameters (the minimum symmetric mean absolute percentage is 26.969%). MultiIA-UNet could be an efficient and accurate landmark detection method for doctors to do cervical vertebral motion analysis.

Three-Component Ru-Catalyzed Regioselective Alkylarylation of Vinylarenes via Meta-Selective C(sp2)-H Bond Functionalization.

We report a novel Ru-catalyzed regioselective alkylarylation of vinylarenes with alkyl halides and arenes via meta-C(sp2)-H bond functionalization to construct 1,1-diarylalkanes that generally show bioactivity. In this transformation, a wide spectrum of primary, secondary, and tertiary alkyl halides and electronically varied arenes was well-tolerated. This reaction is characterized by its exquisite regioselectivity of vinylarenes, unique meta-C(sp2)-H selectivity, and redox-neutral conditions. The mechanism presented was supported by radical probes and kinetic isotope effect studies.

Ion-Specific Effects on Vesicle-to-Micelle Transitions of an Amino Acid Surfactant Probed by Chemical Trapping.

Ion-specific effects widely exist in biological and chemical systems and cannot be explained by classical theories. The complexity of ion-specific effects in protein systems at the molecular level necessitates the use of mimetic models involving smaller molecules, such as amino acids, oligopeptides, and other organic molecules bearing amide bonds. Therefore, it is of theoretical value to determine the effect of additional salts on the aggregation transitions of acyl amino acid surfactants. Herein, the effects of specific tetraalkylammonium ions (TAA+) on sodium lauroyl glycinate (SLG) aggregation were studied by dynamic light scattering (DLS) and transmission electron microscopy. Although previous studies have shown that the kosmotropic TAA+ ions tend to induce micellar growth or micelle-to-vesicle transitions of some anionic surfactants, TAA+ addition in the present study induced partial vesicle-to-micelle transitions in SLG solutions. The chemical trapping (CT) method was employed to estimate changes in the interfacial molarities of water, amide bonds, and carboxylate groups during such transitions. The vesicle-to-micelle transitions were accompanied by a marked rise in interfacial water molarity and a decline in interfacial amide bonds molarity, suggesting that the hydrated TAA+ entered the interfacial region and disrupted hydrogen bonding, thus preventing the SLG monomers from packing tightly. Molecular dynamic simulation was also performed to demonstrate the salt-induced cleavage of amide-amide bonds between SLG headgroups. Furthermore, both CT and DLS results show that the ability of tetraalkylammonium cations to induce such transitions increased with increasing size and hydrophobicity of the cation, which follows the Hofmeister series. The current study offers critical molecular-level evidence for understanding the specific effects of tetraalkylammonium ions on the aggregation transitions of an acyl amino acid surfactant.

Intermittent chest tube clamping decreases chest tube duration time and drainage volume after lung cancer surgery in patients without air leak: an open-label, randomized controlled trial.

Background: Our previous retrospective study proved the safety and effectiveness of chest tube clamping in terms of shortening chest tube duration. However, it needed to be verified by a prospective study. This study sought to determine if intermittent chest tube clamping decreases chest tube duration and total drainage volume after lung cancer surgery in patients without air leak. Methods: Patients with resectable lung cancer scheduled to undergo lobectomy were identified as potential candidates. Once the re-expansion of the lung was confirmed via radiography the morning of postoperative day 1 and no air leak was detected, 180 patients were randomly assigned to intermittent chest tube clamping (the clamping group, n=90) or continuous gravity drainage (the control group, n=90). The primary outcome was chest tube drainage duration. Pleural drainage volume and adverse events were also recorded. Results: Of 180 patients, 12 were subsequently withdrawn from the study for various reasons. In the intention-to-treat analysis, the chest tube drainage duration was significantly shorter {median [interquartile range]: 2 [2, 3] vs. 3 [2, 3] days; P=0.009}, and total drainage volume was much less (mean ± standard deviation: 516.73±410.9 vs. 657.8±448.2 mL; P=0.029) in the clamping group than the control group. In the per-protocol analysis, the chest tube drainage duration was significantly shorter {median [interquartile range]: 2 [2, 3] vs. 3 [2, 3] days; P=0.007}, and total drainage volume was much less (mean ± standard deviation: 437.8±213.9 vs. 604.8±352.8 mL; P=0.001) in the clamping group than the control group. Further, the clamping group showed a major improvement in plasma albumin declination at discharge (mean ± standard deviation: 7.7±2.9 vs. 9.0±5.2 g/L; P=0.040). No severe adverse events were observed in either 2 groups. Conclusions: Our study indicates that chest tube clamping decreased the duration of chest tube drainage and drainage volume without causing adverse effects. Its wider application may help reduce medical costs and increase patient comfort. Trial Registration: ClinicalTrials.gov NCT03379350.

Feasibility study of hallux valgus measurement with a deep convolutional neural network based on landmark detection.

