Immunotherapeutic effects of Glycyrrhiza glabra and Glycyrrhizic Acid on Leishmania major-infection BALB/C mice.

Treatment of cutaneous leishmaniasis (CL) is a public health problem in endemic areas. The objective of the current study was to investigate the immunotherapeutic activities of the hydroalcoholic extract of Glycyrrhiza glabra (HEG) and glycyrrhizic acid (GA) in the treatment of Leishmania major (L. major)-infected BALB/c mice. In this study, the effect of HEG and GA was checked in vitro on growth of L. major promastigote and amastigote using MTT assay and microscopic counting, respectively. For in vivo experiment, the lesion induced by L. major on BALB/c mice were treated intraperitoneally with HEG, GA, meglumine antimoniate or phosphate buffer saline (negative control) for one month. Then, the lesion development and the parasite burden of the lymph node was assessed, the cytokine response (IFN-γ and IL-4) to Leishmania antigens was evaluated using ELISA method. The results showed that HEG and GA significantly inhibited the growth of L. major promastigotes and amastigotes, the lesion development, parasite burden in the lymph nodes, level of IFN-γ and the ratio of IFN-γ/IL-4 in HEG, GA and meglumine antimoniate-treated mice were significantly higher compared with the negative control group, there was no difference between the HEG, GA and meglumine antimoniate group. It is concluded that hydroalcoholic extract of G. glabra and glycyrrhizic acid showed therapeutic and immunomodulatory effects on L. major-infected BALB/c mice.

Biophysical and ultrasonographic changes of acute Old World cutaneous leishmaniasis skin lesions in comparison with uninvolved skin: A possible tool for non-invasive early detection and treatment outcome assessment.

Cutaneous leishmaniasis (CL) is a skin disease caused by intracellular protozoa, which is endemic in Iran. The goal of this study was to compare biophysical characteristics in CL lesions with uninvolved skin. Stratum corneum hydration, transepidermal water loss, surface friction, pH, sebum, melanin, erythema, temperature, elasticity parameters (R0, R2, and R5), thickness and echo-density of epidermis and dermis were measured on the active erythematous indurated part of a typical CL lesion in 20 patients, and compared with the same location on the other side of the body as control. Paired t-test was used for statistical analyses and a p < 0.05 was considered significant. Melanin content, R2 and echo-density of dermis were significantly lower, whereas transepidermal water loss, friction index, pH, erythema index, temperature, and the thickness of dermis were significantly higher in CL lesions. There was no significant difference in stratum corneum hydration, sebum, R0, R5, thickness of epidermis, and density of epidermis between CL and normal skin. CL lesions are characterized by certain changes in biophysical and ultrasonographic properties, which are mostly correlated with histological features. These changes are likely to be useful in the non-invasive early detection of CL and also as treatment outcome measures for clinical trials of new treatment modalities for CL in the future.

Evolution of antigen-specific immune responses in cutaneous leishmaniasis patients.

AIMS: Despite immunization appearing to be the most appropriate strategy for long-term control of the vector-borne leishmaniases, no sustainable vaccine is currently available against any form of leishmaniasis. We therefore evaluated, in the context of vaccine antigen candidates, antigen-specific immune response at various stages of cutaneous leishmaniasis (CL). METHODS AND RESULTS: Peripheral blood mononuclear cells (PBMC) isolated from healthy volunteers and CL patients (caused by either Leishmania major or L tropica) were incubated with crude Leishmania proteins (soluble Leishmania antigen; SLA), single recombinant proteins (TSA, LeIF, LmSTI1) or chimeric fusion proteins (LEISH-F2 and LEISH-F3). The concentrations of immune modulatory cytokines were then determined. While we did not detect appreciable antigen-specific IL-5 secretion, SLA induced secretion of interleukin (IL)-10 in cultures from early active lesion CL patients and even from healthy individuals. Conversely, interferon (IFN)-γ responses to SLA and recombinant proteins followed a similar pattern, developing only in the late active CL lesion phase. Once established, antigen-specific IFN-γ responses persisted in cured CL patients. CONCLUSION: Together, our results provide further insight into the development of immune responses during CL and further validate the selection of LEISH-F2 and LEISH-F3 as vaccine antigen candidates.

