The effect of BMI on survival outcome of breast cancer patients: a systematic review and meta-analysis.

OBJECTIVE: The main goal of the present research is to explore the potential link of body mass index (BMI) with different survival metrics in breast cancer patients. Our aim is to offer the latest and most thorough meta-analysis, assessing the strength and reliability of the connection that BMI has with prognostic indicators in this disease. PATIENTS AND METHODS: As of January 2024, we conducted a systematic literature search across PubMed, Embase, Web of Science, and the Cochrane Library databases. Our search aimed to identify studies examining BMI as an exposure factor, with breast cancer patients constituting the study population, and utilizing adjusted hazard ratio (HR) as the data type of interest. RESULTS: The evidence synthesis incorporated a total of 61 eligible articles involving 201,006 patients. Being underweight posed a risk factor for overall survival (OS) in breast cancer patients compared to normal weight (HR 1.15, 95% CI 0.98-1.35; P = 0.08). Overweight or obesity, in comparison to normal weight, was a risk factor for OS (HR 1.18, 95% CI 1.14-1.23; P < 0.00001), disease-free survival (DFS) (HR 1.11, 95% CI 1.08-1.13; P < 0.00001), relapse-free survival (RFS) (HR 1.14, 95% CI 1.06-1.22; P = 0.03), and breast cancer-specific survival (BCSS) (HR 1.18, 95% CI 1.11-1.26; P < 0.00001), but not for progression-free survival (PFS) (HR 0.91, 95% CI 0.76-1.10; P = 0.33). Notably, in subgroup analyses, overweight patients achieved prolonged PFS (HR 0.80, 95% CI 0.64-0.99; P = 0.04), and compared to the obese population, the overweight cohort exhibited a significant difference in OS (HR 1.11, 95% CI 1.05-1.16; P < 0.00001) and DFS (HR 1.06, 95% CI 1.03-1.10; P = 0.0004), with a considerably stronger association. Furthermore, compared to HER- patients, HER + patients exhibited a greater predictive value for OS (HR 1.23, 95% CI 1.10-1.37; P = 0.0004), RFS (HR 1.30, 95% CI 1.03-1.64; P < 0.00001), and DFS (HR 1.10, 95% CI 1.03-1.17; P = 0.003). CONCLUSIONS: The results of our meta-analysis reveal a notable association between BMI and various survival measures in breast cancer prognosis. These findings provide a solid basis for predicting breast cancer outcomes and implementing more effective therapeutic approaches.

Multiomics analysis of homologous recombination deficiency across cancer types.

There remains ongoing debate regarding the association of homologous recombination deficiency (HRD) with patient survival across various malignancies, highlighting the need for a comprehensive understanding of HRD's role in different cancer types. Based on data from databases, we conducted a multivariable omics analysis on HRD in 33 cancer types, focusing mainly on 23 cancers in which HRD was significantly associated with patient overall survival (OS) rates. This analysis included the mechanisms related to patient prognosis, gene expression, gene mutation, and signaling pathways. In this study, HRD was found to be significantly associated with patient prognosis, but its impact varied among different cancers. HRD was linked to different outcomes for patients with distinct tumor subtypes and was correlated with clinical features such as clinical stage and tumor grade. Driver gene mutations, including TP53, MUC4, KRAS, HRAS, FLG, ANK3, BRCA2, ATRX, FGFR3, NFE2L2, MAP3K1, PIK3CA, CIC, FUBP1, ALB, CTNNB1, and MED12, were associated with HRD across specific cancer types. We also analyzed differentially expressed genes (DEGs) and differentially methylated regions (DMRs) in relation to HRD levels in these cancers. Furthermore, we explored the correlation between HRD and signaling pathways, as well as immune cell infiltration. Overall, our findings contribute to a comprehensive understanding of HRD's multifaceted role in cancer.

CTHRC1 is associated with BRAF(V600E) mutation and correlates with prognosis, immune cell infiltration, and drug resistance in colon cancer, thyroid cancer, and melanoma.

