MICAL-L2, as an estrogen-responsive gene, is involved in ER-positive breast cancer cell progression and tamoxifen sensitivity via the AKT/mTOR pathway.

Endocrine treatment, particularly tamoxifen, has shown significant improvement in the prognosis of patients with estrogen receptor-positive (ER-positive) breast cancer. However, the clinical utility of this treatment is often hindered by the development of endocrine resistance. Therefore, a comprehensive understanding of the underlying mechanisms driving ER-positive breast cancer carcinogenesis and endocrine resistance is crucial to overcome this clinical challenge. In this study, we investigated the expression of MICAL-L2 in ER-positive breast cancer and its impact on patient prognosis. We observed a significant upregulation of MICAL-L2 expression in ER-positive breast cancer, which correlated with a poorer prognosis in these patients. Furthermore, we found that estrogen-ERß signaling promoted the expression of MICAL-L2. Functionally, our study demonstrated that MICAL-L2 not only played an oncogenic role in ER-positive breast cancer tumorigenesis but also influenced the sensitivity of ER-positive breast cancer cells to tamoxifen. Mechanistically, as an estrogen-responsive gene, MICAL-L2 facilitated the activation of the AKT/mTOR signaling pathway in ER-positive breast cancer cells. Collectively, our findings suggest that MICAL-L2 could serve as a potential prognostic marker for ER-positive breast cancer and represent a promising molecular target for improving endocrine treatment and developing therapeutic approaches for this subtype of breast cancer.

A study on the catalytic domain of pork phospholipase A2: Enzymatic properties and hydrolysis characteristics of phosphatidylcholine and its hydroperoxide.

Endogenous phospholipase A2 (PLA2) plays an important role in phospholipids degradation during cured meat products manufacturing. The present study was undertaken to reveal more information about the endogenous PLA2 in muscles and its role in degradation of intramuscular phospholipids. With the catalytic domain of pork calcium-independent PLA2 (iPLA2cd), impacts of physic-chemical factors on the activity were investigated and substrate specificity of the enzyme were tested respectively. The optimum temperature and pH of pork iPLA2cd were 40 °C and 7.5, respectively. The iPLA2cd could be stimulated by adequate contents of NaCl and ATP, and inhibited by CaCl2 and NaNO2. For native phospholipids, the iPLA2cd was of a little higher affinity towards phosphatidylcholine (PC) than phosphatidylethanolamine (PE), phosphoserine (PS) and phosphatidylinositol (PI). The iPLA2cd could preferentially hydrolyze peroxidized PC over the native PC. The results would help better understand the degradation of phospholipids and the role played by endogenous enzymes during meat products manufacturing.

Analysis of risk factors associated with diffuse alveolar haemorrhage in patients with ANCA-associated vasculitis and construction of a risk prediction model using line graph.

OBJECTIVES: This study aims to analyse the risk factors associated with diffuse alveolar haemorrhage (DAH) in patients with ANCA-associated vasculitis (AAV) and construct a risk prediction model using line graph. METHODS: A retrospective study was conducted from January 2012 to May 2023 at the First Clinical College of Three Gorges University, focusing on patients diagnosed with AAV. Clinical and laboratory data were collected from these patients. The potential predictors subsets of high-risk AAV combined with DAH were screened by LASSO regression and 10-fold cross-validation method, and determined by using multivariate Logistic regression analysis, then were used for developing a prediction nomogram for high-risk AAV combined with DAH using the R software. ROC curve analysis was used to validate the model's stability. Internal validation was performed using a bootstrap method. The discrimination of the nomogram was determined by calculating the average consistency index(C-index). The calibration curve was used to assess the calibration of the nomogram. RESULTS: A total of 234 patients with AAV were included, among whom 85 developed DAH, with an incidence rate of 36%, and the average age was 63±12. Multivariable logistic regression analysis showed that Age [OR=1.037 (95%CI: 1.006, 1.071), p=0.019], platelet count (PLT) [OR=0.996 (95%CI: 0.992, 0.999), p=0.029], ESR [OR=1.028 (95%CI: 1.015, 1.042), p<0.01], HB [OR=0.978 (95%CI: 0.959, 0.996), p=0.024], and haematuria [OR=3.77 (95%CI: 1.677, 8.976), p=0.001] were found to be independent predictors of AAV combined with DAH and were used to construct a nomogram. The AUCROC values of the nomogram for DAH in AAV patients was 0.852 (95%CI: 0.801, 0.903), and the C-index could reach 0.824 after internal verification, showing good differentiation and consistency. CONCLUSIONS: The new nomogram, which included age, Hb, ESR, PLT and haematuria as variables, had the potential to predict the risk of AAV patients complicated with DAH.

