An interactive dose optimizer based on population pharmacokinetic study to guide dosing of methotrexate in Chinese patients with osteosarcoma.

PURPOSE: Osteosarcoma is a rare tumor with an incidence of 4.4 cases per million per year in adolescent. High-dose methotrexate (HD-MTX) is the standard first-line chemotherapeutic agent for osteosarcoma. However, its efficacy can vary significantly among individuals due to wide pharmacokinetic variability. Despite this, only a few population pharmacokinetics (popPK) models based on Chinese patients with osteosarcoma have been reported. Thus, this study aimed to develop a HD-MTX popPK model and an individual model-based dose optimizer for osteosarcoma therapy. METHOD: A total of 680 MTX serum concentrations from 57 patients with osteosarcoma were measured at the end of MTX infusion and 10 h, 24 h, 48 h, and 72 h after the start of infusion. Using the first-order conditional estimation method with NONMEM, a popPK model was estimated. Goodness-of-fit plots, visual predictive checks, and bootstrap analysis were generated to evaluate the final model. A dose optimizer tool was developed based on the validated models using R Shiny. Additionally, clinical data from 12 patients with newly diagnosed osteosarcoma were collected and used as the validation set to preliminarily verify the predictive ability of the popPK model and the dose optimizer tool. RESULTS: Body surface area (BSA) was the most significant covariate for compartment distribution. Creatinine clearance (CrCL) and co-administration of NSAIDs were introduced as predictors for central compartmental and peripheral compartmental clearance, respectively. Co-administration of NSAIDs was associated with significantly higher MTX concentrations at 72 h (p = 0.019). The dose optimizer tool exhibited a high consistency in predicting MTX AUC compared to the actual AUC (r = 0.821, p < 0.001) in the validation set. CONCLUSION: The dose optimizer tool could be used to estimate individual PK parameters, and optimize personalized MTX therapy in particular patients.

The value of preoperative neutrophil/lymphocyte ratio in predicting the severity of cholecystolithiasis with cholecystitis in elderly patients.

BACKGROUND: This study aims to assess the effectiveness of neutrophil/lymphocyte ratio (NLR) and C-reactive protein (CRP) in diagnosing cholecystolithiasis with cholecystitis in elderly patients. Additionally, the study seeks to determine the predictive value of preoperative NLR in determining the severity of the condition in this population. METHODS: This study is a retrospective cohort study, including 160 elderly patients with cholecystolithiasis with cholecystitis (45 cases of simple cholecystitis, 58 cases of suppurative cholecystitis, 57 cases of gangrenous cholecystitis) and 60 cases of normal gallbladder histology. The study collected clinical data of the patients detected the preoperative CRP content, neutrophil, and lymphocyte levels through blood routine tests, and calculated the NLR value. The diagnostic value of NLR and CRP was determined by using the Receiver Operating Characteristic Curve (ROC), and the optimal value of preoperative NLR related to the severity of elderly patients with cholecystolithiasis with cholecystitis was identified. RESULTS: This study found that for elderly patients with cholecystolithiasis with cholecystitis, preoperative NLR and CRP levels can be used to distinguish the condition. The critical value for NLR was found to be 2.995 (95% CI, 0.9465-0.9853; P < 0.001) with an area under the ROC curve of 0.9659, while the critical value for CRP was 13.05 (95% CI, 0.9284-0.9830; P < 0.001) with an area under the ROC curve of 0.9557. Both NLR and CRP were found to have equivalent diagnostic abilities. Additionally, the study found that there were significant differences in neutrophil and lymphocyte levels in elderly patients with different severity levels, with NLR increasing as severity increased (P < 0.001). The study identified cut-off values for preoperative NLR that could distinguish Simple cholecystitis and Purulent cholecystitis, as well as Purulent cholecystitis and Gangrenous cholecystitis in elderly patients with cholecystolithiasis, with respective AUCs of 0.8441 (95% CI: 0.7642-0.9239; P < 0.001) and 0.7886(95% CI: 0.7050-0.8721, P < 0.001), sensitivities of 91.38% and 87.72%, and specificities of 73.33% and 63.79%. CONCLUSIONS: Preoperative NLR and CRP values can serve as indicators to detect cholecystolithiasis with cholecystitis in elderly patients. Additionally, NLR has been recognized as a potential tool to differentiate the severity of cholecystolithiasis with cholecystitis in the elderly population.

