Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy.

Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase (PARP) inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase acknowledged for its regulatory roles in immune cell function, cell adhesion, and vascular development. This study presents evidence indicating that Syk expression in high-grade serous ovarian cancer and triple-negative breast cancers promotes DNA double-strand break resection, homologous recombination (HR), and subsequent therapeutic resistance. Our investigations reveal that Syk is activated by ATM following DNA damage and is recruited to DNA double-strand breaks by NBS1. Once localized to the break site, Syk phosphorylates CtIP, a pivotal mediator of resection and HR, at Thr-847 to promote repair activity, particularly in Syk-expressing cancer cells. Inhibition of Syk or its genetic deletion impedes CtIP Thr-847 phosphorylation and overcomes the resistant phenotype. Collectively, our findings suggest a model wherein Syk fosters therapeutic resistance by promoting DNA resection and HR through a hitherto uncharacterized ATM-Syk-CtIP pathway. Moreover, Syk emerges as a promising tumor-specific target to sensitize Syk-expressing tumors to PARP inhibitors, radiation and other DNA-targeted therapies.

Impact of continuous care on cardiac function in patients with lung cancer complicated by coronary heart disease.

BACKGROUND: Despite sharing similar pathogenic factors, cancer and coronary heart disease (CHD) occur in comparable populations at similar ages and possess similar susceptibility factors. Consequently, it is increasingly commonplace for patients to experience the simultaneous occurrence of cancer and CHD, a trend that is steadily rising. AIM: To determine the impacts of continuing care on lung cancer patients with CHD following percutaneous coronary intervention (PCI). METHODS: There were 94 lung cancer patients with CHD following PCI who were randomly assigned to the intervention group (n = 38) and the control group (n = 41). In the intervention group, continuing care was provided, while in the control group, routine care was provided. An evaluation of cardiac and pulmonary function, medication compliance, a 6-min walk test, and patient quality of life was performed. RESULTS: Differences between the two groups were significant in left ventricular ejection fraction, 6-min walk test, oxygen uptake, quality of life and medication compliance (P < 0.05). In comparison with the control group, the enhancement in the intervention group was more significant. The intervention group had more patients with high medication compliance than the control group, with a statistically significant difference (P < 0.05). CONCLUSION: After undergoing PCI, lung patients with CHD could benefit from continued care in terms of cardiac and pulmonary function, medications compliance, and quality of life.

Seven chromatin regulators as immune cell infiltration characteristics, potential diagnostic biomarkers and drugs prediction in hepatocellular carcinoma.

Treatment is challenging due to the heterogeneity of hepatocellular carcinoma (HCC). Chromatin regulators (CRs) are important in epigenetics and are closely associated with HCC. We obtained HCC-related expression data and relevant clinical data from The Cancer Genome Atlas (TCGA) databases. Then, we crossed the differentially expressed genes (DEGs), immune-related genes and CRs to obtain immune-related chromatin regulators differentially expressed genes (IRCR DEGs). Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to select the prognostic gene and construct a risk model for predicting prognosis in HCC, followed by a correlation analysis of risk scores with clinical characteristics. Finally, we also carried out immune microenvironment analysis and drug sensitivity analysis, the correlation between risk score and clinical characteristics was analyzed. In addition, we carried out immune microenvironment analysis and drug sensitivity analysis. Functional analysis suggested that IRCR DEGs was mainly enriched in chromatin-related biological processes. We identified and validated PPARGC1A, DUSP1, APOBEC3A, AIRE, HDAC11, HMGB2 and APOBEC3B as prognostic biomarkers for the risk model construction. The model was also related to immune cell infiltration, and the expression of CD48, CTLA4, HHLA2, TNFSF9 and TNFSF15 was higher in high-risk group. HCC patients in the high-risk group were more sensitive to Axitinib, Docetaxel, Erlotinib, and Metformin. In this study, we construct a prognostic model of immune-associated chromatin regulators, which provides new ideas and research directions for the accurate treatment of HCC.

Case report: Treatment-resistant depression with acute psychosis in an adolescent girl with Cushing's syndrome.

Cushing's syndrome (CS) is a rare disease with multiple somatic signs and a high prevalence of co-occurring depression. However, the characteristics of depression secondary to CS and the differences from major depression have not been described in detail. In this case, we report a 17-year-old girl with treatment-resistant depression with a series of atypical features and acute psychotic episodes, which is a rare condition secondary to CS. This case showed a more detailed profile of depression secondary to CS and highlighted the differences with major depression in clinical features, and it will improve insight into the differential diagnosis especially when the symptoms are not typical.

IL-4 as a potential biomarker for differentiating major depressive disorder from bipolar depression.

