OBJECTIVES: The metabolomics technique of LC-MS/MS combined with data analysis was used to detect changes and differences in metabolic profiles in the vitreous humor of early rat carcasses found in water, and to explore the feasibility of its use for early postmortem submersion interval (PMSI) estimation and the cause of death determination. METHODS: The experimental model was established in natural lake water with 100 SD rats were randomly divided into a drowning group (n=50) and a postmortem (CO₂ suffocation) immediately submersion group (n=50). Vitreous humor was extracted from 10 rats in each group at 0, 6, 12, 18 and 24 h postmortem for metabolomics analyses, of which 8 were used as the training set to build the model, and 2 were used as test set. PCA and PLS multivariate statistical analysis were performed to explore the differences in metabolic profiles among PMSI and causes of death in the training set samples. Then random forest (RF) algorithm was used to screen several biomarkers to establish a model. RESULTS: PCA and PLS analysis showed that the metabolic profiles had time regularity, but no differences were found among different causes of death. Thirteen small molecule biomarkers with good temporal correlation were selected by RF algorithm. A simple PMSI estimation model was constructed based on this indicator set, and the data of the test samples showed the mean absolute error (MAE) of the model was 0.847 h. CONCLUSIONS The 13 metabolic markers screened in the vitreous humor of rat corpses in water had good correlations with the early PMSI. The simplified PMSI estimation model constructed by RF can be used to estimate the PMSI. Additionally, the metabolic profiles of vitreous humor cannot be used for early identification of cause of death in water carcasses.
Animals ; Biomarkers/metabolism* ; Cadaver ; Chromatography, Liquid ; Immersion ; Postmortem Changes ; Rats ; Rats, Sprague-Dawley ; Tandem Mass Spectrometry ; Vitreous Body/metabolism* ; Water/metabolism*

3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Child, Preschool ; DNA Mutational Analysis ; Disorder of Sex Development, 46,XY/genetics* ; Female ; Humans ; Membrane Proteins/genetics* ; Mutation

BACKGROUNDThree randomised trials have demonstrated that combining bevacizumab with first-line chemotherapy significantly improves progression-free survival versus chemotherapy alone in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). However, data from Chinese populations are limited and possible differences between ethnic and geographic populations are unknown. This study was conducted to determine whether there are differences in safety and efficacy in patients with HER2-negative LR/mRC between Chinese and Western populations after they receive first-line bevacizumab combined with taxane-based therapy.

METHODSIn the single-arm, open-label, Avastin Therapy for Advanced Breast Cancer (ATHENA) study (NCT00448591), patients with HER2-negative LR/mBC received first-line bevacizumab (investigator's choice of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) combined with taxane-based therapy. The primary endpoint was safety profile and the secondary is time to progression (TTP). A subpopulation analysis was conducted to assess safety and efficacy in Chinese patients.

RESULTSOf 2264 patients treated in ATHENA, 202 were enrolled in China. Bevacizumab was combined with docetaxel in 90% of Chinese patients and paclitaxel in 10%. The most common grade 3/4 adverse events were diarrhoea (in 5.0% of patients) and hypertension (in 2.5% of patients). Grade 3/4 proteinuria occurred in 0.5%. After median follow-up of 17.6 months and events in 56% of patients, median TTP was 9.0 months (95%CI, 8.4-11.1). Overall survival data were immature.

CONCLUSIONSWe found no evidence of increased bevacizumab-related toxicity or reduced efficacy in Chinese LR/mBC patients receiving first-line bevacizumab-taxane therapy compared with predominantly Western populations. The safety profile was generally similar to previously reported LR/mBC trials. Subtle differences may be attributable to different lifestyle and cardiovascular risk factors in Chinese patients compared with the overall population. It appears reasonable to extrapolate findings from bevacizumab-based randomised trials to Chinese populations.

Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized ; adverse effects ; therapeutic use ; Antineoplastic Agents ; adverse effects ; therapeutic use ; Bevacizumab ; Breast Neoplasms ; drug therapy ; genetics ; metabolism ; Bridged-Ring Compounds ; adverse effects ; therapeutic use ; Female ; Humans ; Middle Aged ; Receptor, ErbB-2 ; genetics ; metabolism ; Taxoids ; adverse effects ; therapeutic use ; Young Adult

The efficacy and safety of bevacizumab with modified irinotecan, leucovorin bolus, and 5-fluorouracil intravenous infusion (mIFL) in the first-line treatment of metastatic colorectal cancer (mCRC) has not been well evaluated in randomized clinical trials in Chinese patients. We conducted a phrase III trial in which patients with previously untreated mCRC were randomized 2:1 to the mIFL [irinotecan (125 mg/m(2)), leucovorin (20 mg/m(2)) bolus, and 5-fluorouracil intravenous infusion (500 mg/m(2)) weekly for four weeks every six weeks] plus bevacizumab (5 mg/kg every two weeks) group and the mIFL group, respectively. Co-primary objectives were progression-free survival (PFS) and 6-month PFS rate. In total, 214 patients were enrolled. Our results showed that addition of bevacizumab to mIFL significantly improved median PFS (4.2 months in the mIFL group vs. 8.3 months in the bevacizumab plus mIFL group, P < 0.001), 6-month PFS rate (25.0% vs. 62.6%, P < 0.001), median overall survival (13.4 months vs. 18.7 months, P = 0.014), and response rate (17% vs. 35%, P = 0.013). Grades 3 and 4 adverse events included diarrhea (21% in the mIFL group and 26% in the bevacizumab plus mIFL group) and neutropenia (19% in the mIFL group and 33% in the bevacizumab plus mIFL group). No wound-healing complications or congestive heart failure occurred. Our results suggested that bevacizumab plus mIFL is effective and well tolerated as first-line treatment for Chinese patients with mCRC. Clinical benefit and safety profiles were consistent with those observed in pivotal phase III trials with mainly Caucasian patients.
Adult ; Aged ; Angiogenesis Inhibitors ; adverse effects ; therapeutic use ; Antibodies, Monoclonal, Humanized ; adverse effects ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Asian Continental Ancestry Group ; Bevacizumab ; Camptothecin ; administration & dosage ; adverse effects ; analogs & derivatives ; Colorectal Neoplasms ; drug therapy ; pathology ; Diarrhea ; chemically induced ; Disease-Free Survival ; Female ; Fluorouracil ; administration & dosage ; adverse effects ; Humans ; Leucovorin ; administration & dosage ; adverse effects ; Male ; Middle Aged ; Neoplasm Metastasis ; Neutropenia ; chemically induced ; Prospective Studies ; Survival Rate ; Young Adult

BACKGROUNDThe high mobility group A1 (HMGA1) proteins are architectural transcription factors found to be overexpressed in lung adenocarcinoma. Lentivirus-mediated RNA interference (RNAi) technology is a powerful tool for silencing endogenous or exogenous genes in human cancer cells. Our preliminary study shows that gemcitabine inhibits growth of the human lung cancer cell line SPCA-1 and induces apoptosis, and this effect might link with down-regulation of HMGA1 expression. This study aimed to investigate the chemosensitivity change of the lung adenocarcinoma cells SPCA-1 after HMGA1 inhibition by lentivirus-mediated RNAi.

METHODSWe studied a highly malignant lung adenocarcinoma cell line (SPCA-1 cells). Lentiviral short-hairpin RNA (shHMGA1) expression vectors targeting HMGA1 were used for generation of lentiviral particles. After being transfected into the lung adenocarcinoma cell line SPCA-1, the expression of HMGA1 was determined by retrotranscriptase polymerase chain reaction (RT-PCR) and Western blotting. The effect of gemcitabine on proliferation of positive and negative cells was observed by methyl thiazolyl tetrazolium (MTT) assay and clonogenic survival assay. Apoptosis was observed by flow cytometery. Chemosensitivity to gemcitabine was determined by IC50 analysis. Caspase activity was quantitated by a caspase colorimetric protease assay kit.