Effect of high-level PM2.5 on survival in lung cancer: a multicenter cohort study from Hebei Province, China.

Globally, air pollution is the fourth leading risk factor for death, while lung cancer (LC) is the leading cause of cancer-related death. The aim of this study was to explore the prognostic factors of LC and the influence of high fine particulate matter (PM2.5) on LC survival. Data on LC patients were collected from 133 hospitals across 11 cities in Hebei Province from 2010 to 2015, and survival status was followed up until 2019. The personal PM2.5 exposure concentration (µg/m3) was matched according to the patient's registered address, calculated from a 5-year average for every patient, and stratified into quartiles. The Kaplan-Meier method was used to estimate overall survival (OS), and Cox's proportional hazard regression model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). The 1-, 3-, and 5-year OS rates of the 6429 patients were 62.9%, 33.2%, and 15.2%, respectively. Advanced age (75 years or older: HR = 2.34, 95% CI: 1.25-4.38), subsite at overlapping (HR = 4.35, 95% CI: 1.70-11.1), poor/undifferentiated differentiation (HR = 1.71, 95% CI: 1.13-2.58), and advanced stages (stage III: HR = 2.53, 95% CI: 1.60-4.00; stage IV: HR = 4.00, 95% CI: 2.63-6.09) were risk factors for survival, while receiving surgical treatment was a protective factor (HR = 0.60, 95% CI: 0.44-0.83). Patients exposed to light pollution had the lowest risk of death with a 26-month median survival time. The risk of death in LC patients was greatest at PM2.5 concentrations of 98.7-108.9 µg/m3, especially for patients at advanced stage (HR = 1.43, 95% CI: 1.29-1.60). Our study indicates that the survival of LC is severely affected by relatively high levels of PM2.5 pollution, especially in those with advanced-stage cancer.

Evaluation of a population-based breast cancer screening in North China.

BACKGROUND: Despite mammography-based screening for breast cancer has been conducted in many countries, there are still little data on participation and diagnostic yield in population-based breast cancer screening in China. METHODS: We enrolled 151,973 eligible women from four cities in Hebei Province within the period 2013-2021 and followed up until December 31, 2021. Participants aged 40-74 who assessed as high risk were invited to undergo breast ultrasound and mammography examination. Overall and group-specific participation rates were calculated. Multivariable analyses were used to estimate the factors associated with participation rates. The diagnostic yield of both screening and no screening groups was calculated. We further analyzed the stage distribution and molecular subtype of breast cancer cases by different modes of cancer detection. RESULTS: A total of 42,547 participants were evaluated to be high risk of breast cancer. Among them, 23,009 subjects undertook screening services, with participation rate of 54.08%. Multivariable logistic regression model showed that aged 45-64, high education level, postmenopausal, current smoking, alcohol consumption, family history of breast cancer, and benign breast disease were associated with increased participation of screening. After median follow-up of 3.79 years, there were 456 breast cancer diagnoses of which 65 were screen-detected breast cancers (SBCs), 27 were interval breast cancers (IBCs), 68 were no screening cancers, and 296 were cancers detected outside the screening program. Among them, 92 participants in the screening group (0.40%) and 364 in the non-screening group (0.28%) had breast cancer detected, which resulted in an odds ratio of 1.42 (95% CI 1.13-1.78; P = 0.003). We observed a higher detection rate of breast cancer in the screening group, with ORs of 2.42 (95% CI 1.72-3.41) for early stage (stages 0-I) and 2.12 (95% CI 1.26-3.54) for luminal A subtype. SBCs had higher proportion of early stage (71.93%) and luminal A subtype (47.22%) than other groups. CONCLUSIONS: The significant differences in breast cancer diagnosis between the screening and non-screening group imply an urgent need for increased breast cancer awareness and early detection in China.