Colon cancer, thyroid cancer, and melanoma are common malignant tumors that seriously threaten human health globally. The B-Raf proto-oncogene, serine/threonine kinase (BRAF)(V600E) mutation is an important driver gene mutation in these cancer types. In this study, we identified that collagen triple helix repeat containing 1 (CTHRC1) expression was associated with the BRAF(V600E) mutation in colon cancer, thyroid cancer, and melanoma. Based on database analysis and clinical tissue studies, CTHRC1 was verified to correlate with poor prognosis and worse clinicopathological features in colon cancer and thyroid cancer patients, but not in patients with melanoma. Several signaling pathways, immune cell infiltration, and immunotherapy markers were associated with CTHRC1 expression. Additionally, a high level of CTHRC1 was correlated with decreased sensitivity to antitumor drugs (vemurafenib, PLX-4720, dabrafenib, and SB-590885) targeting the BRAF(V600E) mutation. This study provides evidence of a significant correlation between CTHRC1 and the BRAF(V600E) mutation, suggesting its potential utility as a diagnostic and prognostic biomarker in human colon cancer, thyroid cancer, and melanoma.

PAK2 promotes proliferation, migration, and invasion of lung squamous cell carcinoma through LIMK1/cofilin signaling pathway.

Although the p21-activated kinase 2 (PAK2) is an essential serine/threonine protein kinase, its role in lung squamous cell carcinoma (LUSC) progression has yet to be fully understood. We analyzed PAK2 mRNA levels and DNA copy numbers as well as protein levels by quantitative real-time PCR and immunohistochemical staining, respectively, in human LUSC tissues and adjacent normal tissues. Then, we used colony formation assays, cell counting kit-8 assays, matrigel invasion assays, wound healing assays and xenograft models in nude mice to investigate the functions of PAK2 in LUSC progression. We demonstrated that the mRNA levels, DNA copy numbers, and protein levels of PAK2 were up-regulated in human LUSC tissues than in adjacent normal tissues. In addition, a higher PAK2 expression was correlated with a poorer prognosis in LUSC patients. In the in vitro study, we found that PAK2 promoted cell growth, migration, invasion, EMT process, and cell morphology regulation in LUSC cells. Furthermore, PAK2 enhanced tumor cell proliferation, migration, and invasion by regulating actin dynamics through the LIMK1/cofilin signaling. Our findings implicated that the PAK2/LIMK1/cofilin signaling pathway is likely a potential clinical marker and therapeutic target for LUSC.

Multiwalled Carbon Nanotubes-Reprogrammed Macrophages Facilitate Breast Cancer Metastasis via NBR2/TBX1 Axis.

In recent years, carbon nanotubes have emerged as a widely used nanomaterial, but their human exposure has become a significant concern. In our former study, we reported that pulmonary exposure of multiwalled carbon nanotubes (MWCNTs) promoted tumor metastasis of breast cancer; macrophages were key effectors of MWCNTs and contributed to the metastasis-promoting procedure in breast cancer, but the underlying molecular mechanisms remain to be explored. As a follow-up study, we herein demonstrated that MWCNT exposure in breast cancer cells and macrophage coculture systems promoted metastasis of breast cancer cells both in vitro and in vivo; macrophages were skewed into M2 polarization by MWCNT exposure. LncRNA NBR2 was screened out to be significantly decreased in MWCNTs-stimulated macrophages through RNA-seq; depletion of NBR2 led to the acquisition of M2 phenotypes in macrophages by activating multiple M2-related pathways. Specifically, NBR2 was found to positively regulate the downstream gene TBX1 through H3k27ac activation. TBX1 silence rescued NBR2-induced impairment of M2 polarization in IL-4 & IL-13-stimulated macrophages. Moreover, NBR2 overexpression mitigated the enhancing effects of MWCNT-exposed macrophages on breast cancer metastasis. This study uncovered the molecular mechanisms underlying breast cancer metastasis induced by MWCNT exposure.

The prevalence and risk factors of rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis.

