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Damage of Intestinal Stem Cells (ISCs) is the main cause of radiation induced-intestinal injury (RIII). Recently, hypoxia Inducible factor (HIF) was verified to be critical for promoting proliferation of ISCs, which suggested a protective role of HIF in the RIII. Thus, we investigated the effect of FG-4592, a novel up-regulator of HIF, on the protection of RIII. With/without FG-4592 treatment, the abdomen of mice was radiated, and intestinal injury was assessed. Especially, by intestinal organoid culture, the multiplication capacity and differentiation features of ISCs were detected. As a result, FG-4592, a novel up-regulator of HIF could remit RIII and promote regeneration and differentiation of ISCs after radiation, which were depended on HIF-2 rather than HIF-1.

BACKGROUND Carotid vulnerable plaque is a major cause of stroke and differs between men and women. Few studies have investigated the differences in carotid plaque features between sexes in a Chinese population. PURPOSE To compare carotid atherosclerotic plaque features between men and women in a Chinese population using magnetic resonance imaging. STUDY TYPE Cross-sectional. SUBJECTS A total of 567 patients (mean age: 61.5 ± 10.1 years; 404 men) who had recent stroke or transient ischemia attack and atherosclerotic plaque in at least one carotid artery. FIELD STRENGTH A 3.0 T. SEQUENCE T1- and T2-weighted turbo spin echo, three-dimensional time-of-flight (TOF) fast field echo and magnetization-prepared rapid acquisition gradient echo sequences. ASSESSMENT Plaque characteristics including lumen area (LA), wall area (WA), total vessel area (TVA), mean wall thickness (MWT), and mean normalized wall index (NWI); presence of calcification, lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), and fibrous cap rupture (FCR); and percent composition area (%area) were evaluated and compared between men and women. STATISTICAL TESTS Independent-sample t test, Mann-Whitney U test, chi-square test, and multiple linear and logistic regressions. RESULTS In symptomatic arteries, men had significantly greater LA (46.2 ± 15.6 mm2 vs. 40.7 ± 12.9 mm2 , P

Radiation protection on male testis is an important task for ionizing radiation‐related workers or people who receive radiotherapy for tumours near the testicle. In recent years, Toll‐like receptors (TLRs), especially TLR4, have been widely studied as a radiation protection target. In this study, we detected that a low‐toxicity TLR4 agonist monophosphoryl lipid A (MPLA) produced obvious radiation protection effects on mice testis. We found that MPLA effectively alleviated testis structure damage and cell apoptosis induced by ionizing radiation (IR). However, as the expression abundance differs a lot in distinct cells and tissues, MPLA seemed not to directly activate TLR4 singling pathway in mice testis. Here, we demonstrated a brand new mechanism for MPLA producing radiation protection effects on testis. We observed a significant activation of TLR4 pathway in macrophages after MPLA stimulation and identified significant changes in macrophage‐derived exosomes protein expression. We proved that after MPLA treatment, macrophage‐derived exosomes played an important role in testis radiation protection, and specially, G‐CSF and MIP‐2 in exosomes are the core molecules in this protection effect.

Atherosclerosis in stroke-related vascular beds is the major cause of stroke. Studies demonstrated that multivascular atherosclerosis is prevalent in stroke patients and those with multivascular plaques had higher risk of recurrent stroke.This study investigated the relationship between homocysteine and multivascular atherosclerosis in stroke-related vascular beds using magnetic resonance imaging.Patients with recent ischemic cerebrovascular symptoms were enrolled and underwent three-dimensional magnetic resonance vessel wall imaging for intracranial arteries, extracranial carotid arteries and aortic arch. Traditional risk factors and homocysteine were measured. Presence of multivascular plaques defined as plaques in at least two stroke-related vascular beds on magnetic resonance imaging was determined. The relationship between homocysteine and characteristics of multivascular plaques was determined.Of 49 enrolled patients (mean age: 56.3 ± 13.8 years; 35 males), 23 had multivascular plaques. Homocysteine (odds ratio, 1.17; 95% confidence interval, 1.02-1.34; p = 0.022) and age (odds ratio, 1.71; 95% confidence interval, 1.22-2.41; p = 0.002) were significantly associated with presence of multivascular plaques. The adjusted associations remained significant (both p 0.05). In discriminating presence of multivascular plaques, the area-under-the-curve of age, homocysteine and combination of them was 0.79, 0.70 and 0.87 respectively.Homocysteine is independently associated with stroke-related multivascular plaques and combination of age and homocysteine has stronger predictive value.

This study aimed to investigate the segment-specific progression of atherosclerotic carotid plaques using serial multi-contrast magnetic resonance (MR) imaging. Symptomatic patients with carotid 30–70% stenosis were recruited and underwent carotid MR vessel wall imaging at baseline and follow-up time point (≥ 6 months after baseline). The location of plaques was determined according to the maximum wall thickness located above or below carotid bifurcation. The baseline and changing characteristics of carotid plaques were compared between plaques above and below carotid bifurcation, and the risk factors for segment-specific plaque progression were analyzed with logistic regression. Ninety-six carotid plaques from 73 patients (mean age 66.5 ± 11.4 years old) were eligible for statistical analysis. Compared with plaques located below carotid bifurcation, those above bifurcation had significantly greater stenosis at baseline (57.2 ± 13.0% vs. 50.4 ± 13.5%, p = 0.016, adjusted p = 0.005) and greater progression rate of carotid wall volume (35.2 ± 68.8 mm3/year vs. 4.2 ± 65.0 mm3/year, p = 0.026, adjusted p = 0.005) before and after adjusting for all clinical risk factors and baseline stenosis and wall volume of carotid arteries. Logistic regression showed that the related risk factors were age, hypertension, and smoke for the progression of plaques located above the bifurcation and age for plaques below the bifurcation, respectively. Plaques located above the bifurcation of carotid arteries had greater annual progression and correlated with more cardiovascular risk factors compared with those located below the bifurcation.