A Bibliometric Analysis of the Role of 3D Technology in Liver Cancer Resection.

BACKGROUND: Liver cancer resection is an effective but complex way to treat liver cancer, and complex anatomy is one of the reasons for the difficulty of surgery. The use of 3D technology can help surgeons cope with this dilemma. This article intends to conduct a bibliometric analysis of the role of 3D technology in liver cancer resection. METHODS: (TS = (3D) OR TS = (three-dimensional)) AND (TS = (((hepatic) OR (liver)) AND ((cancer) OR (tumor) OR (neoplasm)))) AND (TS = (excision) OR TS = (resection)) was used as a search strategy for data collection in the Web of Science (WoS) Core Collection. CiteSpace, Carrot2 and Microsoft Office Excel were used for data analysis. RESULTS: Three hundred and eighty-eight relevant articles were obtained. Their annual and journal distribution maps were produced. Countries/regions and institutions collaboration, author collaboration, references co-citations and their clusters and keywords co-occurrences and their clusters were constructed. Carrot2 cluster analysis was performed. CONCLUSIONS: There was an overall upward trend in the number of publications. China's contribution was greater, and the USA had greater influence. Southern Med Univ was the most influential institution. However, the cooperation between institutions still needs to be further strengthened. Surgical Endoscopy and Other Interventional Techniques was the most published journal. Couinaud C and Soyer P were the authors with the highest citations and centrality, respectively. "Liver planning software accurately predicts postoperative liver volume and measures early regeneration" was the most influential article. 3D printing, 3D CT and 3D reconstruction may be the mainstream of current research, and augmented reality (AR) may be a future hot spot.

Biological cell trapping and manipulation of a photonic nanojet by a specific microcone-shaped optical fiber tip.

Trapping and manipulating mesoscopic biological cells with high precision and flexibility are very important for numerous biomedical applications. In particular, a photonic nanojet based on a non-resonance focusing phenomenon can serve as a powerful tool for manipulating red blood cells and tumor cells in blood. In this study, we demonstrate an approach to trap and drive cells using a high-quality photonic nanojet which is produced by a specific microcone-shaped optical-fiber tip. The dynamic chemical etching method is used to fabricate optical-fiber probes with a microcone-shaped tip. Optical forces and potentials exerted on a red blood cell by a microcone-shaped fiber tips are analyzed based on finite-difference time-domain calculations. Optical trapping and driving experiments are done using breast cancer cells and red blood cells. Furthermore, a cell chain is formed by adjusting the magnitude of the optical force. The real-time backscattering intensities of multiple cells are detected, and highly sensitive trapping is achieved. This microcone-shaped optical fiber probe is potentially a powerful device for dynamic cell assembly, optical sorting, and the precise diagnosis of vascular diseases.

Ultrasound-guided superficial cervical plexus block combined with clavipectoral fascial plane block or interscalene brachial plexus block in clavicle surgery: a single-centre, double-blind, randomized controlled trial.

The sensory innervation of the clavicle is complex, and the best regional block technology for clavicular surgery has yet to be determined. The purpose of this study was to compare the application of ultrasound-guided superficial cervical plexus block combined with clavipectoral fascial plane block verses interscalene brachial plexus block in clavicular surgery. Fifty patients undergoing internal fixation surgery for elective clavicle fractures were randomly divided into two groups (n = 25 for each group): group I and group II. Superficial cervical plexus block combined with clavipectoral fascial plane block was used in group I, and superficial cervical plexus block combined with interscalene brachial plexus block was used in group II. The primary outcome measure was the duration of analgesia. The duration of analgesia in group I was significantly longer than that in group II (P < 0.05). The modified Bromage scale function score in group II was lower than that in group I (P < 0.01). There was no significant difference in the skin acupuncture pain score 30 min after block and visual analog scale (VAS) scores at 6 and 12 h after surgery. However, the 24 h VAS score in group I was lower than that in group II (P < 0.05). The incidence of diaphragmatic paralysis was significantly increased in group II (P < 0.01). Ultrasound-guided superficial cervical plexus block combined with clavipectoral fascial plane block can be used for clavicular surgery. It has a long postoperative analgesia time, can retain the motor function of the involved upper limb and does not cause hemidiaphragmatic paresis.Clinical trial number and registry URL: Clinical Trials.gov; Trial registration number: ChiCTR2000039383; Date of registration: 25 October 2020.