BACKGROUND: Interstitial lung disease (ILD) is the most widespread and fatal pulmonary complication of rheumatoid arthritis (RA). Existing knowledge on the prevalence and risk factors of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is inconclusive. Therefore, we designed this review to address this gap. MATERIALS AND METHODS: To find relevant observational studies discussing the prevalence and/or risk factors of RA-ILD, EMBASE, Web of Science, PubMed, and the Cochrane Library were explored. The pooled odds ratios (ORs) / hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated with a fixed/ random effects model. While subgroup analysis, meta-regression analysis and sensitivity analysis were carried out to determine the sources of heterogeneity, the I2 statistic was utilized to assess between-studies heterogeneity. Funnel plots and Egger's test were employed to assess publication bias. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, our review was conducted. RESULTS: A total of 56 studies with 11,851 RA-ILD patients were included in this meta-analysis. The pooled prevalence of RA-ILD was 18.7% (95% CI 15.8-21.6) with significant heterogeneity (I2 = 96.4%). The prevalence of RA-ILD was found to be more likely as a result of several identified factors, including male sex (ORs = 1.92 95% CI 1.70-2.16), older age (WMDs = 6.89, 95% CI 3.10-10.67), having a smoking history (ORs =1.91, 95% CI 1.48-2.47), pulmonary comorbidities predicted (HRs = 2.08, 95% CI 1.89-2.30), longer RA duration (ORs = 1.03, 95% CI 1.01-1.05), older age of RA onset (WMDs =4.46, 95% CI 0.63-8.29), positive RF (HRs = 1.15, 95%CI 0.75-1.77; ORs = 2.11, 95%CI 1.65-2.68), positive ACPA (ORs = 2.11, 95%CI 1.65-2.68), higher ESR (ORs = 1.008, 95%CI 1.002-1.014), moderate and high DAS28 (≥3.2) (ORs = 1.87, 95%CI 1.36-2.58), rheumatoid nodules (ORs = 1.87, 95% CI 1.18-2.98), LEF use (ORs = 1.42, 95%CI 1.08-1.87) and steroid use (HRs= 1.70, 1.13-2.55). The use of biological agents was a protective factor (HRs = 0.77, 95% CI 0.69-0.87). CONCLUSION(S): The pooled prevalence of RA-ILD in our study was approximately 18.7%. Furthermore, we identified 13 risk factors for RA-ILD, including male sex, older age, having a smoking history, pulmonary comorbidities, older age of RA onset, longer RA duration, positive RF, positive ACPA, higher ESR, moderate and high DAS28 (≥3.2), rheumatoid nodules, LEF use and steroid use. Additionally, biological agents use was a protective factor.

Ropivacaine as a novel AKT1 specific inhibitor regulates the stemness of breast cancer.

BACKGROUND: Ropivacaine, a local anesthetic, exhibits anti-tumor effects in various cancer types. However, its specific functions and the molecular mechanisms involved in breast cancer cell stemness remain elusive. METHODS: The effects of ropivacaine on breast cancer stemness were investigated by in vitro and in vivo assays (i.e., FACs, MTT assay, mammosphere formation assay, transwell assays, western blot, and xenograft model). RNA-seq, bioinformatics analysis, Western blot, Luciferase reporter assay, and CHIP assay were used to explore the mechanistic roles of ropivacaine subsequently. RESULTS: Our study showed that ropivacaine remarkably suppressed stem cells-like properties of breast cancer cells both in vitro and in vivo. RNA-seq analysis identified GGT1 as the downstream target gene responding to ropivacaine. High GGT1 levels are positively associated with a poor prognosis in breast cancer. Ropivacaine inhibited GGT1 expression by interacting with the catalytic domain of AKT1 directly to impair its kinase activity with resultant inactivation of NF-κB. Interestingly, NF-κB can bind to the promoter region of GGT1. KEGG and GSEA analysis indicated silence of GGT1 inhibited activation of NF-κB signaling pathway. Depletion of GGT1 diminished stem phenotypes of breast cancer cells, indicating the formation of NF-κB /AKT1/GGT1/NF-κB positive feedback loop in the regulation of ropivacaine-repressed stemness in breast cancer cells. CONCLUSION: Our finding revealed that local anesthetic ropivacaine attenuated breast cancer stemness through AKT1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast cancer treatment.

First detection of cutavirus DNA in stools of patients with rheumatic diseases in Guangzhou, China.

Cutavirus (CuV) is a novel protoparvovirus possibly associated with diarrhea and cutaneous T-cell lymphomas. Patients with rheumatic disease are immunosuppressed and may be more vulnerable to pathogenic viruses. A descriptive study was conducted among hospitalized patients with rheumatic diseases and individuals undergoing medical health check-ups between June 2019 and June 2022 in Guangzhou, China. Stool samples of subjects were tested for CuV DNA. Demographic and fecal examination data of patients were obtained from electronic medical records. A total of 505 patients with rheumatic diseases and 244 individuals who underwent medical health check-ups were included in the study. Of the patients with rheumatic disease, 5.74% [95% confidence interval (CI): 4.03%-8.12%] were positive for CuV DNA, while no individual in the medical health check-up group was positive, indicating a close correlation between CuV and rheumatic disease. Men and patients with rheumatoid arthritis or ankylosing spondylitis, according to the disease classification, were more susceptible to being infected with CuV (P â€‹< â€‹0.01). After adjustments, being male remained the only significant factor, with an adjusted odd ratio (OR) of 4.4 (95% CI: 1.7-11.4, P â€‹= â€‹0.002). Phylogenetic analysis of the CuV VP2 sequences showed three diverse clades, one of which was segregated to be a single branching independent of previously known sequences, which is possible a new genotype.

