Enantioselective Alkynylation of 2-Aryl-3H-indol-3-ones via Cooperative Catalysis of Copper/Chiral Phosphoric Acid.

A facile enantioselective alkynylation of cyclic ketimines attached to a neutral functional group utilizing the dual Cu(I)-CPA catalysis is described. The strategy of the alkynylation of 2-aryl-3H-indol-3-one directly to chiral propargylic amines containing indolin-3-one moiety in good yields and enantioselectivities. Moreover, gram-scale synthesis of chiral propargylamines based C2-quaternary indolin-3-ones was performed. The synthetic applications were confirmed by transformations of the products with no decrease in the yield and enantioselectivity.

B(C6F5)3-catalyzed ß-C(sp3)-H alkylation of tertiary amines with 2-aryl-3H-indol-3-ones.

The ß-C-H functionalization of amines is one of the most powerful tools for the synthesis of saturated nitrogen-containing heterocycles in organic synthesis. However, the ß-C-H functionalization of amines via redox-neutral addition with cyclic-ketimines is still unprecedented. Herein, the ß-C-H functionalization of tertiary amines is described, providing the corresponding 1,3-diamines containing the indolin-3-one moiety in high yields via the B(C6F5)3-catalyzed borrowing hydrogen strategy. According to the experimental results, a possible catalytic cycle has been proposed to rationalize the process of this reaction. Notably, the ß-C-H alkylation of amines is external oxidant- and transition-metal-free, which makes a significant contribution to promoting economical chemical synthesis.

Organocatalyzed Enantioselective Aza-Morita-Baylis-Hillman Reaction of Cyclic Ketimine with α,ß-Unsaturated γ-Butyrolactam.

The enantioselective aza-MBH reaction is an efficient strategy for constructing novel carbon-carbon bonds, providing access to multitudinous chiral densely functionalized MBH products. However, the enantioselective aza-MBH reaction of cyclic-ketimines that would generate a versatile synthon is still missing and challenging. Herein, we developed a challenging direct organocatalytic asymmetric aza-MBH reaction involving cyclic ketimines attached to a neutral functional group. Moreover, the α,ß-unsaturated γ-butyrolactam was utilized as a rare nucleophile alkene in this work. The reactions provide enantiomerically enriched 2-alkenyl-2-phenyl-1,2-dihydro-3H-indol-3-ones, bearing with a tetra-substituted stereogenic center. Moreover, this reaction features high α-selectivities, high enantioselectivities (up to 99% ee), and good yields (up to 80%).

Asymmetric aza-Friedel-Crafts Reaction of Cyclic Ketimines with 5-Aminopyrazole Derivatives: Expedient Access to Pyrazole-Based C2-quaternary Indolin-3-Ones.

A chiral phosphoric acid-catalyzed enantioselective aza-Friedel-Crafts reaction of 5-aminopyrazole derivatives with cyclic ketimines attached to a neutral functional group is reported. This protocol allows the formation of pyrazole-based C2-quaternary indolin-3-ones with high enantioselectivities and regioselectivities. Moreover, gram-scale synthesis of the 5-aminopyrazole-based C2-quaternary indolin-3-ones was performed, with no decrease in the yield and enantioselectivity.

Chiral phosphoric acid-catalyzed enantioselective aza-Friedel-Crafts reaction of naphthols and electron-rich phenols with 2-aryl-3H-indol-3-ones.

The enantioselective aza-Friedel-Crafts reaction is one of the most straightforward and efficient strategies for constructing a new carbon-carbon bond bearing quaternary stereocenter in organic synthesis, but the catalytic asymmetric aza-Friedel-Crafts reaction of naphthols/phenols with cyclic-ketimines attached to a neutral functional group remains still relatively unexplored. Herein, a highly enantioselective aza-Friedel-Crafts reaction of cyclic-ketimines and naphthols/phenols has been realized using a chiral phosphoric acid catalyst. A variety of chiral aminonaphthols (chiral indolin-3-ones) containing a quaternary stereocenter at the C2 position were obtained with excellent outcomes (up to 97% yield, 98% ee). Moreover, the synthetic utility of the enantiomerically enriched chiral aminonaphthols was demonstrated in some efficient transformations. According to the experimental results, a possible transition state model has been proposed to rationalize the origin of asymmetric induction.

Analysis of the Relationship between Scleritis and T Cell Activation in Patients with Hepatocellular Carcinoma Treated with PD-1 Carrelizumab.