Association of tumor necrosis factor-α -308 G/A gene polymorphism with coronary artery diseases: An evidence-based study.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of death worldwide and remains a major health problem, providing the rationale for identification of molecular markers for detection of individuals at high risk of developing CAD. Tumor necrosis factor-α (TNF-α) plays a crucial role in the pathogenesis of CAD. We have therefore explored the association of TNF-α 308 (G/A) gene polymorphism in 903 individuals with/without CAD. METHODS: TNF-α 308 gene polymorphism was analyzed in 903 subjects of whom 222 were healthy controls. Among the 681 patients who were investigated angiographically, 468 had ≧50% stenosis and 213 patients had <50% stenosis. Biochemical profiles (eg, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting blood glucose, and CRP) were evaluated. Associations between TNF-α genotypes with biochemical and anthropometric characteristics were determined. RESULTS: The frequencies of TNF-α-AA or AG genotypes were significantly lower in patients classified as CAD patients with ≥ or <50% obstruction in at least one coronary artery, compared to the control group. We observed that CAD patients with ≥50% stenosis and with AA genotype were associated with higher risk of CAD with OR of 3.56 (95%CI: 1.02-12.41; P=.046) using multivariate analysis. Moreover, we found that TNF-α-308-AA genotype was associated with blood pressure and CRP level in CAD patients, compared to the wild type-genotype. CONCLUSION: Our data showed an association of TNF-α-308G/A polymorphism with CAD patients with ≥50% obstruction, supporting the need for further investigations on the role of TNF-α-308G/A polymorphism with hypertension.

Effects of Curcumin on Serum Vitamin E Concentrations in Individuals with Metabolic Syndrome.

Vitamin E is an important lipid-soluble antioxidant. The aim of the present study was to investigate the effect of curcumin on serum vitamin E levels in subjects with metabolic syndrome (MetS). A total of 120 subjects aged 18-65 years old with MetS were recruited in this study according to the International Diabetic Federation Criteria. Included subjects were randomized into three groups: subjects receiving lecithinized curcumin (1 g/day equivalent to 200-mg pure curcumin per day) for a period of 6 weeks )n = 40), patients receiving unformulated curcumin (1 g/day) for a period of 6 weeks )n = 40) and a control group receiving placebo for the same period (n = 40). Vitamin E was determined in all patients before and after the intervention using high-performance liquid chromatography method. Results showed that curcumin has no improving effect on serum levels of vitamin E (p > 0.05). There were significant differences between pre-trial and post-trial levels of vitamin E/low-density lipoprotein cholesterol ratio (p < 0.05), vitamin E/high-density lipoprotein cholesterol ratio (p < 0.05), vitamin E/total cholesterol ratio (p < 0.01) and vitamin E/triglyceride ratio (p < 0.05) between the three groups of the study. Results of the present study did not suggest any improving effect of curcumin supplementation on serum vitamin E concentrations in subjects with MetS. Copyright © 2017 John Wiley & Sons, Ltd.

Anti Leishmania activity of Lucilia sericata and Calliphora vicina maggots in laboratory models.