Establishment and validation of a prognostic model for gastric cancer patients of Hebei Province in China.

BACKGROUND: Hebei Province is a high-risk area for gastric cancer in China, and there is currently no survival prediction model for gastric cancer patients in Hebei Province. This study aimed to build the best survival prediction model for gastric cancer patients in Hebei Province. METHODS: The development dataset included 1,993 hospitalized gastric cancer patients from the Hebei Cancer Registration Project during 2016 and 2017. Three tree-based machine learning methods [survival trees (ST), random survival forests (RSF), and gradient boosting machines (GBM)] and Cox, were used to develop the models by ten-fold cross validation with 200 iterations. California Chinese hospitalized gastric cancer patients were used as external test models. In addition, we compared the multivariable group with the Tumor Node Metastasis (TNM) group. RESULTS: The 3- and 5-year cancer-specific survival (CSS) rates of the development dataset were 57.07% and 44.48%, respectively. For predicting the 3-year CSS rates of gastric cancer patients of multivariable group, the C-indexes in train datasets were 0.75, 0.72, 0.79 and 0.76 for Cox, ST, RSF and GBM. Multivariable group performed better than TNM group. The predictive ability of Cox and RSF were superior to ST and GBM. A nomogram was established to predict the 3- and 5-year CSS rates of gastric cancer patients. CONCLUSIONS: The nomogram was useful for facilitating clinicians to predict the survival of gastric cancer patients, and identifying high-risk patients so as to adopt more reasonable treatment plans.

Glycohemoglobin: A new warning strategy for non-alcoholic fatty liver disease: Study from the NHANES 2017- 2020.

Context: The development and progression of Non-alcoholic Fatty Liver Disease (NAFLD) is associated with type 2 diabetes mellitus (T2DM), but there are no studies to demonstrate whether blood glucose levels are associated with the progression of NAFLD. Objective: Alterations in glucose metabolism may cause hepatic steatosis and inflammatory responses, leading to hepatocyte damage and promoting NAFLD's progression. Since glycohemoglobin reflects current blood glucose levels and is easily detectable, the present study aimed to investigate whether glycohemoglobin is associated with liver stiffness in patients with NAFLD. Methods: We studied 1510 NAFLD patients aged 20-80 in NHANES 2017- March 2020, who were defined using the controlled attenuation parameter (CAP) ≥263 dB/m. Multivariable linear regressions were used to assess the independent association between glycohemoglobin and median liver stiffness measurements (LSM) after adjusting for potential confounders. Subsequently, they were subjected to curve fitting and threshold effect analysis. Stratified analysis was used to find the variables affecting the relationship. Results: Glycohemoglobin and median LSM showed a positive correlation in different models (ß (95% CI): Crude Model: 1.460 (1.053, 1.867); Model 1: 1.476 (1.066, 1.885); Model 2: 1.517 (0.919, 2.115)), and this correlation disappeared when glycohemoglobin ≥8.6%. Furthermore, this correlation was more pronounced in the non-diabetic and former smoking subgroups. Conclusion: In patients with NAFLD, glycohemoglobin may reflect the degree of liver stiffness, and preventing excessive glycohemoglobin may have a positive effect on slowing the progression of NAFLD especially in non-diabetic and former smokers.

Concept of photonic hook scalpel generated by shaped fiber tip with asymmetric radiation.

