ABSTRACT
Hypoxia-activated prodrugs that specifically target tumor tissues were designed by attaching the nitro-aromatic ring carrier molecules that can be degraded in the hypoxic microenvironment of the tumor to the hydroxyamidine group of IDO1 inhibitor compound B and epacadostat. Eleven prodrug compounds were synthesized and their structures were confirmed by 1H NMR and HR-MS. Compounds F-1 and F-6, which had a higher stability and drug release rate, were identified by an in vitro stability assay, nitroreductase reduction assay, MTT assay, and an in vivo tumor tissue hypoxia degradation assay, and then evaluated for anti-tumor efficacy in vivo. The results showed that prodrug F-1 inhibited tumor growth by 67.41%, which was significantly higher than 42.31% for the starting drug group. It appeared that the inhibition of IDO1 in the tumor tissue was different from the overall inhibition of IDO1 in vivo. Animal treatment procedures were carried out with the approval of the Animal Care and Use Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College.
ABSTRACT
Objective To compare metabolite ratios in the basal ganglia regions between preterm and term neonates and analyze the correlation between metabolite ratio and postmenstrual age(PMA)using 2D magnetic resonance spectroscopy(MRS)at 3.0T,so as to explore the value of MRS in evaluating neonatal brain development.Methods Normal neonates who underwent 3.0T MRS exam ination were recruited.Axial 2D MRS was performed with the point-resolved spectroscopy sequence(PRESS)(echo time/repetition time,144 ms/1 000 ms) through the basal ganglia covering three regions of interest(ROI)(i.e.bilateral lenticular nucleus,thalamus and white matter beside the anterior horn of lateral ventricle).The peak areas ratios of Cho/Cr,NAA/Cho and NAA/Cr were calculated.Metabolite ratios were compared between preterm and term neonates,and between three ROIs. Correlation between metabolite ratio and PMA was further analyzed.Results Totally 54 neonates were included(preterm/term,27/27).In all the three ROIs,preterm neonates presented significantly higher Cho/Cr(P<0.05) and significantly lower NAA/Cho ratios(P<0.001)than those of term neonates;higher NAA/Cr ratio was only observed in the lenticular nucleus of preterm neonates(P<0.001).Significant differences in metabolite ratios were detected among the three ROIs in preterm group(P<0.05).For term group,metabolite ratios differed between lenticular nucleus and white matter beside the anterior horn of the lateral ventricle(P<0.01),while no difference between lenticular nucleus and thalamus was found(P>0.05).Significant correlation between metabolite ratio and PMA was found in all the three ROIs except NAA/Cr ratio in the white matter beside the anterior horn of the lateral ventricle.To be specific,we found linear negative correlation of Cho/Cr ratio(r= -0.325,-0.633,-0.438) and positive correlation of NAA/Cho ratio(r = 0.604,0.773,0.483)in all the three ROIs,but negative correlations of NAA/Cr ratio(r=0.487,0.367)in lenticular nucleus and thalamus with PMA.Conclusion Our findings suggest the tempo-spatial pattern of neonatal brain metabolite development in terms of anatomic location and PMA.Besides,the multi-voxel MRS presents potentials in establishing the normal topologic and age-matched reference in neonates and thus making brain maturation assessment and detection of early abnormal metabolism.
ABSTRACT
<p><b>OBJECTIVE</b>To estimate the cost-effectiveness of once-in-a-lifetime cervical cancer screening program and to predict the optimal modality for its operation on women living in rural and urban areas of China, based on Markov modeling and simulation.</p><p><b>METHODS</b>Three modalities including visual inspection with acetic acid plus Lugol's iodine (VIA/VILI), conventional Pap Smear (Pap Smear), and simple HPV DNA testing (careHPV) were hypothesized for the rural cohort, whereas other five modalities including Pap Smear, liquid-based cytology (LBC), simple HPV DNA testing (careHPV), Hybrid Capture 2 HPV DNA testing (HC2), and LBC plus HC2 (LBC + HC2) were tested for the urban cohort. A Markov model was constructed based on the factors as natural history, screening, diagnosis and treatment on cervical cancer using data related to the epidemics and the costs from rural and urban areas of the country. Long-term effectiveness and cost-effectiveness were predicted through simulation of the model.