Acetylation-dependent regulation of core spliceosome modulates hepatocellular carcinoma cassette exons and sensitivity to PARP inhibitors.

Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.

Transcriptome Analysis and Identification of Cadmium-Induced Oxidative Stress Response Genes in Different Meretrix meretrix Developmental Stages.

Cadmium (Cd) is one of the major pollutants in the aquatic environment, and it can easily accumulate in aquatic animals and result in toxic effects by changing the metabolism of the body, causing a serious impact on the immune system, reproductive system, and the development of offspring. The clam Meretrix meretrix is one of the commercially important species that is cultivated in large-scale aquaculture in China. To elucidate the underlying molecular mechanisms of Cd2+ in the developmental processes, fertilized eggs and larvae of M. meretrix at different developmental stages were exposed to Cd2+ (27.2 mg L-1 in natural seawater) or just natural seawater without Cd2+ (control), and high-throughput transcriptome sequencing and immunohistochemistry techniques were used to analyze the toxic effects of Cd on larvae at different early developmental stages. The results revealed 31,914 genes were differentially expressed in the different stages of M. meretrix development upon treatment with Cd2+. Ten of these genes were differentially expressed in all stages of development examined, but they comprised only six unigenes (CCO, Ndh, HPX, A2M, STF, and pro-C3), all of which were related to the oxidative stress response. Under Cd exposure, the expression levels of CCO and Ndh were significantly upregulated in D-shaped and pediveliger larvae, while pro-C3 expression was significantly upregulated in the fertilized egg, D-shaped larva, and pediveliger. Moreover, HPX, A2M, and STF expression levels in the fertilized egg and pediveliger larvae were also significantly upregulated. In contrast, CCO, Ndh, HPX, A2M, STF, and pro-C3 expression levels in the postlarva were all downregulated under Cd exposure. Besides the genes with changes in expression identified by the transcriptome, the expression of two other oxidative stress-related genes (MT and Nfr2) was also found to change significantly in the different developmental stages of M. meretrix upon Cd exposure, confirming their roles in combating oxidative stress. Overall, the findings of this study indicated that Cd would interfere with cellular respiration, ion transport, and immune response through inducing oxidative stress, and changes in the expression of oxidative stress-related genes might be an important step for M. meretrix to deal with the adverse effects of Cd at different stages of its development.

Tumor size is associated with adjuvant chemotherapy benefit in T1N0M0 triple-negative breast cancer: a multicenter and propensity score matched analysis.

Background: Triple-negative breast cancer (TNBC) is characterized by aggressive phonotypes and relatively poor outcomes. There are controversies on the effect of adjuvant chemotherapy in small (T1N0M0) TNBCs, especially among T1a-b patients. This study evaluated the survival benefit of adjuvant chemotherapy and influential factors in T1N0M0 TNBC patients. Methods: All T1N0M0 TNBC patients were identified from the Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB) between January 2009 and December 2021. Propensity score matched (PSM) was applied to create a matched cohort. We used Kaplan-Meier analysis and Cox regression models to evaluate the associations of adjuvant chemotherapy with breast cancer-free interval (BCFI) and overall survival (OS). Stratified analysis according to different influential factors was also performed. Results: In total, 1,113 T1N0M0 TNBC patients (297 T1a, T1b and 816 T1c) were enrolled, including 928 patients with adjuvant chemotherapy and 185 patients without adjuvant chemotherapy. After matching 441 patients by using PSM analysis, 294 patients with chemotherapy and 147 patients without chemotherapy were identified. Patients with or without chemotherapy had similar BCFI (P=0.241) and OS (P=0.509). However, regarding patients with different tumor sizes, adjuvant chemotherapy could significantly improve BCFI in T1c patients (5-year BCFI: 92.1% vs. 79.5%, P=0.035) but not in T1a-b patients (5-year BCFI: 93.6% vs. 94.6%, P=0.546). No significant difference in OS was observed among patients with different tumor sizes. Subgroup analysis found that only tumor size was significantly associated with adjuvant chemotherapy benefit in terms of BCFI (Pinteraction=0.021) and OS (Pinteraction=0.040). Conclusions: The survival benefit of adjuvant chemotherapy was significantly associated with tumor size in T1N0M0 TNBC. Benefit of adjuvant chemotherapy was found in T1c, but not in T1a-b patients. Our findings do not support the routine use of chemotherapy in patients with T1a-bN0 TNBC.

Assessment of toxic metal pollution in Yueqing Bay and the extent of metal-induced oxidative stress in Tegillarca granosa raised in this water.

