Arsenic trioxide augments immunogenic cell death and induces cGAS-STING-IFN pathway activation in hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and immunotherapy. Arsenic trioxide (ATO) has emerged as a cytotoxic agent effective for treating solid tumors, including advanced HCC. However, its effectiveness in HCC treatment remains limited, and the underlying mechanisms are still uncertain. Therefore, this study aimed to characterize the effects and mechanisms of ATO in HCC. By evaluating the susceptibilities of human and murine HCC cell lines to ATO treatment, we discovered that HCC cells exhibited a range of sensitivity to ATO treatment, highlighting their inherent heterogeneity. A gene signature comprising 265 genes was identified to distinguish ATO-sensitive from ATO-insensitive cells. According to this signature, HCC patients have also been classified and exhibited differential features of ATO response. Our results showed that ATO treatment induced reactive oxygen species (ROS) accumulation and the activation of multiple cell death modalities, including necroptosis and ferroptosis, in ATO-sensitive HCC cells. Meanwhile, elevated tumoral immunogenicity was also observed in ATO-sensitive HCC cells. Similar effects were not observed in ATO-insensitive cells. We reported that ATO treatment induced mitochondrial injury and mtDNA release into the cytoplasm in ATO-sensitive HCC tumors. This subsequently activated the cGAS-STING-IFN axis, facilitating CD8+ T cell infiltration and activation. However, we found that the IFN pathway also induced tumoral PD-L1 expression, potentially antagonizing ATO-mediated immune attack. Additional anti-PD1 therapy promoted the anti-tumor response of ATO in ATO-sensitive HCC tumors. In summary, our data indicate that heterogeneous ATO responses exist in HCC tumors, and ATO treatment significantly induces immunogenic cell death (ICD) and activates the tumor-derived mtDNA-STING-IFN axis. These findings may offer a new perspective on the clinical treatment of HCC and warrant further study.

Equivariant Line Graph Neural Network for Protein-Ligand Binding Affinity Prediction.

Binding affinity prediction of three-dimensional (3D) protein-ligand complexes is critical for drug repositioning and virtual drug screening. Existing approaches usually transform a 3D protein-ligand complex to a two-dimensional (2D) graph, and then use graph neural networks (GNNs) to predict its binding affinity. However, the node and edge features of the 2D graph are extracted based on invariant local coordinate systems of the 3D complex. As a result, these approaches can not fully learn the global information of the complex, such as the physical symmetry and the topological information of bonds. To address these issues, we propose a novel Equivariant Line Graph Network (ELGN) for binding affinity prediction of 3D protein-ligand complexes. The proposed ELGN firstly adds a super node to the 3D complex, and then builds a line graph based on the 3D complex. After that, ELGN uses a new E(3)-equivariant network layer to pass the messages between nodes and edges based on the global coordinate system of the 3D complex. Experimental results on two real datasets demonstrate the effectiveness of ELGN over several state-of-the-art baselines.

Ferric particle-assisted LDI-MS platform for metabolic fingerprinting of diabetic retinopathy.

OBJECTIVES: To explore the metabolic fingerprints of diabetic retinopathy (DR) in individuals with type 2 diabetes using a newly-developed laser desorption/ionization mass spectrometry (LDI-MS) platform assisted by ferric particles. METHODS: Metabolic fingerprinting was performed using a ferric particle-assisted LDI-MS platform. A nested population-based case-control study was performed on 216 DR cases and 216 control individuals with type 2 diabetes. RESULTS: DR cases and control individuals with type 2 diabetes were comparable for a list of clinical factors. The newly-developed LDI-MS platform allowed us to draw the blueprint of plasma metabolic fingerprints from participants with and without DR. The neural network afforded diagnostic performance with an average area under curve value of 0.928 for discovery cohort and 0.905 for validation cohort (95 % confidence interval: 0.902-0.954 and 0.845-0.965, respectively). Tandem MS and Fourier transform ion cyclotron resonance MS with ultrahigh resolution identified seven specific metabolites that were significantly associated with DR in fully adjusted models. Of these metabolites, dihydrobiopterin, phosphoserine, N-arachidonoylglycine, and 3-methylhistamine levels in plasma were first reported to show the associations. CONCLUSIONS: This work advances the design of metabolic analysis for DR and holds the potential to promise as an efficient tool for clinical management of DR.

