Copper-Nanoparticle-Induced Neurotoxic Effect and Oxidative Stress in the Early Developmental Stage of Zebrafish (Danio rerio).

Copper nanoparticles (CuNPs) are extensively used in electronics, cosmetics, fungicides, and various other fields due to their distinctive qualities. However, this widespread usage can contribute to environmental contamination and heightened health risks for living organisms. Despite their prevalent use, the ecological impacts and biosafety of CuNPs remain inadequately understood. The present study aims to delve into the potential toxic effects of CuNPs on zebrafish (Danio rerio) embryos, focusing on multiple indexes such as embryonic development, neurotoxicity, oxidative stress, and inflammatory response. The results revealed a notable increase in the death rate and deformity rate, alongside varying degrees of decrease in hatching rate and heart rate following CuNPs exposure. Particularly, the frequency of spontaneous tail coiling significantly declined under exposure to CuNPs at concentrations of 500 µg/L. Furthermore, CuNPs exposure induced alterations in the transcriptional expression of GABA signaling pathway-related genes (gabra1, gad, abat, and gat1), indicating potential impacts on GABA synthesis, release, catabolism, recovery, and receptor binding. Additionally, CuNPs triggered oxidative stress, evidenced by disruption in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, along with elevated malondialdehyde (MDA) levels. This oxidative stress subsequently led to a proinflammatory cascade, as demonstrated by the increased transcriptional expression of inflammatory markers (il-1ß, tnf-α, il-6, and il-8). Comparative analysis with copper ion (provided as CuCl2) exposure highlighted more significant changes in most indexes with CuCl2, indicating greater toxicity compared to CuNPs at equivalent concentrations. In conclusion, these findings provide valuable insights into the toxic effects of CuNPs on zebrafish embryo development and neurotransmitter conduction. Furthermore, they present technical methodologies for assessing environmental and health risks associated with CuNPs, contributing to a better understanding of their biosafety and ecological impact.

The correlation between systemic inflammatory markers and efficiency for advanced gastric cancer patients treated with ICIs combined with chemotherapy.

Currently lacking research to explore the correlation between inflammatory markers and the efficacy of immune checkpoint inhibitors (ICIs) combined with chemotherapy in the treatment of advanced gastric cancer. This study is a retrospective study and included patients with advanced gastric cancer who receiving ICIs combined with chemotherapy from January 2020 to December 2022. We analysed the relationship between systemic inflammatory markers and the efficacy of ICIs combined chemotherapy and constructed a clinical prediction model. A nomogram was constructed based on the results of the bidirectional stepwise regression model. A total of 197 patients were enrolled in the training group, with a median follow-up period of time 26 months. Kaplan Meier analysis showed that the median OS of patients with low systemic immune-inflammatory index (SII) and low platelet to lymphocyte ratio (PLR) was superior to those with high SII and PLR. Univariate and multivariate Cox regression analysis showed that SII, NLR, PLR, and N stage as independent prognostic factors for OS. Adding SII to the conventional model improved the predictive ability of the 12-month OS. A total of 95 patients were included in the validation group, and external validation of the SII-based nomogram showed favourable predictive performance. Baseline SII, PLR, and N stage may serve as independent predictive factors for survival outcomes in advanced gastric cancer patients undergoing ICIs combined with chemotherapy. The SII-based nomogram can provide intuitive and accurate prognosis prediction of individual patients.

Correlation between mismatch repair and survival of patients with gastric cancer after 5-FU-based adjuvant chemotherapy.