Yueqing Bay is an important economic shellfish culture zone in Zhejiang Province, China. However, increased pollution in the water caused by toxic metals has led to the bioaccumulation of toxic metals in cockles such as Tegillarca granosa, and the consequence of toxic metal-associated toxicity in these animals. This study aimed to assess the concentration of toxic metals in the water and sediment in four different sites (Baisha, Qingjiang, Nanyue, and Wengyang) within Yueqing Bay and to evaluate the extent of metal bioaccumulation in T. granosa raised in the aquaculture farms located within the four sites, as well as the changes in biomarkers in T. granosa in response to the metals. The assessment was carried out at two different times of the year, January and July. The water and sediment samples taken from the aquaculture farms in Baisha (S1), Qingjiang (S2) and Nanyue (S3) were found to have a comprehensive toxic metal pollution index (Pc) <1, indicating that these farms were not polluted. However, the water and sediment samples taken from the aquaculture farm in Wengyang (S4) had a Pc between 1 and 2, indicating mild toxic metal pollution. The edible risk assessments (HQ) of T. granosa in all four farms were <1, and therefore, these cockles could be considered safe for human consumption. The toxic metal enrichment in T. granosa exhibited a strong correlation with the toxic metal content in the sediment. In all four farms, CAT and SOD activity levels in the visceral mass of T. granosa were higher than those found in the foot, and a significantly higher level of CAT activity was detected in July compared with January. Similarly, MDA and H2O2 contents in the visceral mass were also higher in July than in January. Tegillarca granosa individuals taken from S4 and S3 farms exhibited significantly higher levels of metallothionein (MT) mRNA and MDA compared with individuals from S1 and S2 farms. Furthermore, the levels of MDA and MT mRNA showed significant positive correlations with Cd, Cr, Hg, and Cu. Elevation of lipid peroxidation in these cockles coincided with increasing levels of endogenous antioxidants. The visceral mass of T. granosa and its MDA level could be used as a tissue indicator and a biochemical marker, respectively, for detecting toxic metal pollution. MT mRNA might also be used as a molecular marker of toxic metal pollution. The integrated biomarker response version 2 (IBRv2) values of the four aquaculture farms in Yueqing Bay showed the order S4 > S3 > S2 > S1, indicating that S4 had the most serious metal-induced stress. Furthermore, the IBRv2 values correlated with the Nemerow composite index (Pc) for all the cockles examined. Thus, as far as the contamination of aquaculture farms in Yueqing Bay by toxic metals is concerned, the aquaculture farm in Wengyang (S4) was mildly contaminated by toxic metals. However, the contamination was relatively low, presenting a low risk for the local population of T. granosa.

Cancer-Associated Adipocytes and Breast Cancer: Intertwining in the Tumor Microenvironment and Challenges for Cancer Therapy.

Adipocytes are the main components in breast tissue, and cancer-associated adipocytes (CAAs) are one of the most important components in the tumor microenvironment of breast cancer (BC). Bidirectional regulation was found between CAAs and BC cells. BC facilitates the dedifferentiation of adjacent adipocytes to form CAAs with morphological and biological changes. CAAs increase the secretion of multiple cytokines and adipokines to promote the tumorigenesis, progression, and metastasis of BC by remodeling the extracellular matrix, changing aromatase expression, and metabolic reprogramming, and shaping the tumor immune microenvironment. CAAs are also associated with the therapeutic response of BC and provide potential targets in BC therapy. The present review provides a comprehensive description of the crosstalk between CAAs and BC and discusses the potential strategies to target CAAs to overcome BC treatment resistance.

Effect of metformin on adverse outcomes in T2DM patients: Systemic review and meta-analysis of observational studies.

Background: The cardiovascular protection effect of metformin on patients with type 2 diabetes mellitus (T2DM) remains inconclusive. This systemic review and meta-analysis were to estimate the effect of metformin on mortality and cardiovascular events among patients with T2DM. Methods: A search of the Pubmed and EMBASE databases up to December 2021 was performed. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled by a random-effects model with an inverse variance method. Results: A total of 39 studies involving 2473009 T2DM patients were adopted. Compared to non-metformin therapy, the use of metformin was not significantly associated with a reduced risk of major adverse cardiovascular event (MACE) (HR = 1.06, 95%CI 0.91-1.22; I 2 = 82%), hospitalization (HR = 0.85, 95%CI 0.64-1.13; I 2 = 98%), heart failure (HR = 0.86, 95%CI 0.60-1.25; I 2 = 99%), stroke (HR = 1.16, 95%CI 0.88-1.53; I 2 = 84%), and risk of AMI (HR = 0.88, 95%CI 0.69-1.14; I 2 = 88%) in T2DM patients. Metformin was also not associated with significantly lowered risk of MACE compared to dipeptidyl peptidase-4 inhibitor (DPP-4i) in T2DM patients (HR = 0.95, 95%CI 0.73-1.23; I 2 = 84%). Conclusions: The effect of metformin on some cardiovascular outcomes was not significantly better than the non-metformin therapy or DPP-4i in T2DM patients based on observational studies.