Use of sterile fly larvae (maggots) of blow flies for the treatment of many different types of skin and soft tissue wounds is called Maggot debridement therapy (MDT). The larvae of blow flies secrete a broad spectrum of compounds with diverse mechanisms of action in the gut and salivary glands called excretion/secretion (ES) products which showed to have antimicrobial activities against Gram negative and positive bacteria. Cutaneous leishmaniasis (CL) which is the common form of leishmaniasis is difficult to treat. In this study, the effect of ES from 2nd and 3rd stages of L. sericata and C. vicina larvae on in vitro Leishmania major amastigote growth in macrophage was evaluated. The effect of ES on Leishmania growth was estimated by assessing the rate of macrophage infection and the number of amastigotes per infected macrophages. In addition, the anti Leishmania activities of larval and ES of L. sericata and C. vicina on the skin lesion induced by L. major infection was evaluated in susceptible BALB/c mice. The results showed that ES of both flies reduced the number of infected macrophages; 2.6 and 1.5-fold using L. sericata ES and C. vicina ES, respectively, and inhibited amastigotes growth in macrophages; 2.03 and 1.36-fold by L. sericata ES and C. vicina ES, respectively as compared to the control group. The results showed that L. sericata ES was significantly more effective than C. vicina ES to inhibit in vitro L. major amastigotes growth, The size of lesion was significantly smaller in BALB/c mice treated with L. sericata ES than treated with C. vicina ES. The results of in vivo experiments suggested that pre-treatment with ES derived from L. sericata may have some protective effects on the development of L. major lesion. Therefore, it seems that maggot ES might be considered as a possible candidate for the treatment of cutaneous leishmaniasis.

Impact of the C1431T Polymorphism of the Peroxisome Proliferator Activated Receptor-Gamma (PPAR-γ) Gene on Fasted Serum Lipid Levels in Patients with Coronary Artery Disease.

BACKGROUND/AIMS: The C1431T polymorphism of peroxisome proliferator activated receptor-γ (PPAR-γ) gene is related to diabetes and metabolic-syndrome. However, studies have been inconclusive about its association with coronary artery disease (CAD) and there have been no studies analyzing the association of this polymorphism with fasted-serum-lipid levels in Iranian-individuals with CAD. We investigated the association of PPAR-γ C1431T-polymorphism with CAD and dyslipidaemia in 787 individuals. METHODS: Anthropometric-parameters and biochemical-measurements were evaluated, followed by genotyping. The association of the genetic-polymorphisms with CAD and lipid-profile was determined by univariate/multivariate-analyses. RESULTS: Patients with CT or CT+TT genotype were at an increased-risk of CAD relative to CC-carriers (adjusted odds ratio: 2.03; 95% confidence interval, 1.01-4.09; p = 0.046). However, in the larger population, CT genotype was present at a higher frequency in the group with a positive angiogram. Furthermore, CT+TT genotypes were associated with an altered fasted-lipid-profile in the initial population sample of patients with a positive angiogram, compared to the group with a negative-angiogram. The angiogram-positive patients carrying the T allele had a significantly higher triglyceride, serum C-reactive protein and fasting-blood-glucose. CONCLUSION: We have found the PPAR-γ C1431T polymorphism was significantly associated with fasted serum lipid profile in individuals with angiographically defined CAD. Since accumulating data support the role of PPAR-γ polymorphisms in CAD, further studies are required to investigate the association of this polymorphism with coronary artery disease.

Neutron Capture Enhances Dose and Reduces Cancer Cell Viability in and out of Beam During Helium and Carbon Ion Therapy.

