Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In the single-arm, phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan showed robust activity in patients with HER2-positive metastatic breast cancer who were refractory or resistant to trastuzumab emtansine; a population with scarce effective treatments. In DESTINY-Breast02, we aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in this patient population. METHODS: This randomised, open-label, multicentre, phase 3 trial was conducted at 227 sites (hospitals, university hospitals, clinics, community centres, and private oncology centres) in North America, Europe, Asia, Australia, Brazil, Israel, and Türkiye. Eligible patients were aged 18 years or older, had unresectable or HER2-positive metastatic breast cancer, previously received trastuzumab emtansine, disease progression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate renal and hepatic function. Patients were randomly assigned (2:1) to receive trastuzumab deruxtecan (intravenously at 5·4 mg/kg once every 3 weeks) or treatment of physician's choice using block randomisation. Treatment of physician's choice was either capecitabine (1250 mg/m2; orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint was progression-free survival based on blinded independent central review in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03523585. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). 608 (100%) patients were included in the full analysis set. The median age was 54·2 years (IQR 45·5-63·4) in the trastuzumab deruxtecan group and 54·7 years (48·0-63·0) in the treatment of physician's choice group. 384 (63%) patients were White, 603 (99%) were female, and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (8·8-26·0) in the treatment of physician's choice group. Median progression-free survival by blinded independent central review was 17·8 months (95% CI 14·3-20·8) in the trastuzumab deruxtecan group versus 6·9 months (5·5-8·4) in the treatment of physician's choice group (HR 0·36 [0·28-0·45]; p<0·0001). The most common treatment-emergent adverse events were nausea (293 [73%] of 404 with trastuzumab deruxtecan vs 73 [37%] of 195 with treatment of physician's choice), vomiting (152 [38%] vs 25 [13%]), alopecia (150 [37%] vs eight [4%]), fatigue (147 [36%] vs 52 [27%]), diarrhoea (109 [27%] vs 105 [54%]), and palmar-plantar erythrodysaesthesia (seven [2%] vs 100 [51%]). Grade 3 or higher treatment-emergent adverse events occurred in 213 (53%) patients receiving trastuzumab deruxtecan versus 86 (44%) receiving treatment of physician's choice; whereas drug-related interstitial lung disease occurred in 42 (10%; including two grade 5 death events) versus one (<1%). INTERPRETATION: DESTINY-Breast02 shows the favourable benefit-risk profile of trastuzumab deruxtecan in patients with HER2 positive metastatic breast cancer, as previously reported in DESTINY-Breast01, and is the first randomised study to show that one antibody-drug conjugate can overcome resistance to a previous one. FUNDING: Daiichi Sankyo and AstraZeneca.

A comprehensive review on the recent advances for 5-aminolevulinic acid production by the engineered bacteria.

5-Aminolevulinic acid (5-ALA) is a non-proteinogenic amino acid essential for synthesizing tetrapyrrole compounds, including heme, chlorophyll, cytochrome, and vitamin B12. As a plant growth regulator, 5-ALA is extensively used in agriculture to enhance crop yield and quality. The complexity and low yield of chemical synthesis methods have led to significant interest in the microbial synthesis of 5-ALA. Advanced strategies, including the: enhancement of precursor and cofactor supply, compartmentalization of key enzymes, product transporters engineering, by-product formation reduction, and biosensor-based dynamic regulation, have been implemented in bacteria for 5-ALA production, significantly advancing its industrialization. This article offers a comprehensive review of recent developments in 5-ALA production using engineered bacteria and presents new insights to propel the field forward.

Targeting inflammatory macrophages rebuilds therapeutic efficacy of DOT1L inhibition in hepatocellular carcinoma.