Bibliometric analysis of IgG4-related disease research from 2003 to 2022 based on Web of Science Core Collection Databases.

This study aimed to perform a bibliometric analysis of the IgG4-related disease (IgG4-RD) research field over the past 20 years to explore its research hotspots and trends. The literature of IgG4-RD published in the Web of Science Core Collection databases was reviewed from January 1, 2003, to April 30, 2022. A bibliometric analysis was carried out using CiteSpace software to evaluate and visualize the evolving dynamics and hotspots in the field of IgG4-RD. A total of 3174 IgG4-RD articles were reviewed. Since 2011, there has been a rapid increase in published literature. Japan is the highest yielding country and Kanazawa University the highest yielding institution. The USA has the highest centrality (0.34) and plays a critical role in cooperation and communication of IgG4-RD research. Nine highly connected clusters of IgG4-RD were observed by keyword analysis. Research hotspots included IgG4-RD involved organs and differentiation from Rosai-Dorfman disease and primary sclerosing cholangitis. Further research topics include pathogenesis, relapse, and malignancy. As a cross-discipline systemic disease, IgG4-RD requires attention by clinicians in multiple fields. This bibliometric analysis can help researchers grasp trends and provide new perspectives for future research on IgG4-RD.

Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia: An Overview of Systematic Reviews.

Background: Hematopoietic stem cell transplantation (HSCT) has become the main treatment for acute myeloid leukemia (AML) and has been studied in many systematic reviews (SRs), but strong conclusions have not been drawn yet. Objective: This study aimed to summarize and critically evaluate the methodological and evidence quality of SRs and meta-analysis on this topic. Methods: PubMed, Embase, the Cochrane Library, and Web of Science were searched for SRs/meta-analyses regarding HSCT for AML. Two reviewers assessed the quality of SRs/meta-analyses in line with AMSTAR-2 and evaluated the strength of evidence quality with the grading of the evaluation system (GRADE) for concerned outcomes independently. Results: 12 SR/Meta articles were included, and the AMSTAR-2 scale showed that the quality grade of all articles was low or very low. GRADE results showed 29 outcomes, 2 of which were high, 12 were moderate, and 15 were low. Limitations and inconsistency were the most important factors leading to degradation, followed by imprecision and publication bias. Allo-SCT had better OS and DFS benefits than auto-SCT and significantly reduced the relapse in intermediate-risk AML/CR1 patients. Auto-SCT was associated with lower TRM than allo-SCT but generally had higher relapse. The results should be confirmed further for the low or moderate evidence quality. Conclusion: Current SRs show that allo-SCT in the treatment of AML might improve the OS, RFS, and DFS. Auto-SCT has significantly lower TRM but higher RR. Whether bone marrow transplantation is superior to nonmyeloablative chemotherapy remains to be evaluated. Meanwhile, the quality of methodology needs to be further improved. The intensity of evidence was uneven, and the high-quality evidence of outcomes was lacking. Considering the limitations of our overview, more rigorous and scientific studies are needed to fully explore the efficacy of different interventions of HSCT in AML, and clinicians should be more cautious in the treatment.

Differentiation of Yin, Yang and Stasis Syndromes in Severe Aplastic Anemia Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation and Their Correlation with Iron Metabolism, cAMP/cGMP, 17-OH-CS and Thyroxine.