Structured light have made deep impacts on modern biotechnology and clinical practice, with numerous optical systems and lasers currently being used in medicine to treat disease. We demonstrate a new concept of fiber-based optical hook scalpel. The subwavelength photonic hook is obtained in the vicinity of a shaped fiber tip with asymmetric radiation. A 1550 nm continuous-wave source, commonly used for medical imaging, has been required. Photonic hook with a lateral feature size less than the half-wavelength is achieved using a hemispherical shaped fiber tip with metallic mask. This breakthrough is carried out in ambient air by using a 4-µm-diameter fiber with a shaped tip. A good correlation is observed between the computed intensity distribution of photonic hook and the tip sizes. Photonic hook generated with a shaped fiber tip, easier to manipulate, shows far-reaching benefits for potential applications such as ophthalmic laser surgery, super-resolution microscopy, photolithography and material processing.

Trends in age of smoking initiation among the Chinese population born between 1950 and 1997.

OBJECTIVES: Smoking prevalence has significantly increased among Chinese adolescences in the past decades. The aim of our study is to investigate the trends and changing patterns in age of smoking initiation among the Chinese population. STUDY DESIGN: Pooled data from the 2006-2015 China Health and Nutrition Survey was used for analysis. A total of 10,032 adults aged ≥18 years who were born between 1950 and 1997 were separated into five birth cohorts (1950-1959, 1960-1969, 1970-1979, 1980-1989 and 1990-1997). METHODS: Age-specific (10-24 years) smoking initiation rates were calculated by gender, educational level and urbanisation. The multiple logistic models were used for estimates of changes in smoking initiation age. RESULTS: The mean age of smoking initiation decreased substantially from 22.0 years (95% confidence interval [CI]: 21.2-22.7) to 17.5 years (95% CI: 16.2-19.1) over five generations. A large decrease was seen in the initiation age group of 15-24 years in the 1980s cohort (15-19 years: odds ratio [OR] = 0.57; 95% CI: 0.19-0.97; 20-24 years: OR = 0.45; 95% CI: 0.18-0.82); a significant decrease was also found in the 1990s cohort (15-19 years: OR = 0.47; 95% CI: 0.11-0.94; 20-24 years old: OR = 0.34; 95% CI: 0.14-0.85). The peak age of smoking initiation changed from 20 years old to 18 years old over the five generations. CONCLUSIONS: The age of smoking initiation has decreased rapidly in the Chinese population in the past decades. Chinese adolescents are becoming the main target group for the tobacco marketing industry, and national legislations are urgently required.

Clinical characteristics and survival of 5283 esophageal cancer patients: A multicenter study from eighteen hospitals across six regions in China.

OBJECTIVE: This study aimed to investigate the potential determining epidemiological and clinical risk factors affecting the survival of esophageal cancer (EC) patients across multiple hospitals in China. METHODS: This was a multicenter study comprising of newly diagnosed EC cases from Beijing, Hebei, Henan, Hubei, Zhejiang, and Guangdong Province of China. Their baseline characteristics and treatment methods data were collected from their medical records. The EpiData software was used for data quality control. The Kaplan-Meier method was used to estimate their overall survival (OS), and the Cox's proportional hazard regression model was used to estimate hazard ratios (HR) and 95% confidence interval (CI). RESULTS: The 3- and 5-year OS rates of the 5283 investigated EC patients were 49.98% and 39.07%, respectively. Their median survival was 36.00 months. The median survival time of females was longer than that of males (females vs. males: 45.00 vs. 33.00, P < 0.001). The 5-year OS rate of patients who never-smoked was higher than that of smokers (never-smokers vs smokers: 40.73% vs. 37.84%, P = 0.001). There was no significant difference in the 5-year OS rate between drinkers and never-drinkers (drinkers vs never-drinkers: 34.22% vs. 29.65%, P = 0.330). In multivariate analysis, pathological stage (stage II: HR = 1.80, 95% CI = 1.40-2.31; stage III: HR = 2.62, 95% CI = 2.06-3.34; stage IV: HR = 3.90, 95% CI = 2.98-5.09), poor differentiation/undifferentiated (HR = 1.34, 95% CI = 1.11-1.63), not married status (HR = 2.45, 95% CI = 1.49-4.04), production and service personnel (HR = 1.36, 95% CI = 1.01-1.83) and farming/fishing (HR = 1.40, 95% CI = 1.12-1.76) were independent prognostic risk factors for poor EC survival. Tumors in the thoracic or abdominal part of the esophagus, female and family history of any cancer were independent factors predictive of a good EC OS. CONCLUSION: Gender, marital status, occupation, family history of any cancer, tumor topographical site, differentiation status, and pathological stage were associated with the survival rate of EC. This study reveals important clinical characteristics of esophageal cancer patients in China and provides helpful information for their clinical management and surveillance.