Study on Proportioning Scheme of Coal System Rocky Similar Material Based on Orthogonal Test.

Similar materials play an important role in model testing. In order to meet the demand for similar materials in modeling tests, such as those on coal mining, coal system rocky similar materials were formulated using yellow sand as a coarse aggregate, heavy calcium carbonate as a fine aggregate, and cement and gypsum as binders. Based on the orthogonal experimental design method, four influencing factors, namely the aggregate-binder ratio, heavy calcium carbonate content, cement-gypsum ratio, and moisture content, were selected. Each factor was designed at five levels. Through weighing, uniaxial compression, Brazilian splitting, and variable-angle plate shear tests on 225 specimens under 25 different ratios, five physico-mechanical property indicators of the material, including density, compressive strength, tensile strength, cohesion, and internal friction angle, were obtained under different ratios. The test results indicate that the similar materials formulated with the above raw materials had a wide range of mechanical properties, which met the simulation needs of different types of coal rocks, such as main coking coal, anthracite, shale, etc., in the similar model test. Range analysis was adopted to analyze the sensitivities to each factor, which showed that the density and internal friction angle of similar materials are mainly controlled by the aggregate-binder ratio; the cement-gypsum ratio mainly controls the compressive strength, tensile strength, and cohesion of the material. Analysis of variance (ANOVA) was adopted to analyze the sensitivities to each factor, which showed that the aggregate-binder ratio had a highly significant effect on the density of the material, the cement-gypsum ratio had a highly significant effect on the compressive and tensile strength of the material, the cement-gypsum ratio had a significant effect on the cohesion and density of the material, and the moisture content had a significant effect on the compressive strength of the material. The remaining factors did not significantly affect the material parameters. The results of this study can provide some reference for the selection of coal system rocky similar materials in subsequent physical modeling tests.

Visible-Light-Mediated Synthesis of C-Alkyl Glycosides via Glycosyl Radical Addition and Aryl Migration.

A visible-light-induced glycoarylation of activated olefins has been accomplished. Glycosyl radicals are generated via radical transfer strategies between (TMS)3SiOH and glycosyl bromides. Subsequent radical translocation and rapid 1,4-aryl migration form ß-sugar amide derivatives, and eight types of sugars are compatible with this reaction. Further, the cascade reaction produced a quaternary carbon center with good functional group adaptability and high regioselectivity in mild conditions.

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.

Cost-effectiveness of ceftazidime/avibactam plus metronidazole versus meropenem as first-line empiric therapy for the treatment of complicated intra-abdominal infections: A study based on the in-vitro surveillance data in China.

BACKGROUND: With the increase in drug resistance rates of pathogens isolated from complicated intra-abdominal infections (cIAIs), ceftazidime/avibactam (CAZ-AVI) is increasingly used clinically. However, given the high drug cost and the fact that not yet covered by the health insurance payment, this study evaluated the cost-effectiveness of CAZ-AVI plus metronidazole versus meropenem as a first-line empiric treatment for cIAIs from the perspective of the Chinese healthcare system. METHODS: A decision analytic model with a one-year time horizon was constructed to assess the cost-effectiveness based on the entire disease course. Model inputs were mainly obtained from clinical studies, published literature, and publicly available databases. Primary outcomes were cost, quality-adjusted life years (QALYs), life years (Lys), and incremental cost-effectiveness ratio (ICER). One-way sensitivity analysis and probabilistic sensitivity analysis were also performed. RESULTS: In the base cases, compared to meropenem, CAZ-AVI plus metronidazole had a shorter mean hospital length of stay (-0.77 days per patient) and longer life expectancy (+0.05 LYs and +0.06 QALYs). CAZ-AVI plus metronidazole had an ICER of $25517/QALY, which is well below the threshold of $31509 per QALY in China. The one-way sensitivity analysis showed that the change of the treatment duration of CAZ-AVI plus metronidazole was the parameter that most influenced the results of the ICER. In probabilistic sensitivity analysis, CAZ-AVI plus metronidazole was the optimal strategy in 75% of simulations at $31510/QALY threshold. CONCLUSIONS: CAZ-AVI plus metronidazole could be considered as a cost-effective option for the empiric treatment of patients with cIAIs in China, and this benefit will be more evident when the price of CAZ-AVI decreases by 23.8%.

