Human myogenic cells have limited ability to proliferate in culture. Although forced expression of telomerase can immortalize some cell types, telomerase alone delays senescence of human primary ...cultured myogenic cells, but fails to immortalize them. In contrast, constitutive expression of both telomerase and the E7 gene from human papillomavirus type 16 immortalizes primary human myogenic cells. We have established an immortalized primary human myogenic cell line preserving multipotentiality by ectopic expression of telomerase and E7. The immortalized human myogenic cells exhibit the phenotypic characteristics of their primary parent, including an ability to undergo myogenic, osteogenic, and adipogenic terminal differentiation under appropriate culture conditions. The immortalized cells will be useful for both basic and applied studies aimed at human muscle disorders. Furthermore, immortalization by transduction of telomerase and E7 represents a useful method by which to expand human myogenic cells in vitro without compromising their ability to differentiate.
Model‐based meta‐analysis of dose response is a sophisticated method to guide dose and regimen selection. In this report, the effects of paclitaxel dose and regimen (weekly or every 3 weeks) on the ...efficacy and safety in cancer patients were quantified by model‐based meta‐analysis of 29 monotherapy trials. Logistic regression models were developed to assess the relationship between dose and objective response rate or neutropenia rate. Survival models were developed to assess the relationship between dose and overall survival or progression‐free survival. Paclitaxel efficacy (e.g., objective response rate, median overall survival, and progression‐free survival) is correlated with average dose per week (mg/m2/week), whereas safety (e.g., neutropenia rate) is correlated with dose per administration (mg/m2). Weekly paclitaxel regimen at 65–80 mg/m2 is supported to have comparable to better efficacy and lower neutropenia incidence than an every‐3‐week regimen at 175 mg/m2.
CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e115; doi:10.1038/psp.2014.14; published online 21 May 2014
An extensive experimental survey of the features of the disassembly of a small quasiprojectile system with A{approx}36, produced in the reactions of 47 MeV/nucleon {sup 40}Ar + {sup 27}Al, {sup ...48}Ti, and {sup 58}Ni, has been carried out. Nuclei in the excitation energy range of 1-9 MeV/nucleon have been investigated employing a new method to reconstruct the quasiprojectile source. At an excitation energy {approx}5.6 MeV/nucleon many observables indicate the presence of maximal fluctuations in the deexcitation processes. These include the normalized second moments of the Campi plot and normalized variances of the distributions of order parameters such as the atomic number of the heaviest fragment Z{sub max} and the total kinetic energy. The evolution of the correlation of the atomic number of the heaviest fragment with that of the second heaviest fragment and a bimodality test are also consistent with a transition in the same excitation energy region. The related phase separation parameter, S{sub p}, shows a significant change of slope at the same excitation energy. In the same region a {delta}-scaling analysis for of the heaviest fragments exhibits a transition to {delta} = 1 scaling, which is predicted to characterize a disordered phase. The fragment topological structure shows that the rank-sorted fragments obey Zipf's law at the point of largest fluctuations, providing another indication of a liquid gas phase transition. The Fisher droplet model critical exponent {tau} {approx} 2.3 obtained from the charge distribution at the same excitation energy is close to the critical exponent of the liquid gas phase transition universality class. The caloric curve for this system shows a monotonic increase of temperature with excitation energy and no apparent plateau. The temperature at the point of maximal fluctuations is 8.3{+-}0.5 MeV. Taking this temperature as the critical temperature and employing the caloric curve information we have extracted the critical exponents {beta},{gamma}, and {sigma} from the data. Their values are also consistent with the values of the universality class of the liquid gas phase transition. Taken together, this body of evidence strongly suggests a phase change in an equilibrated mesoscopic system at, or extremely close to, the critical point.
