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Concept: Doubling time


Purpose: To identify patient characteristics and magnetic resonance (MR) imaging findings associated with subsequent hypervascularization in hypovascular nodules that show hypointensity on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with chronic liver diseases. Materials and Methods: Institutional review board approval was obtained, and informed consent was waived. At multiple follow-up gadoxetic acid-enhanced MR imaging examinations of 68 patients, 160 hypovascular nodules were retrospectively reviewed. A Cox regression model for hypervascularization was developed to explore the association of baseline characteristics, including patient factors (Child-Pugh classification, etiology of liver disease, history of local therapy for hepatocellular carcinoma [HCC], and coexistence of hypervascular HCC) and MR imaging findings (fat content, signal intensity on T2-weighted images, and nodule size). In addition, the growth rate was calculated as the reciprocal of tumor volume doubling time to investigate its relationship with subsequent hypervascularization by using receiver operating characteristic and Kaplan-Meier analyses. Results: The prevalence of subsequent hypervascularization was 31% (50 of 160 nodules). Independent Cox multivariable predictors of increased risk of hypervascularization were hyperintensity on T2-weighted images (hazard ratio [HR] = 8.7; 95% confidence interval [CI]: 3.6, 20.8), previous local therapy for hypervascular HCC (HR = 5.0; 95% CI: 1.8, 13.6), Child-Pugh B cirrhosis (HR = 3.6; 95% CI: 1.4, 9.5) and coexistence of hypervascular HCC (HR = 2.0; 95% CI: 1.0, 3.8). The mean growth rate was significantly higher in nodules that showed subsequent hypervascularization than in those without hypervascularization. Kaplan-Meier analysis based on the receiver operating characteristic cutoff level (1.8 × 10(-3)/day [tumor volume doubling time, 542 days]) showed that nodules with a higher growth rate had a significantly higher incidence of hypervascularization (P = 5.2 × 10(-8), log-rank test). Conclusion: Hyperintensity on T2-weighted images is an independent and strong risk factor at baseline for subsequent hypervascularization in hypovascular nodules in patients with chronic liver disease. Tumor volume doubling time of less than 542 days was associated with a high rate of subsequent hypervascularization. © RSNA, 2013.

Concepts: Epidemiology, Cancer, Proportional hazards models, Cirrhosis, Magnetic resonance imaging, Liver disease, Chronic liver disease, Doubling time


The current study was conducted to better characterize the association between overall survival (OS) from metastatic thyroid cancer and the rate of structural disease progression.

Concepts: Cancer, Breast cancer, Metastasis, Oncology, Lung cancer, Prostate cancer, Types of cancer, Doubling time


The study objectives include, enhancing the proliferations of aged bone marrow stem cells (BMSCs) and adipose stem cells (ADSCs); and evaluating the shelf lives of clinical grade chondrogenically induced cells from both samples. ADSCs and BMSCs from 56 patients (76 ± 8 yrs) were proliferated using basal medium (FD) and at (5, 10, 15, 20 and 25) ng/ml of basal fibroblast growth factor (bFGF). They were induced to chondrogenic lineage and stored for more than 120 hrs in FD, serum, Dulbecco’s phosphate buffered saline (DPBS) and saline at 4 °C. In FD, cells stagnated and BMSCs' population doubling time (PDT) was 137 ± 30 hrs, while ADSCs' was 129.7 ± 40 hrs. bFGF caused PDT’s decrease to 24.5 ± 5.8 hrs in BMSCs and 22.0 ± 6.5 hrs in ADSCs (p = 0.0001). Both cells were positive to stem cell markers before inductions and thereafter, expressed significantly high chondrogenic genes (p = 0.0001). On shelf life, both cells maintained viabilities and counts above 70% in FD and serum after 120 hrs. BMSCs' viabilities in DPBS fell below 70% after 96 hrs and saline after 72 hrs. ADSCs' viability fell below 70% in DPBS after 24 hrs and saline within 24 hrs. Concentrations between 20 ng/ml bFGF is ideal for aged adult cells' proliferation and delivery time of induced BMSCs and ADSCs can be 120 hrs in 4 °C serum.

Concepts: Stem cell, Bone marrow, Cellular differentiation, Fibroblast growth factor, Adult stem cell, Stem cell marker, Basic fibroblast growth factor, Doubling time


The goal of this work was to develop a mathematical model to predict Kaplan-Meier survival curves for chemotherapy combined with radiation in Non-Small Cell Lung Cancer patients for use in clinical trial design. The Gompertz model was used to describe tumor growth, radiation effect was simulated by the linear-quadratic model with an α/β-ratio of 10, and chemotherapy effect was based on the log-cell kill model. To account for repopulation during treatment, we considered two independent methods: 1) kickoff-repopulation using exponential growth with a decreased volume doubling time, or 2) Gompertz-repopulation using the gradually accelerating growth rate with tumor shrinkage. The input parameters were independently estimated by fitting to the SEER database for untreated tumors, RTOG-8808 for radiation only, and RTOG-9410 for sequential chemo-radiation. Applying the model, the benefit from concurrent chemo-radiation comparing to sequential for stage III patients was predicted to be a 6.6% and 6.2% improvement in overall survival for 3 and 5-years respectively, comparing well to the 5.3% and 4.5% observed in RTOG-9410. In summary, a mathematical model was developed to model tumor growth over extended periods of time, and can be used for the optimization of combined chemo-radiation scheduling and sequencing.