BACKGROUND: Almost all adjuvant chemotherapy regimens for gastric cancer recommended by guidelines are fluorouracil (5-FU) based, and 5-FU-based adjuvant chemotherapy plays an important role in reducing the recurrence of gastric cancer after surgery. However, the effect of mismatch repair (MMR) status on survival after 5-FU-based adjuvant chemotherapy in patients with gastric cancer remains controversial. MATERIALS AND METHODS: We prospectively included patients with gastric cancer who underwent radical gastrectomy between March 14, 2017 and September 30, 2021. The included patients received 5-FU-based adjuvant chemotherapy or surgery alone. The MMR status of patients was divided into MMR proficient (pMMR) and MMR defective (dMMR) according to four MMR proteins. Peripheral blood was collected for systemic inflammation analysis. The main purpose of this study was to analyze the effect of MMR status on survival after 5-FU-based adjuvant chemotherapy in patients with gastric cancer. We also analyzed the differences in systemic inflammation levels in different MMR status and their impact on survival. RESULTS: A total of 479 patients were enrolled, with a median follow-up period of time was 36 months. In the surgery alone group, dMMR gastric cancer had better disease-free survival (DFS) (hazard ratio [HR] = 4.33, 95% confidence interval [CI] 1.25-15.02, p = 0.02) than pMMR, and in the adjuvant chemotherapy group, there was no significant difference in DFS (HR = 1.16, 95% CI 0.65-2.07, p = 0.61) between dMMR and pMMR gastric cancer. The same results were seen for overall survival (OS). In addition, the result show that in the dMMR group, there was no difference in DFS (HR = 1.62, 95% CI 0.46-5.77, p = 0.45) between patients receiving adjuvant chemotherapy and those receiving surgery alone. In the pMMR group, the DFS values (HR = 0.59, 95%CI 0.35-0.99, p = 0.04) of patients receiving adjuvant chemotherapy were better than those of patients receiving surgery alone, and the same results were observed for OS. In addition, among pMMR patients, patients with a low platelet lymphocyte ratio (PLR) who received 5-FU adjuvant chemotherapy and those with a low neutrophil lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) who received surgery alone had better DFS and OS. CONCLUSION: To our knowledge, this is the first prospective study to specifically explore the correlation between MMR and survival of patients with gastric cancer after 5-FU-based adjuvant chemotherapy. The results showed that gastric cancer patients with pMMR can benefit from 5-FU-based adjuvant chemotherapy, but those with dMMR cannot. Among pMMR patients, lower PLR and SII values with surgery alone and lower NLRs in those receiving 5-FU-based adjuvant chemotherapy were associated with higher DFS and OS.

Impact of platinum-based chemotherapy on the prognosis of early triple-negative breast cancer: a systematic review and meta-analysis.

Although platinum-based chemotherapy can improve pathologic complete response (pCR) in patients with triple-negative breast cancer (TNBC), the impact on survival of platinum-based neoadjuvant and adjuvant chemotherapy is still controversial. Our meta-analysis aimed at analyzing survival with platinum-based neoadjuvant and adjuvant chemotherapy in patients with TNBC. We searched PubMed, EMBASE, MEDLINE, Cochrane databases, and several major conferences up to January 2021. Fixed and random models were used for our meta-analysis. Disease-free survival (DFS), overall survival (OS), and side effects data were extracted from the included literature in addition to the corresponding pooled hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs). A total of nine studies involving 3247 patients were included. The pooled analysis suggested that compared with anthracycline- and/or paclitaxel-based chemotherapy, platinum-based chemotherapy could further improve DFS (HR = 0.56, 95% CI 0.45-0.67, p < 0.01) and OS (HR = 0.54, 95% CI 0.38-0.70, p < 0.01) in patients with TNBC. The subgroup analysis showed that platinum-based chemotherapy could further improve DFS (HR = 0.59, 95% CI 0.43-0.74, p < 0.01) and OS (HR = 0.61, 95% CI 0.40-0.83, p < 0.01) in neoadjuvant chemotherapy and DFS (HR = 0.53, 95% CI 0.37-0.69, p < 0.01) and OS (HR = 0.46, 95% CI 0.23-0.69, p < 0.01) in adjuvant chemotherapy compared with anthracycline- and/or paclitaxel-based chemotherapy in patients with TNBC. In addition, compared with anthracycline-based chemotherapy, platinum-based chemotherapy without anthracycline chemotherapy could further improve DFS (HR = 0.53, 95% CI 0.37-0.70, p < 0.01) and OS (HR = 0.46, 95%CI 0.19-0.72, p < 0.01) in patients with TNBC. Compared with anthracycline- and/or paclitaxel-based chemotherapy, all-grade diarrhea, fatigue, and grade ≥ 3 anemia were higher in platinum-based chemotherapy. In contrast, all-grade anemia, leukopenia, neutropenia, peripheral neuropathy, myalgia/arthralgia, cardiac toxicity were lower in platinum-based chemotherapy; grade ≥ 3 leukopenia, neutropenia and myalgia/arthralgia were also lower. Compared with anthracycline- and/or paclitaxel-based chemotherapy, platinum-based chemotherapy was more associated with improved DFS and OS in TNBC patients. The benefit of survival is consistent with platinum-based neoadjuvant and adjuvant chemotherapy. The side effects of platinum-based chemotherapy are tolerable.