Tuning the Selectivity of Liquid Products of CO2RR by Cu-Ag Alloying.

The combination of Cu and Ag presents a promising way to steer the CO2 reduction products through regulating the surface active sites. However, the difficulty in forming the CuAg alloy with a controllable atomic ratio impedes the in-depth understanding of the structure-activity relationship of CuAg catalysts. Herein, we use E-beam evaporation to synthesize a series of CuAg films with uniform distribution and controllable stoichiometry to reveal the real reaction mechanism on CuAg for the electrochemical CO2 reduction process. Compared with Cu, the Cu1-xAgx (x = 0.05-0.2) alloy showed an apparent suppression of HCOOH and the ratio between C2 liquid products (e.g., ethanol and acetate) and C1 liquid product (HCOOH) is also increased. Operando synchrotron radiation Fourier transform infrared spectroscopy results suggest that the introduction of Ag into the Cu phase can significantly strengthen the absorbed *CO and *OCCO intermediates and suppress the O-C-O intermediates. This research provides a reliable way to inhibit the generation of HCOOH and enhance the production of liquid C2 products during CO2RR and presents a guideline for the future manipulation of copper catalysts by alloying.

Comparison of 4 label-based immunochromatographic assays for the detection of Escherichia coli O157:H7 in milk.

Immunochromatographic assays (ICA) are widely used to detect pathogens. In this study, we used traditional gold nanoparticles (GNP), quantum dots (QD), fluorescent nanoparticles (FNP), and europium (Eu) (III) chelate nanoparticles (EuNP) as ICA labels. We first compared the ability of the 4 ICA test strips to quantitatively detect Escherichia coli O157:H7 in milk. We then optimized various parameters influencing the ICA. The sensitivity to E. coli O157:H7 of the GNP-ICA, QD-ICA, FNP-ICA, and EuNP-ICA was 2.5 × 104, 5 × 103, 1.0 × 103, and 5.0 × 102 cfu mL-1, respectively. The EuNP-ICA exhibited the highest sensitivity. The amounts of monoclonal antibodies (mAb) per GNP-ICA, QD-ICA, FNP-ICA, and EuNP-ICA test strip were 0.16, 0.37, 0.04, and 0.10 µg, respectively. The corresponding coefficients of variation were 7.4 to 15.8%, 10.4 to 18.6%, 2.7 to 7.8%, and 6.9 to 10.5%, respectively. The FNP-ICA required the least mAb per test strip and had the best coefficient of variation. The linear ranges of GNP-ICA, QD-ICA, FNP-ICA, and EuNP-ICA were 1.0 × 104 to 1.0 × 106, 2.5 × 103 to 1.0 × 106, 2.5 × 102 to 2.5 × 105, and 2.5 × 102 to 2.5 × 105 cfu mL-1, respectively. The FNP-ICA and EuNP-ICA had wider linear ranges than GNP-ICA and QD-ICA. Additionally, the FNP-ICA and EuNP-ICA showed better tolerance than GNP-ICA and QD-ICA in the milk samples. The FNP-ICA and EuNP-ICA showed remarkable potential for detection of pathogens in milk.

Comparison of immunochromatographic assays based on fluorescent microsphere and quantum-dot submicrobead for quantitative detection of aflatoxin M1 in milk.

The performance of fluorescent microsphere immunochromatographic assay (FM-ICA) and quantum-dot submicrobead immunochromatographic assay (QB-ICA) was systematically and comprehensively compared in quantitative detection of aflatoxin M1 in milk. Under optimum conditions, the advantages of FM-ICA include lower limit of detection of 42.3 pg/mL with better accuracy, precision, reliability, and practicability. The advantages of QB-ICA include shorter detection time and lower monoclonal antibody consumption. The 2 ICA were consistent with liquid chromatography-tandem mass spectrometry. This study serves as a reference for selecting appropriate fluorescent labels for the immunochromatographic assay of aflatoxin M1.

Flavonolignans from Elymus natans L. and Phytotoxic Activities.