PURPOSE: Neutron capture enhanced particle therapy (NCEPT) is a proposed augmentation of charged particle therapy that exploits thermal neutrons generated internally, within the treatment volume via nuclear fragmentation, to deliver a biochemically targeted radiation dose to cancer cells. This work is the first experimental demonstration of NCEPT, performed using both carbon and helium ion beams with 2 different targeted neutron capture agents (NCAs). METHODS AND MATERIALS: Human glioblastoma cells (T98G) were irradiated by carbon and helium ion beams in the presence of NCAs [10B]-BPA and [157Gd]-DOTA-TPP. Cells were positioned within a polymethyl methacrylate phantom either laterally adjacent to or within a 100 × 100 × 60 mm spread out Bragg peak (SOBP). The effect of NCAs and location relative to the SOBP on the cells was measured by cell growth and survival assays in 6 independent experiments. Neutron fluence within the phantom was characterized by quantifying the neutron activation of gold foil. RESULTS: Cells placed inside the treatment volume reached 10% survival by 2 Gy of carbon or 2 to 3 Gy of helium in the presence of NCAs compared with 5 Gy of carbon and 7 Gy of helium with no NCA. Cells placed adjacent to the treatment volume showed a dose-dependent decrease in cell growth when treated with NCAs, reaching 10% survival by 6 Gy of carbon or helium (to the treatment volume), compared with no detectable effect on cells without NCA. The mean thermal neutron fluence at the center of the SOBP was approximately 2.2 × 109 n/cm2/Gy (relative biological effectiveness) for the carbon beam and 5.8 × 109 n/cm2/Gy (relative biological effectiveness) for the helium beam and gradually decreased in all directions. CONCLUSIONS: The addition of NCAs to cancer cells during carbon and helium beam irradiation has a measurable effect on cell survival and growth in vitro. Through the capture of internally generated neutrons, NCEPT introduces the concept of a biochemically targeted radiation dose to charged particle therapy. NCEPT enables the established pharmaceuticals and concepts of neutron capture therapy to be applied to a wider range of deeply situated and diffuse tumors, by targeting this dose to microinfiltrates and cells outside of defined treatment regions. These results also demonstrate the potential for NCEPT to provide an increased dose to tumor tissue within the treatment volume, with a reduction in radiation doses to off-target tissue.

CCR7+ central and CCR7- effector memory CD4+ T cells in human cutaneous leishmaniasis.

PURPOSE: The profile of central (=T(CM)) and effector (=T(EM)) memory CD4(+) T cell subsets and the possible role as surrogate markers of protection is studied in the volunteers with history of cutaneous leishmaniasis (HCL). METHODS: Profile of T cell subsets based on CCR7/CD45RA expressions and phenotypic changes after soluble Leishmania antigen (SLA) stimulation were analyzed. Then, sorted CD4(+)CD45RO(-)CD45RA(+) naïve T, CD4(+)CD45RO(+)CD45RA(-)CCR7(-) T(EM,) CD4(+)CD45RO(+)CD45RA(-)CCR7(+) T(CM) subsets were cultured with SLA for proliferation, cytokine production and intracellular cytokine assays. RESULTS: In the HCL and control volunteers, the mean frequencies of CD4(+)CD45RA(+)CCR7(+) naïve T cells and CD4(+)CD45RA(-)CCR7(-) T(EM) cells were higher than the other subsets before culture. Frequency of naïve T cells and CD4(+)CD45RA(-)CCR7(+) T(CM) cells was significantly decreased (P=0.01 for naïve T and P<0.05 for T(CM) cells) and frequency of T(EM) cells was significantly increased after SLA stimulation compared to before culture (P<0.001). By CFSE labeling, CD4(+)CD45RO(+)CD45RA(-)CCR7(+) T(CM) cells showed more proliferation potential than CD4(+)CD45RO(+)CD45RA(-)CCR7(-) T(EM) cells. Stimulation of the T(EM) cells in HCL volunteers induced a significantly higher IFN-γ production (P=0.04) with higher number of intracellular IFN-γ positive cells (P=0.032) than the same cells from controls. A significantly higher number of T(CM) cells produced IL-2 in HCL volunteers compared with controls (P<0.05). Most of the intracellular IFN-γ positive T(EM) cells were proliferating CFSE-dim populations (P<0.05). CONCLUSIONS: A combination of Leishmania-reactive IFN-γ producing CD4(+)CD45RO(+)CD45RA(-)CCR7(-) T(EM) and Leishmania-reactive IL-2 producing CD4(+)CD45RO(+)CD45RA(-)CCR7(+) T(CM) are identified in individuals with history of CL which might play a role in protective recall immune response against Leishmania infection.

Effects of supplementation with curcuminoids on dyslipidemia in obese patients: a randomized crossover trial.

