Proton radiotherapy has seen an increasing role in the treatment of hepatocellular carcinoma (HCC). Historically, external beam radiotherapy has played a very limited role in HCC due to a high incidence of toxicity to surrounding normal structures. The ability to deliver a high dose of radiation to the tumor is a key factor in improving outcomes in HCC. Advances in photon radiotherapy have improved dose conformity and allowed dose escalation to the tumor. However, despite these advances there is still a large volume of normal liver that receives a considerable radiation dose during treatment. Proton beams do not have an exit dose along the beam path once they enter the body. The inherent physical attributes of proton radiotherapy offer a way to maximize tumor control via dose escalation while avoiding excessive radiation to the remaining liver, thus increasing biological effectiveness. In this review we discuss the physical attributes and rationale for proton radiotherapy in HCC. We also review recent literature regarding clinical outcomes of using proton radiotherapy for the treatment of HCC.

Over the past decade, a growing community of researchers has emerged around the use of COnstraint-Based Reconstruction and Analysis (COBRA) methods to simulate, analyze and predict a variety of metabolic phenotypes using genome-scale models. The COBRA Toolbox, a MATLAB package for implementing COBRA methods, was presented earlier. Here we present a significant update of this in silico ToolBox. Version 2.0 of the COBRA Toolbox expands the scope of computations by including in silico analysis methods developed since its original release. New functions include: (1) network gap filling, (2) 13C analysis, (3) metabolic engineering, (4) omics-guided analysis, and (5) visualization. As with the first version, the COBRA Toolbox reads and writes Systems Biology Markup Language formatted models. In version 2.0, we improved performance, usability, and the level of documentation. A suite of test scripts can now be used to learn the core functionality of the Toolbox and validate results. This Toolbox lowers the barrier of entry to use powerful COBRA methods.

Background

The 5 G/5 G genotype of PAI-1 polymorphism is linked to decreased plasminogen activator inhibitor-1 (PAI-1) levels and it has been suggested that lower PAI-1 levels may provide protective effects on inflammation, local microcirculatory disturbance, and fibrotic changes, which are likely associated with development of sudden sensorineural hearing loss (SSNHL).

Methods

The association of the 4 G/5 G PAI-1 polymorphism with the development and clinical outcome of SSNHL is evaluated via a case control study. 103 patients with SSNHL and 113 age and sex-matched controls were enrolled at University of Ferrara, Italy and hearing loss outcome was measured at least 3 months after the onset of hearing loss. DNA was isolated from peripheral blood using the QIAamp kit and the 4 G/5 G polymorphism in the −675 promoter region was genotyped with an allele-specific PCR. Genotype distribution was tested in patients and compared to controls by chi-square and odd-ratio analysis. The codominant and recessive models were used for the multiple logistic regression analyses of the PAI-1 gene allele.

Results

In this population, 5 G/5 G genotype had a two-time lower frequency in SSNHL patients compared to healthy controls (15.5% vs 30.1%) and was associated with decreased odds compared to 4 G/5 G genotype (OR 0.37, 95% CI 0.19-0.75, p = 0.005). In addition, the patients with 5 G/5 G genotype showed a trend of more than 2 times higher ratio of hearing recovery (> 20 dB) after systemic corticosteroid treatment compared to 4 G/5 G genotype (OR 2.3, 95% CI 0.32 - 16.83, p = 0.39), suggesting a better clinical outcome.

Conclusions

The 5 G/5 G genotype of PAI-1 may be associated with a reduced risk of SSNHL in the Italian population.

Even among asymptomatic people at low risk (<10%) by Framingham Risk Score (FRS), high coronary artery calcium (CAC) scores signify higher predicted risk of coronary heart disease (CHD) events. We sought to determine non-invasive factors (without radiation exposure) significantly associated with CAC in low-risk, asymptomatic persons. In a cross-sectional analysis, we studied 3046 participants from MESA at low 10-year predicted risk (FRS <10%) for CHD events. Multivariable logistic regression was used to assess the association of novel markers with presence of any CAC (CAC >0) and advanced CAC (CAC ≥ 300). CAC >0 and CAC ≥ 300 were present in 30% and 3.5% of participants, respectively. Factor VIIIc, fibrinogen and sICAM were each associated with CAC presence (P ≤ 0.02); and C-reactive protein, D-dimer and carotid intima-media thickness (CIMT) with advanced CAC (P ≤ 0.03). The base model combining traditional risk factors had excellent discrimination for advanced CAC (C-statistic, 0.808). Addition of the 2 best-fit models combining biomarkers plus/minus CIMT improved the c-statistics to 0.822 and 0.820, respectively. All 3 models calibrated well, but were similar in estimating individual risk probabilities for advanced CAC (prevalence = 9.97%, 10.63% and 10.10% in the highest quartiles of predicted probabilities versus 0.26%, 0.26% and 0.26% in the lowest quartiles, respectively). In conclusion, in low risk individuals, traditional risk factors alone predicted advanced CAC with high discrimination and calibration. Biomarker combinations +/− CIMT were also significantly associated with advanced CAC, but improvement in prediction and estimation of clinical risk were modest compared to traditional risk factors alone.