Exploratory study of fathers providing Kangaroo Care in a Neonatal Intensive Care Unit.

AIM AND OBJECTIVES: To explore fathers' views and experiences of providing Kangaroo Care (KC) to their baby cared for in a Neonatal Intensive Care Unit (NICU). BACKGROUND: Kangaroo Care has been known to improve the health outcome for preterm, low birth weight and medically vulnerable term infants and achieve the optimal perinatal health wellbeing for parents and infants. Historically, mothers are considered as the dominant KC providers, whereas fathers are spectators and have been overlooked. Little is known about the fathers' perspectives in providing KC in NICUs. METHODS: Individual semi-structured interviews were conducted with 10 fathers who delivered KC to their baby when in the NICU. Data were analysed using Braun and Clarke's six-phase thematical framework. The Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist was followed to report this qualitative study. FINDINGS: Fathers in this study identified they were passing a silent language of love and connecting with their baby by the act of KC in a challenging environment. Three themes emerged: 'Positive psychological connection', 'Embracing father-infant Kangaroo Care' and 'Challenges to father-infant Kangaroo Care'. CONCLUSION: The findings of this study show KC enhances the bonding and attachment between fathers and infants. The conceptualisation of the paternal role in caregiving to a newborn is evolving as a contemporary practice. Further research is warranted to confirm or refute the study findings. Policies and facilities should be modified to include father-infant KC within the fields of neonatal care. RELEVANCE TO CLINICAL PRACTICE: It is important for nurses and other health professionals to support and enable fathers to give KC. Father-infant KC is recommended in neonatal care settings.

Expression and clinical prognostic value of CYB561 in breast cancer.

PURPOSE: The expression of cytochrome B561 (CYB561) and its role in breast cancer (BC) prognosis remain unclear. We analyzed the differential expression and prognostic value of CYB561 using online databases and a clinical cohort through bioinformatics and immunohistochemistry. METHODS: The differential expression of CYB561 and its association with BC were analyzed using the tumor immune estimation resource (TIMER), gene expression profiling interaction analysis2 (GEPIA2), Human Protein Atlas, Cancer Cell Line Encyclopedia, and Kaplan-Meier Plotter website. Important pathways of CYB561 enrichment were explored using gene set enrichment analysis. Immunohistochemistry detected CYB561 expression in normal breast, breast hyperplasia, ductal carcinoma in situ (DCIS), para-cancer, and invasive BC groups. Association between CYB561 expression and BC prognosis was analyzed using Kaplan-Meier and Cox regression analyses. RESULTS: CYB561 mRNA expression was higher in GEPIA and TIMER BC patients than in para-cancer tissues. CYB561 was expressed in the glandular epithelium and myoepithelium, with positive localization in the cytoplasm and cell membrane. CYB561 protein expression significantly differed among the groups. CYB561 expression was correlated with ERBB2/HER2 and infiltrating CD4+ T cells in GEPIA and TIMER BC patients and associated with HER2 status, histological grade, and molecular subtypes in the clinical cohort but not related to tumor-infiltrating lymphocytes. CYB561 mRNA overexpression predicted reduced recurrence-free survival and overall survival in BC. Patients with CYB561 expression had significantly reduced overall survival and increased risk of death. CONCLUSION: CYB561 can serve as an effective clinical prognostic biomarker for BC.