Concepts: Scientific method, Clinical trial, Cancer, Oncology, Lung cancer, Chemotherapy, Radiation therapy, Doubling time


We report a semiautomated synthesis of sequence and architecturally defined, unimolecular macromolecules through a marriage of multistep flow synthesis and iterative exponential growth (Flow-IEG). The Flow-IEG system performs three reactions and an in-line purification in a total residence time of under 10 min, effectively doubling the molecular weight of an oligomeric species in an uninterrupted reaction sequence. Further iterations using the Flow-IEG system enable an exponential increase in molecular weight. Incorporating a variety of monomer structures and branching units provides control over polymer sequence and architecture. The synthesis of a uniform macromolecule with a molecular weight of 4,023 g/mol is demonstrated. The user-friendly nature, scalability, and modularity of Flow-IEG provide a general strategy for the automated synthesis of sequence-defined, unimolecular macromolecules. Flow-IEG is thus an enabling tool for theory validation, structure-property studies, and advanced applications in biotechnology and materials science.

Concepts: Molecule, Polymer chemistry, Engineering, Exponential growth, Geometric progression, Doubling time


We have previously reported characteristics of canine corneal epithelial cells in vitro and found that canine corneal epithelial cells could maintain their proliferative capacity even after continuous culture without the use of feeder cells and growth promoting additives. The objective of this study was to elucidate proliferative characteristics of canine corneal epithelial cells independent of feeder cells and growth promoting additives, with the aim of developing a spontaneously derived corneal epithelial cell line. Canine and rabbit corneal epithelial cells were harvested from the limbus and cultured with, or without, feeder cells and growth promoting additives, and both were passaged continuously until growth arrest. Canine corneal epithelial cells could proliferate independently, and could be passaged more times than rabbit cells. A canine corneal epithelial cell line, cCEpi, which could be passaged more than 100 times without using feeder cells and growth promoting additives, was established. cCEpi cells maintained a cell morphology close to the primary culture and expressed p63, cytokeratin 15 (K15), and K3. Although changes in colony morphology, shortening of the population doubling time and a heteroploid karyotype were observed, cCEpi was not tumorigenic. Stratified cell sheets cultured from cCEpi were morphologically and immunohistologically similar to sheets cultivated from early passage cells. In conclusion, canine corneal epithelial cells can proliferate independent of feeder cells and growth promoting additives. cCEpi maintains properties similar to normal corneal epithelial cells and could be a useful source for studies in cellular biology and for developing novel therapies.

Concepts: Cell, Cell biology, Epithelium, Cell culture, Endothelium, Cornea, Corneal epithelium, Doubling time


OBJECTIVE The optimal adjuvant management for atypical meningiomas remains controversial. The aim of this study was to review long-term outcomes to identify potential prognostic factors for disease progression. METHODS From August 1992 to August 2013, 70 patients with atypical meningioma were treated at the authors' institution. Pathology revision was performed based on WHO 2007 criteria. Patients with multiple tumors, neurofibromatosis Type 2, or inadequate imaging follow-up were not eligible. The authors performed pre- and postoperative serial measurements of tumor volume from MRI. Age, sex, tumor location, bone involvement, brain invasion, mitotic figures, preoperative disease volume, extent of resection, tumor growth rates, use of adjuvant postoperative radiation therapy (PORT), and residual tumor volume at the time of radiation therapy (RT) were assessed by univariate and multivariate analysis to determine their potential impact on disease progression. RESULTS Forty patients (57%) underwent gross-total resection (GTR) and 30 (43%) underwent subtotal resection (STR). PORT was delivered to 12 patients (30%) with a GTR and in only 4 (13%) with an STR. The 5-year progression-free survival (PFS) rate for patients in the GTR group with or without PORT was 100% and 54.1%, respectively (p = 0.0058). PFS for patients in the STR group with or without PORT was 75% and 0%, respectively (p = 0.0026). On multivariate analysis, STR and PORT were the only independent significant prognostic factors for disease progression with hazard ratios of 5.4873 (95% CI 2.19-13.72, p = 0.0003) and 0.0464 (95% CI 0.0059-0.364, p = 0.0035), respectively. Based on Youden’s index statistic, a cutoff residual tumor volume of more than 8.76 cm3 at the time of RT was associated with worse PFS (13.6% vs 56%, p = 0.0079). Before receiving RT, the median relative and absolute growth rates and tumor doubling time for patients were 124.2%/year, 4.8 cm3/year, and 1.67 years, respectively. These indices changed after RT to 0.245%/year, -0.09 cm3/year, and -0.005 year, respectively (p < 0.05). CONCLUSIONS In atypical meningioma, the use of PORT is associated with improved PFS even in patients who undergo GTR. Patients with residual tumor volume larger than 8.76 cm3 have an increased risk of disease progression and should be considered for early RT.