Practical Strategies for Health Education during Pregnancy and Childbirth Period in Foreign Countries and Their Implications to China / 中国医学伦理学

Under the macro background of the comprehensive liberalization of the "three-child policy" and the strengthening attention to the health of women and children, China has increasingly attached importance to the topic of women’s health education and made various attempts in health education during pregnancy and childbirth period, including traditional education, situational teaching, health lecture, health salon and other forms. However, there are still some problems, such as serious stereotype and homogenization, and rigid education. The effectiveness of health education during pregnancy and childbirth period needs to be improved. By drawing on the practical experience of health education during pregnancy and childbirth period abroad, this paper aimed to comprehensively improve maternal health literacy in China, and provide a assistance for building a healthy China.

Regioselective synthesis of spirocyclic pyrrolines via a palladium-catalyzed Narasaka-Heck/C-H activation/[4 + 2] annulation cascade reaction.

A novel palladium-catalyzed spirocyclization through sequential Narasaka-Heck cyclization, C-H activation and [4 + 2] annulation has been developed. In this reaction, cheap and readily available 2-chlorobenzoic acid or ethyl phenylpropiolate was employed as the C2 insertion unit to react with γ,δ-unsaturated oxime ester. The key step in this transformation is the regioselective insertion of the C2 synthon into the spiro-palladacycle intermediate that is formed by the δ-C-H activation process, thereby efficiently assembling a series of spirocyclic pyrrolines with high regiocontrol. Furthermore, density functional theory (DFT) calculations and control experiments were performed to gain some insights into the reaction mechanism.

Congenital intestinal malrotation with gastric wall defects causing extensive gut necrosis and short gut syndrome: A case report.

BACKGROUND: Congenital intestinal malrotation (CIM) is a common malformation in neonates. Early diagnosis and surgical intervention can improve the prognosis. CIM combined with congenital gastric wall defect is a potentially fatal condition. We present a severe case of CIM with gastric wall defect causing extensive gut necrosis and short gut syndrome. After three operations, the neonate survived and subsequently showed normal growth and development during infancy. CASE SUMMARY: A male neonate (age: 4 d) was hospitalized due to bloody stools and vomiting for 2 d, and abdominal distention for 1 d. Emergent exploratory laparotomy revealed black purplish discoloration of the bowel loops. Bowel alignment was abnormal with congestion and dilatation of the entire intestine, and clockwise mesentery volvulus (720°). The posterior wall of the gastric body near the greater curvature showed a defect in the muscularis layer (approximately 5.5 cm), and a circular perforation (approximately 3 cm diameter) at the center of this defect. Ladd's procedure was performed and gastric wall defect was repaired. Third operation performed 53 d after birth revealed extensive adherence of small intestine and peritoneum, and adhesion angulated between many small intestinal loops. We performed intestinal adhesiolysis, resection of necrotic intestine, and small bowel anastomosis. CONCLUSION: This case highlights that prolonged medical treatment may help improve intestinal salvage after surgical removal of necrotic intestines, and improve patient prognosis.

Correlation between the accumulation of skin glycosylation end products and the development of type 2 diabetic peripheral neuropathy.