OBJECTIVE: To develop a deep learning algorithm based on automatic detection of landmarks that can be used to automatically calculate forefoot imaging parameters from radiographs and test its performance. MATERIALS AND METHODS: A total of 1023 weight-bearing dorsoplantar (DP) radiographs were included. A total of 776 radiographs were used for training and verification of the model, and 247 radiographs were used for testing the performance of the model. The radiologists manually marked 18 landmarks on each image. By training our model to automatically label these landmarks, 4 imaging parameters commonly used for the diagnosis of hallux valgus could be measured, including the first-second intermetatarsal angle (IMA), hallux valgus angle (HVA), hallux interphalangeal angle (HIA), and distal metatarsal articular angle (DMAA). The reference standard was determined by the radiologists' measurements. The percentage of correct key points (PCK), intragroup correlation coefficient (ICC), Pearson correlation coefficient (r), root mean square error (RMSE), and mean absolute error (MAE) between the predicted value of the model and the reference standard were calculated. The Bland-Altman plot shows the mean difference and 95% LoA. RESULTS: The PCK was 84-99% at the 3-mm threshold. The correlation between the observed and predicted values of the four angles was high (ICC: 0.89-0.96, r: 0.81-0.97, RMSE: 3.76-6.77, MAE: 3.22-5.52). However, there was a systematic error between the model predicted value and the reference standard (the mean difference ranged from - 3.00 to - 5.08°, and the standard deviation ranged from 2.25 to 4.47°). CONCLUSION: Our model can accurately identify landmarks, but there is a certain amount of error in the angle measurement, which needs further improvement.

Photoredox-catalyzed redox-neutral difluoroalkylation to construct perfluoroketones with difluoroenoxysilanes.

A mild and facile approach to construct various perfluoroketones via photo-catalyzed difluoroalkylation of difluoroenoxysilanes is developed. The reaction includes a strategy of combination of two fluorine-containing functional groups, which confers the reaction with characteristics like high efficiency, mild conditions, and broad scope. A variety of fluoroalkyl halides including perfluoroalkyl iodides, bromo difluoro esters and amides can be employed as radical precursors. Control experiments indicate that a single-electron transfer pathway may be involved in the reaction.

Inflammatory factor-based prognostic risk stratification for patients with metastatic castration-resistant prostate cancer treated with docetaxel.

To develop a simple inflammatory factor-based prognostic risk stratification system for patients with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel as the initial treatment, we reviewed the data of 399 consecutive patients who received first-line docetaxel chemotherapy between January 2013 and June 2019 retrospectively. The optimal cut-off values for the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in terms of survival were calculated by ROC curves. Patients were stratified into favourable (lower NLR and lower PLR), intermediate (higher NLR and lower PLR, or lower NLR and higher PLR) and poor (higher NLR and higher PLR) groups. Kaplan-Meier curves were drawn to evaluate overall survival (OS) and progression-free survival (PFS). The ROC curve analysis determined the cut-offs for the NLR and PLR to be 2.355 and 104.275 respectively. Multivariate Cox regression analysis showed that being in the poor patient group (NLR ≥2.355 and PLR ≥104.275) was an independent prognostic risk factor and Kaplan-Meier curves analysis revealed that respondents with NLR <2.355 and PLR <104.275 had significantly longer OS and PFS. So it can be concluded that concurrently high NLR and PLR values are predictors for poor chemotherapy outcomes after androgen deprivation therapy failure in patients with mCRPC.

Cu-Catalyzed Direct C-H Alkylation of Polyfluoroarenes via Remote C(sp3)-H Functionalization in Carboxamides.

A novel dehydrogenative coupling reaction of N-fluorocarboxamides with polyfluoroarenes forming C(sp2)-C(sp3) bonds enabled by copper catalysis has been accomplished. N-Fluorocarboxamides are postulated to undergo copper-mediated dehydrogenative cross-coupling reaction with electron-deficient polyfluoroarenes via a radical pathway. Benzylic C-H bonds and aliphatic C-H bonds in N-fluorocarboxamides could proceed smoothly and demonstrated excellent regioselectivity. The detailed mechanism presented is supported by control experiments and density functional theory calculations.

Copper-Catalyzed Radical Aryl Migration Approach for the Preparation of Cyanoalkylsulfonylated Oxindoles/Cyanoalkyl Amides.

A copper-catalyzed radical cross-coupling of oxime esters and activated alkenes is accomplished for the synthesis of cyanoalkylsulfonylated oxindoles and cyanoalkyl amides via an aryl migration strategy. Specifically, the subsequent mechanism research indicates that the unique desulfonylation and sulfone addition processes were involved in the transformation. This transformation is identified as having good functional group applicability with two different quaternary stereocenter in a regioselective manner, which is controlled by the substituent group of the nitrogen.