Ras inhibitor farnesylthiosalicylic acid conjugated with IR783 dye exhibits improved tumor-targeting and altered anti-breast cancer mechanisms in mice.

Ras has long been viewed as a promising target for cancer therapy. Farnesylthiosalicylic acid (FTS), as the only Ras inhibitor has ever entered phase II clinical trials, has yielded disappointing results due to its strong hydrophobicity, poor tumor-targeting capacity, and low therapeutic efficiency. Thus, enhancing hydrophilicity and tumor-targeting capacity of FTS for improving its therapeutic efficacy is of great significance. In this study we conjugated FTS with a cancer-targeting small molecule dye IR783 and characterized the anticancer properties of the conjugate FTS-IR783. We showed that IR783 conjugation greatly improved the hydrophilicity, tumor-targeting and therapeutic potential of FTS. After a single oral administration in Balb/c mice, the relative bioavailability of FTS-IR783 was increased by 90.7% compared with FTS. We demonstrated that organic anion transporting polypeptide (OATP) and endocytosis synergistically drove the uptake of the FTS-IR783 conjugate in breast cancer MDA-MB-231 cells, resulting in superior tumor-targeting ability of the conjugate both in vitro and in vivo. We further revealed that FTS-IR783 conjugate could bind with and directly activate AMPK rather than affecting Ras, and subsequently regulate the TSC2/mTOR signaling pathway, thus achieving 2-10-fold increased anti-cancer therapeutic efficacy against 6 human breast cancer cell lines compared to FTS both in vivo and in vitro. Overall, our data highlights a promising approach for the modification of the anti-tumor drug FTS using IR783 and makes it possible to return FTS back to the clinic with a better efficacy.

Sevoflurane promotes migration, invasion, and colony-forming ability of human glioblastoma cells possibly via increasing the expression of cell surface protein 44.

Surgical resection of primary solid tumor under anesthesia remains a common practice. It has been concerned whether general anesthetics, especially volatile anesthetics, may promote the growth, migration, and invasion of cancer cells. In this study, we examined the effects of sevoflurane on human glioblastoma cells and determined the role of cluster of differentiation (CD) 44, a cell surface protein involved in cell growth, migration, and invasion, in sevoflurane's effects. We showed that exposure to 1%-4% sevoflurane did not change the cell proliferation, but concentration-dependently increased the invasion of human glioblastoma U251 cells. Furthermore, 4% sevoflurane significantly increased the migration and colony-forming ability of U251 cells. Similar results were observed in human glioblastoma A172 cells. Exposure to sevoflurane concentration-dependently increased the activity of calpains, a group of cysteine proteinases, and CD44 protein in U251 and A172 cells. Knockdown of CD44 with siRNA abolished sevoflurane-induced increases in calpain activity, migration, invasion, and colony-forming ability of U251 cells. Inhalation of 4% sevoflurane significantly increased the tumor volume and invasion/migration distance of U87 cells from the tumor mass in the nude mice bearing human glioblastoma U87 xenograft in the brain. The aggravation by sevoflurane was attenuated by CD44 silencing. In conclusion, sevoflurane increases the migration, invasion, and colony-forming ability of human glioblastoma cells in vitro, and their tumor volume and invasion/migration in vivo. Sevoflurane enhances these cancer cell biology features via increasing the expression of CD44.

Synthesis and Biological Evaluation of Genistein-IR783 Conjugate: Cancer Cell Targeted Delivery in MCF-7 for Superior Anti-Cancer Therapy.