PLCD3, a flotillin2-interacting protein, is involved in proliferation, migration and invasion of nasopharyngeal carcinoma cells.

Phospholipase C (PLC) is a pivotal enzyme in the phosphoinositide pathway that promotes the second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), to participate in eukaryotic signal transduction. Several PLC isozymes are associated with cancer, such as PLC-ß1, PLC-δ1, PLC-ε and PLC-γ1. However, the role of PLC-δ3 (PLCD3) in nasopharyngeal carcinoma (NPC) has not been investigated to date. In our previous study, we demonstrated that flotillin2 (Flot2) plays a pro-neoplastic role in NPC and is involved in tumour progression and metastasis. In the present study, we screened the interacting proteins of Flot2 using the yeast two-hybrid (Y2H) method and verified the interaction between PLCD3 and Flot2 by co-immunoprecipitation. We also investigated the biological functions of PLCD3 in NPC. Inhibition of PLCD3 expression impaired the malignant potential of 5-8F, a highly metastatic NPC cell line, by restraining its growth, proliferation, mobility and migration. The present study demonstrated that PLCD3 may be an oncogenic protein in NPC and that it plays an important role in the progression of NPC partially by interacting with Flot2.

Ruthenium(II) polypyridyl complexes: cellular uptake, cell image and apoptosis of HeLa cancer cells induced by double targets.

Studies have shown that ruthenium complexes have relatively strong anticancer activity, cell uptake of drugs have a crucial impact on the pharmacological activity, using autofluorescence of ruthenium complexes could effectively track cancer cells and drug distribution, transport accurately in real time. In this work, we present the synthesis and detailed characterization of two novel Ru(II) complexes with hydrophobic ancillary ligands, namely [Ru(bpy)2(5-idip)](2+) (RBD) and [Ru(phen)2(5-idip)](2+) (RPD) (5-idip = 2-indole-[4,5-f][1,10]phenanthroline). We have shown that RPD can enter the HeLa cells efficiently through non-endocytotic, but energy-dependent mechanism and first accumulated in lysosomes, and then escape from the lysosomes and localize within the nuclei, efficiently lead to the inhibition of DNA transcription and translation and induced cell apoptosis. Further studies on the mechanism of apoptosis in HeLa cells demonstrate that RPD is able to induce mitochondria-mediated apoptosis in HeLa cells through activation of initiator caspase-9 and down-stream effector caspase-3 and -7 and cleavage of PARP. We have also demonstrated that RPD bind to telomeric G-quadruplex DNA effectively and selectively, together with increased p21 and p16 expression. Our findings suggest that RPD induces HeLa cell apoptosis through mitochondria-mediated pathway and inhibition of telomerase activity. RPD may be a candidate for further evaluation as a chemotherapeutic agent for human cancers.

Anticancer activity for targeting telomeric G-quadruplex and antiangiogenesis of a novel Ru(II)-Se complex.

A new Ru(II)-Se complex, Ru(bpy)2L2Cl2 (bpy = 2,2'-bipyridine, L = 1,10-phenanthrolineselenazole) (Ru-Se) has been synthesized and characterized. The G-quadruplex DNA-binding properties of the complex and its selenium ligand (Phen-Se) were evaluated by thermal denaturation study, polymerase chain reaction (PCR) stop assay, and telomerase repeat amplification protocol (TRAP). The results showed that the obtained complex could induce and stabilize G-quadruplex structure as well as exhibit potent inhibitory activity against telomerase. In vitro cytotoxicity studies showed that complex Ru-Se inhibited the cancer cell growth through apoptosis. However, the presence of the ligand Phen-Se did not appear to have a significant effect either on G-quadruplex binding or on biological activity. Furthermore, the cell migration assay and the tube formation assay also demonstrated that the complex Ru-Se significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration, and tube formation. These findings indicate that the Ru-Se complex may be a potential telomerase inhibitor and a viable drug candidate in antiangiogenesis for anticancer therapies.