Dyslipidemia is a leading risk factor for cardiovascular disease and is also a common feature of obesity. Curcumin is a bioactive phytochemical with well-known antioxidant, anti-inflammatory, and cardioprotective properties. The present study investigated the hypolipidemic activity of curcumin in obese individuals. Participants (n = 30) were treated with curcuminoids (1 g/day), or placebo in a randomized, double-blind, placebo-controlled, crossover trial. Serum concentrations of total cholesterol, triglycerides, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, together with anthropometric parameters and high-sensitivity C-reactive protein were measured before and after each treatment period. Anthropometric parameters including weight, BMI, waist circumference, hip circumference, arm circumference, and body fat remained statistically unchanged by the end of trial (p > 0.05). As for the lipid profile parameters, serum triglycerides were significantly reduced following curcumin supplementation (p = 0.009). However, curcuminoids were not found to affect serum levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein (p > 0.05). In summary, the findings of the present study indicated that curcuminoid supplementation (1 g/day for 30 days) leads to a significant reduction in serum triglycerides concentrations but do not have a significant influence on other lipid profile parameters as well as body mass index and body fat.

Curcuminoids modulate pro-oxidant-antioxidant balance but not the immune response to heat shock protein 27 and oxidized LDL in obese individuals.

Curcuminoids have potentially important functional qualities including anti-inflammatory and antioxidant properties. In this randomized double-blind placebo-controlled cross-over trial, the effects of a curcuminoid supplement on serum pro-oxidant-antioxidant balance (PAB) and antibody titres to Hsp27 (anti-Hsp27) and oxLDL (anti-oxLDL) were investigated. Thirty obese individuals were randomized to receive either curcuminoids (1 g/day) or placebo for a period of 30 days. After a wash-out period of 2 weeks, subjects were crossed over to the alternate regimen for another 30 days. Serum PAB along with anti-Hsp27 and anti-oxLDL titres was measured at the beginning and at the end of each study period. There was no significant carry-over effect for any of the assessed parameters. Curcuminoid supplementation was associated with a significant decrease in PAB (p = 0.044). However, no significant change was observed in serum concentrations of anti-Hsp27 or anti-oxLDL (p > 0.05). These findings suggest that oral curcuminoids supplementation (1g/day) is effective in reducing oxidative stress burden, though this needs to be validated in larger study populations.

Radiosensitization effect of radiofrequency hyperthermia in the presence of PEGylated-gold nanoparticles on the MCF-7 breast cancer cells under 6 MeV electron irradiation.

Purpose: The purpose of the study was to investigate the radiosensitization effect of radiofrequency (RF) hyperthermia in combination with PEGylated gold nanoparticles (PEG-GNPs) on MCF-7 breast cancer cells under electron beam radiotherapy (EBRT) based on the clonogenic assay. Materials and Methods: The cell death of MCF-7 breast cancer cells treated with 13.56 MHz capacitive RF hyperthermia (power: 150W) for 2, 5, 10, and 15 min combined with 6 MeV EBRT, with a dose of 2 Gy, was evaluated in the presence of 20 nm PEG-GNPs with a low nontoxic concentration (20 mg/l). All the treatment groups were incubated for 14 days. Thereafter, survival fractions and viability of the cells were calculated and analyzed against the control group. Results: The presence of PEG-GNPs inside the MCF-7 cancer cells during electron irradiation decreased cell survival significantly (16.7%) compared to irradiated cells without GNPs. Applying hyperthermia before electron irradiation with a capacitive RF system decreased cell survival by about 53.7%, while hyperthermia without irradiation did not show any significant effect on cell survival. Combining the hyperthermia with the presence of PEG-GNPs in the cells decreased the cell survival by about 67% at the electron irradiation, showing their additive radiosensitization effect. Conclusion: Low nontoxic concentration of 20 nm PEG-GNPs increases the radiosensitization effect of combining 6 MeV EBRT and RF hyperthermia on MCF-7 cancer cells. Combining hyperthermia with PEG-GNPs in electron radiotherapy could be an appropriate method for enhancing radiotherapy effectiveness on cancerous cells which can be studied on different cells and electron energies in future research.

