Standardized Herbal Formula PM014 Inhibits Radiation-Induced Pulmonary Inflammation in Mice

Radiation therapy is widely used for thoracic cancers. However, it occasionally causes radiation-induced lung injuries, including pneumonitis and fibrosis. Chung-Sang-Bo-Ha-Tang (CSBHT) has been traditionally used to treat chronic pulmonary disease in Korea. PM014, a modified herbal formula derived from CSBHT, contains medicinal herbs of seven species. In our previous studies, PM014 exhibited anti-inflammatory effects in a chronic obstructive pulmonary disease model. In this study, we have evaluated the effects of PM014 on radiation-induced lung inflammation. Mice in the treatment group were orally administered PM014 six times for 2 weeks. Effects of PM014 on radiation pneumonitis were evaluated based on histological findings and differential cell count in bronchoalveolar lavage fluid. PM014 treatment significantly inhibited immune cell recruitment and collagen deposition in lung tissue. Normal lung volume, evaluated by radiological analysis, in PM014-treated mice was higher compared to that in irradiated control mice. PM014-treated mice exhibited significant changes in inspiratory capacity, compliance and tissue damping and elastance. Additionally, PM014 treatment resulted in the downregulation of inflammatory cytokines, chemokines, and fibrosis-related genes and a reduction in the transforming growth factor-β1-positive cell population in lung tissue. Thus, PM014 is a potent therapeutic agent for radiation-induced lung fibrosis and inflammation.ope

Phase II trial of concurrent radiation and weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell Lymphoma: Consortium for Improving Survival of Lymphoma study

PURPOSE: On the basis of the benefits of frontline radiation in early-stage, extranodal, natural killer (NK)/T-cell lymphoma (ENKTL), we conducted a phase II trial of concurrent chemoradiotherapy (CCRT) followed by three cycles of etoposide, ifosfamide, cisplatin, and dexamethasone (VIPD). PATIENTS AND METHODS: Thirty patients with newly diagnosed, stages IE to IIE, nasal ENKTL received CCRT (ie radiation 40 to 52.8 Gy and cisplatin 30 mg/m(2) weekly). Three cycles of VIPD (etoposide 100 mg/m(2) days 1 through 3, ifosfamide 1,200 mg/m(2) days 1 through 3, cisplatin 33 mg/m(2) days 1 through 3, and dexamethasone 40 mg days 1 through 4) were scheduled after CCRT. RESULTS: All patients completed CCRT, which resulted in 100% response that included 22 complete responses (CRs) and eight partial responses (PRs). The CR rate after CCRT was 73.3% (ie, 22 of 30 responses; 95% CI, 57.46 to 89.13). Twenty-six of 30 patients completed the planned three cycles of VIPD, whereas four patients did not because they withdrew (n = 2) or because they had an infection (n = 2). The overall response rate and the CR rate were 83.3% (ie; 25 of 30 responses; 95% CI, 65.28 to 94.36) and 80.0% (ie, 24 of 30 responses; 95% CI, 65.69 to 94.31), respectively. Only one patient experienced grade 3 toxicity during CCRT (nausea), whereas 12 of 29 patients experienced grade 4 neutropenia. The estimated 3-year, progression-free and overall survival rates were 85.19% (95% CI, 72.48 to 97.90) and 86.28% (95% CI, 73.97 to 98.59), respectively. CONCLUSION: Patients with newly diagnosed, stages IE to IIE, nasal ENKTL are best treated with frontline CCRT.ope

Radiation Treatment for Prostate Cancer

Selecting the optimal treatment of each stage of prostate cancer is very challenging, partly because the options for treatment today are far better than they were ten years ago, but also because not enough reliable data are available on which to base the decisions. Accordingly, scientifically controlled, long-term studies are still needed to compare the benefits and risks of the various treatments. In the process of counseling and discussing therapeutic options with patients with prostate cancer, it is important to present all available data regarding the variable natural history of this disease, prognostic significance of the diagnosis, potential therapeutic benefit of the various modalities, and immediate as well as late treatment-related sequelae. Radiation therapy can be given either as external beam radiation over perhaps 6 or 7 weeks or as an implant of radioactive seeds (brachytherapy) directly into the prostate. In external beam radiation, high energy x-rays are aimed at the tumor and the area immediately surrounding it. In brachytherapy, radioactive seeds are inserted through needles into the prostate gland under the guidance of transrectally taken ultrasound pictures. This article will describe recent advances in external beam radiotherapy [3D conformal radiotherapy (3D-CRT) & Intensity Modulated Radiotherapy (IMRT)], indications of radiotherapy, response evaluation and assessment of relapse after the radiation treatment for prostate cancer, and radiation-related complications.ope

Identification of molecular signatures involved in radiation-induced lung fibrosis