Background: Multiplanar reconstruction (MPR) of High Resolution Computed Tomography (HRCT) makes it possible to achieve a clear view of inner ear structures. However, no agreement was reached on the standard measurement of inner ear. Objectives: To establish standard inner ear measurements for building criteria for cochlear structure evaluation. Material and Methods: HRCT scanning of the temporal bones of 82 cases with normal inner ear structures and 104 cases with an EVA and bilaterally sensorineural hearing loss (SNHL) was performed. Three standard cochlear plane and one vestibular plane were reconstructed by MPR. Results: Normative data of inner ear was measured and formulated. The most common malformation found in cases with EVA was incomplete partition type II (IP-II; 90.4%). The IP-II group had significantly greater modiolar height, cochlear aperture width, vestibular area, and vestibule width than did the control group. Different degrees of IP-II modiolar defects were observed using MPR. Conclusions and Significance: Standard cochlear plane can help us to evaluate the cochlear structure. The MPR standard measurement of inner ear is clinically valuable for the diagnosis and cochlear implant of EVA.

Severe ionizing radiation causes the acute lethal damage of haematopoietic system and gastrointestinal tract. Here, we found CL429, the novel chimeric TLR2/NOD2 agonist, exhibited significant radioprotective effects in mice. CL429 increased mice survival, protected mice against the lethal damage of haematopoietic system and gastrointestinal tract. CL429 was more effective than equivalent amounts of monospecific (TLR2 or NOD2) and combination (TLR2 + NOD2) of molecules in preventing radiation‐induced death. The radioprotection of CL429 was mainly mediated by activating TLR2 and partially activating NOD2. CL429‐induced radioprotection was largely dependent on the activation of TLR2‐MyD88‐NF‐κB signalling pathway. In conclusion, the data suggested that the co‐activation of TLR2 and NOD2 could induce significant synergistic radioprotective effects and CL429 might be a potential high‐efficiency selective agent.

Objective Patients receiving carbon-ion radiation therapy and astronauts exploring outer space are inevitably exposed to heavy ion radiation. The aim of this study was to develop radioprotectors to minimize the injuries induced by carbon ion radiation. Methods Heat-killed Salmonella Typhimurium (HKST) was administered to mice by gavage prior to irradiation with a 12C6+ heavy ion accelerator. Hematoxylin and eosin staining and immunofluorescence TdT-mediated dUTP Nick-End Labeling staining were used to assess the radioprotective effect of HKST on organ damage and levels of apoptosis, respectively, in mice. To investigate the mechanism underlying the radioprotective effect of HKST, levels of the pro-apoptotic proteins BAX and caspase 3 as well as interferon-regulatory factor (IRF) 3/7 in the femur, testis and intestine were assessed using immunofluorescence. Results Injuries induced by carbon ion radiation were significantly eased by pretreatment with HKST. Both apoptosis and high expression levels of pro-apoptotic proteins induced by heavy ion radiation were inhibited by HKST pretreatment. The radioprotective effect of HKST was associated with stimulation of Toll-like receptor signaling mediated by enhanced IRF3 and IRF7 signaling. Conclusion HKST was an effective radioprotector alleviating damage to multiple organs caused by heavy ion radiation.

Aim: The present study aimed to investigate the association between shape and location of atherosclerotic plaques and intraplaque hemorrhage (IPH) in carotid arteries using magnetic resonance (MR) imaging. Methods: Overall, 114 symptomatic patients (mean age: 64.9±10.9 years; 81 males) who underwent MR imaging and had advanced carotid plaques were included in analysis. IPH presence and carotid plaque shape and location (below and above bifurcation) were evaluated. The plaque shape was defined as follows: type-I: the arc-length of plaque is greater in the upstream; type-II: the arc-length of plaque in downstream and upstream is equal; and type-III: the arc-length of plaque is greater in downstream. The plaque shape and location were compared between plaques with and without IPH and their associations with IPH were determined. Results: Of 181detectedplaques, 57 (31.5%) had IPH. Compared with plaques without IPH, those with IPH had higher incidence of the plaque shape of type-I (66.7% vs. 32.2%, P

Aim: To investigate the association between the volumes of different aging intraplaque hemorrhage (IPH) and minor fibrous cap disruption (MFCD) in carotid arteries. Methods: Patients with cerebrovascular symptoms and carotid atherosclerotic plaques determined by ultrasound were recruited and underwent multi-contrast magnetic resonance (MR) vessel wall imaging for carotid arteries. Carotid plaques with IPH on MR imaging were included in the analysis. The age (fresh or recent) and the volume of IPH for each plaque were evaluated. Results: In total, 41 carotid plaques in 37 patients (mean age 70.2 ± 11.0 years old; 32 males) were eligible for statistical analysis. The absolute volume of fresh IPH in plaques with MFCD was significantly larger than that in plaques without MFCD (109.83 ± 75.49 mm3 vs. 30.54 ± 20.62 mm3, P = 0.002). Logistic regression showed that the absolute volume of fresh IPH was significantly associated with MFCD before (odds ratio [OR], 1.735; 95% confidence interval [CI], 1.127–2.670; P = 0.012) and after adjusting for confounding factors (OR, 1.823; 95% CI, 1.076–3.090; P = 0.026). There was no significant association between recent IPH volume and MFCD (P > 0.05). Conclusion: The volume of fresh IPH is independently associated with MFCD in carotid plaques, suggesting that integrity of fibrous cap may change with different age and size of IPH.

Background Ionizing radiation often causes severe injuries to radiosensitive tissues, especially haematopoietic system. Novel radioprotective drugs with low toxicity and high effectiveness are required. Prolyl hydroxylases domain (PHD) inhibitors have been reported to protect against radiation‐induced gastrointestinal toxicity. In this study, we demonstrated the protective effects of a PHD inhibitor, roxadustat (FG‐4592), against radiation‐induced haematopoietic injuries in vitro and in vivo. Methods Tissue injuries were evaluated by Haematoxilin‐Eosin (HE) staining assay. HSCs were determined by flow cytometry with the Lin−Sca‐1+c‐Kit+ (LSK) phenotype. Cell apoptosis was determined by Annexin V/PI staining assay. Immunofluorescence was performed to measure radiation‐induced DNA damage. A western blot assay was used to detect the changes of proteins related to apoptosis. Results We found that FG‐4592 pretreatment increased survival rate of irradiated mice and protected bone marrow and spleen from damages. Number of bone marrow cells (BMCs) and LSK cells were also increased both in irradiated mice and recipients after bone marrow transplantation (BMT). FG‐4592 also protected cells against radiation‐induced apoptosis and double strand break of DNA. Conclusions Our data showed that FG‐4592 exhibited radioprotective properties in haematopoietic system both in vivo and in vitro through up‐regulating HIF‐1α, indicating a potential role of FG‐4592 as a novel radioprotector.