Diagnosis of Human Cutaneous Leishmaniasis: A Comparative Study Using CL Detect™ Dipstick, Direct Smear and Polymerase Chain Reaction Methods.

INTRODUCTION: In most of the endemic areas, the detection of CL is based on searching for amastigotes using the direct smear method. Since expert microscopists are not usually available in every laboratory, false diagnoses are a disaster that happens. Therefore, the aim of current research is to evaluate the validity of the CL Detect™ Rapid Test (CDRT) for diagnosis CL in comparison to direct smear and polymerase chain reaction (PCR) methods. METHODS: A total of 70 patients with skin lesions suspected to be CL were recruited. Skin samples from the lesions were collected and used for direct microscopic examination and the PCR method. Furthermore, the skin sample was collected in accordance with the manufacturer's instructions for the CDRT-based rapid diagnostic test. RESULTS: Of 70 samples, 51 and 35 samples were positive by direct smear examination and the CDRT, respectively. The PCR showed positive results in 59 samples; 50 and 9 samples were identified as Leishmania major and Leishmania tropica, respectively. The sensitivity and specificity were calculated to be 68.6% (95% CI 54.11-80.89%) and 100% (95% CI 82.35-100%). When the results of CDRT were compared to the microscopic examinations, an agreement of 77.14% was seen between the CDRT and microscopic examination. In addition, the sensitivity and specificity were 59.32% (95% CI 45.75-71.93%) and 100% (95% CI 71.5-100%) when the CDRT was compared to PCR assay (as gold standard) and an agreement (65.71%) was found between CDRT and PCR assay. CONCLUSION: As the CDRT is simple, rapid, and does not require great proficiency, it is recommended for use in the detection of CL caused by L. major or L. tropica as a diagnostic method, especially in areas with limited access to expert microscopists.

Tumour status prediction by means of carbon-ion beam irradiation: comparison of washout rates between in-beam PET and DCE-MRI in rats.

Objective.Tumour response to radiation therapy appears as changes in tumour vascular condition. There are several methods for analysing tumour blood circulatory changes one of which is dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), but there is no method that can observe the tumour vascular condition and physiological changes at the site of radiation therapy. Positron emission tomography (PET) has been applied for treatment verification in charged particle therapy, which is based on the detection of positron emitters produced through nuclear fragmentation reactions in a patient's body. However, the produced positron emitters are washed out biologically depending on the tumour vascular condition. This means that measuring the biological washout rate may allow evaluation of the tumour radiation response, in a similar manner to DCE-MRI. Therefore, this study compared the washout rates in rats between in-beam PET during12C ion beam irradiation and DCE-MRI.Approach.Different vascular conditions of the tumour model were prepared for six nude rats. The tumour of each nude rat was irradiated by a12C ion beam with simultaneous in-beam PET measurement. In 10-12 h, the DCE-MRI experiment was performed for the same six nude rats. The biological washout rate of the produced positron emitters (k2,1st) and the MRI contrast agent (k2a) were derived using the single tissue compartment model.Main results.A linear correlation was observed betweenk2,1standk2a, and they were inversely related to fractional necrotic volume.Significance.This is the first animal study which confirmed the biological washout rate of in-beam PET correlates closely with tumour vascular condition measured with the MRI contrast agent administrated intravenously.

The in vitro effect of nanoliposomal amphotericin B against two clinically important dermatophytes.