OBJECTIVE: To better understanding and differentiation of traditional Chinese medicine (TCM) syndromes in severe aplastic anemia (SAA) patients undergoing hematopoietic stem cell transplantation (Allo-HSCT) and their correlation with iron metabolism, cAMP/cGMP, 17-OH-CS and thyroxine. METHODS: Eighteen patients with SAA who underwent HSCT were enrolled. The syndrome was evaluated before conditioning and days after stem cell reinfusion (-10d, -1d, +7d, +30d, +60d, and +90d). The correlation of TCM syndrome (Yin, Yang, and stasis) to cyclic nucleotides, 17-OH-CS, thyroxine, and iron metabolism were analyzed and compared to data from normal subjects. RESULTS: More "Yin deficiency" (n=11, 11/18) syndrome was observed before HSCT, and nearly 61% was complicated with "blood stasis". After conditioning, the proportion of "kidney Yin and Yang deficiency" increased to 61.6%. Fourteen days after HSCT, the syndrome developed into "Spleen-Kidney Yang Deficiency," and the stasis score decreased. On +90day, majority patients were diagnosed with "Kidney Yang Deficiency" (35.7%) or "Spleen-Kidney Yang Deficiency" (28.6%), and 88.9% were diagnosed without stasis. The correlation analysis showed that cGMP might represent "Deficient Yang" as well as low total triiodothyronine (T3) and free T3 (FT3). There was also a positive relation between labile plasma iron (LPI), hepcidin, soluble transferrin receptor (sTfR), and "Yin deficiency", and the last two factors, along with marrow nitric oxide synthase were also positively related to "Stasis" syndrome. CONCLUSION: During HSCT, the syndrome evolved from "kidney Yin and Yang deficiency" to "kidney Yang deficiency" or "spleen-kidney Yang deficiency", and the "stasis" along with "Yin deficiency" syndromes were quickly relieved within 90 days. The changes of cyclic nucleotides, 17-OH-CS, thyroxine, and iron metabolism indexes can be applied for better differentiation of TCM syndrome.

Epidemiology and genetic characteristics of murine kobuvirus from faecal samples of Rattus losea, Rattus tanezumi and Rattus norvegicus in southern China.

Recently, murine kobuvirus (MuKV), a novel member of the family Picornaviridae, was identified in faecal samples of Rattus norvegicus in China. The limited information on the circulation of MuKV in other murine rodent species prompted us to investigate its prevalence and conduct a genetic characterization of MuKV in Rattus losea, Rattus tanezumi and Rattus norvegicus in China. Between 2015 and 2017, 243 faecal samples of these three murine rodent species from three regions in southern China were screened for the presence of MuKV. The overall prevalence was 23.0% (56/243). Three complete MuKV polyprotein sequences were acquired, and the genome organization was determined. Phylogenetic analyses suggested that our sequences were closely related to Chinese strains and belong to the species Aichivirus A in the genus Kobuvirus. Additional studies are required to understand the true prevalence of MuKV in murine rodent populations in China.

Influencing Factors and Prognostic Value of 18F-FDG PET/CT Metabolic and Volumetric Parameters in Non-Small Cell Lung Cancer.

OBJECTIVE: This study aims to explore factors influencing metabolic and volumetric parameters of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging in non-small cell lung cancer (NSCLC) and the predictive value for prognosis of NSCLC. METHODS: Retrospective analysis was performed on 133 NSCLC patients who received 18F-FDG PET/CT imaging. After 18F-FDG injection at 3.7 MBq/kg, 1 h early imaging and 2 h delayed imaging were performed. The metabolic and volumetric parameters such as SUVmax, SUVpeak, SULmax, SULpeak, MTV and TLG were measured. The tumor markers including CFYRA21-1, NSE, SCC-ag and the immunohistochemical biomarkers including Ki-67, P53 and CK-7 were examined. All patients were followed up for 24 months, and the 1-year and 2-year overall survival rate (OS) were recorded. RESULTS: There were significant differences in metabolic and volumetric parameters (SUVmax, SUVpeak, SULmax, SULpeak and TLG) between adenocarcinoma and squamous cell carcinoma of NSCLC. SUVmax, SUVpeak, SULmax, SULpeak, MTV and TLG were correlated with tumor marker NSE and TNM stage. MTV and TLG were related to CYFRA21-1, and only MTV was associated with SCC-ag. SUVpeak and SULmax were related to P53. In addition, early SULpeak and delayed MTV were significant prognostic factors of 1-year OS, while early SUVpeak, delayed TLG and delayed MTV were predictive factors of 2-year OS in NSCLC. CONCLUSION: The metabolic and volumetric parameters of 18F-FDG PET/CT were related to a variety of factors such as NSE, CFYRA21-1, SCC-ag, P53 and TNM stage, and have a predictive value in prognosis of NSCLC.

Prevalence and contributory factors of anxiety and depression among pregnant women in the post-pandemic era of COVID-19 in Shenzhen, China.

