The validity and reliability of mixed-dentition analysis methods: a systematic review

BackgroundThe authors conducted a literature review to determine the validity and reliability of mixed-dentition analysis (MDA) methods used to predict permanent tooth size in the mixed dentition and to evaluate the effect of relevant variables.Types of Studies ReviewedThe authors searched eight online databases for studies of MDA. They selected 39 articles. Inclusion criteria included assessment of mesiodistal tooth width predictions of canines and premolars, use of study-model measurements with or without radiographs, reliability and validity of MDA values and a minimum sample size of 10.ResultsAll MDA methods had positively correlated validity and high intrarater reliability. Mean differences were less than 2 millimeters with correlation coefficients that tended to be above 0.6. Correlation coefficients were less variable with multiple linear regression equations (MLREs) than with simple linear regression equations (SLREs) with the study-model method, but the opposite was true with the radiographic method. Polymorphisms based on ethnicity, sex, jaw or side of mouth did not meaningfully influence the validity of SLRE predictions, but some differences were apparent with the use of MLRE predictions.Clinical ImplicationsThe results of this review call into question the clinical implications of the multiple variations of MDA that have been described in the literature.     

Cultured astrocytes do not release adenosine during hypoxic conditions

Recent reports based on a chemiluminescent enzymatic assay for detection of adenosine conclude that cultured astrocytes release adenosine during mildly hypoxic conditions. If so, astrocytes may suppress neural activity in early stages of hypoxia. The aim of this study was to reevaluate the observation using high-performance liquid chromatography (HPLC). The HPLC analysis showed that exposure to 20 or 120 minutes of mild hypoxia failed to increase release of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine from cultured astrocytes. Similar results were obtained using a chemiluminescent enzymatic assay. Moreover, since the chemiluminescent enzymatic assay relies on hydrogen peroxide generation, release of free-radical scavengers from hypoxic cells can interfere with the assay. Accordingly, adenosine added to samples collected from hypoxic cultures could not be detected using the chemiluminescent enzymatic assay. Furthermore, addition of free-radical scavengers sharply reduced the sensitivity of adenosine detection. Conversely, use of a single-step assay inflated measured values due to the inability of the assay to distinguish adenosine and its metabolite inosine. These results show that cultured astrocytes do not release adenosine during mild hypoxia, an observation consistent with their high resistance to hypoxia.     

The inhibition of miR-21 promotes apoptosis and chemosensitivity in ovarian cancer

Background

MicroRNAs have been implicated in tumorigenesis, drug resistance, and prognosis in cancer. We investigated the role of microRNA-21 (miR-21) in regulating ovarian cancer drug resistance.

Methods

We used parental and cisplatin resistant ovarian cell lines to demonstrate the role of miR-21 in drug resistance and investigated the gene targets of miR-21. Fresh tumor specimens were used to validate our in vitro findings.

Results

Cisplatin resistant ovarian cells were four-fold more resistant compared to the parental cell line. MiR-21 was overexpressed in the resistant cell line on microRNA microarray, which was subsequently validated with qRT-PCR. Using anti-microRNA inhibitors, we demonstrated that miR-21 attenuation reversed the drug resistant phenotype in both the resistant and parental cell lines. The inhibition of miR-21 induced apoptosis based on annexin V-FITC immunostaining. Using Western blot analysis, miR-21 knockdown enhanced the expression of tumor suppressor PDCD4, and attenuated apoptosis inhibitor c-IAP2. Using 101 specimens from advanced ovarian cancer patients enrolled in The Cancer Genome Atlas, we found that women with tumors that overexpressed miR-21 were associated with a shorter progression-free survival.

Conclusion

Our data suggest that miR-21 regulates drug resistance via apoptosis and cellular survival pathways. Targeting miR-21 may have clinical utility in the treatment of resistant ovarian cancer.     

A prognostic nomogram to predict overall survival in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy

Objective

To develop a nomogram to predict overall survival (OS) in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy.

Methods

A multicenter retrospective study was conducted. Potential prognostic variables included age; stage; grade; histology; performance status; residual disease; presence of ascites and/or pleural effusions; number of chemotherapy regimens, treatment-free interval (TFI) prior to bevacizumab administration, and platinum sensitivity. Multivariate analysis was performed using Cox proportional hazards regression. The predictive model was developed into a nomogram to predict five-year OS.

Results

312 women with recurrent ovarian cancer treated with bevacizumab and chemotherapy were identified; median age was 59 (range: 19–85); 86% women had advanced stage (III–IV) disease. The majority had serous histology (74%), high grade cancers (93.5%), and optimal cytoreductions (69.5%). Fifty-one percent of women received greater than two prior chemotherapeutic regimens. TFI (AHR = 0.98, 95% CI 0.97–1.00, p = 0.022) was the only statistically significant predictor in a multivariate progression-free survival (PFS) analysis. In a multivariate OS analysis, prior number of chemotherapy regimens, TFI, platinum sensitivity, and presence of ascites were significant. A nomogram to predict five-year OS was constructed and internally validated (bootstrap-corrected concordance index = 0.737).

Conclusion

Our multivariate model identified prior number of chemotherapy regimens, TFI, platinum sensitivity, and the presence of ascites as prognostic variables for OS in women with recurrent ovarian cancer treated with bevacizumab combined with chemotherapy. Our nomogram to predict five-year OS may be used to identify women who may benefit from bevacizumab and chemotherapy, but further validation is needed.     