Effect of CDK4/6 Inhibitors on Tumor Immune Microenvironment.

Cancer is an abnormal proliferation of cells that is stimulated by cyclin-dependent kinases (CDKs) and defective cell cycle regulation. The essential agent that drive the cell cycle, CDK4/6, would be activated by proliferative signals. Activated CDK4/6 results in the phosphorylation of the neuroblastoma protein (RB) and the release of the transcription factor E2F, which promotes the cell cycle progression. CDK4/6 inhibitor (CDK4/6i) has been currently a research focus, which inhibits the CDK4/6-RB-E2F axis, thereby reducing the cell cycle transition from G1 to S phase and mediating the cell cycle arrest. This action helps achieve an anti-tumor effect. Recent research has demonstrated that CDK4/6i, in addition to contributing to cell cycle arrest, is also essential for the interaction between the tumor cells and the host immune system, i.e., activating the immune system, strengthening the tumor antigen presentation, and reducing the number of regulatory T cells (Treg). Additionally, CDK4/6i would elevate the level of PD-L1, an immunosuppressive factor, in tumor cells, and CDK4/6i in combination with anti-PD-L1 therapy would more effectively reduce the tumor growth. Our results showed that CDK4/6i caused autophagy and senescence in tumor cells. Herein, the impact of CDK4/6i on the immune microenvironment of malignant tumors was mainly focused, as well as their interaction with immune checkpoint inhibitors in affecting anti-tumor immunity.

Current advances and development strategies of orally bioavailable PROTACs.

Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last half decade, we have witnessed several PROTACs initiated phase I/II/III clinical trials, which inspired us a lot. However, the structure of PROTACs beyond "rule of 5" resulted in developing PROTACs with acceptable oral pharmacokinetic (PK) properties remain one of the biggest bottleneck tasks. Many reports have demonstrated that it is possible to access orally bioavailable PROTACs through rational ligand and linker modifications. In this review, we systematically reviewed and highlighted the most recent advances in orally bioavailable PROTACs development, especially focused on the medicinal chemistry campaign of discovery process and in vivo oral PK properties. Moreover, the constructive strategies for developing oral PROTACs were proposed comprehensively. Collectively, we believe that the strategies summarized here may provide references for further development of oral PROTACs.

Effectiveness and Safety of Bu Shen Kai Qiao Fang in the Treatment of Alzheimer's Disease: Study Protocol for a Multicenter, Prospective, Real-World Clinical Trial.