In order to explore the function of inhibiting the immune effect, the relationship between programmed death receptor 1 (PD-1) carrelizumab in the treatment of hepatocellular carcinoma-induced scleritis and T cell activation is investigated. A total of 120 patients with primary liver cancer treated in the department of oncology of our hospital from July 2020 to January 2022 are selected and treated with carrelizumab. According to the occurrence of PD-1 carrelizumab treatment, the patients are divided into the scleritis group and nonscleritis group. The levels of T cells, PD-1, PD-L1 proteins, and serum inflammatory factors at different time points are compared. The experimental results show that the occurrence of scleritis after liver cancer treatment with PD-1 carrelizumab is closely associated with Treg cells, the percentage of Th17 cells, the expression of PD-1, PD-L1 proteins, and inflammatory factors. It is clearly evident that PD-1 carrelizumab can increase the risk of scleritis by affecting T cell activation.

Effects of image-guided adaptive radiotherapy combined with hepatic artery chemoembolization in primary liver cancer patients.

OBJECTIVE: The study aimed to explore the effects of image-guided adaptive radiotherapy combined with hepatic artery chemoembolization on the immune function of primary liver cancer patients. METHODS: The study included 84 primary liver cancer patients who received treatment at our hospital between April 2018 and January 2020. They were divided into the control group (n=42, hepatic artery chemoembolization) and the study group (n=42, image-guided adaptive radiotherapy combined with hepatic artery chemoembolization) using the random number table method. AFP, ALT, AST, CA724, CA242 and immune function before and after treatment were compared in the two groups and the short-term efficacy and adverse events (AEs) were statistically analyzed. The two groups were followed up. RESULTS: After treatment, the study group had a higher ORR and DCR compared to the control group, and the difference was statistically significant (P < 0.05). There was no statistical difference in the levels of AFP, ALT, AST, CA724 and CA242 between the two groups before treatment (P > 05). After treatment, the study group had lower levels of AFP, ALT, AST, CA724 and CA242 than the control group, and the difference was statistically significant (P < 0.05). There was no statistical difference in the levels of CD4+, CD8+, and CD4+/CD8+ before treatment in the two groups (P > 05). After treatment, the study group had higher levels of CD4+ and CD4+/CD8+ but lower levels of CD8+ compared to the control group, and the difference was statistically significant (P < 0.05). In the study group, 2 patients developed radiation-induced liver disease, and the incidence was 4.76% (2/42), which occurred at 4 and 6 weeks after the end of radiotherapy, respectively. The patients mainly had elevated transaminases, ascites, and liver enlargement and hepatoprotection and nutritional support were provided, and the patients gradually recovered after treatment. There was no statistical difference in the incidence of AEs between the two groups (p > 0.05). All patients in the study completed follow up and the follow up completion rate was 100%. The median duration of follow up was 22.5 months. In the study group, 12 of 42 patients (28.57%) died and 21 cases (50.00%) had recurrence. In the control group, 21 of 42 cases (50.00%) died and 27 cases (64.29%) recurred. At 1 year, there was no statistical difference in ORR and DCR between the two groups (P > 0.05) and at 2 years, the study group had a higher ORR and DCR than the control group, and the difference was statistically significant (P < 0.05). CONCLUSION: Image-guided adaptive radiotherapy combined with hepatic artery chemoembolization may improve the immune function of primary liver cancer patients and is of important clinical application value.

A fatal multiple-lesion, inflammatory, pseudotumor in the lung: a rare case report.

An inflammatory pseudotumor is considered a benign form of lesion marked by a proliferation of myofibroblasts with different degrees of inflammatory infiltrates. Pulmonary inflammatory pseudotumors (PIPs) are extremely rare in middle-aged adults. Normally, a PIP has a single lesion, and can be controlled constantly by surgery and drugs. In this paper, we report a case study of a 51-year-old male patient who presented with multiple inflammatory pseudotumors in lungs, thoracic spine, ribs, left humerusl, derived from PIPs throughout his body, which indicated a long disease term and significant recrudescence. After 6 surgeries (a wedge resection of the right lower lobe, a removal of three thoracic vertebral lesions, a removal of left humeral tumor lesion, a right lower lobe resection, local cryoablation of right lung, debridement of left upper-arm osteomyelitis and soft tissue infection), radiotherapy for lesions of left humerus destruction at a total dose of 20 Gy/10 F, and systematic treatments (30 mg prednisone acetate daily for 6 weeks, 50 mg compound cyclophosphamide tablets for 2 weeks; antibiotics, blood transfusions, nutritional support), his symptoms improved but reoccurred. The patient ultimately died of septic shock. Our case report highlights that the progression of a PIP to a malignant form requires further research. A multiple-lesion PIP that does not respond to systemic treatment can be highly dangerous.

Fluorescence copolymer-based dual-signal monitoring tyrosinase activity and its inhibitor screening via blue-green emission transformation.