Background/Aims: This study investigated the radioprotective properties of three classes of CpG-oligodeoxynucleotides (CpG-ODNs) and the underlying mechanisms. Methods: Mice irradiated at different doses(7Gy or 9Gy) were treated with or without ODNs(50μg via intraperitoneal injection). Assays were performed to determine survival rate and the number of white blood cell in peripheral blood. The levels of granulocyte-colony stimulating factor(G-CSF), interleukin 6(IL-6) and interferon-α (IFN-α) were measured using enzyme-linked immunosorbent assay (ELISA). Results: Survival rate of mice irradiated in 7Gy was increased from 50% to about 100% with ODNs pretreatment. ODNs administration increased the number of WBCs of irradiated mice. G-CSF, IL-6 and IFN-α levels were up-regulated with ODNs treatment. Conclusion: All three classes of ODNs protected mice from irradiation-induced injuries. B-class ODNs exhibited the most potent radioprotective property via the up-regulation of G-CSF and IL-6.

Background/Aims: Radiation therapy is an important treatment for thoracic cancer; however, side effects accompanied with radiotherapy lead to limited tumor control and a decline in patient quality of life. Among these side effects, radiation-induced lung injury (RILI) is the most serious and common. Hence, an effective remedy for RILI is needed. Mesenchymal stromal cells (MSCs) are multipotent adult stem cells that have been demonstrated to be an effective treatment in some disease caused by tissue damage. However, unlike other injuries, RILI received limited therapeutic effects from implanted MSCs due to local hypoxia and extensive reactive oxygen species (ROS) in irradiated lungs. Since the poor survival of MSCs is primarily due to hypoxia and ROS generation, we hypothesize that persistent and adaptive hypoxia treatment induces enhanced resistance to hypoxic stress in implanted MSC. The aim of this study is to investigate whether persistent and adaptive hypoxia treatment of bmMSCs prior to their transplantation in injured mice enhanced survival and improved curative effects in RILI. Methods: Primary bmMSCs were obtained from the marrow of six-week-old male C57BL6/J mice and were cultured either under normoxic conditions (21% O2) or hypoxic conditions (2.5% O2). Mice were injected with normoxia/hypoxia MSCs after thoracic irradiation (20 Gy). The therapeutic effects of MSCs on RILI were assessed by pathological examinations that included H&E staining, Masson staining and α-SMA staining; meanwhile, inflammatory factors were measured using an ELISA. The morphology of MSCs in vitro was recorded using a microscope and identified by flow cytometry, cell viability was measured using the CCK-8 assay, the potential for proliferation was detected by the EdU assay, and ROS levels were measured using a ROS fluorogenic probe. In addition, HIF-1α and several survival pathway proteins (Akt, p-Akt, Caspase-3) were also detected by western blotting. Results: Implanted MSCs alleviated both early radiation-induced pneumonia and late pulmonary fibrosis. However, hypoxia MSCs displayed a more pronounced therapeutic effect compared to normoxia MSCs. Compared to normoxia MSCs, the hypoxia MSCs demonstrated greater cell viability, an enhanced proliferation potential, decreased ROS levels and increased resistance to hypoxia and ROS stress. In addition, hypoxia MSCs achieved higher activation levels of HIF-1α and Akt, and HIF-1α played a critical role in the development of resistance. Conclusion: Hypoxia enhances the therapeutic effect of mesenchymal stromal cells on radiation-induced lung injury by promoting MSC proliferation and improving their antioxidant ability, mediated by HIF-1α.

MicroRNA-143 has been implicated in tumor metastasis by directly targeting Bcl-2, and microRNA-143 expression is decreased in several human tumors. However, the expression and targets of miR-143 in radiation carcinogenesis remain unclear. We found that the expression of miR-143 is down-regulated and the expression of B7H1 (Pdcd1) is up-regulated in radiation-induced thymic lymphoma model in BALB/c mice. Additionally, overexpression of miR-143 strongly inhibited cell proliferation and increased cell apoptosis and its down-regulation promoted cell proliferation and reduced cell apoptosis. We also determined that there is an inverse correlation between miR-143 expression and B7H1 protein expression in radiation-induced thymic lymphoma samples, and miR-143 targets B7H1 in a 3'UTR-dependent manner. In addition, we found that adenovirus over-expression of pre-miR-143 reduced tumorigenesis in vivo. Finally, we conclude that down-regulated expression of miR-143 and up-regulation of its direct target B7H1 may indicate a novel therapeutic method for radiation-induced thymic lymphoma by increased expression of miR-143 or inhibition of B7H1.

Background/Aims: The hematopoietic system is vulnerable to ionizing radiation and is often severely damaged by radiation. Molecules affecting radioresistance include Toll-like receptor 2. We investigated whether Zymosan-A, a novel TLR2 agonist, can protect the hematopoietic system from radiation-induced damage after total body irradiation. Methods: Mice were exposed to total body radiation after treatment with Zymosan-A or normal saline, and their survival was recorded. Tissue damage was evaluated by hematoxylin–eosin staining. The number of nucleated cells in bone marrow was determined by flow cytometry. Cell viability and apoptosis assay were determined by CCK-8 assay and flow cytometry assay. Enzyme-linked immunosorbent assay was used to detect the level of cytokines. Results: Zymosan-A protected mice from radiation-induced death and prevented radiation-induced hematopoietic system damage. Zymosan-A also promoted cell viability and inhibited cell apoptosis caused by radiation, induced radioprotective effects via TLR2, upregulated IL-6, IL-11, IL-12, and TNF-α in vivo. Conclusion: Zymosan-A can provide protection against radiation-induced hematopoietic system damage by targeting the TLR2 signaling pathway. Thus, Zymosan-A can be potentially effective radioprotectant.