The flavonoid-based natural product genistein is a biologically active compound possessing promising anti-oxidant and anti-cancer properties. Poor pharmacokinetics along with low potency limit however the therapeutic application of genistein in cancer therapy. In order to overcome those limitations and to expand its therapeutic window of efficacy, we sought to covalently attach genistein with a heptamethine cyanine dye-IR 783-for cancer cell targeting and enhanced delivery to tumors. Herein we report the synthesis, a selective detailed characterization and preliminary in vitro/in vivo biological evaluation of genistein-IR 783 conjugate 4. The conjugate 4 displayed improved potency against human breast cancer MCF-7 cells (10.4 ± 1.0 µM) as compared with the parent genistein (24.8 ± 0.5 µM) or IR 783 (25.7 ± 0.7 µM) and exhibited selective high uptake in MCF-7 as against the normal mammary gland MCF-10A cells in various assays. In the cell viability assay, conjugate 4 exhibited over threefold lower potency against MCF-10A cells (32.1 ± 1.1 µM) suggesting that the anti-cancer profile of parent genistein is significantly improved upon conjugation with the dye IR783. Furthermore, the genistein-IR783 conjugate 4 was shown to be especially accumulated in MCF-7 cancer cells by fluorescent intensity measurements and inverted fluorescence microscopy in fixed cells as well as in live cells with time via live cell confocal fluorescence imaging. The mechanism-based uptake inhibition of conjugate 4 was observed with OATPs inhibitor BSP and in part with amiloride, as a macropinocytosis inhibitor. For the first time we have shown amiloride inhibited uptake of cyanine dye by about ~40%. Finally, genistein-IR 783 conjugate 4 was shown to be localized in MCF-7 tumor xenografts of mice breast cancer model via in vivo near infrared fluorescence (NIRF) imaging. In conclusion, conjugation of genistein with cyanine dye IR783 indeed improved its pharmacological profile by cancer cell selective uptake and targeting and therefore warrants further investigations as a new anti-cancer therapeutics derived from natural product genistein.

Multidrug-resistant organisms may be associated with bed allocation and utilization efficiency in healthcare institutions, based on national monitoring data from China (2014-2020).

Analyzing the influence of the bed allocation and utilization efficiency in healthcare institutions on the isolation proportion of Multidrug-resistant organisms (MDROs) to provide data to support prevention and control of MDROs. In this study, the provincial panel data from 2014 to 2020 in China on health resource indicators, including the number of beds per 1,000 population, hospital bed utilization rate, and average hospital stay from 2014 to 2020 in China were used to analyze the relationship between bed allocation or utilization efficiency and MDROs by the panel data quantile regression model. It was shown that the number of beds per 1,000 population had a negative effect on the isolation proportion of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, vancomycin-resistant Enterococcus faecium, penicillin-resistant Streptococcus pneumoniae, methicillin-resistant coagulase-negative Staphylococcus, and cefotaxime or ceftriaxone resistant Escherichia coli (regression coefficient < 0, P < 0.05). The utilization rate of hospital bed had a positive effect on the isolation proportion of methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative Staphylococcus, vancomycin-resistant Enterococcus faecium, penicillin-resistant Streptococcus pneumoniae, cefotaxime or ceftriaxone resistant Escherichia coli, carbapenem-resistant Escherichia coli, cefotaxime or ceftriaxone resistant Klebsiella pneumoniae, carbapenem-resistant Klebsiella pneumoniae, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii (regression coefficient > 0, P < 0.05). The average hospital stay had a positive effect on the isolation proportion for several antibiotic-resistant organisms, including methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative Staphylococcus, vancomycin-resistant Enterococcus faecalis, vancomycin-resistant Enterococcus faecium, penicillin-resistant Streptococcus pneumoniae, cefotaxime or ceftriaxone resistant Escherichia coli, carbapenem-resistant Escherichia coli, quinolone-resistant Escherichia coli, cefotaxime or ceftriaxone resistant Klebsiella pneumoniae, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii (regression coefficient > 0, P < 0.05). Bed allocation and utilization efficiency in healthcare institutions may affect the isolation proportion of MDROs in varying degrees.

Video-assisted bystander cardiopulmonary resuscitation improves the quality of chest compressions during simulated cardiac arrests: A systemic review and meta-analysis.

BACKGROUND: It remains unclear whether video aids can improve the quality of bystander cardiopulmonary resuscitation (CPR). AIM: To summarize simulation-based studies aiming at improving bystander CPR associated with the quality of chest compression and time-related quality parameters. METHODS: The systematic review was conducted according to the PRISMA guidelines. All relevant studies were searched through PubMed, EMBASE, Medline and Cochrane Library databases. The risk of bias was evaluated using the Cochrane collaboration tool. RESULTS: A total of 259 studies were eligible for inclusion, and 6 randomised controlled trial studies were ultimately included. The results of meta-analysis indicated that video-assisted CPR (V-CPR) was significantly associated with the improved mean chest compression rate [OR = 0.66 (0.49-0.82), P < 0.001], and the proportion of chest compression with correct hand positioning [OR = 1.63 (0.71-2.55), P < 0.001]. However, the difference in mean chest compression depth was not statistically significant [OR = 0.18 (-0.07-0.42), P = 0.15], and V-CPR was not associated with the time to first chest compression compared to telecommunicator CPR [OR = -0.12 (-0.88-0.63), P = 0.75]. CONCLUSION: Video real-time guidance by the dispatcher can improve the quality of bystander CPR to a certain extent. However, the quality is still not ideal, and there is a lack of guidance caused by poor video signal or inadequate interaction.