Epigenetic reprogramming is a promising therapeutic strategy for aggressive cancers, but its limitations in vivo remain unclear. Here, we showed, in detailed studies of data regarding 410 patients with human hepatocellular carcinoma (HCC), that increased histone methyltransferase DOT1L triggered epithelial-mesenchymal transition-mediated metastasis and served as a therapeutic target for human HCC. Unexpectedly, although targeting DOT1L in vitro abrogated the invasive potential of hepatoma cells, abrogation of DOT1L signals hardly affected the metastasis of hepatoma in vivo. Macrophages, which constitute the major cellular component of the stroma, abrogated the anti-metastatic effect of DOT1L targeting. Mechanistically, NF-κB signal elicited by macrophage inflammatory response operated via a non-epigenetic machinery to eliminate the therapeutic efficacy of DOT1L targeting. Importantly, therapeutic strategy combining DOT1L-targeted therapy with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited cancer regression. Moreover, we found that the densities of macrophages in HCC determined malignant cell DOT1L-associated clinical outcome of the patients. Our results provide insight into the crosstalk between epigenetic reprogramming and cancer microenvironments and suggest that strategies to influence the functional activities of inflammatory cells may benefit epigenetic reprogramming therapy.

Impact of age, sex, and thyroid autoimmunity on the association between selenium intake and type 2 diabetes mellitus.

BACKGROUND: The association between dietary selenium(Se) intake and type 2 diabetes mellitus (T2DM) remains controversial. The present study aimed to investigate this association using data from the National Health and Nutrition Examination Survey (NHANES) database for the years 2007-2012. METHODS: Three thousand seventy three individuals aged 20 years and above were eligible for inclusion in this cross-sectional study. The average age of the participants was 50.74 years and the proportions of males and females were nearly equal (49.12% vs. 50.88%). The odds ratios (OR) of the association between dietary Se intake (log2-transformed) and T2DM were examined through the multivariate logistic regression model. Subgroup analyses were conducted based on age, sex, and thyroid autoimmunity to assess the potential impact of these variables on the relationship. Fitted smoothing curves and threshold effect analysis were conducted to describe the nonlinear relationship. RESULTS: In the fully adjusted model, a significant positive association between Se intake and T2DM was observed (OR = 1.49, 95% CI: 1.16, 1.90, p = 0.0017). After stratifying the data by age, sex, and thyroid autoimmunity, a significant positive association between Se intake and T2DM was observed in individuals under 65 years of age, males, and those with negative thyroid autoimmunity. A two-segment linear regression model was analyzed for sex stratification, revealing a threshold effect in males with an inflection point of 90.51 µg, and an inverted U-shaped relationship in females with an inflection point of 109.90 µg, respectively. CONCLUSIONS: The present study found a positive relationship between Se intake and the prevalence of T2DM. This association is particularly significant in younger individuals, males, and those with negative thyroid autoimmunity. Our results should be validated in future large prospective studies in different populations.

Personality traits and co-occurrence of depressive symptoms and high BMI: a prospective cohort study.

We assess the associations between personality traits and co-occurrence of depressive symptoms and high BMI from adolescence to early adulthood. We employed a nationally representative cohort in China from 2010 to 2020 year. We included adolescents aged 10-19 years without depressive symptoms and unhealthy weight status (obesity, overweight, or thinness) at baseline and excluded those without any measurement of depressive symptoms or BMI at follow-ups. We assessed baseline personality traits in 7 dimensions of conscientiousness, openness, neuroticism, agreeableness, extraversion, self-esteem, and responsibility. We also assessed the combined effects of these 7 dimensions of personality traits by generating individual-level personality trait risk scores based on the weighted sum of all these 7 dimensions of personality traits. We measured the co-occurrence of depressive symptoms and high BMI using both a single measurement of depressive symptoms and BMI at the last follow-up and repeated measurements of them over 10 years. We used the multinomial logistic regression models to examine the exposure-outcome associations. At baseline, we included 1778 individuals (mean age: 14.4 year; female: 853 (48.0%)). At follow-ups, we observed increased risk of co-occurrence of depressive symptoms and high BMI per 1-SD increase in neuroticism score (1.95-2.38 odds ratio) or 1-SD decrease in self-esteem and conscientiousness (0.63-0.80 odds ratio; all P values < 0.05); we observed no evidence of associations between openness, agreeableness, extraversion, or responsibility and the risk of co-occurrence of depressive symptoms and high BMI (all P values > 0.05). For the combined effects of the 7 dimensions of personality traits, we found an elevated risk of co-occurrence of depressive symptoms and high BMI per 1-SD increase in the personality trait risk scores (OR (95% CI), single measurement at the last follow-up: 2.01, 1.66 to 2.43; trajectory classification using the repeated measurements 2.30, 1.55 to 3.42; average level using the repeated measurements: 2.27, 1.93 to 2.67). In this national cohort in China, personality traits were found to be associated with the co-occurrence of depressive symptoms and high BMI from adolescence to early adulthood. These findings highlight the importance of stratifying individuals based on their personality traits and providing targeted interventions for those at risk of comorbid depression and obesity.