Background: Alzheimer's disease (AD) is a common degenerative disease of the nervous system with serious impact on quality of life of patients and their families. With an aging population, AD has become a major public health problem in China and worldwide. However, the physiological and pathological mechanisms of AD have not been fully elucidated, and there is a lack of effective prevention and clinical treatment methods. Many studies have found that traditional Chinese medicine (TCM) has a good therapeutic effect on cognitive function in AD patients. Bu Shen Kai Qiao Fang (BSKQF) is one such Chinese herbal preparation used in the treatment of AD. We designed a protocol for a real-world clinical study of BSKQF combined with Donepezil hydrochloride (DH) to evaluate the efficacy and safety of this approach in the treatment of AD patients. Methods: This is a protocol for a real-world, multicenter, prospective, observational cohort study. The study will recruit 860 AD patients from four hospitals across China. Equal numbers of patients will be treated with BSKQF and DH or with DH only. The criteria for grouping are based primarily on patient preference. Outcome measures include scores on the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MOCA) and will be recorded at baseline, and at one, two and three months after enrollment. The plasma Aß42 and plasma Tau levels of participating patients will also be measured by ELISA at baseline and after 3 months of treatment. Safety metrics and adverse events (AEs) of participating patients will be monitored and recorded. Discussion: This study will evaluate the clinical efficacy and safety of BSKQF in the treatment of AD. The results will provide reliable evidence for the clinical application of BSKQF in the treatment of AD. Study Registration: Trial registration: Chinese Clinical Trial Registry, NO. ChiCTR2000039670, Registered 5 November 2020 https://www.chictr.org.cn/showprojEN.html?proj=63800.

Microwave ablation induces abscopal effect via enhanced systemic antitumor immunity in colorectal cancer.

Background: Thermal ablation is the primary procedure for the local treatment of lung metastases. It is known that radiotherapy and cryoablation can stimulate an abscopal effect, while the occurrence of abscopal effect induced by microwave ablation is less; the cellular and molecular mechanisms involved in the abscopal effect after microwave ablation should be further elucidated. Methods: CT26 tumor-bearing Balb/c mice were treated with microwave ablation with several combinations of ablation power and time duration. The growth of primary or abscopal tumors and the survival of mice were both monitored; moreover, immune profiles in abscopal tumors, spleens, and lymph nodes were examined by flow cytometry. Results: Microwave ablation suppressed tumor growth in both primary and abscopal tumors. Both local and systemic T-cell responses were induced by microwave ablation. Furthermore, the mice exhibiting significant abscopal effect after microwave ablation markedly elevated Th1 cell proportion both in the abscopal tumors and spleens. Conclusions: Microwave ablation at 3 w-3 min not only suppressed tumor growth in the primary tumors but also stimulated an abscopal effect in the CT26-bearing mice via the improvement of systemic and intratumoral antitumor immunity.

Crosstalk between microwave ablation and ferroptosis: The next hot topic?

Microwave ablation has been one form of thermal ablation in treatments for many tumors, which can locally control unresectable tumors. Ferroptosis is iron-dependent cell death caused by the cumulative reactive oxygen species and lipid peroxidation products. Recently, increasing evidence has shown that ferroptosis might play a vital role in MWA-induced tumor suppression. In this article, we briefly illustrate the concept of ferroptosis, the related signal pathways and inducers, the basic principle of microwave ablation in killing tumors, and the key molecules released after microwave ablation. Then, we describe the cross-talking molecules between microwave ablation and ferroptosis, and discussed the potential mechanism of microwave ablation-induced ferroptosis. This review explores the therapeutic target of ferroptosis in enhancing the systemic antitumor effect after microwave ablation, providing theoretical support in combinational microwave ablation with pro-ferroptosis therapy.

Knowledge mapping analysis of mental health research on COVID-19.

Objective: A bibliometric analysis of COVID-19 is conducted to examine the developmental context, research hotspots, and frontiers of mental health. Methods: Using the Web of Science Core Collection (WOSCC), we have retrieved articles on mental health research related to COVID-19 which were published between 2019 and 2021. The coauthorship of countries, institutes, and authors was analyzed using VOSviewer 1.6.17, and the co-citation map of authors/references was analyzed as well. CiteSpace version 5.8.R3 was used to analyze keyword clusters and forecast research frontiers. Results: There were 8,856 articles retrieved, including 10,559 research institutes and 1,407 academic journals. The most published country and institutes were the United States (2190) and the University of London (373). Wang, Chengyu owned the highest co-citations (1810). Frontier topics can be identified by trending keywords, including "anxiety," "depression," "psychological distress," "quarantine," "post-traumatic stress disorder (PTSD)," "insomnia," and "Healthcare workers." Conclusion: The most common psychological problems of people during the epidemic are anxiety and depression. Insomnia and PTSD need to be solved under the normalization of the epidemic. GAD-7 and PHQ-9 scales are the most convenient and effective for screening anxiety and depression. Healthcare workers, older adults, and college students should be concerned, and social and family support is essential.