In radiotherapy, radiation (IR)-induced lung fibrosis has severe and dose-limiting side effects. To elucidate the molecular effects of IR fibrosis, we examined the fibrosis process in irradiated mouse lung tissues. High focal IR (90 Gy) was exposed to a 3-mm volume of the left lung in C57BL6 mice. In the diffused irradiation, 20 Gy dose delivered with a 7-mm collimator almost covered the entire left lung. Histological examination for lung tissues of both irradiated and neighboring regions was done for 4 weeks after irradiation. Long-term effects (12 months) of 20Gy IR were compared on a diffuse region of the left lung and non-irradiated right lung. Fibrosis was initiated as early as 2 weeks after IR in the irradiated lung region and neighboring region. Upregulation of gtse1 in both 90Gy-irradiated and neighboring regions was observed. Upregulation of fgl1 in both 20Gy diffused irradiated and non-irradiated lungs was identified. When gtse1 or flg1 was knock-downed, TGFβ or IR-induced epithelial-mesenchymal transition was inhibited, accompanied with the inhibition of cellular migration, suggesting fibrosisresponsible genes. Immunofluorescence analysis using mouse fibrotic lung tissues suggested that fibrotic regions showed increased expressions of Gtse1 and Fgl1, indicating novel molecular signatures of gtse1and fgl1 for IR-induced lung fibrosis. Even though their molecular mechanisms and IR doses or irradiated volumes for lung fibrosis may be different, these genes may be novel targets for understanding IR-induced lung fibrosis and in treatment strategies. KEY MESSAGES: Upregulation of gtse1 by 90Gy focal irradiation and upregulation of fgl1 by 20Gy diffused irradiation are identified in mouse lung fibrosis model. Gtse1 and Fgl1 are involved in radiation or TGFβ-induced epithelial-mesenchymal transition. Radiation-induced fibrotic regions of mouse lungs showed increased expressions of Gtse1 and Fgl1. Gtse1 and Fgl1 are suggested to be novel targets for radiation-induced lung fibrosis.ope

Management of Locally Advanced Non-small Cell Lung Cancer

Locally advanced Non-small cell lung cancer (NSCLC) is a commonly encountered diagnosis. Historically the treatment of locally advanced NSCLC has involved radiation therapy. Clinical trials have shown a benefit to the addition of chemotherapy. In recent years studies have further defined the role of chemotherapy by provided data showing the benefit of concurrent chemotherapy and radiation therapy followed by consolidation with more chemotherapy. Technological advances in radiation therapy have made dose escalation feasible and the current treatment paradigm is now evolving further as dose escalation data becomes availableope

Optimizing tissue-clearing conditions based on analysis of the critical factors affecting tissue-clearing procedures

Tissue-clearing techniques have received great attention for volume imaging and for the potential to be applied in optical diagnosis. In principle, tissue clearing is achieved by reducing light scattering through a combination of lipid removal, size change, and matching of the refractive index (RI) between the imaging solution and the tissue. However, the contributions of these major factors in tissue clearing have not been systematically evaluated yet. In this study, we experimentally measured and mathematically calculated the contribution of these factors to the clearing of four organs (brain, liver, kidney, and lung). We found that these factors differentially influence the maximal clearing efficacy of tissues and the diffusivity of materials inside the tissue. We propose that these physical properties of organs can be utilized for the quality control (Q/C) process during tissue clearing, as well as for the monitoring of the pathological changes of tissues.ope

An antibody against L1 cell adhesion molecule inhibits cardiotoxicity by regulating persistent DNA damage

Targeting the molecular pathways underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin (Dox) could reduce the morbidity and mortality associated with these anticancer treatments. Here, we find that vascular endothelial cells (ECs) with persistent DNA damage induced by irradiation and Dox treatment exhibit a fibrotic phenotype (endothelial-mesenchymal transition, EndMT) correlating with the colocalization of L1CAM and persistent DNA damage foci. We demonstrate that treatment with the anti-L1CAM antibody Ab417 decreases L1CAM overexpression and nuclear translocation and persistent DNA damage foci. We show that in whole-heart-irradiated mice, EC-specific p53 deletion increases vascular fibrosis and the colocalization of L1CAM and DNA damage foci, while Ab417 attenuates these effects. We also demonstrate that Ab417 prevents cardiac dysfunction-related decrease in fractional shortening and prolongs survival after whole-heart irradiation or Dox treatment. We show that cardiomyopathy patient-derived cardiovascular ECs with persistent DNA damage show upregulated L1CAM and EndMT, indicating clinical applicability of Ab417. We conclude that controlling vascular DNA damage by inhibiting nuclear L1CAM translocation might effectively prevent anticancer therapy-associated cardiotoxicity.ope

Prostate-Specific Antigen Bounce after 125I Brachytherapy Using Stranded Seeds with Intraoperative Optimization for Prostate Cancer