</p><p><b>RESULTS</b>Compared to the non-screening scenario, the amount of life years saved were 277.97 - 2727.53 and 134.02 - 1446.84 years per 100 000 women, respectively, for different cohorts in rural and urban areas. The cost-effectiveness ratios were 1520.99 - 2453.74 and 3847.35 - 44 570.35 RMB per life year saved, respectively, for different cohorts in rural and urban areas. The incremental cost-effective ratio for careHPV starting from 40 years old (careHPV@40) and careHPV from 30 years old (careHPV@30) dominated other strategies for the rural cohort, while careHPV@40, careHPV@30, HC2 from 30 years old (HC2@30), and LBC + HC2 from 30 years old (LBC + HC2@30) were dominant for the urban cohort.</p><p><b>CONCLUSION</b>All eight once-in-a-lifetime cervical cancer screening modalities were cost-effective based on our model. In particular, careHPV screening starting from 40 years old seemed to be the most cost-effective one for women living in both rural and urban areas.</p>
Subject(s)
Adult , Female , Humans , Middle Aged , Age Factors , Cost-Benefit Analysis , Early Detection of Cancer , Mass Screening , Economics , Outcome and Process Assessment, Health Care , Uterine Cervical Neoplasms , DiagnosisABSTRACT
<p><b>OBJECTIVE</b>To investigate the prevalence and related risk factors of prehypertension in Hangzhou, Shaoxing,Jiaxing city, Zhejiang province.</p><p><b>METHODS</b>3200 people were selected by stratified cluster random sampling method, and statistical methods including chi-square test, and logistic regression through SAS 9.0 were used.</p><p><b>RESULTS</b>The prevalence of pre- hypertension was 45.9%, higher for males and urban population, with significant differences seen between males and female(49.0% vs. 48.0%, P < 0.05), urban and rural areas(59.31% vs. 44.15%, P < 0.05). Data from the multiple factor logistic analysis showed that risk factors of prehypertension would include: older age, types of profession, under low education level, being urban residents, overweight and obesity, hyper triglyceride, and family history of hypertension, with ORs and 95% CI as 0.99 (0.98-0.99), 1.28(1.07-1.28), 1.31(1.10-1.56), 1.50(1.11-2.02), 1.33(0.98-1.81), 1.60 (1.19-2.16)and 1.18(1.00-1.39), respectively.</p><p><b>CONCLUSION</b>Prehypertension prevalence was found high in the studied district, especially in urban residents with low education level. Strategies including reduction on risk factors as obesity and hyper triglyceride through health education as well as lifestyle modification should be taken to hold back the increasing trend on prehypertension in Zhejiang.</p>
Subject(s)
Adolescent , Aged , Female , Humans , Male , Middle Aged , China , Epidemiology , Hypertension , Epidemiology , Logistic Models , Prehypertension , Epidemiology , Prevalence , Risk FactorsABSTRACT
<p><b>OBJECTIVE</b>To explore the appropriate strategies which are suitable for the areas with diverse health and economic resource settings in China by estimating the life outcomes and cost-effectiveness of several cervical cancer screening strategies.</p><p><b>METHODS</b>Markov model was used to calculate the long-term effectiveness, utility, benefit and cost among screened and unscreened cohorts in rural and urban areas, and then analyses of cost-effectiveness, cost-utility and cost-benefit were performed. The assessed screening strategies were acetic acid of visual inspection combined with Lugol's iodine staining (VIA/VILI), conventional Pap smear and simple HPV DNA testing (careHPV) in rural areas, and conventional Pap smear, simple HPV DNA testing (careHPV), HPV DNA testing (HC2) and liquid-based cytology (LBC) alone or combined with HPV DNA testing (LBC+HC2) in urban areas. We estimated the life outcomes and cost-effectiveness of the above screening strategies at one-year, 3-year and 5-year intervals.</p><p><b>RESULTS</b>All of the screening strategies were effective to decrease cervical cancer mortality and to increase life years, with a trend of shorter screening interval having better effectiveness. However, no matter in urban or rural areas, compared with careHPV testing at 5-year interval, the costs of other screening strategies were 1.28 - 13.86 folds, 1.31 - 14.14 folds, and 1.27 - 12.80 folds higher to avoid one death, to save a year of life, and a QALY, and the benefit per cost of other screening strategies was 9.9%-90.2%.</p><p><b>CONCLUSIONS</b>careHPV testing at 5-year interval has the best cost-effectiveness performance and the highest benefit-cost ratio with the moderate life outcomes. It is the optimal cervical cancer screening strategy to be generalized in our country. careHPV testing at 3 years interval can be considered in more developed areas to achieve better effectiveness.</p>