6-Benzyl-3-[(6-chloro-pyridin-3-yl)meth-yl]-6,7-dihydro-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-imine.

The title compound, C(17)H(14)ClN(7), crystallizes with two independent mol-ecules in the asymmetric unit. Inter-molecular N-H⋯N and C-H⋯N hydrogen bonds contribute to the stability of the crystal structure. In addition, weak C-H⋯π and π-π stacking [centroid-centroid distances of 3.699 (8) and 3.699 (6) Å] interactions are observed.

2-Anilino-3-(2-hy-droxy-phen-yl)quinazolin-4(3H)-one methanol monosolvate.

In the title compound, C(20)H(15)N(3)O(2)·CH(3)OH, the quinazolin-one ring system is approximately planar, the dihedral angle between the pyrimidinone ring and the adjacent benzene ring being 1.73 (6)°. The pyrimidinone ring makes dihedral angles of 77.58 (6) and 29.62 (6)°, respectively, with the hy-droxy-phenyl and phenyl rings. In the crystal, the components are connected by O-H⋯O and C-H⋯O hydrogen bonds, forming a zigzag chain along the b axis.

2-Anilino-3-(2-hy-droxy-phen-yl)quinazolin-4(3H)-one-triphenyl-phosphine oxide (1/1).

In the title compound, C(20)H(15)N(3)O(2)·C(18)H(15)OP, the pyrimidinone heterocycle and the fused phenyl ring are inclined at 1.92 (7)°. Only the hy-droxy group is involved in hydrogen bonding, whereas the amino group is shielded from potential acceptors.

Human distribution and spatial-temporal clustering analysis of human brucellosis in China from 2012 to 2016.

BACKGROUND: Brucellosis is a major public health issue in China, while its temporal and spatial distribution have not been studied in depth. This study aims to better understand the epidemiology of brucellosis in the mainland of China, by investigating the human, temporal and spatial distribution and clustering characteristics of the disease. METHODS: Human brucellosis data from the mainland of China between 2012 and 2016 were obtained from the China Information System for Disease Control and Prevention. The spatial autocorrelation analysis of ArcGIS10.6 and the spatial-temporal scanning analysis of SaTScan software were used to identify potential changes in the spatial and temporal distribution of human brucellosis in the mainland of China during the study period. RESULTS: A total of 244 348 human brucellosis cases were reported during the study period of 2012-2016. The average incidence of human brucellosis was higher in the 40-65 age group. The temporal clustering analysis showed that the high incidence of brucellosis occurred between March and July. The spatial clustering analysis showed that the location of brucellosis clustering in the mainland of China remained relatively fixed, mainly concentrated in most parts of northern China. The results of the spatial-temporal clustering analysis showed that Heilongjiang represents a primary clustering area, and the Tibet, Shanxi and Hubei provinces represent three secondary clustering areas. CONCLUSIONS: Human brucellosis remains a widespread challenge, particularly in northern China. The clustering analysis highlights potential high-risk human groups, time frames and areas, which may require special plans and resources to monitor and control the disease.

6-Allyl-3-(6-chloro-3-pyridylmeth-yl)-6,7-dihydro-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-imine.

The title compound, C(13)H(12)ClN(7), crystallizes with two independent mol-ecules in the asymmetric unit, each with similar geometries. The dihedral angles between the triazole and pyrimidine rings are 0.45 (9) and 1.00 (10)° in the two mol-ecules. A number of N-H⋯N hydrogen bonds co-operate with C-H⋯N contacts, forming a supra-molecular array in the ab plane. C-H⋯π inter-actions are also present. One of the vinyl groups was found to be disordered so that the C(H)=CH(2) atoms were resolved over two positions with the major component having a site occupancy factor of 0.539 (4).