Prostate-specific antigen (PSA) bounce is common in patients undergoing 125I brachytherapy (BT), and our study investigated its clinical features. A total of 100 patients who underwent BT were analyzed. PSA bounce and large bounce were defined as an increase of ≥0.2 and ≥2.0 ng/mL above the initial PSA nadir, respectively, with a subsequent decline without treatment. Biochemical failure was defined using the Phoenix definition (nadir +2 ng/mL), except for a large bounce. With a median follow-up of 49 months, 45% and 7% of the patients experienced bounce and large bounce, respectively. The median time to bounce was 24 months, and the median PSA value at the bounce spike was 1.62 ng/mL, a median raise of 0.44 ng/mL compared to the pre-bounce nadir. The median time to bounce recovery was 4 months. The post-bounce nadir was obtained at a median of 36 months after low-dose-rate BT. On univariate analysis, age, the PSA nadir value at 2 years, and prostate volume were significant factors for PSA bounce. The PSA nadir value at 2 years remained significant in multivariate analysis. We should carefully monitor young patients with high prostate volume having a >0.5 PSA nadir value at 2 years for PSA bounce.ope

정상 및 고혈압 백서에서 대사물질에 의한 심근수축 변화와 기전

학위논문 (석사)-- 서울대학교 대학원 : 의과학과, 2014. 2. 장은화.Fatty acid-dependent metabolism is predominant in cardiac ATP production that maintains normal contractile function of the heart. However, excessive fat or fatty acids (metabolic syndrome) are the precursors of cardiovascular complications, such as ventricular arrhythmias (sudden cardiac death), heart failure and stroke. Insulin resistance in muscle is one of the key underlying mechanisms for the adverse effects of increased metabolites. Until recently, investigation of metabolic substrates regulation of cardiac contractile function and insulin responsiveness in vitro is lacking. Therefore, we design to study whether supplementation of metabolic substrates (oleic acid 200M, palmitic acid 100M, linolic acid 100M, lactate 1 mM, pyruvate 100M and carnitine 50M) to normal tyrode (NT) perfusate (termed nutrition full, NF) affects basal and beta-adrenergic left ventricular (LV) myocyte contractility and changes insulin response in normal and angiotensin II (Ang II)-induced hypertensive rat hearts. Our results demonstrated that basal and isoprenaline (ISO, 100 nM)-stimulated myocyte shortening (field stimulation, 2Hz, 36 ± 1 oC) were significantly increased with NF in LV myocytes from normal and hypertensive rat hearts. In NT, insulin (10 nM) abolished ISO-increase in LV myocyte contraction from normal rats. This effect was prevented by nitric oxide synthase (NOS) inhibitor, L-NG-nitroarginine methyl ester (L-NAME, 1mM) but not by neuronal NOS (nNOS) inhibition with S-methyl-L-thiocitrulline (SMTC, 100 nM), suggesting eNOS-mediated anti-adrenergic response of insulin. In NF, insulin did not change basal or ISO-stimulated myocyte contraction in either group, suggesting reduced insulin response. Furthermore, L-NAME did not affect myocyte contraction in the presence or absence of insulin in NF. On the other hand, ISO induced spontaneous contractions (arrhythmias) in NF and the percentage of arrhythmic incidence was significantly greater in hypertension. Ranolazine (10 M), inhibitor of carnitine palmitoyl transferase 1 (CPT-1), that is known to inhibit late Na+ current, did not affect NF-enhancement of myocyte contraction in normal or hypertensive hearts but significantly reduced arrhythmias in both groups. Interestingly, SMTC significantly increased arrhythmias in normal but reduced it in hypertension, suggesting contrasting roles nNOS play in the rhythmic contraction in the presence of metabolic substrates between normal and hypertension. Taken together, our results demonstrate that metabolic substrate supplementation improves myocyte contraction but impairs insulin response and induces arrhythmias with beta-adrenergic stimulation. nNOS plays an important role in cardiac arrhythmogenesis in the presence of metabolic stress.Abstract i Contents iii List of table and figures iv List of abbrevlation.......................................................viii Introduction 1 Material and Methods 7 Results 15 Part I 15 Part II 27 Discussion 39 References 43 Abstract in Korean 48Maste

Efferocytosis and enhanced FPR2 expression following apoptotic cell instillation attenuate radiation-induced lung inflammation and fibrosis

Lung inflammation and fibrosis are common side effects of radiotherapy that can lead to serious reduction in the quality of life of patients. However, no effective treatment is available, and the mechanisms underlying its pathophysiology are poorly understood. Irradiation increases formyl peptide receptor 2 (FPR2) expression in lung tissue, and FPR2 agonists are known to promote the uptake of apoptosis cells, referred to as efferocytosis that is a hallmark of the resolution of inflammation. Herein, in a mouse model of radiation-induced lung injury (RILI), efferocytosis was induced by injecting apoptotic cells into the lung through the trachea, and its correlation with FPR expression and the effect of efferocytosis and FPR expression on RILI were assessed. Interestingly, when apoptotic cells were injected into the lung, the radiation-induced increase in FPR2 expression was further amplified. In the mouse model of RILI, apoptotic cell instillation reduced the volume of the damaged lung and prevented the decrease in lung function. Additionally, the expression of inflammatory cytokines, fibrosis-related markers, and oxidative stress-related markers was reduced by apoptotic cell instillation. Co-administration of apoptotic Jurkat cells and WRW4, the FPR2 antagonist, reversed these effects. These findings suggest that efferocytosis induced by apoptotic cell instillation and enhanced FPR2 expression attenuate RILI, thereby alleviating lung inflammation and fibrosis.ope