Subject(s)
Adult , Female , Humans , Middle Aged , Acetic Acid , Uterine Cervical Dysplasia , Diagnosis , Economics , Epidemiology , Virology , China , Epidemiology , Cost-Benefit Analysis , Cytological Techniques , DNA, Viral , Early Detection of Cancer , Economics , Methods , Human Papillomavirus DNA Tests , Iodides , Markov Chains , Mass Screening , Economics , Methods , Models, Biological , Models, Statistical , Papanicolaou Test , Quality-Adjusted Life Years , Rural Population , Urban Population , Uterine Cervical Neoplasms , Diagnosis , Economics , Epidemiology , Virology , Vaginal SmearsABSTRACT
<p><b>OBJECTIVE</b>To evaluate the antitumor efficacy of streptavidin-tagged interleukin-4 (IL-4-SA) bifunctional fusion protein in the immunotherapy of mouse model of superficial bladder cancer.</p><p><b>METHODS</b>IL-4-SA fusion protein was prepared and its biological activity was determined. One day after MB49 cell implantation, 100 µl of 1 mg/ml NHS-PEO4-biotin was instilled into the bladder for 30 minutes, followed by intravesical instillation of 100 µl PBS, GFP-SA+IL-4 or IL-4-SA and incubation for 1 hour. The bladder irrigation was performed twice a week for three weeks. The CTL cytotoxicity and profile of CD8(+) tumor-infiltrating lymphocytes were analyzed.</p><p><b>RESULTS</b>The IL-4-SA fusion protein was durably anchored to the biotinylated mucosal surface of bladder wall for up to 5 days.On day 80 after the implantation of MB49 cells, all of PBS-treated mice died, and 8 out of 10 mice in the GFP-SA-treated group died from tumor burden.In contrast, 5 out of 10 mice in the IL-4-SA-treated group were tumor-free. The MB49 tumor-specific cytotoxicity from mice in the IL-4-SA group was (11.3 ± 1.2)%, (22.7 ± 1.5)% and (31.0 ± 3.0)% at the effector to target ratios of 1:1, 25:1 and 50:1, respectively. But the corresponding cytotoxicity was (4.3 ± 0.6)%, (9.0 ± 1.0)% and (14.3 ± 1.5)% in the GFP-SA+IL-4 group, and (3.3 ± 0.6)%, (7.3 ± 0.6)%, (12.7 ± 2.1)% in the PBS group. The tumor-specific cytotoxicity in the SA-CD40L group was significantly higher than that in the control groups (P < 0.05). The infiltrating CD8(+) T cells in tumors in the IL-4-SA-treated group were increased compare with those in other groups.</p><p><b>CONCLUSION</b>Intravesical anchoring of IL-4-SA elicites strong and long-lasting immunoprotection against superficial bladder cancer, and the novel immunotherapy may be an attractive therapeutic alternative in future.</p>
Subject(s)
Animals , Humans , Male , Mice , Administration, Intravesical , Biotinylation , CD8-Positive T-Lymphocytes , Pathology , Cell Line, Tumor , Immunotherapy , Methods , Interleukin-4 , Metabolism , Therapeutic Uses , Mice, Inbred C57BL , Neoplasm Transplantation , Recombinant Fusion Proteins , Metabolism , Therapeutic Uses , Streptavidin , Metabolism , Therapeutic Uses , Urinary Bladder Neoplasms , Metabolism , TherapeuticsABSTRACT
To establish a platform for high throughput screening and in vitro evaluating novel metabolic enzyme-targeted inhibitors towards anti-malarial drugs, a lactate dehydrogenase gene of Plasmodium falciparum (PfLDH) was amplified from the Hainan isolate FCC1/HN. The fusion expression vectors, pGEX-2TK and pET-29a( + ), were utilized to introduce the PfLDH gene into strains of Escherichia coli, BL21 and BL21 (DE3), for over-expression. Consequently, the enzymatic activity of PfLDH was successfully detected in the suspension of lytic bacteria. The PfLDH gene cloned in pGEX-2TK was mainly expressed as inclusion bodies, while the same gene cloned in pET-29a( + ) was nearly expressed in a soluble form of PfLDH, demonstrating the latter vehicle might be more suitable for the large-scale preparation of recombinant PfLDH. Furthermore, according to the electrophoregram of SDS-PAGE and the sequencing data, a series of truncated PfLDH sequences generated randomly from gene amplification were screened and cloned, from which four pre-matured genes with a terminator mutation, PfLDH-delta271, -delta236, -delta167 and -delta53 coding for 45, 80, 149 and 263 amino acid residues, were individually recovered. Through the gene expression and enzymatic activity measurement, the effect of pre-matured terminator mutation on the activity of PfLDH was evaluated, which should pave the way for probing the relationship between structure and function of PfLDH.