AIMS: The present study aimed to investigate the antifungal activity of amphotericin B-loaded nanoliposomes against Trichophyton interdigitale and Trichophyton rubrum. Moreover, it was attempted to assess the obtained resistance in vitro. METHODS: In total, 29 archived clinical strains, namely, T. interdigitale (n = 16) and T. rubrum (n = 13), were included in this study. These strains were determined using a previous ITS1-ITS2 region sequence. Moreover, a liposomal formulation of amphotericin B was formulated by a thin-film hydration method. Particle size, polydispersity index (PdI), and zeta potential (ZP) were measured by a Zetasizer. Furthermore, physicochemical properties, such as appearance, aggregation of particles, particle size, PdI, and ZP, were determined at 0-, 1-, and 3-month intervals. A scanning electron microscope (SEM) was also used to examine nanoparticles structure. The minimum inhibitory concentration (MIC) of amphotericin B-loaded nanoliposomes, itraconazole, efinaconazole, terbinafine, and ciclopirox was determined according to the protocol of the broth microdilution method of CLSI M38-A2. The morphological changes of T. interdigitale and T. rubrum strains exposed to the amphotericin B-loaded nanoliposomes were observed using SEM. RESULTS: The amphotericin B-loaded nanoliposomes displayed a lower MIC compared to those of the amphotericin B and liposomes when used separately. Based on the results, amphotericin B-loaded nanoliposomes induced no drug resistance in any of the tested strains. CONCLUSION: Accordingly, amphotericin B-loaded nanoliposomes can be a potent antifungal for the topical treatment of onychomycosis. There was no in vitro evidence regarding the resistance of the tested strains to amphotericin B-loaded nanoliposomes. This reflects that amphotericin B-loaded nanoliposomes have a low probability to induce drug resistance in dermatophyte species.

Measurement of biological washout rates depending on tumor vascular status in15O in-beam rat-PET.

Objective.The biological washout of positron emitters should be modeled and corrected in order to achieve quantitative dose range verification in charged particle therapy based on positron emission tomography (PET). This biological washout effect is affected by physiological environmental conditions such as blood perfusion and metabolism, but the correlation to tumour pathology has not been studied yet.Approach.The aim of this study was to investigate the dependence of the biological washout rate on tumour vascular status in rat irradiation. Two types of tumour vascularity conditions, perfused and hypoxic, were modelled with nude rats. The rats were irradiated by a radioactive15O ion beam and time activity curves were acquired by dynamic in-beam PET measurement. Tumour tissue sections were obtained to observe the histology as well. The biological washout rate was derived using a single-compartment model with two decay components (medium decay,k2mand slow decay,k2s).Main results.Allk2mvalues in the vascular perfused tumour tissue were higher than the values of the normal tissue. Allk2mvalues in the hypoxic tumour tissue were much lower than the values of the vascular perfused tumour tissue and slightly lower than the values of the normal tissue.Significance.The dependency of the biological washout on the tumour vasculature conditions was experimentally shown.

Feasibility of triple gamma ray imaging of10C for range verification in ion therapy.

Objective.In carbon ion therapy, the visualization of the range of incident particles in a patient body is important for treatment verification. In-beam positron emission tomography (PET) imaging is one of the methods to verify the treatment in ion therapy due to the high quality of PET images. We have shown the feasibility of in-beam PET imaging of radioactive15O and11C ion beams for range verification using our OpenPET system. Recently, we developed a whole gamma imager (WGI) that can simultaneously work as PET, single gamma ray and triple gamma ray imaging. The WGI has high potential to detect the location of10C, which emits positrons with a simultaneous gamma ray of 718 keV, within the patient's body during ion therapy.Approach.In this work, we focus on investigating the performance of WGI for10C imaging and its feasibility for range verification in carbon ion therapy. First, the performance of the WGI was studied to image a10C point source using the Geant4 toolkit. Then, the feasibility of WGI was investigated for an irradiated polymethyl methacrylate (PMMA) phantom with a10C ion beam at the carbon therapy facility of the Heavy Ion Medical Accelerator in Chiba.Main results.The average spatial resolution and sensitivity for the simulated10C point source at the centre of the field of view were 5.5 mm FWHM and 0.010%, respectively. The depth dose of the10C ion beam was measured, and the triple gamma image of10C nuclides for an irradiated PMMA phantom was obtained by applying a simple back projection to the detected triple gammas.Significance.The shift between Bragg peak position and position of the peak of the triple gamma image in an irradiated PMMA phantom was 2.8 ± 0.8 mm, which demonstrates the capability of triple gamma imaging using WGI for range verification of10C ion beams.