BACKGROUND: The accumulation of advanced glycation end products (AGEs) occurring in skin tissues can be measured by AGE Reader. Here, we assessed the correlation between AGEs values and the development of type 2 diabetic peripheral neuropathy (DPN). METHODS: The basic clinical information of 560 patients with T2DM was collected through an electronic system. AGEs and diabetic complication risk score was measured by AGE Reader, a non-invasive optical signal detector. All of the participants were classified into 4 groups based on Dyck criteria: grade 0 (non-DPN group), grade 1 (early stage group), grade 2 (middle stage group) and grade 3 (advanced group). Pearson correlation analysis and Spearman correlation analysis were used to evaluate the correlation between AGEs and other indexes. The sensitivity and specificity of glycosylated products were evaluated by ROC curve. RESULTS: With the increase of DPN severity, the accumulative AGEs showed an increasing trend. Significant differences (P = 0.000) of AGEs were found among grades 0, 1, 2, and 3 of DPN, and significant differences (P = 0.000) of AGEs were found between grades 1 and 3. There were significant differences in DPN risk score between grades 0, 1, 2, and 3, between grades 1, 2, and 3, and between grades 2 and 3 (P < 0.01 or P < 0.05). AGEs were positively correlated with age, blood uric acid, disease course, systolic blood pressure, the risk scores of the four major complications of diabetes, renal function indicators (serum creatinine, Cystatin C, homocysteine, the ratio of urinary albumin and creatinine, urinary microalbumin, α-microglobulin, urinary transferrin, urinary immunoglobulin), inflammatory indicators (white blood cell count, neutrophil count, neutrophil-to-lymphocyte ratio, C-reactive protein), and TCSS score. However, it was negatively correlated with BMI,fasting insulin, insulin 1-3 h postprandial, lymphocyte count, HOMA insulin resistance index and estimated glomerular filtration rate. The area under the AGEs cumulant and neuropathy risk score curve was 0.769 and 0.743, respectively. The confidence intervals were (71.2-82.6%) and (68.8-79.9%), respectively. The maximum Youden's index of AGEs cumulant was 0.440, and the corresponding AGEs cumulant value was 77.65. The corresponding sensitivity and specificity were 0.731 and 0.709, respectively. Furthermore, the maximum Youden's index of neuropathy risk score was 0.385, and the corresponding neuropathy risk score was 66.25. The corresponding sensitivity and the specificity were 0.676 and 0.709, respectively. CONCLUSION: The cumulative amount of skin AGEs can be used as the diagnostic index and the prediction and evaluation index of DPN severity. Moreover, the diabetic peripheral neuropathy risk score can predict the risk of DPN in patients with T2DM.

Ni-Catalyzed Remote Radical/Cross-Electrophile Coupling Cascade for Selective C(sp3)-H Arylation.

An innovative 1,5-HAT cascade strategy has been advanced for the nickel-catalyzed distal arylation via cross-electrophile coupling. Through specific migration, the remote C(sp3)-H bond is regioselectively activated, and Ar-I as the available electrophile is used for the construction of the C(sp3)-C(sp2) bond. This method also has broad applicability for benzylic and aliphatic N-fluorocarboxamides with yields up to 80%. Furthermore, a series of control experiments demonstrated that this reaction is probably initiated by a radical process.

Ultrafast exciton delocalization and localization dynamics of a perylene bisimide quadruple π-stack: a nonadiabatic dynamics simulation.

Unraveling the photogenerated exciton dynamics of π-stacked molecular aggregates is of great importance for both fundamental studies and industrial applications. Among various π-stacked molecular aggregates, perylene tetracarboxylic acid bisimide (PBI) based aggregates are regarded as one of the prototypes due to their inherent high fluorescence quantum yield and excellent photostability and flexibility in controlling intermolecular forces via chemical modifications. However, the exciton dynamics of these PBI based aggregates remain elusive up to now. In this work, we have first employed LR-TDDFT-based nonadiabatic dynamics simulations and static electronic structure calculations to investigate the ultrafast exciton dynamics of a newly synthesized perylene bisimide quadruple (PBQ) π-stack. Upon photoexcitation, the S6 to S10 states are the most likely populated excited states, which can be regarded as a combination of local excited (LE) excitons and charge transfer (CT) excitons of those four PBI chromophores. Then, the excited PBQ π-stack relaxes ultrafast to the lowest lying excited S1 state within 500 fs, which is accompanied by the complicated exciton conversion as well as exciton localization/delocalization dynamics. In short, the initially populated hybrid LE and CT excitons convert to the LE excitons of B/C and A/D, in which the LE excitons of B/C contribute the most (∼0.44) while the LE excitons of A/D also have minor contributions (0.21), indicating the formation of the localized excimer state. We use the notations A/B/C/D here to represent the four PBI fragments of PBQ π-stacks along the direction perpendicular to the PBI molecular plane. Additionally, using a recently defined root mean square deviation (RMSD) of electron and hole spatial distributions along three Cartesian coordinates, we could investigate the exciton localization/delocalization dynamics in a quantitative way. Our simulation results indicate that the photoinduced electrons and holes of the PBQ π-stack exhibit an ultrafast localization(∼10 fs)-delocalization(∼60 fs)-localization(∼200 fs) dynamics, during which both LE and CT excitons play crucial roles. Our present work is not only consistent with previous experimental studies, but also provides more detailed insights into the relevant processes, which might be useful for the future design of PBI based optoelectronic devices with improved performances.