RESULTSHMGA1-siRNA silenced its target mRNA specifically and effectively in SPCA-1 cells. The apoptotic rates of the scramble control group were (7.43 ± 0.21)%, (11.00 ± 0.20)%, and (14.93 ± 0.31)%, and the apoptotic rates in the silenced group were (9.53 ± 0.42)%, (16.67 ± 0.45)%, and (25.40 ± 0.79)% under exposure to 0.05, 0.5 and 5.0 µg/ml of gemcitabine (P < 0.05). The IC(50) of the silenced group was (0.309 ± 0.003) µg/ml which was significantly lower than in the scramble control group, (0.653 ± 0.003) µg/ml (P < 0.05). It reduced cancer cell proliferation and increased apoptotic cell death after being treated with gemcitabine compared with the scramble control group. HMGA1 silencing resulted in reduction in the phosphorylation of Akt, and promoted the activation of caspases 3, 8 and 9 upon exposure to gemcitabine.

CONCLUSIONSLentivirus-mediated RNA interference of HMGA1 enhanced chemosensitivity to gemcitabine in lung adenocarcinoma cells. The mechanism may be associated with the PI-3K/Akt signal pathway. HMGA1 may represent a novel therapeutic target in lung cancer.

Antimetabolites, Antineoplastic ; pharmacology ; Blotting, Western ; Calcium-Transporting ATPases ; genetics ; metabolism ; Caspase 3 ; genetics ; metabolism ; Caspase 8 ; genetics ; metabolism ; Caspase 9 ; genetics ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Deoxycytidine ; analogs & derivatives ; pharmacology ; Flow Cytometry ; Genetic Vectors ; genetics ; HMGA Proteins ; genetics ; metabolism ; Humans ; Lentivirus ; genetics ; RNA Interference ; physiology ; Reverse Transcriptase Polymerase Chain Reaction

Objective To summarize the clinical effects and experiences of rapid pore cranial drilling and ventricular drainage treatment on ventricular hemorrhage to evaluate the performance of rapid pore cranial drilling. Methods The clinical data of 3571 patients with ventricular hemorrhage performed the rapid pore cranial drilling and ventricular drainage treatment from 13 hospitals of Shandong province since 1977 were retrospectively analyzed and concluded; these data were compared with those in patients received traditional Dandy's device. Results In these 3571 patients, the cure rate was 27.1%, the improvement rate was 49.1%, and the death rate was 23.8%. Rapid pore drilling needed no scalp incision, no suction, no coagulation, or no special lighting, only needed puncturing the scalp, drilling through the cranium and dura matter, implanting drainage tube and stitching it up; one can manage it in about 5 minutes at bedside; while the traditional Dandy's drilling occupied 3 people in the operating room, needed more than 20 procedures, and plus the time transporting the patient, it needed at least 60 minutes or more to finfish the procedures. Rapid pore cranial drill device is superior to Dandy's cranial drill device in operating procedures, technical performance, operation conditions, personnel and time-consuming. Conclusion Rapid pore cranial drilling greatly simplifies the operating procedures, saves precious time for the seriously ill patients, reduces the mortality and improves the effectiveness of the treatment. After 35 years of clinical practice, to those patients seriously ill needed ventricular drainage treatment to rescue their lives, rapid pore cranial drilling is superior to traditional Dandy's drill technic, and is an effective method treating such diseases.

OBJECTIVETo evaluate the application of (18)F-FDG PET/CT in diagnosis of classic fever of unknown origin.

METHODSA total of 27 consecutive patients with classic fever of unknown origin (FUO) (19 men, 8 women; aged 24-82 y) underwent (18)F-FDG PET/CT scans. The images were interpreted by visual inspection and semiquantitative analysis(standardized uptake value, SUV). Final diagnosis was based on histopathology or clinical follow-up.