Pilot study of safety and efficacy of topical liposomal amphotericin B for cutaneous leishmaniasis caused by Leishmania major in Islamic Republic of Iran.

Background: Topical nanoliposomes containing 0.4% amphotericin B (Lip-AmB 0.4%) have shown promising safety results in preclinical and phase 1 clinical trials in healthy volunteers. Aims: To evaluate safety and efficacy of Lip-AmB 0.4% in cutaneous leishmaniasis patients. Methods: Fourteen patients with a total of 84 lesions received national standard treatment of weekly intralesional meglumine antimoniate with biweekly cryotherapy, or daily intramuscular meglumine antimoniate (20 mg/kg/day for 14 days), and topical Lip-AmB 0.4% twice daily for 28 days. Twenty-two patients with a total of 46 lesions (7 at most) were treated with topical Lip-AmB 0.4% alone twice daily for 28 days. Thirty patients with a total of 68 lesions received national standard treatment of weekly intralesional meglumine antimoniate (to blanch around the lesion) and biweekly cryotherapy. Results: Sixty-six patients with cutaneous leishmaniasis lesions completed the study. In the safety evaluation, 2 of the 36 patients evaluated reported a tolerable burning sensation and they preferred to continue treatment. Twelve (92%) of 14 patients with 84 lesions who received national standard treatment combined with Lip-AmB 0.4% completed the study with complete cure. In 1 of the patients with 4 lesions, 1 lesion showed complete cure and 3 showed partial cure. Among 22 patients with 46 lesions who received only topical LipAmB 0.4%, 19 completed the study and 18 showed complete cure (95% efficacy). In the 30 patients who received national standard treatment alone, 33 lesions in 15 patients showed complete cure (48.5%) on day 42 follow-up. Conclusion: Lip-AmB 0.4% alone or in combination with national standard treatment is safe with high-efficacy rate and warrants further investigation during phase 3 clinical trials.

An inception network for positron emission tomography based dose estimation in carbon ion therapy.

Objective. We aim to evaluate a method for estimating 1D physical dose deposition profiles in carbon ion therapy via analysis of dynamic PET images using a deep residual learning convolutional neural network (CNN). The method is validated using Monte Carlo simulations of12C ion spread-out Bragg peak (SOBP) profiles, and demonstrated with an experimental PET image.Approach. A set of dose deposition and positron annihilation profiles for monoenergetic12C ion pencil beams in PMMA are first generated using Monte Carlo simulations. From these, a set of random polyenergetic dose and positron annihilation profiles are synthesised and used to train the CNN. Performance is evaluated by generating a second set of simulated12C ion SOBP profiles (one 116 mm SOBP profile and ten 60 mm SOBP profiles), and using the trained neural network to estimate the dose profile deposited by each beam and the position of the distal edge of the SOBP. Next, the same methods are used to evaluate the network using an experimental PET image, obtained after irradiating a PMMA phantom with a12C ion beam at QST's Heavy Ion Medical Accelerator in Chiba facility in Chiba, Japan. The performance of the CNN is compared to that of a recently published iterative technique using the same simulated and experimental12C SOBP profiles.Main results. The CNN estimated the simulated dose profiles with a mean relative error (MRE) of 0.7% ± 1.0% and the distal edge position with an accuracy of 0.1 mm ± 0.2 mm, and estimate the dose delivered by the experimental12C ion beam with a MRE of 3.7%, and the distal edge with an accuracy of 1.7 mm.Significance. The CNN was able to produce estimates of the dose distribution with comparable or improved accuracy and computational efficiency compared to the iterative method and other similar PET-based direct dose quantification techniques.