Telomere length inversely correlates with radiosensitivity in human carcinoma cells with the same tissue background.

A relationship between telomeres and radiosensitivity has been established by several studies based on non-mammalian model systems, mouse models, and few human genetic diseases. However, the relationship has not been proven in human carcinoma cells, which have more clinical significance than these other models. The present study aims to determine whether telomere length is related to radiosensitivity in human carcinoma cells, and to examine the influence of tissue or genetic background. Two HEp-2 larynx squamous carcinoma cell lines, eight hepatocellular carcinoma cell lines, and five breast cancer cell lines were used. Telomere length was determined by terminal restriction fragment (TRF) Southern blot analysis and cell survival was measured by a colony-forming assay. Our results indicated that there was a significant negative correlation of telomere length and radiosensitivity in the same tissue-derived cell lines, with or without the same genetic background. Thus, telomere length may be used as a promising tool to predict the radiosensitivity of human carcinomas.

Elevated red cell distribution width contributes to a poor prognosis in patients with esophageal carcinoma.

BACKGROUND: The red cell distribution width (RDW) has also been reported to reliably reflect the inflammation and nutrition status and predict the prognosis across several types of cancer, however, the prognostic value of RDW in esophageal carcinoma has seldom been studied. METHODS: A retrospective study was performed to assess the prognostic value of RDW in patients with esophageal carcinoma by the Kaplan-Meier analysis and multivariate Cox regression proportional hazard model. All enrolled patients were divided into high RDW group (≧15%) and low RDW group (<15%) according to the detected RDW values. RESULTS: Clinical and laboratory data from a total of 179 patients with esophageal carcinoma were retrieved. With a median follow-up of 21months, the high RDW group exhibited a shorter disease-free survival (DFS) (p<0.001) and an unfavorable overall survival (OS) (p<0.001) in the univariate analysis. The multivariate analysis revealed that elevated RDW at diagnosis was an independent prognostic factor for shorter PFS (p=0.043, HR=1.907, 95% CI=1.020-3.565) and poor OS (p=0.042, HR=1.895, 95% CI=1.023-3.508) after adjustment with other cancer-related prognostic factors. CONCLUSION: The present study suggests that elevated preoperative RDW(≧15%) at the diagnosis may independently predict poorer disease-free and overall survival among patients with esophageal carcinoma.

[Reversal effect of PI-3K/Akt pathway inhibitor LY294002 on multidrug resistance of ovarian cancer cell line A2780/Taxol].

BACKGROUND & OBJECTIVE: Previous studies had showed that phosphatidylinositol 3 kinase (PI-3K) can suppress cell apoptosis. The inhibitor of PI-3K has been used to investigate the mechanisms of PI-3K-induced oncogenesis. This study was to investigate the reversal effect of LY294002, a PI-3K/Akt inhibitor, on paclitaxel-resistance of ovarian carcinoma cell line A2780/Taxol. METHODS: A2780/Taxol cells were treated with LY294002. Cell apoptosis was analyzed by flow cytometry (FCM). The 50% inhibition concentration (IC50) of paclitaxel for A2780/Taxol cells was determined by MTT assay. The expression of multidrug resistance 1 (MDR1) mRNA was assessed by reverse transcription-polymerase chain reaction (RT-PCR). The expression of phosphated Akt and P-glycoprotein (P-gp) were detected by Western blot. RESULTS: When treated for 24 h, the apoptosis rate of A2780/Taxol cells was significantly higher in 10 and 50 micromol/L LY294002 groups than in control group [(8.84+/-1.65)% and (20.78+/-2.47)% vs. (1.25+/-0.78)%, P<0.05], the IC50 of paclitaxel for A2780/Taxol cells was decreased significantly (P<0.01) with the highest reverse efficiency of (78.08+/-0.37)%. Moreover, the expression of MDR1 gene, and the phosphorylation of Akt and P-gp in A2780/Taxol cells were decreased. CONCLUSIONS: The activation of PI-3K/Akt pathway plays an important role in paclitaxel-resistance of ovarian carcinoma cells. PI-3K/Akt inhibitor, LY294002 has a reversal effect on the paclitaxel-resistance of A2780/Taxol cells.