Background and aims Dynamic contrast-enhanced MR imaging (DCE-MRI) provides a noninvasive approach to the functional status of carotid adventitial vasa vasorum . Contrast extravasation rate, or K trans , derived from kinetic modeling of adventitial enhancement, has been correlated with plaque neovascularization and inflammation. This study sought to clarify the clinical implications of K trans by evaluating its relationship with documented cardiovascular events (CVE). Methods Seventy patients with carotid plaque at clinical ultrasound examination were recruited and imaged with a previously-described bright-blood DCE-MRI protocol (spatial resolution: 0.55 × 0.58 mm 2 ; time resolution: 18 s). Patients were classified by the presence of documented coronary and/or cerebrovascular events. Adventitial K trans was estimated via kinetic modeling of outer wall enhancement as captured by DCE-MRI. Results After excluding six patients with insufficient image quality, 64 patients (66 ± 12 years, 51 male) had DCE-MRI measurements. Patients with documented CVE showed significantly higher adventitial K trans than those without (0.056 ± 0.024 versus 0.034 ± 0.008 min −1 , p p > 0.05): 0.054 ± 0.027 min −1 in patients with coronary events alone, 0.056 ± 0.018 min −1 in patients with cerebrovascular events alone, and 0.069 ± 0.022 min −1 in patients with both. Carotid adventitial K trans was negatively correlated with time since clinical event (Spearman's rho = −0.40, p = 0.003). Conclusions Patients with documented CVE demonstrated increased rate of contrast extravasation from carotid adventitial vasa vasorum on DCE-MRI irrespective of the territory of events. Systemic factors implicated in the pathophysiology of acute atherothrombotic events may influence the functional status of adventitial vasa vasorum .

With more powerful penetrability and ionizing capability, high energetic neutron radiation (HENR) often poses greater threats than photon radiation, especially on such occasions as nuclear bomb exposure, nuclear accidents, aerospace conduction, and neutron-based radiotherapy. Therefore, there emerges an urgent unmet demand in exploring highly efficient radioprotectants against HENR. In the present study, high-throughput 14.1 MeV neutrons were generated by the high-intensity D-T fusion neutron generator (HINEG) and succeeded in establishing the acute radiation syndrome (ARS) mouse model induced by HENR. A series of preclinical studies, including morphopathological assessment, flow cytometry, peripheral complete blood, and bone marrow karyocyte counting, were applied showing much more serious detriments of HENR than the photon radiation. In specific, it was indicated that surviving fraction of polydatin- (PD-) treated mice could appreciably increase to up to 100% when they were exposed to HENR. Moreover, polydatin contributed much in alleviating the HENR-induced mouse body weight loss, spleen and testis indexes decrease, and the microstructure alterations of both the spleen and the bone marrow. Furthermore, we found that the HENR-damaged hematopoiesis was greatly prevented by PD treatment in such aspects as bone marrow hemocytogenesis, splenocytes balancing, or even the peripheral blood cellularity. The additional IHC investigations revealed that PD could exert potent hematopoiesis-promoting effects against HENR via suppressing apoptosis and promoting the antioxidative enzymes such as HO-1.

Background: Exposure to ionizing radiation (IR) often causes severe damage to radiosensitive tissues, which limits the use of radiotherapy in cancer patients. Novel safe and effective radioprotectant is urgently required. It has been reported toll like receptor 2 (TLR2) plays a critical role in radioresistance. In this study, we demonstrated the protective effects of Heat-Killed Mycobacterium tuberculosis (HKMT), a potent TLR2 agonist, against IR. Methods: Cell survival and apoptosis were determined by CCK-8 assay and Annexin V assay, respectively. An immunofluorescence staining assay was used to detect the translocation of nuclear faktor-kappa beta (NF-kB) p65. Tissue damage was evaluated by Haematoxilin-Eosin (HE) staining assay. We also used a flow cytometry assay to measure the number of nucleated cells and CD34+ hemopoietic stem cells in bone marrow. A western blot assay was used to detect the changes of proteins involving TLR signaling pathway. Results: We found that HKMT increased cell viability and inhibited cell apoptosis after irradiation. HKMT induced NF-kB translocation and activated Erk1/2, p38 signaling pathway. HKMT also protected bone marrow and testis from destruction. Radiation-induced decreases of nucleated cells and CD34+ hemopoietic stem cells in bone marrow were also inhibited by HKMT treatment. We found that radiation caused increase of inflammatory cytokines was also suppressed by HKMT. Conclusion: Our data showed that HKMT exhibited radioprotective effects in vivo and in vitro through activating NF-kB and MAPK signaling pathway, suggesting a potential of HKMT as novel radioprotector.

Background Statin therapy can improve plaque stability. However, the time course of effects of statin on adventitial angiogenesis and plaque neovascularization has not been studied. Objective The objective of the study was to investigate whether statin therapy reduces plaque neovascularization, associated with adventitial angiogenesis, over 24 months as assessed by using carotid dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods Forty-three lipid treatment–naive subjects with asymptomatic carotid atherosclerosis received rosuvastatin (5–20 mg/d) to lower low-density lipoprotein cholesterol to Results Adventitia Vp and adventitia Ktrans were significantly correlated with plaque Vp and plaque Ktrans at baseline. Rosuvastatin significantly reduced both adventitial and plaque Vp significantly at 3 months from 0.121 ± 0.064 to 0.085 ± 0.049 (P = .008) and from 0.096 ± 0.052 to 0.067 ± 0.043 (P = .013). Adventitial and plaque Vp continued to decrease by 43% and 34% at 12 months and by 49% and 45% at 24 months. However, the continued reductions from 3 to 12 months and from 12 to 24 months were not statistically significant. Adventitial and plaque Ktrans showed similar trends, but nonstatistically significant decreases during the 24 months of treatment. Conclusions Rosuvastatin therapy rapidly and significantly decreased adventitial and plaque neovascularization at 3 months followed by continued, but nonstatistically significant, decreases at 12 and 24 months.

Injury-induced by ionizing radiation (IR) severely reduces the quality of life of victims. The development of radiation protectors is regarded as one of the most resultful strategies to alleviate damages caused by IR exposure. In the present study, we investigated the radioprotective effects of the agonist of nucleotide-binding-oligomerization-domain-containing proteins 2 called murabutide (MBD) and clarified the potential mechanisms. Our results showed that the pretreatment with MBD effectively protected cultured cells and mice against IR-induced toxicity and the pretreatment with MBD in vitro and in vitro also inhibited apoptosis caused by IR exposure. The downregulation of γ-H2AX and the upregulation of ATR signaling pathways by MBD treatment indicated that the radioprotective effects of MBD were due to the stimulation of DNA damage response (DDR) pathway to repair DNA double-strand breaks caused by IR exposure. As the radioprotective effects of MBD were diminished by the ATR selective inhibitor rather than the ATM inhibitor, ATR pathway was confirmed to be a more crucial checkpoint pathway in mediating the stimulation of DDR pathway by MBD. Taken together, our data provide a novel and effective protector to relieve the injury induced by IR exposure.

