In this issue of the Biomedical Journal, we take a look at some of the benefits of proton therapy, which is an emerging technique in cancer treatment and highlight an animal study, showing that a common fruit ripening agent is toxic when used in excessive doses. Finally, this issue includes reports that shed light on the genetics of stroke and childhood leukemia.

Caveolae are small invaginations of the plasma membrane in cells. In addition to their classically described functions in cell signaling and membrane trafficking, it was recently shown that caveolae act also as plasma membrane sensors that respond immediately to acute mechanical stresses. Caveolin 1 (Cav1), the main component of caveolae, is a multifunctional scaffolding protein that can remodel the extracellular environment. Caveolae dysfunction, due to mutations in  caveolins, has been linked to several human diseases called "caveolinopathies," including muscular dystrophies, cardiac disease, infection, osteoporosis, and cancer. The role of caveolae and/or Cav1 remains controversial particularly in tumor progression. Cav1 function has been associated with several steps of cancerogenesis such as tumor growth, cell migration, metastasis, and angiogenesis, yet it was observed that Cav1 could affect these steps in a positive or negative manner. Here, we discuss the possible function of caveolae and Cav1 in tumor progression in the context of their recently discovered role in cell mechanics.

Cancer is a worldwide health problem leading to a high incidence of morbidity and mortality. Malignant transformation can occur by expression of oncogenes, over-expression and deregulated activation of proto-oncogenes, and inactivation of tumor suppressor genes. These cellular actions occur through stimulation of oncogenic signaling pathways. Nitric oxide (NO) can induce genetic changes in cells and its intracellular generation can lead to tumor formation and progression. It can also promote anti-tumor activities. The pro- and anti-tumor activities of NO are dependent on its intracellular concentration, cell compartmentalization, and cell sensitivity. NO affects a number of oncogenic signaling pathways. This review focuses on two oncogenic signaling pathways: NO-EGFR-Src-FAK and NO-Ras-EGFR-ERK1/2 MAP kinases. In these pathways, low to intermediate concentrations of NO/S-nitrosothiols (RSNOs) stimulate oncogenic signaling, while high concentrations of NO/RSNO stimulate anti-oncogenic signaling. Increasing knowledge on pro- and anti-tumorigenic activities of NO and related reactive species such as RSNOs has fostered the research and synthesis of novel NO-based chemotherapeutic agents. RSNOs, effective as NO donors and trans-nitrosylating agents under appropriate conditions, may operate as potential chemotherapeutic agents.

The potential benefits of proton therapy have been established in pediatric cancer, skull base tumor, uveal melanoma, and other types of cancers. Western and Asian countries, however, have differences in the pattern of cancer incidence; this leads to the difference in patient demographics for proton therapy. Furthermore, the advancement of the scanning beam technique in proton therapy greatly expands the capability of proton therapy in disease sites with great complexity. In this review, we focus on the cancers with high incidence in Taiwan, based on the Cancer Registry Annual Report, 2011, Taiwan. The potential case number and clinical benefits from proton therapy are evaluated and discussed. Two endemic cancers, hepatocellular carcinoma and head and neck cancer, are considered to be the major disease types appropriate for proton therapy in Taiwan. Primary lung cancer and left side breast cancer, which are popular in western countries as well as in Taiwan, are included for discussion. The issue of cost-effectiveness for proton therapy is also reviewed. Finally, we point out the clinical trials that should be conducted for proton therapy in Taiwan.

When compared to photon beams, particle beams have distinct spatial distributions on the energy depositions in both the macroscopic and microscopic volumes. In a macroscopic volume, the absorbed dose distribution shows a rapid increase near the particle range, that is, Bragg peak, as particle penetrates deep inside the tissue. In a microscopic volume, individual particle deposits its energy along the particle track by producing localized ionizations through the formation of clusters. These highly localized clusters can induce complex types of deoxyribonucleic acid (DNA) damage which are more difficult to repair and lead to higher relative biological effectiveness (RBE) as compared to photons. To describe the biological actions, biophysical models on a microscopic level have been developed. In this review, microdosimetric approaches are discussed for the determination of RBE at different depths in a patient under particle therapy. These approaches apply the microdosimetric lineal energy spectra obtained from measurements or calculations. Methods to determine these spectra will be focused on the tissue equivalent proportional counter and the Monte Carlo program. Combining the lineal energy spectrum and the biological model, RBE can be determined. Three biological models are presented. A simplified model applies the dose-mean lineal energy and the measured RBE (linear energy transfer) data. A more detailed model makes use of the full lineal energy spectrum and the biological weighting function spectrum. A comprehensive model calculates the spectrum-averaged yields of DNA damages caused by all primary and secondary particles of a particle beam. Results of these models are presented for proton beams.