Tyrosinase (TYR) is a crucial enzyme in melanin metabolism and catecholamine production, its abnormal overexpression is closely associated with many human diseases involving melanoma cancer, vitiligo, Parkinson's disease and so on. Herein, a dual-signal fluorescence sensing system for monitoring TYR activity is constructed depending on the transformation of blue-green fluorescence emission of copolymer. The developed sensing system is based on TYR catalyzing the hydroxylation of mono-phenol to o-diphenol and the conversion of fluorescence copolymer (FCP) blue emission (430 nm) and green emission (535 nm) in the presence of PEI. In the system, both blue and green emission exhibit a high selectivity and sensitivity (S/B up to 300 and 30 for blue and green emission, respectively) toward TYR in the range from 0.5 to 2.5 U/mL with the detection limit of 0.002 U/mL and 0.06 U/mL, respectively. Additionally, this assay is used to detect TYR in human serum with excellent recovery even at 30% human serum concentrations. Furthermore, it still has been successfully applied to TYR inhibitor screening by taking kojic acid as a model. We believe that our developed sensor has great potential application in TYR-associated disease diagnosis and treatment and drug discovery.

Efficacy of argon-helium cryoablation and its effects on immune function of patients with neck malignant tumours.

OBJECTIVES: Our study aimed to investigate the clinical efficacy of argon-helium cryoablation and its effects on the immune function of patients with neck malignant tumours. DESIGN: Retrospective study. SETTING: Single-institution academic tertiary care centre. METHODS: Totally, 180 patients harbouring head and neck malignant tumours were divided into the argon-helium cryoablation group (n = 150) and the radiotherapy group (n = 50). The efficacy of the two groups was compared, and the immune function was observed. RESULTS: The short-term clinical effect of the argon-helium cryoablation group was significantly higher than that of the radiotherapy group (P < .05). After treatment, the CD3+, CD4+, CD8+ and CD4+/CD8+ of the argon-helium cryoablation group were significantly better than those of the radiotherapy group (P < .001). The results of TNF-α, IL-1 ß and CRP in the argon-helium cryoablation group were significantly better than that in the radiotherapy group (P < .001). CONCLUSION: Argon-helium cryoablation could effectively improve the immune function, 5-year survival rate and local remission rate.

Topochemical assembly of levodopa nanoparticles network as a high-performance biosensing platform coupling with π-π stacking and electrostatic repulsion interactions.

Topochemical assembly carbon materials with unique structure rarely investigated and reported. Herein, we demonstrate the feasibility of using topochemical assembly levodopa nanoparticles with dendritic structure (LNDS) network as a new high-performance biosensing platform based on noncovalent functionalization of LNDS with a fluorescent oligonucleotide. The proposed platform is dependent on the competition of π-π stacking and electrostatic repulsion interactions between LNDS and fluorescent oligonucleotide. The obtained LNDS with 96.1% quenching efficiency is synthesized by using levodopa as the single precursor by natural oxidation or microwave irradiation. The constructed platform can be used for simple and efficient probing single-nucleotide polymorphisms (SNPs) and cDNA by fluorescence restoration with a highly sensitivity and selectivity, remarkably superior to those based on graphenes. Additionally, an aptasensor is further constructed for small molecule ATP detention in serum with a low detection limit of 4 µM. To the best of our knowledge, this is the first attempt to use LNDS to design a biosensing platform, and therefore opens possibilities for new types of nanoparticle-based molecule approaches, and sequencing technologies.

Blue and green emission-transformed fluorescent copolymer: Specific detection of levodopa of anti-Parkinson drug in human serum.

Levodopa, commonly used anti-Parkinson drugs in the clinic, is the most significant prodrug of dopamine that plays important roles in the treatment of Parkinson's disease. Therefore, monitoring content of levodopa of anti-parkinson drugs in human serum is extremely necessary. Herein, a simple, fast and low-cost method for levodopa detection is proposed depending on the in situ formation of blue and green emission fluorescent copolymer (FCP). The proposed method is based on the conversion of fluorescence emission peak of FCP from blue (430 nm) to green emission (535 nm) in 2 h. In this sensing system, both blue and green emission exhibit a high selectivity and sensitivity for levodopa determination in the range from 0 to 50 µM with a detection limit of 0.2 µM and 0.36 µM, respectively. Among them green emission FCP shows excellent recovery even at human serum concentrations up to 30%. Additionally, the proposed method was successfully applied to assess the content of levodopa in three anti-Parkinson drugs (carbidopa and levodopa CR tablets, levodopa and benserazide hydrochloride tablets, and levodopa tablets). More importantly, the levodopa determination of three anti-Parkinson drugs in human serum also exhibit an excellent recovery. Therefore, our strategy provides a promising method for mechanism study and treatment of Parkinson's disease.

Oncological outcomes of addition of anti-PD1/PD-L1 to chemotherapy in the therapy of patients with advanced gastric or gastro-oesophageal junction cancer: A meta-analysis.