Identification of the GTPase IMAP family as an immune-related prognostic biomarker in the breast cancer tumor microenvironment.

INTRODUCTION: Breast cancer is the most common malignancy threatening women's health worldwide. The GTPase IMAP family genes are proteins belonging to the immune-associated nucleotide subfamily of the GTP-binding superfamily and nucleotide-binding proteins. However, little is known about the role of different GTPase IMAP family genes in breast cancer. METHODS: We obtained differential genes from the GEPIA and UALCAN databases and then used the Kaplan-Meier plotter, The Human Protein Atlas, NetworkAnalyst, STRING, and TIMER to analyze the prognostic value, protein expression, and immune cell infiltration of the GTPase IMAP family in patients with breast cancer. RESULTS: Among the GIMAP family genes, the expression levels of GIMAP1, GIMAP5, GIMAP6, GIMAP7, and GIMAP8 were significantly low in breast tumor tissues. In the overall population, patients with high expression of all genes of the GIMAP family had a significantly higher overall survival (OS), with the most significant increase correlated with the GIMAP2 gene (hazard ratio [HR] = 0.45, 95% confidence interval [CI], 0.34-0.59, P = 3.1e-09). However, patients with high expression of the GIMAP family genes in triple-negative breast cancer compared to those with low expression had a significant OS benefit, with the most pronounced benefit correlated with the GIMAP2 gene (HR = 0.37, 95% CI, 0.23-0.59, P = 1.4e-05). GIMAP7 and GIMAP8 were significantly upregulated in breast tumor tissues. The expression of genes in different GIMAP families was positively correlated with the infiltration and expression of six immune cell types (B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells). CONCLUSION: This study may provide novel insights into the selection of GIMAP family prognostic biomarkers for breast cancer.

Efficacy and Safety of Apatinib for Elderly Patients with Advanced or Metastatic Gastric Cancer After Failure of at Least First-Line Chemotherapy: A Multi-Center, Single-Arm, Phase II Study.

BACKGROUND: Apatinib improves progression-free survival and overall survival with an acceptable safety profile in Chinese patients with chemotherapy-refractory advanced or metastatic gastric cancer. However, the efficacy and safety of apatinib are unclear for elderly patients. This study was undertaken to prospectively investigate the efficacy and safety of apatinib for elderly patients with unresectable advanced or metastatic gastric cancer, who experienced progression to at least one lines of chemotherapy. METHODS: This open-label, single-arm, phase II study enrolled patients aged ≥60 years with advanced gastric cancer, who experienced progression to one or more lines of chemotherapy at five centers in China. Patients received apatinib in an oral dose of 500mg or 250mg daily according to the research physicians' decision. The primary end point was progression-free survival, and the secondary end points were objective response rate, disease control rate, overall survival, and safety. RESULTS: Forty-eight patients were enrolled between June 2017 and September 2019. The median age was 65.5 years (range 60-80 years). Twenty-seven patients (56.3%) started treatment with an initial dose of 500 mg and 21 patients (43.7%) with 250 mg. The median progression-free survival and overall survival were 3.00 months (95% confidence interval, 2.17-3.84) and 8.10 months (95% confidence interval, 4.35-11.85), respectively. The objective response rate and disease control rate assessed by the investigators were 16.7% and 72.9%, respectively. The common side effects were fatigue (58.3%), hypertension (47.9%), abdominal pain (33.3%), proteinuria (29.2%), leukopenia (22.9%), and neutropenia (20.8%). Hypertension (22.9%) was the major grade 3/4 toxicity. CONCLUSION: These data suggest that apatinib is effective and relatively tolerable for elderly patients with unresectable advanced or metastatic gastric cancer who have received at least first-line chemotherapy.