Over-expression of BCAT1, a c-Myc target gene, induces cell proliferation, migration and invasion in nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common malignant tumor in southern China and Southeast Asia, but its molecular mechanisms of pathogenesis are poorly understood. Our previous work has demonstrated that BCAT1 mRNA is over expressed in NPC and knocking down its expression in 5-8F NPC cell line can potently inhibit cell cycle progression and cell proliferation. However, the mechanism of BCAT1 up-regulation and its functional role in NPC development remain to be elucidated yet. METHODS: Immunohistochemistry (IHC) method was utilized to detect the expression of BCAT1 protein in NPC at different pathological stages. The roles of gene mutation, DNA amplification and transcription factor c-Myc in regulating BCAT1 expression were analyzed using PCR-sequencing, quantitative polymerase chain reaction (qPCR), IHC, ChIP and luciferase reporter system, respectively. The functions of BCAT1 in colony formation, cell migration and invasion properties were evaluated by RNA interference (RNAi). RESULTS: The positive rates of BCAT1 protein expression in normal epithelia, low-to-moderate grade atypical hyperplasia tissues, high-grade atypical hyperplasia tissues and NPC tissues were 23.6% (17/72), 75% (18/24), 88.9% (8/9) and 88.8% (71/80), respectively. Only one SNP site in exon1 was detected, and 42.4% (12/28) of the NPC tissues displayed the amplification of microsatellite loci in BCAT1. C-Myc could directly bind to the c-Myc binding site in promoter region of BCAT1 and up-regulate its expression. The mRNA and protein of c-Myc and BCAT1 were co-expressed in 53.6% (15/28) and 59.1% (13/22) of NPC tissues, respectively, and BCAT1 mRNA expression was also down-regulated in c-Myc knockdown cell lines. In addition, BCAT1 knockdown cells demonstrated reduced proliferation and decreased cell migration and invasion abilities. CONCLUSIONS: Our study indicates that gene amplification and c-Myc up-regulation are responsible for BCAT1 overexpression in primary NPC, and overexpression of BCAT1 induces cell proliferation, migration and invasion. The results suggest that BCAT1 may be a novel molecular target for the diagnosis and treatment of NPC.

Ruthenium (II) polypyridyl complexes stabilize the bcl-2 promoter quadruplex and induce apoptosis of Hela tumor cells.

In the present study, the interaction between GC-rich sequence of bcl-2 gene P1 promoter (Pu39) and two ruthenium (II) polypyridyl complexes, [Ru(bpy)2(tip)]²âº (1) and [Ru(phen)2(tip)]²âº (2), was investigated by UV-Visible, fluorescence spectroscopy, circular dichroism, fluorescence resonance energy transfer melting assay and polymerase chain reaction stop assay. Those experimental results indicated that the two complexes can effectively stabilize the G-quadruplex of Pu39. It was found that the complex 2 exhibited greater cytotoxic activity than 1 against human Hela cells and can enter into Hela cells in a short period of time to effectively induce apoptosis of cells. Further experiments found that complexes 1 and 2 had as potent inhibitory effects on ECV-304 cell migration as suramin. Those noteworthy results provide new insights into the development of anticancer agents for targeting G-quadruplex DNA.

Ruthenium(II) polypyridyl complexes as G-quadruplex inducing and stabilizing ligands in telomeric DNA.