BACKGROUND: Pregnant women are emotionally vulnerable and have suffered great psychological impacts. Following the coronavirus disease 2019 (COVID-19) outbreak, a study was undertaken of the prevalence of, and factors contributing to, symptoms of anxiety and depression among pregnant women in Shenzhen, China. METHODS: A cross-sectional study on pregnant women was conducted from September to December 2020 in Shenzhen, using a random-recruit method. The General Anxiety Disorder (GAD-7) and Patient Health Questionnaire (PHQ-9) surveys were used to evaluate symptoms of anxiety and depression. A multivariate logistic regression model was developed to explore factors potentially associated with symptoms of anxiety and depression during pregnancy. RESULTS: A total of 3,434 pregnant women aged 15 to 59 years were enrolled. Symptoms of anxiety and depression were present in 9.8% and 6.9%, respectively. Logistic regression analysis using a stepwise procedure revealed that an increased risk of symptoms of anxiety and depression was associated with unmarried/divorced/widowed, unemployed, received professional psychological counseling, family dysfunction, the first trimester of pregnancy, pregnancy complications and vaginal bleeding, unplanned pregnancy, decline in household income and disputes between partners caused by the COVID-19 pandemic, consumption of alcoholic drinks by women and their partners, smoking, lack of exercise and sedentary lifestyle. Women with education from junior high school through college were less likely to experience symptoms of prenatal depression. CONCLUSIONS: Our study revealed factors associated with psychological symptoms among pregnant women in the post-COVID-19-pandemic era. These results should help to update guidance for psychological interventions for pregnant women during the period of COVID-19.

The efficacy and safety of combined ipilimumab and nivolumab versus ipilimumab in patients with Stage III/IV unresectable melanoma: A systematic review and meta-analysis.

Background: In this meta-analysis, we compared the clinical efficacy and safety of ipilimumab/nivolumab combination therapy with those of ipilimumab monotherapy for stage III/IV unresectable melanoma. Materials and Methods: A search for randomized controlled trials (RCTs) reported by relevant studies conducted up to May 2021 was performed in the PubMed, Cochrane Library, Embase, CNKI, Wanfang, and VIP databases. Literature screening, data extraction, and quality evaluation were conducted independently by two researchers. The target parameters were complete response (CR), partial response (PR), objective response rate (ORR), time to progression (TTP), overall survival (OS), adverse events (AEs), and AEs in each organ system. Results: Ten articles reporting the results of three RCTs, including 790 subjects, were evaluated. In the pooled results, the CR (risk ratio [RR] = 4.48, 95% confidence interval [CI] [2.73, 7.33]), PR (RR = 2.82, 95% CI [2.09, 3.81]), and ORR (RR=3.31, 95%CI[2.60, 4.20]) were statistically different between the two treatment groups. The CR, PR, and ORR in the combination therapy group were 22.00% (90/409), 36.43% (149/409), and 58.44% (239/409), respectively, versus 4.97% (18/362), 12.98% (47/362), and 17.96% (65/362), respectively, in the monotherapy group. There were significant differences in TTP and OS between the two groups (TTP: hazard ratio [HR] = 0.41, 95% CI [0.35, 0.49]; OS: HR = 0.55, 95% CI [0.45, 0.67]). PFS and OS were longer in the combination therapy group than in the monotherapy group. The incidence of treatment-related AEs (TRAEs) and AEs leading to death (RR = 1.00, 95% CI [0.97, 1.02]; RR = 2.28, 95% CI [0.54, 9.55], respectively) was not significantly different, but the incidence of Grade 3-4 AEs and AEs leading to discontinuation was higher in the combination therapy group than in the monotherapy group (RR = 1.81, 95% CI [1.15, 2.86]); RR = 2.66, 95% CI [2.02, 3.52], respectively). Conclusions: Ipilimumab/nivolumab combination therapy was more effective than ipilimumab monotherapy for patients with stage III/IV unresectable melanoma. Although the incidence of TRAEs did not differ between the two groups, the severity of cases (Grade 3-4 AEs and AEs leading to discontinuation) was lower in the monotherapy group than in the combination therapy group. Additional high-quality studies are needed to verify the efficacy and safety of this drug combination, determine the optimal dosage, and explore additional potential drug combinations.

Preliminary safety assessment of oridonin in zebrafish.