We aimed to investigate the differential diagnosis of depressive episodes in patients with major depressive disorder (MDD) and bipolar disorder (BD) using peripheral blood cytokine expression levels. The levels of interleukin (IL)-2, IL-6, IL-10, IL-17, IL4, and IL-12; interferon (IFN)-γ; and tumor necrosis factor (TNF)-α were measured in patients with MDD and BD presenting acute episodes in an inpatient psychiatric setting. The expression levels of IL-6, IL-10, IL-17, and IFN-γ in the MDD and BD groups were higher than those in the control group (P < .05), but there was no significant difference between the patient groups and control group. Only the expression levels of TNF-α and IL-4 were higher in both groups than in the control group, and the BD group had higher levels than the MDD group (P < .05). The expression levels of IL-17, IFN-γ, IL-10, and IL-4 were significantly higher in BD-related manic episodes than in BD-related depressive episodes (P < .05). IL-6, IFN-γ, TNF-α, IL-10, and IL-4 levels were higher in BD-related depressive episodes than in MDD-related depressive episodes (P < .05). The receiver operating characteristic curve test for MDD and BD and the area under the curve for IL-4 revealed good clinical predictability. Patients with MDD and BD exhibited different cytokine profiles when experiencing acute episodes; patients with BD exhibited a more severe immune-inflammatory response system-compensatory immunoregulatory response system (CIRS) imbalance. IL-4 was found to have diagnostic value in differentiating between active depressive episodes in MDD and BD.

Identifying the Antitumor Effects of Curcumin on Lung Adenocarcinoma Using Comprehensive Bioinformatics Analysis.

Background: As the main component of turmeric (Curcuma longa L.), curcumin is widely used in the treatment of various diseases. Previous studies have demonstrated that curcumin has great potential as a therapeutic agent, but the lack of understanding of the functional mechanism of the drug has hindered the widespread use of the natural product. In the present study, we used comprehensive bioinformatics analysis and in vitro experiments to explore the anti-tumor mechanism of curcumin. Materials and Methods: LUAD mRNA expression data were obtained from TCGA database and differentially expressed genes (DEGs) were identified using R software. Functional enrichment analysis was conducted to further clarify its biological properties and hub genes were identified by a protein-protein interaction (PPI) network analysis. Survival analysis and molecular docking were used to analyze the effectiveness of the hub genes. By an in vitro study, we evaluated whether curcumin could influence the proliferation, migration, and invasion activities of LUAD cells. Results: In this study, 1783 DEGs from LUAD tissue samples compared to normal samples were evaluated. Functional enrichment analysis and the PPI network revealed the characteristics of the DEGs. We performed a topological analysis and identified 10 hub genes. Of these, six genes (INS, GCG, SST, F2, AHSG, and NPY) were identified as potentially effective biomarkers of LUAD. The molecular docking results indicated that curcumin targets in regulating lung cancer may be INS and GCG. We found that curcumin significantly inhibited the proliferation, migration, and invasion of LUAD cells and significantly decreased the expression of the INS and GCG genes. Conclusion: The results of this study suggest that the therapeutic effects of curcumin on LUAD may be achieved through the intervention of INS and GCG, which may act as potential biomarkers for LUAD prevention and treatment.

The Efficacy and Safety of Diyushengbai Tablet on Preventing and Treating Leukopenia Caused by Radiotherapy and Chemotherapy Against Tumor: A Systematic Review and Meta-Analysis.

Background: Leukopenia is one of the side effects of radiotherapy and chemotherapy. Diyushengbai tablet (DYT) is used to prevent and treat leukopenia caused by various reasons. A meta-analysis was performed to systematically analyze the therapeutic effects of DYT on preventing and treating leukopenia caused by radiotherapy and chemotherapy. Objectives: This study aimed to systematically evaluate the efficacy and safety of DYT in preventing and treating leukopenia caused by radiotherapy and chemotherapy. Methods: We performed a comprehensive literature search of electronic databases such as PubMed, The Cochrane Library, China Knowledge Network (CNKI), China Biomedical Literature Database (CBM), Wanfang Data Knowledge Service Platform, and VIP, through November of 2021. The scanning reports deadline is until November 2021. The bias risk evaluation criteria developed by the Cochrane collaborative organization were used to evaluate the literature quality of the included studies. The RevMan5.4 software was used to analyze the data, and the Stata16.0 was used to perform the Egger test. Results: After selecting all the databases, a total of 41 reports which involved 3,793 cases were analyzed. Meta-analysis showed that DYT could significantly reduce the white blood cell (WBC) suppression caused by radiotherapy and chemotherapy and improve the patients' WBC counts and neutrophils, compared with the efficacy of other oral WBC-elevating drugs such as Leucogen tablets and Batilol tablets and additional utilization of granulocyte colony-stimulating factor (G-CSF). The results of meta-analysis showed that for preventive medication purpose, the overall incidence of leukocyte suppression was [RR = 0.74, 95%CI (0.59, 0.92), p = 0.006], and the white blood cell count was [MD = 1.12, 95%CI (0.95, 1.29), p < 0.00001]; while for therapeutic purpose, the incidence of overall leukocyte suppression was [RR = 0.61, 95%CI (0.38, 0.95), p = 0.03], and the white blood cell count was [MD = 1.20, 95%CI (0.77, 1.62), p < 0.00001]. More importantly, the additional use of DYT can reduce the application amount of G-CSF. The results showed that the application of G-CSF can be reduced by an average of 1.57 from the beginning of treatment to return normal white blood cells around 2.23 in two cycles of chemotherapy. Conclusion: DYT is more effective in preventing and treating leukopenia caused by radiotherapy and chemotherapy than other oral WBC-elevating drugs, which have a high clinical value.