Efficacy of robot-assisted gait training on lower extremity function in subacute stroke patients: a systematic review and meta-analysis.

BACKGROUND: Robot-Assisted Gait Training (RAGT) is a novel technology widely employed in the field of neurological rehabilitation for patients with subacute stroke. However, the effectiveness of RAGT compared to conventional gait training (CGT) in improving lower extremity function remains a topic of debate. This study aimed to investigate and compare the effects of RAGT and CGT on lower extremity movement in patients with subacute stroke. METHODS: Comprehensive search was conducted across multiple databases, including PubMed, Web of Science, Cochrane Library, EBSCO, Embase, Scopus, China National Knowledge Infrastructure, Wan Fang, SinoMed and Vip Journal Integration Platform. The database retrieval was performed up until July 9, 2024. Meta-analysis was conducted using RevMan 5.4 software. RESULTS: A total of 24 RCTs were included in the analysis. The results indicate that, compared with CGT, RAGT led to significant improvements in the Fugl-Meyer Assessment for Lower Extremity [MD = 2.10, 95%CI (0.62, 3.59), P = 0.005], Functional Ambulation Category[MD = 0.44, 95%CI (0.23, 0.65), P < 0.001], Berg Balance Scale [MD = 4.55, 95%CI (3.00, 6.11), P < 0.001], Timed Up and Go test [MD = -4.05, 95%CI (-5.12, -2.98), P < 0.001], and 6-Minute Walk Test [MD = 30.66, 95%CI (22.36, 38.97), P < 0.001] for patients with subacute stroke. However, it did not show a significant effect on the 10-Meter Walk Test [MD = 0.06, 95%CI (-0.01, 0.14), P = 0.08]. CONCLUSIONS: This study provides evidence that RAGT can enhance lower extremity function, balance function, walking ability, and endurance levels compared to CGT. However, the quality of evidence for improvements in gait speed remains low.

A phase 1b single-arm trial of intratumoral oncolytic virus V937 in combination with pembrolizumab in patients with advanced melanoma: results from the CAPRA study.

BACKGROUND: CAPRA (NCT02565992) evaluated Coxsackievirus A21 (V937) + pembrolizumab for metastatic/unresectable stage IIIB-IV melanoma. METHODS: Patients received intratumoral V937 on days 1, 3, 5, and 8 (then every 3 weeks [Q3W]) and intravenous pembrolizumab 2 mg/kg Q3W from day 8. Primary endpoint was safety. RESULTS: Median time from first dose to data cutoff was 32.0 months. No dose-limiting toxicities occurred; 14% (5/36) of patients experienced grade 3‒5 treatment-related adverse events. Objective response rate was 47% (complete response, 22%). Among 17 responders, 14 (82%) had responses ≥ 6 months. Among 8 patients previously treated with immunotherapy, 3 responded (1 complete, 2 partial). Responses were associated with increased serum CXCL10 and CCL22, suggesting viral replication contributes to antitumor immunity. For responders versus nonresponders, there was no difference in baseline tumor PD-L1 expression, ICAM1 expression, or CD3+ infiltrates. Surprisingly, the baseline cell density of CD3+CD8- T cells in the tumor microenvironment was significantly lower in responders compared with nonresponders (P = 0.0179). CONCLUSIONS: These findings suggest responses to this combination may be seen even in patients without a typical "immune-active" microenvironment. TRIAL REGISTRATION NUMBER: NCT02565992.