Recombinant Porcine 12-Lipoxygenase Catalytic Domain: Effect of Inhibitors, Selectivity of Substrates and Specificity of Oxidation Products of Linoleic Acid.

Lipoxygenase (LOX) is a major endogenous enzyme for the enzymatic oxidation of lipids during meat storage and meat product manufacturing. In the present work, some characteristics, i.e., effects of inhibitors, selectivity of substrates and specificity of oxidation products, were studied using recombinant porcine 12-lipoxygenase catalytic domain (12-LOXcd). Several familiar inhibitors were found inhibit the activity of recombinant porcine 12-LOXcd;nordihydroguaiaretic acid demonstrated the strongest inhibitory effect. The enzyme could oxygenate common polyunsaturated fatty acids, and showed the highest affinity to linoleic acid (LA), followed by arachidonic acid (AA), linolenic acid (LN) and docosahexaenoic acid (DHA). Under the action of porcine 12-LOXcd, LA was oxidized into four hydroxyoctadecadienoic acid (HODE) isomers, i.e., 13-Z,E-HODE, 13-E,E-HODE, 9-Z,E-HODE and 9-E,E-HODE. Variation of pH not only affected the yield of LA oxidation products, but also the distribution of HODE isomers. These results indicated that endogenous LOX activity and LOX-catalyzed lipid oxidation can be regulated during meat storage and meat product manufacturing.

Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer.

BACKGROUND: The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer. METHODS: This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures. RESULTS: DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression. CONCLUSIONS: This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming. TRIAL REGISTRATION: Not applicable (non-interventional study). CRUK Internal Database Number 14232.

Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines.

The urea cycle (UC) removes the excess nitrogen and ammonia generated by nitrogen-containing compound composites or protein breakdown in the human body. Research has shown that changes in UC enzymes are not only related to tumorigenesis and tumor development but also associated with poor survival in hepatocellular, breast, and colorectal cancers (CRC), etc. Cytoplasmic ornithine, the intermediate product of the urea cycle, is a specific substrate for ornithine decarboxylase (ODC, also known as ODC1) for the production of putrescine and is required for tumor growth. Polyamines (spermidine, spermine, and their precursor putrescine) play central roles in more than half of the steps of colorectal tumorigenesis. Given the close connection between polyamines and cancer, the regulation of polyamine metabolic pathways has attracted attention regarding the mechanisms of action of chemical drugs used to prevent CRC, as the drug most widely used for treating type 2 diabetes (T2D), metformin (Met) exhibits antitumor activity against a variety of cancer cells, with a vaguely defined mechanism. In addition, the influence of metformin on the UC and putrescine generation in colorectal cancer has remained unclear. In our study, we investigated the effect of metformin on the UC and putrescine generation of CRC in vivo and in vitro and elucidated the underlying mechanisms. In nude mice bearing HCT116 tumor xenografts, the administration of metformin inhibited tumor growth without affecting body weight. In addition, metformin treatment increased the expression of monophosphate (AMP)-activated protein kinase (AMPK) and p53 in both HCT116 xenografts and colorectal cancer cell lines and decreased the expression of the urea cycle enzymes, including carbamoyl phosphate synthase 1 (CPS1), arginase 1 (ARG1), ornithine trans-carbamylase (OTC), and ODC. The putrescine levels in both HCT116 xenografts and HCT116 cells decreased after metformin treatment. These results demonstrate that metformin inhibited CRC cell proliferation via activating AMPK/p53 and that there was an association between metformin, urea cycle inhibition and a reduction in putrescine generation.