Background: The stopping power and range tables published by the National Institute of Standards and Technology (NIST) were obtained by assuming continuous slowing down approximation (CSDA). This study examined more detail depth dose characteristics of ideal proton beams using the particle therapy simulation framework (PTSim) Monte Carlo technique. Methods: Simulation for parallel broad field geometry (PBFG) was replaced by the pencil beam geometry (PBG) for improved simulation efficiency. Depth dose distributions (Bragg peak, BP) for beam energies from 69.44 to 230.71 MeV at 5 mm range interval were obtained. This study used seven parameters, R _peak, R ₉₀, R ₈₀, R ₅₀, full width at half maximum (FWHM), W _80-20, and peak-to-entrance ratio to represent BP characteristics. The resulting energy-range relationships were fitted into third order polynomial formulae. In addition, initial beam energy spreads at 0-1% (1σ) of the mean incident energies at 70, 110, 150, 190, and 230 MeV were added into the simulation to uncover their impact on BP shapes. Results: The study results reveal deeper penetration, broader FWHM and decreased peak-to-entrance dose ratio at increasing beam energy. Study results for beams with initial energy spreads show that R ₈₀ can be a good indicator to characterize initial mean energy. They also suggest FWHM is more sensitive than the width of 80-to-20% distal fall-off in finding initial energy spread. Conclusion: Detail depth dose characteristics for monoenergetic proton beams and beams with initial energy spreads within therapeutic energy ranges were reported. These data can serve as a good reference for a clinical practitioner in their daily practice.

Background: This study presents the Monte Carlo N-Particles Transport Code, Extension (MCNPX) simulation of proton dose distributions in a water phantom. Methods: In this study, fluence and dose distributions from an incident proton pencil beam were calculated as a function of depth in a water phantom. Moreover, lateral dose distributions were also studied to understand the deviation among different MC simulations and the pencil beam algorithm. MCNPX codes were used to model the transport and interactions of particles in the water phantom using its built-in "repeated structures" feature. Mesh Tally was used in which the track lengths were distributed in a defined cell and then converted into doses and fluences. Two different scenarios were studied including a proton equilibrium case and a proton disequilibrium case. Results: For the proton equilibrium case, proton fluence and dose in depths beyond the Bragg peak were slightly perturbed by the choice of the simulated particle types. The dose from secondary particles was about three orders smaller, but its simulation consumed significant computing time. This suggests that the simulation of secondary particles may only be necessary for radiation safety issues for proton therapy. For the proton disequilibrium case, the impacts of different multiple Coulomb scattering (MCS) models were studied. Depth dose distributions of a 70 MeV proton pencil beam in a water phantom obtained from MCNPX, Geometry and Track, version 4, and the pencil beam algorithm showed significant deviations between each other, because of different MCS models used. Conclusions: Careful modelling of MCS is necessary when proton disequilibrium exists.

Background: Chemicals that are commonly used for artificial ripening and to increase the shelf life of fruits and vegetables are ethylene, ethane, calcium carbide, and ethephon. The present study was conducted to study the effect of ethephon on the morphometry of rat liver. Methods: Ethephon was administered by oral gavage tube to 10 adult Wistar albino rats at a dose of 200 mg/kg body weight/day for 14 days. Ten controls were maintained. The animals were sacrificed within 24 h of administering the last dose by perfusion with formal saline under anesthesia. Liver was dissected and processed for paraffin embedding. Histomorphometric studies were done on randomly selected sections of the liver and the data obtained were tabulated and statistically analyzed. Results: In the experimental rats, the hepatocytes had a mean long and short diameter of 15.02 ± 4.20 and 12.08 ± 3.02 μm, respectively. In the control animals, the mean long and short diameters were found to be 16.5 ± 3.59 and 13.9 ± 3.59 μm, respectively. The nucleus of the hepatocytes had a mean long and short diameter of 5.08 ± 1.93 and 5.08 ± 1.93 μm, respectively, in the ethephon-treated rats and 6.15 ± 1.72 and 6.05 ± 1.68 μm, respectively, in the control animals. The decrease in diameters of the hepatocytes and their nuclei was statistically significant. At some sites, the parenchyma showed pyknotic nucleus and inflammatory infiltrations. There was a statistically significant increase in the diameters of the central vein and sinusoids. Dilatation of the bile canaliculi was seen in between the hepatocytes. Conclusion: The plant growth regulator, insecticide, and fruit ripener, ethephon, caused inflammatory and degenerative changes in the liver with associated cholestasis, probably suggestive of toxic hepatitis.