Oxidation of Toluene over Mesoporous MnO2/CeO2 Nanosphere Catalysts: Effects of the MnO2 Precursor and the Type of Support.

Toluene is the most common volatile organic compound (VOC), and the MnO2-based catalyst is one of the excellent nonprecious metal catalysts for toluene oxidation. In this study, the effects of MnO2 precursors and the support types on the oxidation performance of toluene were systematically explored. The results showed that the 15MnO2/MS-CeO2-N catalyst with Mn(NO3)2·4H2O as the precursor and the mesoporous CeO2 nanosphere (MS-CeO2) as the support exhibited the most excellent performance. To reveal the reason behind this phenomenon, the calcination process of the catalyst precursor and the reaction process of toluene oxidation were investigated by in situ DRIFTS. It was found that the MnO2 precursor and the type of catalyst support could have a large effect on the reaction pathway and the produced intermediates. Therefore, the roles of the MnO2 precursor and the type of support should be key considerations when developing the high-performance MnO2-based toluene oxidation catalyst.

PD-L1 dimerisation induced by biphenyl derivatives mediates anti-breast cancer activity via the non-immune PD-L1-AKT-mTOR/Bcl2 pathway.

Recent studies on biphenyl-containing compounds, a type of PD-1/PD-L1 blocker which binds to PD-L1 and induces dimerisation, have focussed on its immune function. Herein, 10 novel biphenyl derivatives were designed and synthesised. The results of the CCK-8 showed that compounds have different anti-tumour activities for tumour cells in the absence of T cells. Particularly, 12j-4 can significantly induce the apoptosis of MDA-MB-231 cells (IC50 = 2.68 ± 0.27 µM). In further studies, 12j-4 has been shown to prevent the phosphorylation of AKT by binding to cytoplasmic PD-L1, which induces apoptosis in MDA-MB-231 cells through non-immune pathways. The inhibition of AKT phosphorylation restores the activity of GSK-3ß, ultimately resulting in the degradation of PD-L1. Besides, in vivo study indicated that 12j-4 repressed tumour growth in nude mice. As these biphenyls exert their anti-tumour effects mainly through non-immune pathways, they are worthy of further study as PD-L1 inhibitors.

Childhood maltreatment influences suicidal behavior: Rumination mediates and regulatory emotional self-efficacy moderates.

To investigate the mediating role of rumination in the association between childhood maltreatment and suicidal behavior, and the moderating role of regulatory emotional self-efficacy, university students (N = 1,458) from 5 universities in China completed questionnaires in classrooms. Path analyses showed emotional maltreatment had the greatest positive association with suicidal behavior and rumination compared with other types of childhood maltreatment. Rumination partly mediated the relationship between childhood maltreatment and suicidal behavior. High regulatory emotional self-efficacy moderated the relation between ruminating childhood maltreatment and suicidal behavior.

Multi-Task Offloading Based on Optimal Stopping Theory in Edge Computing Empowered Internet of Vehicles.

Vehicular edge computing is a new computing paradigm. By introducing edge computing into the Internet of Vehicles (IoV), service providers are able to serve users with low-latency services, as edge computing deploys resources (e.g., computation, storage, and bandwidth) at the side close to the IoV users. When mobile nodes are moving and generating structured tasks, they can connect with the roadside units (RSUs) and then choose a proper time and several suitable Mobile Edge Computing (MEC) servers to offload the tasks. However, how to offload tasks in sequence efficiently is challenging. In response to this problem, in this paper, we propose a time-optimized, multi-task-offloading model adopting the principles of Optimal Stopping Theory (OST) with the objective of maximizing the probability of offloading to the optimal servers. When the server utilization is close to uniformly distributed, we propose another OST-based model with the objective of minimizing the total offloading delay. The proposed models are experimentally compared and evaluated with related OST models using simulated data sets and real data sets, and sensitivity analysis is performed. The results show that the proposed offloading models can be efficiently implemented in the mobile nodes and significantly reduce the total expected processing time of the tasks.