This study aimed to investigate the association between age and progression of carotid atherosclerotic plaques using serial high resolution magnetic resonance imaging (MRI). Symptomatic patients who had carotid atherosclerosis with 30–70% stenosis were enrolled in this study. Carotid MRI was performed at baseline and follow-up time point (≥ 6 months after baseline), respectively. The characteristics of carotid plaque progression among different age groups (> 75 years old, 60–75 years old and 75 years old: 91.3%, 60–75 years old: 65.7% and 75 years old: 39.0 (4.3–104.6) mm3, 60–75 years old: 28.7 (− 28.0 to 73.7) mm3 and 75 years old: 6.1 (− 3.5 to 17.2) mm2, 60–75 years old: 2.4 (− 4.7 to 15.1) mm2 and

It has been reported dysregulation of certain microRNAs (miRNAs / miRs) is involved in tumorigenesis. However, the miRNAs associated with radiocarcinogenesis remain undefined. In this study, we validated the upregulation of miR-467a in radiation-induced mouse thymic lymphoma tissues. Then, we investigated whether miR-467a functions as an oncogenic miRNA in thymic lymphoma cells. For this purpose, we assessed the biological effect of miR-467a on thymic lymphoma cells. Using miRNA microarray, we found four miRNAs (miR-467a, miR-762, miR-455 and miR-714) were among the most upregulated (>4-fold) miRNAs in tumor tissues. Bioinformatics prediction suggests miR-467a may potentially regulate apoptosis pathway via targeting Fas and Bax. Consistently, in miR-467a-transfected cells, both proliferation and colony formation ability were significantly increased with decrease of apoptosis rate, while, in miR-467a-knockdown cells, proliferation was suppressed with increase of apoptosis rate, indicating that miR-467a may be involved in the regulation of apoptosis. Furthermore, miR-467a-knockdown resulted in smaller tumors and better prognosis in an in vivo tumor-transplanted model. To explain the mechanism of apoptosis suppression by miR-467a, we explore the expression of candidate target genes (Fas and Bax) in miR-467a-transfected relative to negative control transfected cells using flow cytometry and immunoblotting. Fas and Bax were commonly downregulated in miR-467a-transfected EL4 and NIH3T3 cells, and all of the genes harbored miR-467a target sequences in the 3'UTR of their mRNA. Fas and Bax were actually downregulated in radiation-induced thymic lymphoma tissues, and therefore both were identified as possible targets of miR-467a in thymic lymphoma. To ascertain whether downregulation of Fas and / or Bax is involved in apoptosis suppression by miR-467a, we transfected vectors expressing Fas and Bax into miR-467a-upregulated EL4 cells. Then we found that both Fas- and Bax-overexpression decreased cell viability with increase of apoptosis rate, indicating that downregulation of Fas and Bax may be at least partly responsible for apoptosis suppression by miR-467a. These data suggest that miR-467a may have oncogenic functions in radiation-induced thymic lymphoma cells and that its increased expression may confer a growth advantage on tumor cells via aberrant expression of Fas and Bax.

It proved that Zymosan‐A protected the haematopoietic system from radiation‐induced damage via Toll‐Like Receptor2 in our previous study. In this study, we investigated the potential mechanism for the radioprotective effects of Zymosan‐A. The mice were treated with Zymosan‐A (50 mg/kg, dissolved in NS) via peritoneal injection 24 and 2 hours before ionizing radiation. Apoptosis of bone marrow cells and the levels of IL‐6, IL‐12, G‐CSF and GM‐CSF were evaluated by flow cytometry assay. DNA damage was determined by γ‐H2AX foci assay. In addition, RNA sequencing was performed to identify differentially expressed genes (DEGs). Zymosan‐A protected bone marrow cells from radiation‐induced apoptosis, up‐regulated IL‐6, IL‐12, G‐CSF and GM‐CSF in bone marrow cells. Zymosan‐A also protected cells from radiation‐induced DNA damage. Moreover, RNA sequencing analysis revealed that Zymosan‐A induced 131 DEGs involved in the regulation of immune system process and inflammatory response. The DEGs were mainly clustered in 18 KEGG pathways which were also associated with immune system processes. Zymosan‐A protected bone marrow cells from radiation‐induced apoptosis and up‐regulated IL‐6, IL‐12, G‐CSF and GM‐CSF. Moreover, Zymosan‐A might also exhibit radioprotective effects through regulating immune system process and inflammatory response. These results provided new knowledge regarding the radioprotective effect of Zymosan‐A.

Background and Purpose— This study aimed to investigate the association between carotid plaque progression and subsequent recurrent events using magnetic resonance imaging. Methods— Sixty-three symptomatic patients with ipsilateral carotid atherosclerotic stenosis (30%–69% stenosis) determined by ultrasound underwent first and second carotid artery magnetic resonance imaging for carotid artery at baseline and ≥6 months after the first scan, respectively. All the patients had clinical follow-up after the second magnetic resonance scan for ≤5 years until the onset of recurrent transient ischemic attack or stroke. Presence/absence of carotid plaque compositional features, particularly intraplaque hemorrhage and fibrous cap rupture was identified. The annual progression of carotid wall volume between 2 magnetic resonance scans was measured. Univariate and multivariate Cox regression was used to calculate the hazard ratio and corresponding 95% confidence interval of carotid plaque features in discriminating recurrent events. Receiver-operating-characteristic-curve analysis was conducted to determine the area-under-the-curve of carotid plaque features in predicting recurrent events. Results— Sixty-three patients (mean age: 66.5±10.0 years old; 54 males) were eligible for final statistics analysis. During a mean follow-up duration of 55.1±13.6 months, 14.3% of patients (n=9) experienced ipsilateral recurrent transient ischemic attack/stroke. The annual progression of carotid wall volume was significantly associated with recurrent events before (hazard ratio, 1.14 per 10 mm 3 ; 95% confidence interval, 1.02–1.27; P =0.019) and after (hazard ratio, 1.19 per 10 mm3; 95% confidence interval, 1.03–1.37; P =0.022) adjusted for confounding factors. In discriminating the recurrence of transient ischemia attack/stroke, receiver–operator curve analysis indicated that combined with annual progression of wall volume, there was a significant incremental improvement in the area-under-the-curve of intraplaque hemorrhage (area-under-the-curve: 0.69–0.81) and fibrous cap rupture (area-under-the-curve: 0.73–0.84). Conclusions— The annual progression of carotid wall volume is independently associated with recurrent ischemic cerebrovascular events, and this measurement has added value for intraplaque hemorrhage and fibrous cap rupture in predicting future events.