Background: Several studies have investigated the association between CYP3A5 * 3 genetic polymorphism and acute lymphoblastic leukemia (ALL) risk in children, but have yielded controversial results. Therefore, we performed a meta-analysis to evaluate synthetically the effect of CYP3A5 * 3 polymorphism on the risk of ALL in children. Methods: Case-control studies investigating the relationship between CYP3A5 * 3 genetic polymorphism and ALL risk in children were included. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of association between CYP3A5 * 3 polymorphism and ALL risk in children. Q-statistic test was used to evaluate the heterogeneity and publication bias was assessed through funnel plot. Results: In total, five case-control studies with 1070 cases and 1125 controls were included in the meta-analysis. Based on the results of heterogeneity, fixed-effects or random-effects models were applied to estimate the pooled ORs. The pooled ORs (95% CIs) for CYP3A5 * 3 heterozygous mutant, homozygous mutant, and (heterozygous + homozygous) mutant were 1.47 (0.97-2.21), 1.05 (0.62-1.79), and 1.67 (1.14-2.44) with P = 0.07, 0.86, and 0.009, respectively. In subgroup analysis, the Z values of CYP3A5 * 3 (heterozygous + homozygous) mutant and children with ALL in Asian and Caucasian populations were 1.34 and 2.51 with P = 0.18 and 0.01, respectively. No significant publication bias was detected by funnel plot. Conclusions: The current meta-analysis showed that there was association between CYP3A5 * 3 polymorphism and the altered risk of ALL in children, especially in Caucasian populations.

Background: Prior studies suggested that protein kinase Cη (PRKCH) 1425G/A polymorphism was associated with lacunar infarction. This study examined whether the association was independent of traditional risk factors in each of the stroke subtypes. Methods: This study included 206 ischemic stroke patients and 337 controls. Multivariable logistic regression was used for analyses. Co-variables of age, sex, hypertension, diabetes mellitus (DM), and smoking were included to delineate independency of associations. Result: PRKCH 1425G/A was associated with ischemic stroke [odds ratio (OR) =1.5, 95% confidence interval (CI): 1.1-2.2, p = 0.024] when adjusted for age and sex. However, the significance of association became borderline when adjusted for co-variables (OR = 1.5, 95% CI: 1.004-2.3, p = 0.048). Of the infarction subtypes, PRKCH 1425G/A was associated with lacunar infarction (OR = 1.8, 95% CI: 1.1-2.9, p = 0.025), which remained significant when adjusted for co-variables (OR = 2.0, 95% CI: 1.1-3.5, p = 0.015). No association was found between the polymorphism and the other infarction subtypes. When stratified by age group, the magnitude of significance became stronger in patients >65 years old. Specifically, PRKCH 1425G/A was significantly associated with ischemic stroke in patients older than 65 years, when adjusted for all co-variables (OR = 2.0, 95% CI: 1.05-3.8, p = 0.036). Still, in patients older than 65 years, the association was only observed in lacunar infarction when adjusted for all co-variables (OR = 4.2, 95% CI: 1.7-10, p = 0.001). No association of PRKCH 1425G/A with stroke and any of the subtypes was identified in patients >65 years old. Conclusion: The association between PRKCH 1425G/A and lacunar infarction was independent of traditional stroke risk factors. PRKCH 1425G/A in stroke susceptibility differed between infarction subtypes and age groups.