Dual-emission ratio fluorescent probes based on carbon dots and gold nanoclusters for visual and fluorescent detection of copper ions.

Blue carbon dots (BCDs) and red gold nanoclusters modified by bovine serum albumin (BSA-Au NCs) were selected as luminescent nanomaterials, and the nanohybrid materials were successfully prepared and applied to the fluorescent measurement of copper ions. The prepared ratio fluorescent probe has two emission peaks near 452 and 654 nm under an excitation of 330 nm. The fluorescence intensity was gradually quenched because Au NCs was aggregated in the presence of Cu2+, resulting in a gradation of the fluorescent color from red to pink to purple to blue for visual detection. BCDs have almost the same fluorescence intensity due to their light stability and chemical inertness to Cu2+ and serve as a background reference in the sensing system. Under the optimal condition, the detection limit (LOD) is 16 nM, the linear range is 0.05-1.85 µM, and the coefficient of determination R2 is 0.9987 for copper determination. Compared with other single probes, the ratio fluorescent probe in the current study has good water solubility, low cytotoxicity, and is easy to synthesize. The nanoprobe provides a high-quality and sensitive visible light platform for monitoring copper ions. Graphical abstract.

Smartphone colorimetric determination of hydrogen peroxide in real samples based on B, N, and S co-doped carbon dots probe.

In this paper, we report the use of a smartphone and B, N, and S co-doped carbon dots (BNS-CDs) as a promising peroxidase mimic to quantify hydrogen peroxide (H2O2). The synthesized BNS-CDs exhibited excellent peroxidase-like activity to catalyze the reaction of the chromogenic substrate 3,3',5,5'-tetramethylbenzidine (TMB) with H2O2 to generate a blue oxide product (ox-TMB) with maximum absorption at 652 nm. Steady-state kinetic analysis demonstrated that the BNS-CDs showed much higher affinity than natural horseradish peroxidase (HRP) for H2O2 due to their small size and larger specific surface area. A smartphone colorimetric readout device was employed to record the RGB (red green blue) value of the ox-TMB solution via the Android application Color Grab for quantitative detection. A good linear relationship (R2 = 0.9970) between the H2O2 concentration and |R-Rblank| value was obtained in the range of 3-30 µM with a limit of detection (LOD) of 0.8 µM. The current method was successfully applied to determine H2O2 in mouthwash and milk with recoveries of 92.70-108.30%. The developed assay is a promising portable detection platform for H2O2 with good sensitivity and selectivity, simple operation, fast response, and low cost. Graphical abstract.

[Effect of Moxibustion on Renal Hemodynamics in Patients with Chronic Kidney Disease].

OBJECTIVE: To evaluate the immediate effect of moxibustion at Shenshu (BL 23) on renal hemodynamics in patients with chronic kidney disease(CKD)．. METHODS: Thirty-two non-dialysis patients with CKD were recruited in this study. Moxibustion was applied at bilateral BL 23 for 30 min. The peak systolic velocity (PSV), end diastolic velocity (EDV) of the interlobar renal artery were measured by Doppler ultrasonography (US) before, and 0 and 15 min after moxibustion. The renal resistance index (RI) was equal to (PSV－EDV)/PSV. The body temperature (T), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) were also monitored at the same time points. RESULTS: After moxibustion, the EVD level at 15 min after moxibustion was significantly increased (P<0.05), and the renal RI levels at 0 and 15 min after moxibustion were significantly down-regulated in comparison with their own pre-treatment (P<0.01). No significant changes were found in the levels of PSV, T, SBP, DBP and HR after moxibustion (P>0.05). CONCLUSION: Moxibustion at BL 23 can increase EDV and reduce renal RI of the interlobar renal artery in patients with CKD, which may be useful in relieving kidney disorders by improving renal blood flow.