RESULTSThe cause of FUO was confirmed by followed investigations in 21 of 27 cases after PET/CT scan, including 10 cases of infection, 4 of noninfectious inflammation, 4 of malignancies and 3 of miscellaneous disorders; and remaining 6 cases were still confirmed FUO. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 100.0 %, 83.3%, 83.3%, 100.0% and 96.3%, respectively.

CONCLUSIONFor patients with fever of unknown origin, (18)F-FDG-PET/CT can be a sensitive, reliable imaging modality. It is suggested that (18)F-FDG-PET/CT should be considered earlier in detecting the causes of FUO, which is difficultly diagnosed by conventional modalities.

Adult ; Aged ; Aged, 80 and over ; Diagnosis, Differential ; Female ; Fever of Unknown Origin ; diagnosis ; diagnostic imaging ; etiology ; Fluorodeoxyglucose F18 ; Humans ; Male ; Middle Aged ; Positron-Emission Tomography ; methods ; Radiopharmaceuticals ; Tomography, X-Ray Computed ; methods ; Young Adult

Objective To evaluate the diagnostic value of ~(99)Tc~m-methoxyisobutylisonitrile (MIBI) SPECT scintigraphy combined Iocalizable CT in the localization of ectopic parathyroid glands in hyperparathyroidism.Methods Retrospective data of surgery,pathology and imaging were collected from 28 patients with hyperfunctioning ectopic parathyroid glands.All cases underwent CT studies.Twenty-five patients had ~(99)Tc~m-MIBI planar imaging first:SPECT scintigraphy combined localizable CT was performed for the patients with abnormal radionuclide foci immediately.The fusion images obtained after reconstruction showed the exact location of the ectopic foci.Operative histopathologic results were regarded as "gold standards".Presuming 4 parathyroid glands as normal findings,findings confirmed by operation and pathology were regarded as positive,otherwise negative.The results of CT and radionuclide imaging were compared by X~2-test of four-foId table.Results Twenty-eight ectopic parathyroid glands were found in 28 patients,all pathologically confirmed as adenomss.CT found 22 foci,of which 17 were true positive,5 false positive,11 false negative,and 79 true negative.~(99)Tc~m-MIBI SPECT scintigraphy combined localizable CT found 23 foci,no false positive,2 false negative,and 75 true negative.The results showed that the sensitivities were 61% (17/28),92%(23/25),specificities 94%(79/84),100%(75/75),accuracies 86%(96/112),98% (98/100),positive predictive values 77%(17/22),100%(23/23),and negative predictive values 88% (79190),97%(75/77),respectively,for CT and radionuclide imaging.~(99)Tc~m-MIBI SPECT scintigraphy combined localizable CT was therefore significantly higher than CT in sensitivity(X~2=6.98,P＜0.01),specificity (X~2=4.61,P＜0.05),accuracy (X~2=10.30,P＜0.01),positive predictive value(X~2=5.88,P＜0.05) and negative predictive value (X~2=5.36,P＜0.05).Conclusion ~(99)Tc~m-MIBI SPECT scintigraphy combined localizable CT is superior to CT alone in the localization of ectopic parathyroid glands in hyperparathyroidism,but false negative can be found in some patients.

OBJECTIVETo understand the influence of accumulation of advanced glycosylation end products (AGE) on wound healing of burn rats complicated with diabetes.

METHODSSeventy-five SD rats were divided into control, diabetes, and aminoguanidine-interfered groups in completely randomized method, with 25 rats in each group. All rats were subjected to deep partial-thickness scald. Diabetes was reproduced in rats of diabetes and aminoguanidine-interfered groups. Rats in aminoguanidine-interfered group were fed with 100 mg x kg(-1) xd (-1) aminoguanidine. Rats were sacrificed on post-scald day (PSD) 0, 3, 7, 14, and 21, and portrait of the wounds were taken. Full-thickness skin tissue specimens were obtained for determination. Specimens of epidermis from back of SD rats were obtained for KC cultivation and verification. Wound healing rate, glucose content in skin tissue, morphologic change in wound tissue, AGE distribution in skin tissue, influence of AGE on proliferation and apoptosis of KC were observed.