Effect of tourniquet use on blood loss, pain, functional recovery, and complications in robot-assisted total knee arthroplasty: a prospective, double-blinded, randomized controlled trial.

BACKGROUND: Robot-assisted total knee arthroplasty (TKA) has been largely studied to confirm its advantages in terms of accurate component positioning, microembolus formation, less blood loss, and so on, but is currently usually performed under tourniquet due to its longer operative time than conventional TKA. The aim of this study was to estimate the effects of tourniquet use in robot-assisted TKA on blood loss, pain, functional recovery, and complications. METHODS: Patients scheduled for robot-assisted TKA were prospectively randomized into a tourniquet or non-tourniquet group (each n = 14). The primary outcome measure was blood loss. The secondary outcome measures were operation time; visual analog scale (VAS) pain scores; time to achieve the first straight-leg raise; swelling of the thigh, knee, and calf; range of motion; Hospital for Special Surgery score; length of stay; and postoperative complications. RESULTS: There was no significant difference in total blood loss between the tourniquet and non-tourniquet groups (738.57 ± 276.158 vs. 866.85 ± 243.422 ml, P = 0.061). The tourniquet group showed significantly lower intraoperative blood loss (P < 0.001), but higher hidden blood loss (P = 0.002). The non-tourniquet group showed better knee range of motion on postoperative days (PODs) 1-3 (all P < 0.001), less thigh swelling on PODs 2 and 3 (P < 0.05), earlier straight-leg raising (P = 0.044), and shorter length of stay (P = 0.044). Thigh pain VAS score at 1 month after surgery was significantly greater in the tourniquet group (P < 0.001), as was knee pain during activity and at rest on PODs 2-3 (all P < 0.05). The tourniquet group also showed a significantly higher rate of tension blisters (28.8% vs. 7.1%, P = 0.038). CONCLUSIONS: Tourniquet use during robot-assisted TKA does not reduce total blood loss, and it appears to increase postoperative pain, aggravate muscle injury, and prolong postoperative recovery. Trial registration ChiCTR, ChiCTR2100041800. Registered 5 January 2021, http://www.chictr.org.cn/index.aspx .

Comparison of Outcomes After Total Knee Arthroplasty Involving Postoperative Neutral or Residual Mild Varus Alignment: A Systematic Review and Meta-analysis.

Comparing mainly clinical and functional outcomes as well as prosthesis survival with neutral and residual mild varus alignment, we searched PubMed, Embase, Cochrane Library and Web of Science databases from 1 January 1974 to 18 December 2020 to identify studies comparing clinical and functional outcomes as well as prosthesis survival in the presence of different alignments after total knee arthroplasty (TKA) for varus knees. The included studies were assessed by two researchers according to the Newcastle-Ottawa Scale (NOS). Postoperative neutral alignment (0° ± 3°) was compared to residual mild varus (3°-6°) and residual severe varus (>6°). Meta-analysis was performed using Review Manager 5.3. The odds ratios (OR) and mean differences (MD) were used to compare dichotomous and continuous variables. The fixed-effect model and random-effect model were used to meta-analyze the data. Nine studies were included in the meta-analysis with 1410 cases of postoperative neutral alignment, 564 of residual mild varus alignment and 175 of residual severe varus alignment following TKA, all of which were published after 2013. Three studies scored 7 points on the NOS, while the remaining studies scored 8 points, suggesting high quality. The pooled mean differences (MDs) of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score were 1.07 [95% confidence interval (CI) -1.06 to 3.20; P = 0.32; I2 = 79%]. The meta-analysis showed that neutral alignment and mild varus alignment were associated with similar the Oxford Knee Score (OKS), Knee Society Knee Score (KS-KS), and Knee Society Function Score (KS-FS), while neutral alignment was associated with lower Forgotten Joint Score (FJS) [mean difference -6.0, 95% confidence interval (CI) -9.37 to -2.64, P = 0.0005]. Neutral alignment was associated with higher KS-KS than severe alignment (M 2.98, 95% CI 1.42 to 4.55, P = 0.0002; I2 = 0%) as well as higher KS-FS (M 8.20, 95% CI 4.58 to 11.82, P < 0.00001; I2 = 0%). Neutral alignment was associated with similar rate of survival as mild varus alignment (95% CI 0.36 to 9.10; P = 0.48; I2 = 65%) or severe varus alignment (95% CI 0.94 to 37.90; P = 0.06; I2 = 61%). There was no statistical difference in others. Residual mild varus alignment after TKA may lead to similar or superior outcomes than neutral alignment in patients with preoperative varus knees, yet the available evidence appears to be insufficient to replace the current gold standard of neutral alignment. Severe varus alignment should be avoided.