Subject(s)
Animals , Cloning, Molecular , Escherichia coli , Genetics , Metabolism , Inclusion Bodies , Genetics , Metabolism , L-Lactate Dehydrogenase , Genetics , Metabolism , Plasmodium falciparum , Genetics , Protozoan Proteins , Genetics , Metabolism , Recombinant Fusion Proteins , Genetics , Metabolism , SolubilityABSTRACT
Biotransformation of bioactive natural leading compounds is a kind of bioprocess in which the structure of the added bioactive natural leading compounds could be modified by biocatalysts(e.g.,enzyme,microbial,plant and animal cells) in order to produce high efficient and low toxicity compounds.The biotransformation purpose of the known bioactive natural leading compounds is to improve its efficiency,or reduce its toxicity,or improve its solubility and bioavailability.The trace and high-valued bioactive natural leading compounds also could be produced by the biotransformation,and the biotransformation of bioactive natural leading compounds is still helpful to study the mechanism of drug metabolism.The current focus of the biotransformation of bioactive natural leading compounds is on the compounds of steroid,quinine,flavone and terpene,and some important biotransformation process has been successfully screened out.Fundamental research should be done in the following fields,such as the biotransformation mechanism of bioactive natural leading compounds,biotransformation process engineering,and the efficiency evaluation of bioproducts produced by biotransformation.The latest biotechnology(e.g.,directed evolution of biocatalyst,combinatorial biotransformation,non-aqueous biotransformation,high throughput screening) should be introduced to the biotransformation of bioactive natural leading compounds,which will boost its fast development.
ABSTRACT
<p><b>OBJECTIVE</b>To ascertain the causation of a pregnant woman with undefined pneumonia reported from the People's Hospital of Tongling city in Anhui province on November 2005.</p><p><b>METHODS</b>Epidemiological and clinical information of the case was collected from the keypersons close to the case and referring to the medical record. A medical observation was carried out on the close contacts of the case and sick or dead poultry. Tracheal aspirates being collected were tested by both RT-PCR and real-time PCR to detect viral nucleic acids of A/H5N1, and were inoculated into special pathogen free (SPF) embryonated hens' eggs.</p><p><b>RESULTS</b>The pregnant woman was found to have been contacted with the sick/dead poultry directly on the 4th day before onset of illness. All the 122 close contacts were healthy after a 10-day medical observation. The major clinical features of the case were viral pneumonia with rapidly developed leukopenia and lymphopenia. The progress to acute respiratory distress syndrome and multiple organ dysfunction syndromes was found at clinical presentation. HA and NA gene of A/H5N1 virus were positive. The 8 gene fragments of A/Anhui/1/2005 (H5N1) isolated from the tracheal aspirates had not carried genes from a human virus through reassortment, and the receptor-binding site of the hemagglutinin was polybasic cleavage site.</p><p><b>CONCLUSION</b>This was the first documented case of H5N1 infection in pregnant woman. The immunotolerant state of pregnancy might have predisposed to the fatal outcome of the patient.</p>
Subject(s)
Adult , Female , Humans , Pregnancy , China , Fatal Outcome , Influenza A Virus, H5N1 Subtype , Genetics , Influenza, Human , Pathology , Multiple Organ Failure , Pneumonia , Virology , Polymerase Chain Reaction , Pregnancy Complications, Infectious , Virology , Respiratory Distress Syndrome , Trachea , VirologyABSTRACT
Objective To analyze the clinical features,epidemiologic information and outcome in confirmed cases of human infection with a highly pathogenic influenza A(H5N1).Methods The clinical features and epidemiologic findings in 2 confirmed cases of avian influenza A(H5N1)in Anhui province,in November 2005.Clinical data on vital signs,physical findings,laboratory tests and roentgenology were obtained by means of retrospective review of the hospital records.Epidemiologic data were collected through interviews of the patients and their relatives.Results In both cases,the diagnosis of influenza A(H5N1)was confirmed by means of viral culture and real-time polymerase chain reaction with specific primers for H5 and N1 in samples obtained from tracheal aspiration.All patients were previously healthy young women and resided in village.They had a clear history of di- rect contact with sick/dead poultry and prepared dead chickens at home for eating(removed feathers, washed,cut)hut no report of confirmed HSN1 animals in the village.The time between exposure and onset of illness were 5 days,no one else in family sick.The time between the onset of illness and hos- pitalization were 5 days and 6 days,respectively.Two patients have initial symptoms of high fever (typically a temperature more than 38℃).The prominent clinical features were those of influenza syndrome,including fever,cough,and shortness of breath.Upper respiratory tract symptoms were absent.The platelet counts were decreased.In both patients,there were marked abnormalities on chest radiography,radiographic changes include bilateral and unilateral lobular consolidations with air bronchograms,and had dramatic worsening of findings.Two patients developed acute respiratory dis- tress syndrome(ARDS)complicated multiple organ dysfunction syndrome(MODS)and died of pro- gressive respiratory failure.Conclusions Exposure to dead poultry within a week before the onset of illness was associated with Influenza A(H5N1)infection in humans,but no definitive evidence of hu man-to-human transmission has been found yet.Influenza A(HSNI)infection,characterized by fe- ver,an influenza-like illness with lower respiratory tract symptoms,carries a high risk of death.