Application of artificial intelligence ensemble learning model in early prediction of atrial fibrillation.

BACKGROUND: Atrial fibrillation is a paroxysmal heart disease without any obvious symptoms for most people during the onset. The electrocardiogram (ECG) at the time other than the onset of this disease is not significantly different from that of normal people, which makes it difficult to detect and diagnose. However, if atrial fibrillation is not detected and treated early, it tends to worsen the condition and increase the possibility of stroke. In this paper, P-wave morphology parameters and heart rate variability feature parameters were simultaneously extracted from the ECG. A total of 31 parameters were used as input variables to perform the modeling of artificial intelligence ensemble learning model. RESULTS: This paper applied three artificial intelligence ensemble learning methods, namely Bagging ensemble learning method, AdaBoost ensemble learning method, and Stacking ensemble learning method. The prediction results of these three artificial intelligence ensemble learning methods were compared. As a result of the comparison, the Stacking ensemble learning method combined with various models finally obtained the best prediction effect with the accuracy of 92%, sensitivity of 88%, specificity of 96%, positive predictive value of 95.7%, negative predictive value of 88.9%, F1 score of 0.9231 and area under receiver operating characteristic curve value of 0.911. CONCLUSION: In feature extraction, this paper combined P-wave morphology parameters and heart rate variability parameters as input parameters for model training, and validated the value of the proposed parameters combination for the improvement of the model's predicting effect. In the calculation of the P-wave morphology parameters, the hybrid Taguchi-genetic algorithm was used to obtain more accurate Gaussian function fitting parameters. The prediction model was trained using the Stacking ensemble learning method, so that the model accuracy had better results, which can further improve the early prediction of atrial fibrillation.

The interplay between ABA/ethylene and NAC TFs in tomato fruit ripening: a review.

KEY MESSAGE: This review contains functional roles of NAC transcription factors in the transcriptional regulation of ripening in tomato fruit, describes the interplay between ABA/ethylene and NAC TFs in tomato fruit ripening. Fruit ripening is regulated by a complex network of transcription factors (TFs) and genetic regulators in response to endogenous hormones and external signals. Studying the regulation of fruit ripening has important significance for controlling fruit quality, enhancing nutritional value, improving storage conditions and extending shelf-life. Plant-specific NAC (named after no apical meristem (NAM), Arabidopsis transcription activator factor 1/2 (ATAF1/2) and Cup-shaped cotyledon (CUC2)) TFs play essential roles in plant development, ripening and stress responses. In this review, we summarize the recent progress on the regulation of NAC TFs in fruit ripening, discuss the interactions between NAC and other factors in controlling fruit development and ripening, and emphasize how NAC TFs are involved in tomato fruit ripening through the ethylene and abscisic acid (ABA) pathways. The signaling network regulating ripening is complex, and both hormones and individual TFs can affect the status or activity of other network participants, which can alter the overall ripening network regulation, including response signals and fruit ripening. Our review helps in the systematic understanding of the regulation of NAC TFs involved in fruit ripening and provides a basis for the development or establishment of complex ripening regulatory network models.

DNA Structure-Stabilized Liquid-Liquid Self-Assembled Ordered Au Nanoparticle Interface for Sensitive Detection of MiRNA 155.

Au nanoparticles (Au NPs) can be self-assembled in a bottom-up orderly manner at the oil-water interface, which is widely used as SERS platforms, but the stability of the Au NP interface needs to be improved due to shaking or shifting and the Brownian motion. The DNA structure with unique sequence specificity, excellent programmability, and flexible end-group modification capability owns good potential to precisely control the plasmonic structure's distance. In this study, a large area of the SERS substrate is obtained from the DNA structure-stabilized self-assembled ordered Au NPs on the cyclohexane-water interface. Combining with the exonuclease III (exo III)-assisted DNA recycling amplification strategy, we construct a liquid-phase SERS biosensor for efficient detection of microRNA 155 (miRNA 155). Compared with the traditional randomly assembled Au NPs on the two-phase interface, the SERS signal is significantly enhanced and more stable. The detection limit of the SERS biosensor for miRNA 155 reached 1.45 fmol/L, which has a very wide linear range (100 fmol/L-5 nmol/L). This work gives an efficient approach to stabilize the self-assembly Au NPs on the liquid-liquid interface, which can broaden the application of SERS analysis.