Knowledge about, attitude and acceptance towards, and predictors of intention to receive the COVID-19 vaccine among cancer patients in Eastern China: A cross-sectional survey / 中西医结合学报

OBJECTIVE@#The coronavirus disease 2019 (COVID-19) pandemic has had a serious impact on health all over the world. Cancer patient, whose immunity is often compromised, faces a huge challenge. Currently, some COVID-19 vaccines are being developed and applied on general population; however, whether cancer patients should take COVID-19 vaccine remains unknown. Our study aimed to explore the knowledge, attitude, acceptance, and predictors of intention to receive the COVID-19 vaccine among cancer patients in Eastern China.@*METHODS@#A cross-sectional study was conducted in Eastern China from June 17th to September 3rd, 2021. Patients were selected using a convenience sampling method. A self-report questionnaire was developed to assess knowledge about the COVID-19 vaccine, attitude towards the vaccine and acceptance of the vaccine; following a review of similar studies previously published in the scientific literature, multivariate logistic regression analysis was used to determine the predictors associated with COVID-19 vaccine acceptance.@*RESULTS@#A total of 2158 cancer patients were enrolled in this study. The rate of vaccine hesitancy was 24.05% (519/2158); further, among the participants of vaccine acceptance, 767 had taken COVID-19 vaccine (35.54%), and 872 were willing to get vaccinated (40.01%). A total of 24 variables including demographic characteristics, clinical status of cancer, impact of COVID-19 pandemic on study participants, patients' knowledge about the COVID-19 vaccine, and attitude towards the vaccine, had significant differences between the "vaccine hesitancy" population and "vaccine acceptance" population. Multivariate logistic regression analysis indicated that parameters including alcohol consumption (odds ratio [OR] = 1.849; 95% confidence interval [CI]: 1.375-2.488; P-reference [P-Ref] < 0.001 vs non-drinkers), income impacted by COVID-19 pandemic (OR = 1.930, 2.037 and 2.688 for mild, moderate, and severe impact, respectively; all P-Ref < 0.01 vs no impact), knowledge of how the vaccine was developed (OR = 1.616; 95% CI: 1.126-2.318; P-Ref = 0.009 vs unknown), believing in the safety of the vaccine (OR = 1.502; 95% CI: 1.024-2.203; P-Ref = 0.038 vs denying the safety of vaccine), willingness to pay for the vaccine (OR = 3.042; 95% CI: 2.376-3.894; P-Ref < 0.001 vs unwilling), and willingness to recommend families and friends to get vaccinated (OR = 2.744; 95% CI: 1.759-4.280; P-Ref < 0.001 vs do not recommend) were contributors to vaccine acceptance. While such as being retired (OR = 0.586; 95% CI: 0.438-0.784; P-Ref < 0.001 vs unemployed), undergoing multiple therapies of cancer (OR = 0.408; 95% CI: 0.221-0.753; P-Ref = 0.004 vs no ongoing treatment), and worrying that the vaccine might deteriorate the prognosis of cancer (OR = 0.393; 95% CI: 0.307-0.504; P-Ref < 0.001 vs might not) were contributors to vaccine hesitancy.@*CONCLUSION@#This study provided preliminary estimates of the rates of vaccine acceptance and vaccine hesitancy among cancer patients in Eastern China. The intention to receive the COVID-19 vaccine was impacted by factors such as patient occupation, alcohol consumption, and some parts of knowledge about and attitude towards COVID-19 vaccine. It is recommended to develop individualized vaccination plans that meet the healthcare needs of cancer patients.

Lewis-Acid-Catalyzed Tandem Cyclization by Ring Expansion of Tertiary Cycloalkanols with Propargyl Alcohols.