Elymus natans, a perennial gramineous grass, plays an important role in animal husbandry and environmental sustenance in the Qinghai-Tibet plateau as a result of its high forage quality and good adaptability to the local environment. A bioassay showed that the extracts of green grasses of E. natans (GG) exhibited stronger phytotoxic activities than withered grasses (WG) against crops and grasses. In view of the secondary metabolites, which may be responsible for the resistance of the plant, the chemical components of GG were investigated. The flavone tricin, E1, and 10 flavonolignans, E2-E11, including three new flavonolignans, E2, E10, and E11, were isolated and identified. As far as we know, this is the first report on the chemical constitutions of the plant until now. The contents of compounds E1 and E4-E7 in GG were significantly higher than those in WG in high-performance liquid chromatography analysis, and they also showed observably phytotoxic activities against lettuce and Festuca arundinacea.

Advantages of time-resolved fluorescent nanobeads compared with fluorescent submicrospheres, quantum dots, and colloidal gold as label in lateral flow assays for detection of ractopamine.

Label selection is a critical factor for improving the sensitivity of lateral flow assay. Time-resolved fluorescent nanobeads, fluorescent submicrospheres, quantum dots, and colloidal gold-based lateral flow assay (TRFN-LFA, FM-LFA, QD-LFA, and CG-LFA) were first systematically compared for the quantitative detection of ractopamine in swine urine based on competitive format. The limits of detection (LOD) of TRFN-LFA, FM-LFA, QD-LFA, and CG-LFA were 7.2, 14.7, 23.6, and 40.1pg/mL in swine urine samples, respectively. The sensitivity of TRFN-LFA was highest. In the quantitative determination of ractopamine (RAC) in swine urine samples, TRFN-LFA exhibited a wide linear range of 5pg/mL to 2500pg/mL with a reliable coefficient of correlation (R2=0.9803). Relatively narrow linear ranges of 10-500pg/mL (FM-LFA) and 25-2500pg/mL (QD-LFA and CG-LFA) were acquired. Approximately 0.005µg of anti-RAC poly antibody (pAb) was used in each TRFN-LFA test strip, whereas 0.02, 0.054, and 0.15µg of pAb were used in each of the FM-LFA, QD-LFA, and CG-LFA test strips, respectively. In addition, TRFN-LFA required the least RAC-BSA antigens and exhibited the shortest detection time compared with the other lateral flow assays. Analysis of the RAC in swine urine samples showed that the result of TRFN-LFA was consistent with that of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and a commercial enzyme-linked immunosorbent assay (ELISA) kit.

Sesquiterpenoids from the roots of Vladimiria muliensis.

An unusual aromadendrane-type sesquiterpenoid with a rare hemiketal-containing 10/3 ring system, named vladimuliecin C (1), and one new eudesmane-type sesquiterpenoid, named vladimuliecin D (4), together with four known sesquiterpenoids, were isolated from the roots of Vladimiria muliensis. The structures of these compounds were elucidated by analysis of spectroscopic data. The absolute configuration of 1 was assigned by X-ray diffraction analysis. A possible biosynthetic process for the formation of 1 is proposed. Compound 1 showed moderate cytotoxicity against three human tumor cell lines.

Effectiveness of an HIV/AIDS educational programme for Chinese nurses.

AIM: This paper reports a study examining the effect of a multifaceted HIV/AIDS educational intervention on the knowledge, attitudes and willingness of Chinese nurses in caring for patients with human immunodeficiency virus. BACKGROUND: The expanding HIV/AIDS epidemic challenges nurses to increase their knowledge about this devastating illness to provide effective HIV/AIDS prevention and care to their patients. HIV/AIDS educational interventions, which were developed for North American and European nurses, have not been studied among nurses in other societies. METHODS: The study employed a pretest, post-test experimental design with 208 nurses from seven Chinese provinces. The intervention consisted of a 5-day workshop comprising didactic lectures interspersed with activities designed to elicit discussion of participants' values and personal feelings about HIV/AIDS. Bloom's Taxonomy and principles of good HIV/AIDS educational practice guided the educational intervention. Outcome variables were HIV/AIDS knowledge, attitude toward patients with HIV/AIDS (including empathy for and desire to avoid these patients) and willingness to provide nursing care to these patients. The data were collected in 2003. FINDINGS: At baseline, HIV/AIDS knowledge was not high and attitudes and willingness to care were neutral. Knowledge, attitudes toward patients with HIV/AIDS and willingness to provide nursing care to these patients were each improved at the conclusion of the workshop (P<0.001). CONCLUSIONS: As the HIV/AIDS epidemic expands, nurses will be called upon to deliver competent, compassionate and comprehensive care to patients and their significant others. Intensive, interactive HIV/AIDS professional workshops can contribute to the national effort by increasing knowledge and improving attitudes towards and willingness to provide nursing care for patients with HIV/AIDS.