Background:Whole brain radiotherapy (WBRT) is the treatment of choice for patients with brain metastases. However, neurocognitive functions (NCFs) decline due to impaired hippocampal neurogenesis might occur thereafter. It is hypothesized that conformal hippocampal avoidance during the course of WBRT (HA-WBRT) might provide meaningful NCF preservation. Our study aims to demonstrate the impact of delivering HA-WBRT on NCF changes in patients receiving WBRT. Methods: Twenty-five patients who were referred for prophylactic cranial irradiation (PCI) or treating oligometastatic brain disease were enrolled in the study. Before the HA-WBRT course, all participants should receive baseline neurocognitive assessment, including memory, executive functions, and psychomotor speed. The primary endpoint was delayed recall, as determined by the change/decline in verbal memory [Wechsler Memory Scale - 3 ^rd edition (WMS III)- Word List score] from the baseline assessment to 4 months after the start of HA-WBRT. Results: Only three patients belonged to the clinical setting of PCI; the remaining 22 patients had oligometastatic brain disease. Regarding neurocognitive outcomes, no statistically significant differences were found between various NCF scores obtained at baseline and at post-radiotherapy intervals, in immediate verbal memory and non-verbal memory, except for delayed recall memory on Word List (F = 5.727, p = 0.048). Conclusions: Functional preservation by hippocampal sparing during WBRT could largely be achieved in this study, which also suggests that HA-WBRT should be a feasible technique preserving neurocognitive functions while maintaining intracranial control.

Background: The present study was undertaken to evaluate the accuracy of methods proposed by Tanaka and Johnston, Moyers, and Bernabé and Flores-Mir to forecast the mesiodistal dimensions of permanent canine and premolars in a North Indian population. Methods: Mesiodistal tooth dimensions were measured from study models representing 68 male and 68 female subjects (aged 12-16 years) of North Indian descent. The mesiodistal dimensions of the teeth were measured using a digital Vernier caliper (providing measurements to 0.01 mm accuracy). The measurements of canine and premolars were summed up and compared with those derived from Tanaka and Johnston equations, Moyers probability tables (75 ^th percentile), and Bernabé and Flores-Mir equations. Results: All the three methods exhibited overestimation of actual sum of permanent canine and premolars in both the arches and genders in this population. Because of the discrepancy observed, new regression analyses in the form of Y = A + B (X) were formulated similar to those proposed by Tanaka and Johnston originally, but separately for males and females. In males, the correlation coefficient between the sum of mesiodistal widths of mandibular incisors and the sum of widths of canine and premolars was 0.637 and 0.685 for maxilla and mandible, respectively. This value was 0.55 for maxilla and 0.64 for mandible in females. These values were found to be statistically significant. Conclusion: All the methods evaluated in the study were found to be inaccurate and they overestimate the mesiodistal widths of permanent canine and premolars in North Indian population. Revised linear regression equations were derived using the data obtained from this population.

Background: A medical record is an important source of information regarding medical care and medical record review plays an important role in the evaluation of the teaching proficiency. The study analyzed the difference between internal and external auditing when conducting medical record review for faculty promotion in a study institute. Methods: We analyzed the scores related to the medical records maintained by applicants for the faculty promotion of attending physicians during the period between 2008 and 2010 at the Chang Gung Memorial Hospital. The scores were obtained from one internal reviewer of the study institute and two external reviewers from other medical centers, and routine scores were obtained from the Committee of Medical Record 1 year before application. Pearson's correlation coefficient was used to analyze the correlation and statistical significance. Results: There were 259 applicants for faculty promotion enrolled in this study [professors (n = 33, 13%), associate professors (n = 63, 24%), assistant professors (n = 90, 35%), lecturers (n = 73, 28%)]. The scores of the external reviewers 1 and 2 were correlated with routine scores (r = 0.187, p = 0.002; r = 0.198, p = 0.001; N= 259), respectively. The correlation between external reviewers' average and ordinary scores was significant for assistant professor (r = 0.334, p = 0.001, n = 90) and professor grades (r = 0.469, p = 0.006, n = 33). However, the internal reviewer scores did not correlate with the routine scores (r = 0.073, p = 0.241, N = 259). Conclusions: The scores from external reviewers correlated more with routine scores than the scores from internal reviewers, suggesting that utilizing an external auditing system of medical records for the faculty promotion of attending physicians is quite feasible and balanced.