Optimal one-stage design and analysis for efficacy expansion in Phase I oncology trials.

BACKGROUND: Contemporary Phase I oncology trials often include efficacy expansion in various tumor indications post dose finding. Preliminary anti-tumor activity from efficacy expansion can aid Go/No-Go decision for Phase 2 or Phase 3 initiation. Tumor cohorts in efficacy expansion are commonly analyzed independently in practice, which are often underpowered due to small sample size. Pooled analysis is also sometimes conducted, but it ignores the heterogeneity of the anti-tumor activity across cohorts. METHODS: We propose an optimal one-stage design and analysis strategy for the efficacy expansion to assess whether the treatment is effective. Allowing heterogeneous anti-tumor effects across tumor cohorts, inactive cohorts are pruned, and the potentially active cohorts are pooled together to gain study power. For a prospective design with a target power, the total sample size across all cohorts is minimized; or for an ad hoc analysis with pre-specified sample size for each cohort, the pruning criteria are optimized to achieve maximum power. The global type I error is controlled after proper multiplicity adjustment, and a penalty adjusted significance level is used for the pooled test. RESULTS: Simulation studies show that the proposed optimal design has desirable operating characteristics in increasing the overall power and detecting more true positive tumor cohorts. CONCLUSION: The proposed optimal design and analysis strategy provides a practical approach to design and analyze heterogeneous efficacy expansion cohorts in a basket setting with global type I and type II error being controlled.

Physiological and metabolic analysis of winter jujube after postharvest treatment with calcium chloride and a composite film.

BACKGROUND: Ziziphus jujuba Miller cv. Dongzao is extremely susceptible to reddening, browning, nutritional loss, and perishability after harvest. In this study, we evaluated the mechanisms of calcium chloride and chitosan/nano-silica composite film treatments on the quality, especially in reddening, by physiological and metabolomic assays. RESULTS: The treatment delayed the decline of phenylalanine ammonia-lyase (PAL), chalcone synthase (CHS), and chalcone isomerase (CHI) activities. Meanwhile, the treated groups retarded the increases in anthocyanin and quercetin contents by inhibiting the gene expressions of flavonol synthase (ZjFLS), dihydroflavonol 4-reductase (ZjDFR), and anthocyanidin synthase (ZjANS), while promoting leucoanthocyanidin reductase (ZjLAR) expression, which leads to retardation of fruit reddening. Anthocyanins were found to be responsible for post-harvest winter jujube reddening through principal component analysis. Results from the technique for order preference by similarity to an ideal solution indicated that the treated group delayed the decline of the quality of 'Dongzao' and extended its shelf life. CONCLUSION: The treatment induced the heightening of flavonoids metabolism. They enhanced the nutritional value and the ability to resist stress by delaying the decline of PAL, CHS, and CHI activities. Meanwhile, the treated groups retarded the increase in anthocyanin and quercetin contents by inhibiting the gene expressions of ZjFLS, ZjDFR, and ZjANS and promoting ZjLAR expression, which leads to retardation of fruit reddening. Anthocyanins are responsible for post-harvest winter jujube reddening. Coating treatment effectively delayed the decline of winter jujube quality. © 2020 Society of Chemical Industry.

Plasma Cell Polarization to the Immunoglobulin G Phenotype in Hepatocellular Carcinomas Involves Epigenetic Alterations and Promotes Hepatoma Progression in Mice.