BACKGROUND: Patients with advanced gastric or gastro-oesophageal junction cancer (GC/GEJC) that fail to respond to prior chemotherapy have poor clinical prognosis. Lately, many trials have paid much attention on the oncological outcomes of immune checkpoint inhibitors (ICI). A new therapy based on programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has recognized as promising prospects for advanced GC/GEJC. We assessed efficacy and safety of PD-L1 antibody versus chemotherapy alone in previously treated non-small cell lung cancer. METHODS: Computerized literature search was done on the published trials in: Pubmed, Embase, Cochrane library updated on June 2019. Randomized controlled trials were selected investigating chemotherapy plus PD-1/PD-L1 versus chemotherapy alone. RESULTS: Three randomized controlled trails were included. The pooled analysis of overall survival (OS) was longer with anti-PD1/PD-L1 than with chemotherapy alone in the OS (OR = 0.66, 95%CI = 0.47-0.92, P = .02) and sub-group OS of GEJC (OR = 0.73, 95%CI = 0.58-0.93, P = .01). Whereas, there is no significant difference in progression-free survival (OR = 0.93, 95%CI = 0.62-1.39, P = .72). The pooling adverse events (AE) data did not achieve advantage in the PD-1/PD-L1 targeted agents (OR = 0.53, 95%CI = 0.13-2.10, P = .36), the same as the treatment-related AE of grade 3 to 5 (OR = 0.53, 95%CI = 0.16-1.74, P = .30). CONCLUSIONS: Treatment of patients with advanced GC/GEJC with PD-1/PD-L1 targeted did result in an improvement in some but not all survival endpoints. Moreover, it had a comparable toxicity profile as compared with chemotherapy alone. More well designed studies are needed to develop a database of all anti-PD1/PD-L1 sub-groups and their individual impact on the differing anti-PD1/PD-L1 treatments.

Development of luminescent nanoswitch for sensing of alkaline phosphatase in human serum based onAl3+-PPi interaction and Cu NCs with AIE properties.

As an important biomarker, alkaline phosphatase (ALP) is one of the most commonly assayed enzymes in clinical practice. Here a novel turn-on fluorescent nanoswitch for ALP assay was suggested. The nanoswitch was easily constructed via two high-affinity ligands between GSH and Al3+ and PPi and Al3+ based on the difference in the affinity. The primary fluorescence of as-prepared GSH capped Cu nanoclusters (NCs) turned on first upon the Al3+ addition due to the Al3+ induced aggregation induced emission (AIE) enhancement based on the high affinity of GSH and Al3+. The presence of PPi then made Al3+ desorb from the surface of GSH capped Cu NCs due to the higher affinity of PPi and Al3+. As a result, the fluorescence of the Cu NCs was quenched. ALP could hydrolyze PPi into phosphate, destroying the PPi-Al3+ complex and releasing Al3+. Thus, the Al3+ binds to GSH again and the fluorescence was restored. The nanoswitch was demonstrated to be sensitive and selective for ALP assay and was successfully used for the ALP assay in the human serum.

[Shengqing Capsule down-regulates estrogen and progesterone receptors in epithelial tissue of gallbladder in guinea pigs with gallstone].

OBJECTIVE: To study the role of estrogen receptor (ER) and progesterone receptor (PR) in the formation of cholesterol calculus and investigate the effects of Shengqing Capsule (SQC), a Chinese patent herbal medicine with the function of soothing liver and draining gallbladder, on ER and PR expressions. METHODS: A total of 80 female guinea pigs were divided into normal control group, untreated group, ursodeoxycholic acid group (UDCA group) and SQC group. The cholesterol gallstone was induced by feeding the guinea pigs with high-fat lithogenic diet. SQC and UDCA were separately administered to the guinea pigs in the SQC group and UDCA group. After 7-week administration, all the animals were sacrificed to calculate the incidence of calculus formation and detect the expressions the ER and PR in the epithelial tissue of gallbladder by immunohistochemical method. RESULTS: Gallstone was cholesterol calculus detected by infrared spectrum. The incidence of calculus formation in the SQC group (27.78%) was significantly lower than that in the untreated group (81.25%) (X(2)=9.721 5, P=0.001 8). On the basis of Reiner standard, the expression distribution of ER and PR increased gradually from the normal control group through the SQC group and UDCA group to the untreated group. Except for the former two groups and the latter two groups, the differences between the other groups and UDCA group were statistically significant (P<0.05). Besides, the differences of positive expression rates between groups were statistically significant (P<0.05). CONCLUSION: Increased expressions of ER and PR are closely related to the formation of cholesterol stone. And Shengqing Capsule can down-regulate the expressions of ER and PR.