The efficacy and toxicity of high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) were investigated for improving the outcomes of patients with relapsed medulloblastoma. A total of 15 patients with relapsed medulloblastoma were enrolled in the KSPNO-S-053 study from May 2005 to May 2007. All patients received approximately 4 cycles of salvage chemotherapy after relapse. Thirteen underwent HDCT/ASCT; CTE and CM regimen were employed for the first HDCT (HDCT1) and second HDCT (HDCT2), respectively, and 7 underwent HDCT2. One transplant related mortality (TRM) due to veno-occlusive disease (VOD) occurred during HDCT1 but HDCT2 was tolerable with no further TRM. The 3-yr overall survival probability and event-free survival rates ±95% confidence intervals (CI) were 33.3±12.2% and 26.7% ±11.4%, respectively. When analysis was confined to only patients who had a complete response (CR) or partial response (PR) prior to HDCT, the probability of 3-yr overall survival rates ±95% CI was 40.0±15.5%. No patients with stable disease (SD) or progressive disease (PD) survived. Survival rates from protocol KSPNO-S-053 are encouraging and show that tumor status prior to HDCT/ASCT is an important factor to consider for improving survival rates of patients with relapsed medulloblastoma.

Purpose

To investigate associations of procoagulants (FVII, FVIII, von Willebrand factor [vWF]) with subclinical atherosclerosis, we examined participants in The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Methods

Clotting factor assays were performed in 1254 participants ages 23–37 (baseline) and repeated at ages 38–50 (follow-up). Carotid intima-media thickness (IMT) was measured at follow-up.

Results

Baseline levels of procoagulants (%): mean (SD) were: FVII: 76(18), FVIII: 102(38), and vWF: 108(47). At follow-up, all had increased by 40%–55%. After age adjustment, mean common carotid (CC) IMT increased from the lowest to the highest tertile of FVII in the total group (0.787 to 0.801, P=0.007), in whites (0.772 to 0.790, P=0.002), and in men (0.807 to 0.827, P=0.015). All associations were attenuated by multivariable adjustment. However, participants with FVII values in the highest tertile at one or both examinations, as compared with those in the lowest tertile, had greater CC-IMT after age and multivariable adjustment (0.806 versus 0.778, P<0.05). Baseline FVIII was associated with greater internal carotid (IC) IMT in the total group, in whites, and in women after age but not multivariable adjustment. No associations were seen for vWF.

Conclusions

FVII is associated with CC-IMT in young adults, but the strength of the association is modified by other cardiovascular disease risk factors, such as body mass index. FVIII is associated with IC IMT only in age-adjusted analyses, and no associations were observed for vWF.

Perturbations in cytosine methylation signals are observed in the majority of human tumors; however, it is as yet unknown how methylation patterns become altered. Epigenetic changes can result in the activation of transforming genes as well as in the silencing of tumor suppressor genes. We report that methyl-CpG-binding proteins (MBPs), specific for methyl-CpG dinucleotides, bind with high affinity to halogenated pyrimidine lesions, previously shown to result from peroxidase-mediated inflammatory processes. Emerging data suggest that the initial binding of MBPs to methyl-CpG sequences may be a seeding event that recruits chromatin-modifying enzymes and DNA methyltransferase, initiating a cascade of events that result in gene silencing. MBD4, a protein with both methyl-binding and glycosylase activity demonstrated repair activity against a series of 5-substituted pyrimidines, with the greatest efficiency against 5-chlorouracil, but undetectable activity against 5-chlorocytosine. The data presented here suggest that halogenated pyrimidine damage products can potentially accumulate and mimic endogenous methylation signals.