Concepts: Cancer, Oncology, Brain tumor, Multivariate statistics, Meningioma, Population growth, Neurofibromatosis type II, Doubling time


Skin vitrification is a promising and alternative tool for the conservation of biodiversity, especially for wild mammals, such as collared peccaries. Several factors can affect the success of this procedure, such as the cryoprotectant solution used. Therefore, this study was carried out to compare the efficiency of various vitrification solutions for recovery of viable cells after in vitro culture of cryopreserved skin tissues derived from the collared peccary, aiming to study the application in biobanking, where cellular use is not immediately required. Then, Dulbecco’s modified Eagle’s medium (DMEM) composed of 2.2 g/L sodium bicarbonate and 10% fetal bovine serum (FBS) was supplemented with 3.0 M ethylene glycol (EG) or 3.0 M dimethyl sulfoxide (DMSO) or 1.5 M EG plus 1.5 M DMSO with or without sucrose (SUC; 0.25 M) to produce six solutions for solid-surface vitrification. After warming, skin tissues were cultured in vitro and recovered cells were analyzed for morphology, adhesion, subconfluence, and proliferative activity for developing the growth curve and determining the population doubling time (PDT), and viability by Trypan Blue. The vitrification did not alter the ability of the tissues to adhere to the culture dish, as well as the day of all explants with cell growth, subconfluence samples, subconfluence total time, and PDT (p > 0.05). Moreover, independent of the cryoprotectant solution used, the vitrification altered the day of all attached explants (p < 0.05). Nevertheless, for viability after the first passage, only the EG-SUC (86.9%) and DMSO-SUC (91.4%) groups maintained viable cell recovery similar to the nonvitrified group (96.3%, p > 0.05). Additionally, for viability after the third passage, only the EG-SUC group maintained the cell quality (88.3%), when compared with the nonvitrified (97.8%, p > 0.05). In conclusion, DMEM with 10% FBS, 3.0 M EG, and 0.25 M sucrose was the most efficient solution for vitrifying collared peccary skin tissues, leading to the in vitro culture of viable cells.

Concepts: Dimethyl sulfoxide, Exponential growth, Cryobiology, Cryoprotectant, Doubling time, Collared Peccary, Pecari, Peccary


An expression for the surviving fraction of a replicating population of cells exposed to permanently incorporated radionuclide is derived from the microdosimetric-kinetic model. It includes dependency on total implant dose, linear energy transfer (LET), decay rate of the radionuclide, the repair rate of potentially lethal lesions in DNA and the volume doubling time of the target population. This is used to obtain an expression for the biologically effective dose (BEDα/β) based on the minimum survival achieved by the implant that is equivalent to, and can be compared and combined with, the BEDα/β calculated for a fractionated course of radiation treatment. Approximate relationships are presented that are useful in the calculation of BEDα/β for alpha- or beta-emitting radionuclides with half-life significantly greater than, or nearly equal to, the approximately 1-h repair half-life of radiation-induced potentially lethal lesions.

Concepts: DNA, Ionizing radiation, Organism, Radioactive decay, Binary relation, Half-life, Radioactivity, Doubling time


The treatment of seeds with systemic insecticides has become a common practice worldwide. However, this prophylactic use of insecticides has been questioned recently because of the potential risks to non-target organisms. This study assessed the non-target effects of chlorantraniliprole and thiamethoxam seed treatments on the life history and walking behavior of Podisus nigrispinus (Dallas), as well as the efficacy of these insecticides for controlling Spodoptera frugiperda (Smith). Thiamethoxam caused mortality of P. nigrispinus, increased the pre-oviposition period, and reduced the oviposition period and the fecundity and survival of females compared to chlorantraniliprole. In contrast, the life expectancy of P. nigrispinus females was prolonged by chlorantraniliprole, which also increased the intrinsic rate of growth (rm) and the finite growth rate (λ), and reduced the population doubling time (DT) compared to thiamethoxam. The net reproductive rate (R0) and mean generation time (T) were not affected by either insecticide treatment, and neither were the walking velocity of P. nigrispinus females, nor the distance they covered. Both chlorantraniliprole and thiamethoxam reduced soybean leaf consumption by S. frugiperda larvae. Given the observed lethal and sublethal effects, soybean seed treatments with chlorantraniliprole and thiamethoxam were judged to present low and moderate risks for P. nigrispinus, respectively.

Concepts: Reproduction, Half-life, Population growth, Army worm, Spodoptera, Doubling time