BACKGROUND & AIMS: Little is known about the composition and generation of plasma cell subsets in patients with hepatocellular carcinoma (HCC) and how these associate with outcomes. We investigated whether, or how, plasma cells differentiate and function in patients with HCC and mice with liver tumors. METHODS: We analyzed subset composition and distribution of plasma cells in HCC samples from 342 patients who underwent curative resection at the Cancer Center of Sun Yat-sen University in China; samples of non-tumor liver tissue were used as controls. We associated plasma cell profiles with patient outcomes. Tissue-derived leukocytes were analyzed by flow cytometry and real-time polymerase chain reaction. The ability of macrophages to regulate plasma cell differentiation was determined in ex vivo cultures of cells from human HCC tissues. C57BL/6 and BALB/c mice were given injections of Hepa1-6 cells, which formed hepatomas, or H22 cells, which formed ascitic hepatomas. Gene expression patterns were analyzed in human HCC, mouse hepatoma, and non-tumor tissues by real-time polymerase chain reaction. Mice with hepatomas were given injections of GSK126 (an inhibitor of histone H3 lysine 27 methyltransferase [EZH2]) and 5-AZA-dC (an inhibitor of DNA methyltransferases); tumor tissues were analyzed by immunofluorescence and immunohistochemistry for the presence of immune cells and cytokines. RESULTS: B cells isolated from HCCs had somatic hypermutations and class-switch recombinations to the IgG phenotype that were not observed in non-tumor tissues. Increased level of plasma cells correlated with poor outcomes of patients. Activated CD4+ T cells from HCCs stimulated C-X-C motif chemokine 10 (CXCL10) production by macrophages. CXCL10 bound CXC chemokine receptor 3 on B cells and signaled via extracellular signal-regulated kinase to cause them to become IgG-producing plasma cells. IgG activated Fc receptors on macrophages and induced them to produce interleukin 6, interleukin 10, and C-C motif chemokine ligand 20 (CCL20). In mice with hepatomas, depletion of B cells prevented generation of these macrophage, increased the anti-tumor T cell response, and reduced growth of hepatomas. However, these effects were lost after injection of CXC chemokine receptor 3-positive plasma cells. Human HCC and mouse hepatoma tissues had increased expression of DNA methyltransferase 1 and EZH2 compared with non-tumor tissues. Injection of mice with GSK126 and 5-AZA-dC induced expression of CXCL10 by tumor cells and caused plasma cell polarization, suppression of the anti-tumor T cell response, and hepatoma growth. CONCLUSIONS: Human HCC tissues contain B cells with class-switch recombinations to the IgG phenotype. Activated CD4+ T cells from HCCs stimulate CXCL10 production by macrophages; CXCL10 binds CXC chemokine receptor 3 on B cells and causes them to become IgG-producing plasma cells. IgG activates Fc receptor in macrophages to produce cytokines that reduce the anti-tumor immune response. In mice with hepatomas, depletion of B cells prevented generation of these macrophages, increased the anti-tumor T cell response, and reduced growth of hepatomas. This pathway involves increased expression of DNA methyltransferase 1 and EZH2 by HCC and hepatoma cells.

A novel potent metal-binding NDM-1 inhibitor was identified by fragment virtual, SPR and NMR screening.

NDM-1 can hydrolyze nearly all available ß-lactam antibiotics, including carbapenems. NDM-1 producing bacterial strains are worldwide threats. It is still very challenging to find a potent NDM-1 inhibitor for clinical use. In our study, we used a metal-binding pharmacophore (MBP) enriched virtual fragment library to screen NDM-1 hits. SPR screening helped to verify the MBP virtual hits and identified a new NDM-1 binder and weak inhibitor A1. A solution NMR study of 15N-labeled NDM-1 showed that A1 disturbed all three residues coordinating the second zinc ion (Zn2) in the active pocket of NDM-1. The perturbation only happened in the presence of zinc ion, indicating that A1 bound to Zn2. Based on the scaffold of A1, we designed and synthesized a series of NDM-1 inhibitors. Several compounds showed synergistic antibacterial activity with meropenem against NDM-1 producing K. pneumoniae.