To investigate whether Rac1 inhibition can alleviate radiation-induced intestinal injury (RIII), meanwhile exist no protection on tumors.Rac1 inhibition was achieved by its specific inhibitor, NSC23766. Mice were pretreated with different intraperitoneal injections, which were normal saline for NS group (N = 9), and 2.5 mg/kg and 5 mg/kg of NSC23766 for Low-Dose group (N = 9) and High-Dose group (N = 9), respectively. After total body irritation (10Gy), small intestinal tissues were collected for Hematoxylin-Eosin (HE) staining and Terminal-deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL). Intestinal epithelial and tumor cell lines, namely MODE-k and CT-26, were used to further study the role of Rac1 inhibition on radiation damage. Flow cytometry was used to detect changes in reactive oxygen species production, cell cycles and mitochondrial membrane potential, the latter was also checked by fluorescence microscope. Changes of protein-expression associated with apoptosis and cell cycles were detected by Western blotting to explain the possible molecular mechanism.Height of intestine villi and depth of crypt were higher (P 0.01) and apoptosis ratio lower (P 0.01) in High-Dose group compared with those in NS group. After radiation, Rac1 inhibition pre-treatment improved the vitality (P 0.01) and reduced the apoptosis (P 0.01) in MODE-k while yielded opposite results in CT-26, and reduced ROS production of MODE-k (P 0.01) while had little effect on that of CT-26. Rac1 inhibition differently affected the cell cycles of normal cells and that of tumor cells.Inhibition of Rac1 could alleviate RIII, meanwhile assist the killing effect of radiation on tumor cells.

Recent studies showed that hydrogen can be used as an effective radioprotective agent through scavenging free radicals. This study was undertaken to evaluate the radioprotective effects of hydrogen on immune system in mice. H(2) was dissolved in physiological saline using an apparatus produced by our department. Spleen index and histological analysis were used to evaluate the splenic structural damage. Spleen superoxide dismutase, GSH, MDA were measured to appraise the antioxidant capacity and a DCF assay for the measurement of radical oxygen species. Cell apoptosis was evaluated by an Annexin V-FITC and propidium iodide staining method as well as the apoptotic proteins such as Bcl-2, Bax, caspase-3 and c-caspase-3. CD4+ and CD8+ T cells subtypes were detected by flow cytometry with FITC-labelled antimouse CD4 and PE antimouse CD8 staining. Real-time PCR was utilized to determine the CD4+ T cell subtypes and related cytokines. Our study demonstrated that pre-treatment with H(2) could increase the spleen index and attenuate the radiation damage on splenic structure. Radical oxygen species level was also reduced by H(2) treatment. H(2) also inhibited radiation-induced apoptosis in splenocytes and down-regulated pro-apoptotic proteins in living mice. Radiation-induced imbalance of T cells was attenuated by H(2). Finally, we found that H(2) could regulate the polarization of CD4+ T cells and the level of related cytokines. This study suggests H(2) as an effective radioprotective agent on immune system by scavenging reactive oxygen species.

Radiation therapy produced unwanted side effect on normal tissues, such as radiodermatitis. Hydrogen was previously shown capable of radiation protective in both animals and cell cultures. The effect of hydrogen was now to be investigated on radiation-induced cutaneous.Development of dermatitis is a frequent side effect of radiotherapy of patients with head-and-neck cancer. Here we analyzed the radioprotective efficacy of hydrogen under conditions of local, single-dose or fractionated radiation treatment, and its possible molecular mechanisms.Rats received either single-dose or fractioned irradiation of the head-and-neck area with or without subcutaneous injection of hydrogen solution before irradiation. In vitro, the effect of hydrogen medium on radiation-induced cell viability, apoptosis, and biochemical assays was measured.Hydrogen significantly reduced the severity of dermatitis, accelerated tissue recovery, and reduced the extent of radiation-induced weight loss in rats after a single dose of 15 or 20 Gy but not 25 Gy of radiation. Hydrogen was also protective from cumulative doses of 30 Gy delivered in three fractions, respectively. Hydrogen also protect HaCaT cells from radiation-induced injury, it could significantly inhibit ionizing injury.These results suggest that hydrogen has a positive effect on acute radiodermatitis.

Background: Aplasitc anemia (AA) is a bone marrow failure syndrome characterized by an immune-mediated destruction of hematopoietic stem cells. Though clinical symptoms could be ameliorated by bone marrow transplantation and/or immunosuppressive therapy, frequent recurrence and especially evolution of clonal hematologic diseases remains problematic clinically. Cytokines such as interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) secreted by autologous T cells are closely related with the development of AA. Hydrogen-rich solution was reported to inhibit the levels of cytokines including INF-γ, TNF-α and IL-6 in vivo in recent studies. This study was to investigate the potential therapeutic effects of hydrogen-rich solution on AA in vivo. Methods: AA model was determined in vivo by mice and body weights of the mice were used as the basic physiological index. Peripheral blood cells were calculated to evaluate the hematologic recovery degree. Bone marrow nucleated cells (BMNCs), tissue histology, as well as CFU-S and CFU-GM forming units were used to evaluate the recovery of bone marrow microenvironment. The ratio of CD4+ and CD8+ cells were examined along with cytokine levels in serum to determine the efficacy of H2-rich solution on the affected immunological functions. Results: Body weight and number of peripheral blood cells were significantly improved for mice in the H2-rich solution treated groups as compared with those with AA. The number of BMNCs and CFUs increased markedly and the bone marrow microenvironment was also improved significantly. The experimental group restrained the cell apoptosis, relieved hyperemia and accelerated tissue repair. The number of CD4+ and CD8+ cells as well as the ratio of CD4/CD8 increased to normal gradually, while the levels of TNF-α, IFN-γ, and IL-6 in serum decreased after H2-rich solution treatment. Conclusion: Our study firstly showed that hydrogen-rich solution accelerated the recovery of either hematological or immunological recovery on aplastic anemia mice. This finding suggests hydrogen-rich solution as a potential clinical therapeutic agent for AA.