A method is presented for the measurement of differential cross-sections of heavy ion elastic scattering induced by Radioactive Ion Beams (RIBs) on the Radioactive Ion Beam Line in Lanzhou (RIBLL) at ...the Heavy-Ion Research Facility in Lanzhou (HIRFL). The disadvantages of broad beam profiles and limited intensities of the RIBs were overcome using large area detectors, two Parallel-Plate Avalanche Counters (PPACs), two double-sided silicon strip detector (DSSD) telescopes, incorporated with Monte Carlo simulations. The PPACs were used to determine the direction and position of the beam particles. The DSSD telescopes were used to measure scattered particles. Small corrections for the misalignment of detectors and the data normalization were made by assuming the pure Rutherford scattering at very forward angles. The method is suitable for the measurement of the cross-sections on heavy targets at low and intermediate energies, and it has been successfully applied to measure the angular distribution of elastic scattering of 7Be on Pb target at Elab=17.9MeV/u.
Calculations using astrophysical equations of state at low densities comparable to that of the neutrino emission surface in supernovae and accretion disks are confronted with experimental results ...from heavy ion collisions. An extension of previous work shows that it is important to include all of the measured experimental data to draw conclusions about the astrophysical equation of state. Armed with this information, the calculations of the astrophysical equation of state are significantly constrained. Predictions of temperatures and densities sampled in black hole accretion disks are compared to those sampled in the experimental data.
Cardiac mortality in Duchenne muscular dystrophy (DMD) has recently become important, because risk of respiratory failure has been reduced due to widespread use of the respirator. The cardiac ...involvement is characterized by distinctive electrocardiographic abnormalities or dilated cardiomyopathy, but the pathogenesis has remained obscure. In research on DMD, Golden retriever-based muscular dystrophy (GRMD) has attracted much attention as an animal model because it resembles DMD, but GRMD is very difficult to maintain because of their severe phenotypes. We therefore established a line of dogs with Beagle-based canine X-linked muscular dystrophy in Japan (CXMDJ) and examined the cardiac involvement.
The cardiac phenotypes of eight CXMDJ and four normal male dogs 2 to 21 months of age were evaluated using electrocardiography, echocardiography, and histopathological examinations.
Increases in the heart rate and decreases in PQ interval compared to a normal littermate were detected in two littermate CXMDJ dogs at 15 months of age or older. Distinct deep Q-waves and increase in Q/R ratios in leads II, III, and aVF were detected by 6-7 months of age in all CXMDJ dogs. In the echocardiogram, one of eight of CXMDJ dogs showed a hyperechoic lesion in the left ventricular posterior wall at 5 months of age, but the rest had not by 6-7 months of age. The left ventricular function in the echocardiogram indicated no abnormality in all CXMDJ dogs by 6-7 months of age. Histopathology revealed myocardial fibrosis, especially in the left ventricular posterobasal wall, in three of eight CXMDJ dogs by 21 months of age.
Cardiac involvement in CXMDJ dogs is milder and has slower progression than that described in GRMD dogs. The distinct deep Q-waves have been ascribed to myocardial fibrosis in the posterobasal region of the left ventricle, but our data showed that they precede the lesion on echocardiogram and histopathology. These findings imply that studies of CXMDJ may reveal not only another causative mechanism of the deep Q-waves but also more information on the pathogenesis in the dystrophin-deficient heart.
Purpose
This study evaluated factors impacting QTc interval in a phase 3 trial of cabozantinib in progressive, metastatic, medullary thyroid cancer (MTC).
Methods
Electrocardiogram (12-lead ECG) ...measurements were obtained at screening, and at pre-dose, and 2, 4, and 6 h post-dose on Days 1 and 29 in a phase 3 study in patients with MTC treated with cabozantinib (140 mg/day). Central tendency analyses were conducted on baseline-corrected QTc values. Linear and nonlinear mixed-effects models were used to evaluate potential factors affecting the QTc interval, including serum electrolytes, patient demographics, and cabozantinib concentration.