Rapid qualitative and quantitative analyses of anthocyanin composition in berries from the Tibetan Plateau with UPLC-quadruple-Orbitrap MS and their antioxidant activities.

Nitraria tangutorum B. (NT), Hippophae rhamnoides L. (HR), Lycium ruthenicum M. (LR), Lycii fructus (LF), Rosa xanthina L. (RX), and Rubuscor chorifolius L. f. (RC) are six berries from Tibetan Plateau. They have been used in traditional folk medicine with a long history, which are rich in anthocyanins. However, detailed study of their anthocyanins remains scarce. Therefore, a method for rapid simultaneous identification and quantification of 12 anthocyanins from berries using UPLC-Quadruple-Orbitrap MS system (UPLC-Q-Orbitrap MS) was established in this work. It was verified with limit of detection (3.86-11.61 µg/L), limit of quantification (3.86-11.61 µg/L), precision (0.95-2.38%), repeatability (0.96-2.08%), stability (0.86-2.31%), mean recovery (95.8-103.1%), recovery range (93.1-107.2%) and RSD less than 5.21%. It was then used in the analysis of anthocyanins in six berries species; 8, 7, 7, 7, 6 and 9 species of anthocyanins have been identified in NT, LF, LR, HR, RC and RX, respectively based on their own retention time and exact mass in positive mode, and for the first time quantified successfully in each berry (31.11 ± 0.42-2978 ± 25.67 µg.g-1). Finally, 2, 2-azinobis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical scavenging activity (0.92 ± 0.12-5.61 ± 0.23 mM TE/100 g), ferric reducing antioxidant power (FRAP) (1.23 ± 0.15-7.42 ± 0.28 mM TE/100 g) and total antioxidant activity (T-AOC) assays were used to evaluate the antioxidant activities of the six berries.

Discovery of SCY45, a Natural Small-Molecule MDM2-p53 Interaction Inhibitor.

The disruption of the MDM2-p53 interaction has been regarded as an attractive strategy for anticancer drug discovery. Here, the natural small-molecule SCY45 was identified as a potent MDM2-p53 interaction inhibitor based on fluorescence polarization and molecular modeling. SCY45 inhibited the MDM2-p53 interaction with an IC50 value of 4.93±0.08 µm. The structural modeling results showed that SCY45 not only had high structural similarity with nutlin-3a, a well-reported MDM2-P53 interaction inhibitor, but also bound to the p53 binding pocket of MDM2 with a binding mode similar to that of nutlin-3a. Moreover, SCY45 reduced the cell viability in cancer cells with MDM2 gene amplification. SCY45 showed the highest inhibition for SJSA-1 cells, which exhibit excessive MDM2 gene amplification, with an IC50 value of 7.54±0.29 µm, whereas SCY45 showed a weaker inhibition for 22Rv1 cells and A549 cells, which have a single copy of the MDM2 gene, with IC50 values of 18.47±0.75 µm and 31.62±1.96 µm, respectively.

Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development.

Anlotinib is a new, orally administered tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. Compared to the effect of placebo, it improved both progression-free survival (PFS) and overall survival (OS) in a phase III trial in patients with advanced non-small-cell lung cancer (NSCLC), despite progression of the cancer after two lines of prior treatments. Recently, the China Food and Drug Administration (CFDA) approved single agent anlotinib as a third-line treatment for patients with advanced NSCLC. Moreover, a randomized phase IIB trial demonstrated that anlotinib significantly prolonged the median PFS in patients with advanced soft tissue sarcoma (STS). Anlotinib also showed promising efficacy in patients with advanced medullary thyroid carcinoma and metastatic renal cell carcinoma (mRCC). The tolerability profile of anlotinib is similar to that of other tyrosine kinase inhibitors that target VEGFR and other tyrosine kinase-mediated pathways; however, anlotinib has a significantly lower incidence of grade 3 or higher side effects compared to that of sunitinib. We review the rationale, clinical evidence, and future perspectives of anlotinib for the treatment of multiple cancers.