It is well known that most of the ionizing radiation-induced damage is caused by hydroxyl radicals (·OH) follows radiolysis of H2O. Molecular hydrogen (H2) has antioxidant activities by selectively reducing ·OH and peroxynitrite(ONOO-). We firstly hypothesized and demonstrated the radioprotective effect of H2 in vitro and in vivo, which was also repeated on different experimental animal models by different departments. A randomized, placebo-controlled study showed that consumption of hydrogen-rich water reduces the biological reaction to radiation-induced oxidative stress without compromising anti-tumor effects. These encouraging results suggested that H2 represents a potentially novel preventative strategy for radiation-induced oxidative injuries. H2 is explosive. Therefore, administration of hydrogen-rich solution (physiological saline/pure water/other solutions saturated with H2) may be more practical in daily life and more suitable for daily consumption. This review focuses on major scientific and clinical advances of hydrogen-rich solution/H2 as a new class of radioprotective agent.

// Hu Liu 1, * , Shichao Wang 2, * , Zhao Wu 2, * , Ziyun Huang 2 , Wei you Chen 2 , Yanyong Yang 1 , Jianguo Cui 1 , Cong Liu 1 , Hainan Zhao 1 , Jiaming Guo 1 , Pei Zhang 1 , Fu Gao 1 , Bailong Li 1 and Jianming Cai 1 1 Department of Radiation Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai, China 2 Fifth Cadet Battalion of Naval Medicine Department, Second Military Medical University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Fu Gao, email: gaofusmmu@163.com Bailong Li, email: libailong2003@163.com Jianming Cai, email: cjm882003@163.com Keywords: acute radiation-induced liver injury, reactive oxygen species (ROS), ATP-sensitive potassium channel (KATP), membrane potential (MP), glibenclamide Received: August 05, 2016 Accepted: February 15, 2017 Published: March 23, 2017 ABSTRACT Background: Acute radiation-induced liver injury is a limitation for hepatoma radiotherapy. Come so far the clinical treatments are insufficient. The effective, specific, low toxicity and novel drugs are in powerful need. Glibenclamide is a common hypoglycemic. Some studies have revealed its relation with intracellular reactive oxygen species, the crucial mediator to radiation injury. This study is aimed to investigate if glibenclamide could act on the acute radiation-induced liver injury. Results: Glibenclamide mitigated acute radiation-induced liver injury of mice, indicating as regression of hepatocellular edema, reduction of hepatic sinusoid, decline in serum ALP level and reduction of hepatocellular apoptosis. Pretreatment of glibenclamide reduced the radiosensitivity of NCTC-1469 cells. In mechanism, glibenclamide elevated cells membrane potential to up-regulate intracellular reactive oxygen species. The increased reactive oxygen species subsequently activated Akt–NF-κB pathway to promote survival of irradiated cells. Methods: BALB/C male mice were intraperitoneal injected with glibenclamide 1 hour before hepatic irradiation. At designed time points the livers were taken to make histological study and bloods were collected to measure serum transaminase. With/without glibenclamide pretreatment the irradiated NCTC-1469 cells were tested apoptosis, viability and proliferation. By western blotting the involved molecules were detected. Conclusions: Glibenclamide, prevents acute radiation-induced liver injury of mice via up-regulating intracellular reactive oxygen species and subsequently activating Akt–NF-κB pathway.

Our recent studies suggest that H2 (hydrogen) has a potential as a novel radioprotector without known toxic side effects. The present study was designed to examine the underlying radioprotective mechanism of H2 and its protective role on irradiated germ cells. Produced by the Fenton reaction and radiolysis of H2O, hydroxyl radicals (•OH) were identified as the free radical species that were reduced by H2. We used a H2 microelectrode to dynamically detect H2 concentration in vivo, and found H2 significantly reduced in situ fluorescence intensity of hydroxyphenyl fluorescein; however, as we treated the mice with H2 after irradiation, the decrease is not significant. We found that pre-treatment of H2 to IR (ionizing radiation) significantly suppressed the reaction of •OH and the cellular macromolecules which caused lipid peroxidation, protein carbonyl and oxidatively damaged DNA. The radioprotective effect of H2 on male germ cells was supported by ameliorated apoptotic findings examined by morphological changes and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling) in testicular tissue, and by preserved viability of stem spermatogonia examined for testicular histological parameters, daily sperm production and sperm quality; we used WR-2721 [S-2-(3-aminopropylamino)ethyl phosphorothioic acid] as a reference compound. Our results represent the first in vivo evidence in support of a radioprotective role of H2 by neutralizing •OH in irradiated tissue with no side effects.

Studies have shown that atherosclerosis in coronary arteries is closely related to that in carotid arteries, but there are few investigations on the correlation between unstable plaques in these 2 vascular beds. The authors aim to investigate the correlation between coronary plaque phenotype and carotid plaque composition.Patients (n = 123) with suspected coronary artery disease underwent computed tomography angiography of coronary arteries. Magnetic resonance imaging of bilateral carotid arteries was performed within 2 weeks after computed tomography angiography. The plaque type in each coronary segment was analyzed. Coronary plaques were classified into 3 types: noncalcified, calcified and mixed. The total number of each plaque type was scored. Carotid plaque with calcification, lipid-rich necrotic core (LRNC) or intraplaque hemorrhage (IPH) in either carotid artery was defined as positive. Logistic regression analysis was used to determine the correlation between coronary plaque phenotype and carotid plaque composition. The area under the receiver-operating characteristic curve (AUC) was calculated.There was a significant correlation between the mixed coronary plaque score and carotid IPH (odds ratio = 1.50, P0.05). The scores for all 3 types of the coronary plaque were significantly correlated with carotid LRNC and calcification. The mixed coronary plaque score had the highest value in predicting carotid IPH (AUC = 0.74). The calcified coronary plaque score showed the highest value in predicting carotid LRNC (AUC = 0.75) and calcification (AUC = 0.75).There was significant correlation between coronary plaque phenotype and carotid plaque composition. A mixed coronary plaque may be suggestive of a high-risk carotid plaque.

Dendritic cells (DC) and myeloid-derived suppressor cells (MDSC) are important cells involved in immune response. DC can be generated from mouse bone marrow (BM) in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. Recent studies have revealed that combined treatment of bone marrow MDSC with LPS plus IFN-γ inhibited the DC development but enhanced MDSC functions, such as NO release and T cell suppression. In our study, bone marrow precursor cells cultures in GM-CSF and IL-4 were treated with poly(I:C) through the culture, Gr1(+)CD11b(+) cells with MDSC functions, such as NO release and T cell suppression were accumulated in the culture system. Then the similar phenomenon was observed in the vesicular stomatitis virus infection in vivo. In conclusion, we demonstrated that the bone marrow precursor cells in the presence of GM-CSF and IL-4 can differentiate into MDSC, which is dependent on the dynamic of interaction with poly(I:C).