Results
Central tendency analysis showed that oral cabozantinib (140 mg/day) produced a 10–15 ms increase in delta–delta Fridericia corrected QT (∆∆QTcF) and delta–delta study-specific corrected QT (∆∆QTcS) on Day 29, but not on Day 1. Further analysis showed that QTcS provided a slightly more accurate QT correction than QTcF. Mixed-effects models evaluating serum electrolytes, age, sex, and cabozantinib concentration showed that decreased serum calcium and potassium could explain the majority of cabozantinib treatment-associated QTcS prolongation observed in this study.
Conclusions
Cabozantinib treatment prolongs the ∆∆QTcF interval by 10–15 ms. There was the absence of a strong relationship between cabozantinib concentration and QTcS prolongation. Cabozantinib treatment effects on serum calcium and potassium best explain the QTcS prolongation observed in this study.
The National Marrow Donor Program (NMDP) receives federal funding to operate a registry of over 4 million volunteer donors for patients in need of a hematopoietic stem cell transplant. Because ...minority patients are less likely to find a suitably matched donor than whites, special efforts have been aimed toward recruitment of minorities. Significant financial resources are required to recruit and tissue type additional volunteer donors.
Population genetics models have been constructed to project likelihoods of finding a human leukocyte antigen (HLA)-matched donor for patients of various racial/ethnic groups. These projections have been made under a variety of strategies for expansion of the NMDP Registry. Cost-effectiveness calculations incorporated donor unavailability and other barriers to transplantation.
At current recruitment rates, the probability of an available HLA-A,B,DRB1 matched donor is projected to increase from 27% to 34%; 45% to 54%; 75% to 79%; and 48% to 55%, for blacks, Asians/Pacific Islanders, whites and Hispanics, respectively, by the year 2007. Substantial increases in minority recruitment would have only modest impacts on these projections. These projections are heavily affected by donor availability rates, which are less than 50% for minority volunteers.
Continued recruitment of additional volunteers can improve the likelihood of finding an HLA-matched donor, but will still leave significant numbers of patients of all racial/ethnic groups without a match. Efforts to improve donor availability (especially among minorities) and to increase the number of patients with access to the NMDP Registry may prove to be more cost-effective means of increasing transplants.
The Goto-Kakizaki (GK) rat is a spontaneously diabetic animal model of non-insulin-dependent diabetes mellitus, which is characterized by progressive loss of β cells in the pancreatic islets with ...fibrosis. In the present study, we examined the effects of sucrose feeding on the islet pathology in this model. Six-week-old GK rats were fed with 30% sucrose for 6 weeks to induce severe hyperglycemia, and their condition was compared with that of nontreated rats. Age-matched normal Wistar rats were also given sucrose for the same periods and used for comparison. The sucrose-treated GK rats showed elevated blood glucose levels on oral glucose tolerance tests at 60 minutes and 120 minutes, representing 123% and 127% of values in untreated GK rats, respectively. At the end of the study, the mean β-cell volume density in GK rats was 50% less than that in untreated Wistar rats. Sucrose feeding further reduced the volume densities of β cells to only 50% of the levels of age-matched GK rats. Apoptotic cells were found in islet β cells only in GK rats fed sucrose (mean 0.067%). There appeared to be more islets that immunohistochemically stained strongly positive with 8-hydroxy-deoxyguanosine as a marker of oxidative damage of DNA in GK rats fed sucrose compared with those not given sucrose. GK rats not fed sucrose showed significantly lower proliferative activity of β cells measured by 5-bromo-2′-deoxyuridine uptake and intensified expression of Bcl-2 immunoreactivities at 6 weeks of age compared with those in age-matched Wistar rats. These two indices were reduced in both GK and Wistar rats with increasing age and were not affected by sucrose feeding in either group. The present study thus indicated that sucrose feeding promoted the apoptosis of β cells in GK rats through increased oxidative stress without altering their proliferative activity.
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