Context: Oridonin, isolated from the leaves of Isodon rubescens (Hemsl.) H.Hara (Lamiaceae), has good antitumor activity. However, its safety in vivo is still unclear. Objective: To investigate the preliminary safety of oridonin in zebrafish. Materials and methods: Embryo, larvae and adult zebrafish (n = 40) were used. Low, medium and high oridonin concentrations (100, 200 and 400 mg/L for embryo; 150, 300 and 600 mg/L for larvae; 200, 400 and 800 mg/L for adult zebrafish) and blank samples were administered. At specific stages of zebrafish development, spontaneous movement, heartbeat, hatching rate, etc., were recorded to assess the developmental effects of oridonin. VEGFA, VEGFR2 and VEGFR3 gene expression were also examined. Results: Low-dose oridonin increased spontaneous movement and hatching rate with median effective doses (ED50) of 115.17 mg/L at 24 h post-fertilization (hpf) and 188.59 mg/L at 54 hpf, but these values decreased at high doses with half maximal inhibitory concentrations (IC50) of 209.11 and 607.84 mg/L. Oridonin decreased heartbeat with IC50 of 285.76 mg/L at 48 hpf, and induced malformation at 120 hpf with half maximal effective concentration (EC50) of 411.94 mg/L. Oridonin also decreased body length with IC50 of 324.78 mg/L at 144 hpf, and increased swimming speed with ED50 of 190.98 mg/L at 120 hpf. The effects of oridonin on zebrafish embryo development may be attributed to the downregulation of VEGFR3 gene expression. Discussions and conclusions: Oridonin showed adverse effects at early stages of zebrafish development. We will perform additional studies on mechanism of oridonin based on VEGFR3.

The Application of Nanotechnology in the Codelivery of Active Constituents of Plants and Chemotherapeutics for Overcoming Physiological Barriers during Antitumor Treatment.

Antitumor therapy using a combination of drugs has shown increased clinical efficacy. Active constituents derived from plants can offer several advantages, such as high efficiacy, low toxicity, extensive effects, and multiple targets. At present, the combination of plants' active constituents and chemotherapeutic drugs has attracted increased attention. Nanodrug delivery systems (NDDSs) have been widely used in tumor-targeted therapy because of their efficacy of delivering antitumor drugs. The in vivo process of tumor-targeted NDDSs has several steps. They include blood circulation, tumor accumulation and penetration, target cell internalization and uptake, and drug release and drug response. In each step, NDDSs encounter multiple barriers that prevent their effective delivery to target sites. Studies have been performed to find alternative strategies to overcome these barriers. We reviewed the recent progress of codelivery of active constituents of plants and chemotherapeutics using NDDSs. Progress into transversing the physiological barriers for more effective in vivo antitumor delivery will be discussed in this review.

The Impact of Residual Neuromuscular Blockade, Oversedation, and Hypothermia on Adverse Respiratory Events in a Postanesthetic Care Unit: A Prospective Study of Prevalence, Predictors, and Outcomes.

BACKGROUND: Residual neuromuscular blockade (RNMB) has been linked to adverse respiratory events (AREs) in the postanesthetic care unit (PACU). However, these events are often not attributed to RNMB by anesthesiologists because they may also be precipitated by other factors including obstructive sleep apnea, opioids, or hypnotic agents. Many anesthesiologists believe RNMB occurs infrequently and is rarely associated with adverse outcomes. This study evaluated the prevalence and predictors of RNMB and AREs. METHODS: This prospective cohort study included 599 adult patients undergoing general anesthesia who received neuromuscular blocking agents. Baseline demographic, surgical, and anesthetic variables were collected. RNMB was defined as a train-of-four ratio below 0.90 measured by electromyography on admission to the PACU. AREs were defined based on the modified Murphy's criteria. RESULTS: RNMB was present in 186 patients (31% [95% confidence interval (CI), 27%-35%]) on admission to the PACU. One or more AREs were experienced by 97 patients (16% [95% CI 13-19]). AREs were more frequent in patients with RNMB (21% vs 14%, P = .033). RNMB was significantly associated with age (adjusted relative risk [RR], 1.17 [95% CI, 1.06-1.29] per 10-year increase), type of operation (adjusted RR, 0.59 [95% CI, 0.34-0.99] for laparoscopic surgery compared with open abdominal surgery), and duration of operation (adjusted RR, 0.59 [95% CI, 0.39-0.86] for ≥90 minutes compared with <90 minutes). Using multivariate logistic regression, AREs were found to be independently associated with decreased level of consciousness (adjusted RR, 4.76 [95% CI, 1.49-6.76] for unrousable/unconscious compared with alert/awake) and lower core temperature (adjusted RR, 1.43 [95% CI, 1.04-1.92] per 1°C decrease). Although univariate analysis found a significant association between AREs and RNMB, the significance became borderline after adjusting for other covariates (adjusted RR, 1.46 [95% CI, 0.99-2.08]). CONCLUSIONS: The prevalence of RNMB in the PACU was >30%. Older age, open abdominal surgery, and duration of operation <90 minutes were associated with increased risk of RNMB in our patients. Our RR estimate for AREs was highest for depressed level of consciousness. When AREs occur in the PACU, potentially preventable causes including RNMB, hypothermia, and reduced level of consciousness should be readily identified and treated appropriately. Delaying extubation until the patient is awake and responsive may reduce AREs.