Rapid Eye Movement Sleep Deprivation Combined With Fluoxetine Protects Against Depression-Induced Damage and Apoptosis in Rat Hippocampi via A1 Adenosine Receptor.

Background: Rapid eye movement sleep deprivation (REMSD) and fluoxetine affect depression, yet the detailed molecular mechanisms were not clear. Methods: Rat depression chronic unpredictable stress was constructed, and the body weight of rats was measured. The efficacy of REMSD and fluoxetine on the pleasure experience, exploration, and cognition of rats with depression was determined by the Sucrose preference test, the open field test, and Morris water task, respectively. The effects of REMSD and fluoxetine on depression-induced damage and apoptosis in rat hippocampi were detected using hematoxylin-eosin staining and terminal transferase-mediated biotin 2'-deoxyuridine, 5'-triphosphate nick end labeling. A1 adenosine receptor content was measured by immunohistochemistry. Relative expressions of the A1 adenosine receptor, proteins related to apoptosis (B Bcl-2-associated X protein; B-cell lymphoma 2), phosphoinositide 3-kinase, P38 mitogen-activated protein kinase, cFos, and adenosine deaminase RNA specific two were quantified by quantitative real-time polymerase chain reaction and Western blot as needed. Results: Depression decreased rat weight. REMSD combined with fluoxetine increased body weight, prompted rat behavior, alleviated depression-induced damage, attenuated apoptosis, and promoted A1 adenosine receptor level in rat hippocampi. Furthermore, the combined therapy upregulated expressions of A1 adenosine receptor, B-cell lymphoma 2, and phosphoinositide 3-kinase but downregulated those of B-cell lymphoma 2-associated X protein, P38 mitogen-activated protein kinase, cFos, and adenosine deaminase RNA specific 2 in the hippocampi of rats with depression. Conclusion:REMSD combined with fluoxetine protected rats against depression-induced damage and apoptosis in the hippocampus via the A1 adenosine receptor, providing a possible treatment strategy for depression.

Nano-realgar suppresses lung cancer stem cell growth by repressing metabolic reprogramming.

BACKGROUND: Recent studies in cancer biology suggest that metabolic glucose reprogramming is a potential target for cancer treatment. However, little is known about drug intervention in the glucose metabolism of cancer stem cells (CSCs) and its related underlying mechanisms. METHODS: The crude realgar powder was Nano-grinded to meets the requirements of Nano-pharmaceutical preparations, and Nano-realgar solution (NRS) was prepared for subsequent experiments. Isolation and characterization of lung cancer stem cells (LCSCs) was performed by magnetic cell sorting (MACS) and immunocytochemistry, respectively. Cell viability and intracellular glucose concentration were detected by MTT assay and glucose oxidase (GOD) kit. Protein expressions related to metabolic reprogramming was detected by ELISA assay. Determination of the expression of HIF-1α and PI3K/Akt/mTOR pathways was carried out by RT-PCR and western blotting analysis. A subcutaneous tumor model in BALB/c-nu mice was successfully established to evaluate the effects of Nano-realgar on tumor growth and histological structure, and the expression of HIF-1α in tumor tissues was measured by immunofluorescence. RESULTS: Nano-realgar inhibits cell viability and induces glucose metabolism in LCSCs, and inhibits protein expression related to metabolic reprogramming in a time- and dose-dependent manner. Nano-realgar downregulated the expression of HIF-1α and PI3K/Akt/mTOR pathways in vitro and in vivo. Nano-realgar inhibits tumor growth and changes the histological structure of tumors through in vivo experiments and consequently inhibits the constitutive activation of HIF-1α signaling. CONCLUSIONS: These results reveal that Nano-realgar inhibits tumor growth in vitro and in vivo by repressing metabolic reprogramming. This inhibitory effect potentially related to the downregulation HIF-1α expression via PI3K/Akt/mTOR pathway.

CD11b deficiency suppresses intestinal tumor growth by reducing myeloid cell recruitment.

Mac-1 (CD11b) is expressed on bone marrow-derived immune cells. CD11b binds to ligands to regulate leukocyte adhesion and migration across the endothelium or epithelium. Here, we employed CD11b knockout mice and an Apc(Min/+) spontaneous intestinal adenoma mouse model to clarify the function of CD11b in intestinal tumorigenesis. We showed that CD11b deficiency may contribute to the inhibition of myeloid cell trafficking to the tumor microenvironment and inactivated Wnt/ß-catenin pathway to suppress tumor growth. This effect was partly mediated by inhibiting the myeloid cell-mediated decrease in TNF-α secretion, which inhibits the recruitment of myeloid-derived suppressor cells to the tumor microenvironment and subsequently induces IFN-γ and CXCL9 production. This work provides evidence for the mechanism by which CD11b may function as an important oncogene and highlights the potential of CD11b as a therapeutic target in CRC.