A new method for the efficient synthesis of hexahydro-1H-fluorene and octahydrobenzo[a]azulene derivatives through a ring-expansion strategy is reported. With an appropriate combination of thulium(III) trifluoromethanesulfonate and 13X molecular sieves, a range of unsaturated polycyclic compounds were obtained in good yields. Mechanism studies reveal that the reaction is more likely to undergo Meyer-Schuster rearrangement, ring expansion, and Friedel-Crafts-type pathways, which provide a conceptually different strategy for the ring opening of tertiary cycloalkanols.

In Vivo Delivery of siRNAs Targeting EGFR and BRD4 Expression by Peptide-Modified Redox Responsive PEG-PEI Nanoparticles for the Treatment of Triple-Negative Breast Cancer.

The study aims to investigate the in vivo distribution, antitumor effect, and safety of cell membrane-penetrating peptide-modified disulfide bond copolymer nanoparticles loaded with small-interfering RNA (siRNA) targeting epidermal growth factor receptor (EGFR) and bromodomain-containing protein 4 (BRD4) in triple-negative breast cancer (TNBC). Polyethylene glycol disulfide bond-linked polyethylenimine (PEG-SS-PEI) was modified with peptides GALA and CREKA and used as vectors to prepare siRNA nanoparticles. The GALA- and CREKA-modified PEG-SS-PEI nanoparticles (GC-NPs) were prepared by mixing siEGFR and siBRD4 (1:1) with GALA-PEG-SS-PEI and CREKA-PEG-SS-PEI (1:1) in an aqueous solution at an N/P ratio of 30:1. Nanoparticles loaded with scrambled siRNA were prepared with the same method. The gene silencing effect on EGFR and BRD4 in vitro was evaluated by Western blotting analysis. TNBC xenograft models were established by subcutaneous injection of MDA-MB-231 cells into female nude mice. At 1, 3, 6, 12, and 24 h after administration of five formulations of Cy5-siRNA (133 µg/10 g) via the tail vein, the mice were observed and imaged for a biodistribution study using an in vivo imaging system. In the pharmacodynamics experiment, tumor-bearing mice were treated with respective siRNA preparations at a dose of 133 µg/10 g for 18 days, and the body weight and tumor size were recorded every other day. The protein expression levels of EGFR, p-EGFR, PI3K, p-PI3K, Akt, p-Akt, BRD4, and c-Myc were determined using Western blotting analysis. Hematological and serum biochemical parameters, organ indices, and HE staining results for the heart, liver, spleen, lung, and kidney were analyzed to evaluate the safety of the nanoparticles. GC-NPs loaded with siEGFR and siBRD4 significantly inhibited the expression of EGFR and BRD4 in vitro. The strongest fluorescence signals were observed in the GC-NP group, especially in tumors, indicating the excellent tumor-targeted delivery of GC-NPs we constructed. Tumor growth was significantly inhibited in the GC-NP-treated group, and the expression of EGFR, p-EGFR, PI3K, p-PI3K, Akt, p-Akt, BRD4, and c-Myc in the tumors decreased by 71%, 68%, 61%, 68%, 48%, 58%, 59%, and 74% compared to the control group, respectively. There was no significant change in hematological parameters, biochemical indices, or tissue morphology in GC-NP-treated mice. SiRNA cotargeting EGFR and BRD4 delivered by GALA- and CREKA-modified PEG-SS-PEI had favorable antitumor effects in vivo toward TNBC with tumor-targeting efficacy and good biocompatibility.

Experimental and Computational Studies of Palladium-Catalyzed Spirocyclization via a Narasaka-Heck/C(sp3 or sp2)-H Activation Cascade Reaction.

The first synthesis of highly strained spirocyclobutane-pyrrolines via a palladium-catalyzed tandem Narasaka-Heck/C(sp3 or sp2)-H activation reaction is reported here. The key step in this transformation is the activation of a δ-C-H bond via an in situ generated σ-alkyl-Pd(II) species to form a five-membered spiro-palladacycle intermediate. The concerted metalation-deprotonation (CMD) process, rate-determining step, and energy barrier of the entire reaction were explored by density functional theory (DFT) calculations. Moreover, a series of control experiments was conducted to probe the rate-determining step and reversibility of the C(sp3)-H activation step.