Combined effects of cadmium and fluoranthene on germination, growth and photosynthesis of soybean seedlings.

The single and combinational effects of cadmium (Cd) and fluoranthene (FLT) on germination, growth and photosynthesis of soybean seedlings were investigated. Exposure to 5, 10, or 15 mg Cd/L or 1, 5, or 10 mg FLT/L individually or in combination significantly decreased germination vigor (3 days) and final germination rate of soybean seeds, except at 1 and 5 mg FLT/L. The results of two-way ANOVA analysis and the Bliss independence model showed that at lower concentrations of FLT (1 mg/L), the interaction between Cd and FLT on germination was antagonistic, whereas the interaction was synergistic when the concentration of FLT was 5 or 10 mg/L and the concentration of Cd was 15 mg/L. Growth, expressed as dry weight, length of shoot and root, leaf area, and photosynthesis, expressed as net photosynthetic rate, intercellular CO2 concentration, chlorophyll contents and fluorescence of soybean seedlings were also reduced by exposure to 5 or 10 mg Cd/L or 1 or 5 mg FLT/L, singly or jointly. Significant antagonistic effects of exposure to 5 or 10 mg Cd/L or 1 or 5 mg FLT/L on shoot growth and photosynthesis were observed, whereas synergy and antagonism of Cd and FLT were both observed for root growth.

[Effects of cycloartocarpin A and artocarpin extracted from Fructus Artocarpin Heterophylli on apoptosis of SMMC-7721 and SGC-7901 cells].

OBJECTIVE: To investigate the effects of cycloartocarpin A (ACR-2) and artocarpin (ACR-3), monomeric compounds isolated from Fructus Artocarpi Heterophylli, on apoptosis of SMMC-7721 and SGC-7901 cell lines. METHODS: SMMC-7721 and SGC-7901 cells were routinely cultured, and divided into experiment group and control group. The SMMC-7721 cells were treated with different concentrations of ACR-2 (3.46 x 10(-3), 13.82 x (-3), 55.30 x 10(-3) mmol/L) and ACR-3 (6.88 x 10(-3), 27.52 x 10(-3), 110.09 x 10(-3) mmol/L), and the SGC-7901 cells were also treated with different concentrations of ACR-2 (8.06 x 10(-3), 32.26 x 10(-3), 129.03 x 10(-3) mmol/L) and ACR-3 (2.87 x 10(-3), 11.47 x 10(-3), 45.87 x 10(-3) mmol/L), with PBS (DMSO<0.1%) as control treatment. Cell apoptosis was measured by double labeled staining with Hoechst33342/propidium iodide (PI) and TdT-mediated dUTP-biotin nick end labeling (TUNEL) and flow cytometry. RESULTS: ACR-2 and ACR-3 could induce apoptosis of SMMC-7721 and SGC-7901 cells. Some of SMMC-7721 and SGC-7901 cells demonstrated typical apoptosis after being treated with ACR-2 and ACR-3. Hoechst33342/PI staining showed that cells were fraught with overlapping nuclei and nuclear debris or lobule, and the nuclear appeared light blue. TUNEL showed that cells permeated with overlapping nuclei and nuclear debris or lobule, and the nuclear appeared brown. Less apoptotic cells were observed in negative control group, and the nuclear appeared light blue. The apoptosis rates of SMMC-7721 and SGC-7901 cells in the ACR-2 and ACR-3 treated groups were significant higher than those in the control group (P<0.05, P<0.01). CONCLUSION: ACR-2 and ACR-3 can induce apoptosis of SMMC-7721 and SGC-7901 cells.