RESULTSWound healing rate of rats was respectively lower in diabetes group than that in control group on PSD 7, 14, and 21 (P < 0.01), but it was obviously higher in aminoguanidine-interfered group than that in the former 2 groups (P < 0.01). Glucose content of rat skin in diabetes group was (2.62 +/- 0.19) mmol/g, and it was (2.58 +/- 0.07) mmol/g in aminoguanidine-interfered group, both higher than that in control group [(1.04 +/- 0.09) mmol/g, P < 0.01]. In control group, limited intensive infiltration of inflammatory cells was found in the wound with necrotic tissue formation which fell off in time, and with no obvious delay of wound healing. In diabetes group, infiltration of inflammatory cells in wounds of rats appeared slowly, but diffusely and persistently; necrotic tissue formed and fell off late in time, with obvious delay of wound healing. In aminoguanidine-interfered group, intensive infiltration of inflammatory cells was observed in time, and the time of necrotic tissue formation and sloughing, and wound healing were respectively earlier than that in diabetes group. Sporadic disposition of small amount of AGE was found in rats in control group. AGE accumulation increased significantly in rats in diabetes group. AGE content decreased significantly in rats in aminoguanidine-interfered group after administration of aminoguanidine. KC proliferation decreased significantly in concentration dependent manner 48 hours after AGE stimulation. Absorbance value of AGE decreased in each AGE-interfered group (P < 0.01). Early Annexin-V positive apoptotic KC rate was obviously higher in 100 ug/mL AGE-interfered group (15.1 +/- 2.3)% than that in control group [(11.2 +/- 1.2)%, P < 0.05]. There was no statistical significance between 100 ug/mL AGE-interfered group (14.3 +/- 3.5)% and control group (15.2 +/- 2.4)% in respect of the rate of double-positive cells apoptosis at final stage (P > 0.05).

CONCLUSIONSHyperglycemia may inhibit proliferation of repairing cells such as KC through AGE accumulation, thus impedes wound healing. Reduction of AGE accumulation could ameliorate wound healing delay due to diabetes.

Animals ; Blood Glucose ; metabolism ; Burns ; complications ; metabolism ; Diabetes Mellitus, Experimental ; complications ; metabolism ; Glycation End Products, Advanced ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Wound Healing

BACKGROUNDGastroesophageal reflux disease with extra-esophageal symptoms, especially those with respiratory distress was attracting more and more attention. The related mechanisms were still in controversy. The purpose of the work was to explore airway inflammation triggered by gastroesophageal reflux.

METHODSSixteen Sprague-Dawley rats were used as study group and 9 as control. In the study group, a plastic extender with a trumpet-shaped distal end was inserted into the lower esophagus to dilate the cardia, the pylorus was ligated. One ml of 0.1 mol/L hydrochloric acid was injected into the stomach. While a simple laparotomy was performed for control animals. All animals from two groups were sacrificed 24 hours after operation. Then tracheotomy was carried and the bronchoalveolar lavage fluid was collected in all animals. Cells in the fluid were counted and levels of interleukin (IL)-5, -6, -8 in it were measured.

RESULTSCompared with control group, the study group presented a neutrophil pattern of airway inflammation and an elevated concentration of IL-5, -6, -8 with no significant difference regarding eosinophil count.

CONCLUSIONThe gastroesophageal reflux-triggered airway inflammation is characterized by a neutrophilic airway inflammation which differed from that caused by asthma, and enhanced levels of IL-5, -6 and -8, which are similar to that caused by asthma.

Animals ; Asthma ; etiology ; Bronchoalveolar Lavage Fluid ; immunology ; Disease Models, Animal ; Female ; Gastroesophageal Reflux ; complications ; Inflammation ; etiology ; Interleukin-5 ; analysis ; Interleukin-6 ; analysis ; Interleukin-8 ; analysis ; Male ; Rats ; Rats, Sprague-Dawley