Beijing Genotype of Mycobacterium tuberculosis Is Significantly Associated with High-Level Fluoroquinolone Resistance in Vietnam

Consecutive fluoroquinolone (FQ)-resistant isolates (n = 109) identified at the Pham Ngoc Thach Hospital for Tuberculosis, Ho Chi Minh City, Vietnam, were sequenced in the quinolone resistance-determining regions of the gyrA and gyrB genes and typed by large sequence polymorphism typing and spoligotyping to identify the Beijing genotype of Mycobacterium tuberculosis. Beijing genotype prevalence was compared with 109 consecutive isolates from newly presenting patients with pulmonary tuberculosis from the hospital outpatient department. Overall, 82.6% (n = 90/109) of isolates had mutations in gyrAB. Nine novel mutations were identified in gyrB (S486F, N538T, T539P, D500A, D500H, D500N, G509A, E540V, and E540D). The influence of these novel gyrB mutations on FQ resistance is not proven. The Beijing genotype was significantly associated with FQ resistance (odds ratio [OR], 2.39 [95% confidence interval {CI}, 1.34 to 4.25]; P = 0.003). Furthermore, Beijing genotype FQ-resistant isolates were significantly more likely than FQ-resistant isolates of other genotypes to have gyrA mutations (OR, 7.75 [95% CI, 2.84 to 21.15]; P = 0.0001) and high-level (>8 μg/ml) FQ resistance (OR, 11.0 [95% CI, 2.6 to 47.0]; P = 0.001). The underlying mechanism of the association of the Beijing genotype with high-level FQ resistance in this setting remains to be determined. The association of the Beijing genotype with relatively high-level FQ resistance conferred by specific gyrA mutations reported here is of grave concern given the epidemic spread of the Beijing genotype and the current hopes for shorter first-line treatment regimens based on FQs.Fluoroquinolones (FQs) are the most promising antituberculous therapeutic agents to be developed in 40 years (9, 31). They are widely used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) despite the lack of clinical trials evaluating optimal doses, duration, and combinations (10, 28, 31). Gatifloxacin is currently in phase III trials as a first-line agent to shorten existing treatment regimens from 6 to 4 months (ClinicalTrials.gov identification number {"type":"clinical-trial","attrs":{"text":"NCT00216385","term_id":"NCT00216385"}}NCT00216385 [http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00216385","term_id":"NCT00216385"}}NCT00216385]), and moxifloxacin is in phase III trials as a first-line substitute for either ethambutol (ETH) (ClinicalTrials.gov identification number {"type":"clinical-trial","attrs":{"text":"NCT00082173","term_id":"NCT00082173"}}NCT00082173 [http://clinicaltrials.gov/show/{"type":"clinical-trial","attrs":{"text":"NCT00082173","term_id":"NCT00082173"}}NCT00082173]) or isoniazid (INH) (ISRCTN register number 85595810 [http://www.controlled-trials.com/ISRCTN85595810]; ClinicalTrials.gov identification number {"type":"clinical-trial","attrs":{"text":"NCT00144417","term_id":"NCT00144417"}}NCT00144417 [www.clinicaltrials.gov/show/{"type":"clinical-trial","attrs":{"text":"NCT00144417","term_id":"NCT00144417"}}NCT00144417]).There is concern about levels of preexisting FQ-resistant TB in regions with high drug resistance rates because these drugs are often available over the counter and are additionally prescribed as broad-spectrum antibiotics for the treatment of undiagnosed respiratory infections (4, 5, 11, 17, 23, 27, 29).Vietnam has some of the highest primary drug resistance rates for Mycobacterium tuberculosis in the world, with over 35% of primary isolates being resistant to one or more first-line drugs (21, 26). Despite this, MDR TB rates remain relatively low, at 2.7% nationally, and the National Tuberculosis Program has achieved World Health Organization (WHO) targets for the detection and cure of TB for the last 10 years (14). An expanded MDR TB management program (formally DOTS-PLUS) will be piloted in the near future; however, the success of standardized regimens will depend heavily on preexisting levels of resistance to the most effective second-line agents, the FQs. At present, no data exist on FQ-resistant TB in Vietnam.In mycobacteria, the FQs bind to DNA gyrase and inhibit DNA replication. Reports in the literature show that the majority (approximately 60%) of FQ-resistant M. tuberculosis isolates carry mutations in the quinolone resistance-determining region (QRDR) of the gyrA gene, and a small number have mutations in the gyrB gene (10). It was previously postulated that efflux pump mechanisms account for FQ resistance in isolates with wild-type gyrAB genes (6).While adherence remains the single most important factor in the emergence of drug-resistant TB, a factor contributing to the high prevalence of INH and streptomycin (STR) resistance in the region may be the high prevalence of strains of Mycobacterium tuberculosis of the Beijing genotype (1-3). The Beijing genotype first attracted attention as being the genotype of the strain responsible (W strain) for several large outbreaks of MDR TB in the United States in the early 1990s (28). It is associated with drug resistance and MDR in Vietnam (1, 3).This study investigated the prevalence of the Beijing genotype among FQ-resistant isolates from southern Vietnam and the associated genotypic mutations and MICs of ofloxacin.