Two ruthenium(ii) polypyridyl complexes [Ru(phen)2(4idip)](ClO4)2 () and [Ru(bpy)2(4idip)](ClO4)2 () (phen = 1,10-phenanthroline, bpy = 2,2'-bipyridine, 4idip = 4-indoleimidazo[4,5-f][1,10]phenanthroline) designed as telomeric G-quadruplex ligands have been synthesized and characterized. The interaction of human telomeric G-quadruplex DNA (HTG21) with the designed ligands was explored by fluorescence analysis, absorption spectroscopy, continuous variation, circular dichroism spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, telomerase repeat amplification protocol (TRAP), and visual studies. The results showed that both complexes could induce and stabilize different G-quadruplex structures by using a 1 : 1 [quadruplex]/[complex] binding mode ratio. Complex exhibited higher interaction ability and better G-quadruplex selectivity than duplex DNA. Furthermore, both ruthenium complexes led to the inhibition of the enzyme telomerase, and complex was the significantly better inhibitor.

Chiral ruthenium(II) polypyridyl complexes: stabilization of g-quadruplex DNA, inhibition of telomerase activity and cellular uptake.

Two ruthenium(II) complexes, Λ-[Ru(phen)(2)(p-HPIP)](2+) and Δ-[Ru(phen)(2)(p-HPIP)](2+), were synthesized and characterized via proton nuclear magnetic resonance spectroscopy, electrospray ionization-mass spectrometry, and circular dichroism spectroscopy. This study aims to clarify the anticancer effect of metal complexes as novel and potent telomerase inhibitors and cellular nucleus target drug. First, the chiral selectivity of the compounds and their ability to stabilize quadruplex DNA were studied via absorption and emission analyses, circular dichroism spectroscopy, fluorescence-resonance energy transfer melting assay, electrophoretic mobility shift assay, and polymerase chain reaction stop assay. The two chiral compounds selectively induced and stabilized the G-quadruplex of telomeric DNA with or without metal cations. These results provide new insights into the development of chiral anticancer agents for G-quadruplex DNA targeting. Telomerase repeat amplification protocol reveals the higher inhibitory activity of Λ-[Ru(phen)(2)(p-HPIP)](2+) against telomerase, suggesting that Λ-[Ru(phen)(2)(p-HPIP)](2+) may be a potential telomerase inhibitor for cancer chemotherapy. MTT assay results show that these chiral complexes have significant antitumor activities in HepG2 cells. More interestingly, cellular uptake and laser-scanning confocal microscopic studies reveal the efficient uptake of Λ-[Ru(phen)(2)(p-HPIP)](2+) by HepG2 cells. This complex then enters the cytoplasm and tends to accumulate in the nucleus. This nuclear penetration of the ruthenium complexes and their subsequent accumulation are associated with the chirality of the isomers as well as with the subtle environment of the ruthenium complexes. Therefore, the nucleus can be the cellular target of chiral ruthenium complexes for anticancer therapy.

Circadian effects on outcome following surgery for intracerebral hemorrhage in humans?

Previous studies indicated that recovery of brain injury involves in circadian system and circadian system also modulates cardiovascular function. The present study was focused on the circadian characteristic of blood pressure (BP) and heart rate (HR) of patients with hypertensive intracerebral hemorrhage (HICH) after neurosurgical operation at the first 24-hour and its relationship to prognosis of HICH. This retrospective study was based on the analysis of circadian rhythm of postoperative patients with HICH who received no anti-hypertensive treatment before operation and during the first 24-hour after operation. Series data of BP and HR after operation were analyzed with cosinor method to determine whether circadian rhythms were present or absent. The patients were divided into two groups, including presence of circadian rhythm group and absence of circadian rhythm group. The basic clinical characteristics of two groups were analyzed with Student's t-test. The percentage of good prognosis in two groups was analyzed with Pearson's Chi-squared test. Statistical results indicated that the percentage of good prognosis was significantly different between the presence and absence group. More cases of good prognosis in presence group of Systolic Blood Pressure (SBP) was discovered than in absence group (p=0.032). The results of Diastolic Blood Pressure (DBP) and HR were similar as SBP was observed in presence group for DBP (p=0.002) and for HR (p=0.001), respectively. We conclude that the presence or absence of circadian rhythm after operation would be an early predictor of the postoperative prognosis from hypertensive intracerebral hemorrhage.