A single-dose of stellate ganglion block for the prevention of postoperative dysrhythmias in patients undergoing thoracoscopic surgery for cancer: A randomised controlled double-blind trial.

BACKGROUND: New-onset arrhythmias and sleep disturbances are frequently observed during the postoperative period in patients undergoing thoracic surgery. OBJECTIVE: We evaluated the effectiveness of a single-dose stellate ganglion block (SGB) to prevent the occurrence of arrhythmias in patients undergoing thoracic surgery for cancer. DESIGN: Randomised controlled double-blind study. SETTING: Single university hospital. PATIENTS: Ninety patients with lung cancer or oesophagal cancer scheduled for elective video-assisted thoracoscopic surgery were randomly randomised into one of two equal groups (the SGB group and control group, n = 40 each). INTERVENTIONS: Patients received a single dose of 5 ml of 0.5% ropivacaine during ultrasound-guided SGB before induction of general anaesthesia in the SGB group. MAIN OUTCOME MEASURES: Holter ECG was continuously monitored during the first 48 postoperative hours, and sleep state was monitored during the first two postoperative nights. RESULTS: The incidences of postoperative supraventricular tachycardias were lower in the SGB group compared with the control group during the first 48 postoperative hours; 11.6 (5/43) vs. 31.8% (14/44), respectively, P = 0.023 (odds ratio 0.28, 95% confidence interval 0.09 to 0.87). The SGB also prolonged the total sleep time and increased the sleep efficiency during the first two postoperative nights. The duration of stage N2 sleep was longer in the SGB group compared with the control group [28 (interquartile range, 14 to 58) to 94 (interquartile range, 69 to 113) min, P = 0.016] on the first postoperative night. There were no differences in the duration of stage N1 and N3 sleep (P = 0.180, 0.086, respectively) on the first postoperative night, and the duration of stage N1, N2 and N3 sleep (P = 0.194, 0.057, 0.405, respectively) on the second postoperative night between the groups. CONCLUSION: A pre-operative SGB effectively prevented the occurrence of postoperative supraventricular tachycardias and improves the objective sleep quality in patients undergoing thoracic surgery for cancer. TRIAL REGISTRATION NUMBER: ChiCTR-1900023064.

Right ventricle may be involved in regional diastolic dysfunction earliest in primary hypertension patients.

BACKGROUND: Impaired ventricular diastolic function is common in hypertensive patients and is one of the major causes of heart failure. Both left and right ventricle diastolic dysfunction have been reported, but the order of involvement is not clear. METHOD: A total of 161 primary hypertensive patients and 40 healthy volunteers were enrolled. Pulsed wave tissue Doppler was used to measure regional diastolic dysfunction (defined as early peak diastolic [Em] and late diastolic [Am] velocity ratios (Em/Am) < 1) at right ventricular tricuspid valve annulus lateral side (RAVP1), right ventricular tricuspid valve annulus septum side (RAVP2), left ventricular mitral valve annulus septum side (LAVP1) and left ventricular mitral annulus lateral side (LAVP2). RESULTS: The prevalence of regional diastolic dysfunction at RAVP1, RAVP2, LAVP1, and LAVP2 was all higher in the hypertensive group (P < .001 for all). In both the hypertensive group and the control group, more cases were presented with RAVP1 diastolic dysfunction, while the least number of cases had LAVP2 diastolic dysfunction. In patients with stage 1 hypertension, most cases had RAVP1, or RAVP1 and RAVP2/LAVP1 diastolic dysfunction, while in patients with more advanced hypertension stages, significantly more cases had both RAVP1 and LAVP2, or all four locations diastolic dysfunction (P < .001). A similar trend was observed in patients with longer hypertension duration (duration of 6-9.9 years and 10-18 years compared with 2-5.9 years of duration, P < .001). CONCLUSIONS: With a more advanced stage and longer duration of hypertension, the range of regional diastolic dysfunction increased, showing a trend from the right ventricular wall, to the septum and left the ventricular wall. In primary hypertension, regional diastolic dysfunction in the right ventricle might happen earlier than that in the septum and the left ventricle.