The purpose of this study was to evaluate the differences in carotid arterial morphology and plaque composition between patients with acute coronary syndrome (ACS) and patients with stable coronary artery disease (SCAD). Twenty-eight patients (12 ACS patients and 16 SCAD patients) underwent carotid high-resolution MRI examination using a 3.0-Tesla (3.0T) MRI scanner. The indicators of carotid arterial morphology included the maximum total vessel area (Max-TVA), mean TVA, minimum lumen area (Min-LA), mean LA, maximum wall area (Max-WA), mean WA, maximum wall thickness (Max-WT), mean WT, maximum normalized wall index (Max-NWI), mean NWI, and maximum stenosis (Max-stenosis). The indicators of plaque composition included the prevalence and mean area percentage (%) of lipid-rich necrotic core (LRNC), calcification (Ca), intraplaque hemorrhage (IPH), and fibrous cap rupture (FCR). None of the indicators of carotid arterial morphology had significant differences (all P > 0.05) between the ACS and SCAD patients. The prevalence and plaque composition area percentage of LRNC, Ca, and IPH did not exhibit significant differences between the two groups. However, carotid plaques in the ACS patients presented a higher prevalence of FCR than SCAD patients (P < 0.05). This study revealed a similar carotid arterial morphology between ACS and SCAD patients. However, FCR is more common in carotid plaques with ACS than in those with SCAD. Ruptured carotid plaques may be a forewarning factor for those patients who are at high risk of ACS.

Dysregulation of certain microRNAs (miRNAs) in cancer can promote tumorigenesis, metastasis and invasion. However, the functions and targets of only a few mammalian miRNAs are known. In particular, the miRNAs that participates in radiation induced carcinogenesis and the miRNAs that target the tumor suppressor gene Big-h3 remain undefined. Here in this study, using a radiation induced thymic lymphoma model in BALB/c mice, we found that the tumor suppressor gene Big-h3 is down-regulated and miR-21 is up-regulated in radiation induced thymic lymphoma tissue samples. We also found inverse correlations between Big-h3 protein and miR-21 expression level among different tissue samples. Furthermore, our data indicated that miR-21 could directly target Big-h3 in a 3′UTR dependent manner. Finally, we found that miR-21 could be induced by TGFβ, and miR-21 has both positive and negative effects in regulating TGFβ signaling. We conclude that miR-21 participates in radiation induced carcinogenesis and it regulates TGFβ signaling.

Dendritic cells (DCs) are the most potent antigen-presenting cells and play a crucial role in the regulation of immune response and migration of DCs into secondary lymphoid tissues also play an important role in the initiation of innate and adaptive immunity. Radiation therapy is now a routine treatment for certain types of cancer and over 20 percent of cancer patients will require radiation therapy during the treatment of their disease. However, the influence of ionizing irradiation on the migratory ability of DCs is largely unknown. In this article, we report that γ ray irradiation can significantly inhibit LPS-triggered up regulation of CCR7 expression and PGE2 production by DC, thus impairing DC migration towards CCL19 in vitro and in vivo. Moreover, γ ray exposed DC also displayed an increased apoptosis rate and decreased cell viability. Furthermore, we demonstrate that exogenous PGE2 can partly reduce the gamma-ray induced migratory impairment and restored CCR7 expression of DC. Our work suggests that γ irradiation affects DC function at multiple steps during the immune response including DC migration, and that PGE2, via control of CCR7 expression, is an important regulator of DC migration.

To evaluate the differences of signal evolution of intraplaque hemorrhage (IPH) and associated stenosis between symptomatic and asymptomatic atherosclerotic carotid arteries. Thirty-three carotid arteries (15 symptomatic and 18 asymptomatic plaques) with recent carotid IPH underwent serial high-resolution MRI examinations on a 3.0-Tesla (3.0T) MRI scanner over a period of 18 months. MR sequences included three-dimensional time-of-flight (3D-TOF), quadruple-inversion-recovery T1-weighted imaging (QIR T1 WI), proton density-weighted imaging (PDWI), and T2-weighted imaging (T2WI). The contrast-to-noise ratios (CNRs) of subsequent IPH during the follow-up period between symptomatic and asymptomatic carotid IPH showed a significant difference on 3D-TOF (P = 0.029), T1 WI (P = 0.005), and PDWI (P = 0.028), except for that on T2WI (P = 0.362). Compared with no significant signal intensity change of symptomatic IPH, CNRs of asymptomatic IPH exhibited a gradually descending trend on all contrast weighted images (P

Background and Purpose— Previous studies have reported that carotid atherosclerosis frequently can be seen in coronary artery disease (CAD) patients. This study sought to determine the prevalence of compositional features in subclinical carotid atherosclerosis by MRI in CAD patients. Methods— Ninety-six subjects with suspected CAD but free of neurological symptoms underwent coronary CT angiography and carotid MRI including 3-dimensional time-of-flight, T1-weighted, T2-weighted, and proton density-weighted sequences at 3 T within a 2-week interval. The coronary artery calcium score (CACS) and degree of stenosis were measured. Areas for carotid lumen, wall, total vessel, and percent wall volume (wall volume/total vessel volume) were measured. The prevalence of carotid calcification, lipid-rich necrotic core, intraplaque hemorrhage, and surface disruption in coronary stenosis and CACS categories were determined. Results— Carotid percent wall volume was correlated with CACS ( P =0.001). Both coronary stenosis and CACS were significantly associated with presence of carotid calcification (OR=5.79 for 1%–49% vs 0% stenosis; OR=10.23 for >50% vs 0% stenosis; OR=10.65 for CACS 1–399 vs CACS 0; and OR=20.28 for CACS >400 vs CACS 0; all P 50% vs 0% stenosis; OR=8.23 for CACS 1–399 vs CACS 0; and OR=11.87 for CACS >400 vs CACS 0; all P Conclusions— Carotid plaque burden and compositional features are significantly associated with CAD severity. The finding of high prevalence of lipid-rich necrotic core in patients with low-grade coronary stenosis and CACS suggests the need for early monitoring of carotid atherosclerosis in CAD patients.

The presence of IPH and/or FCR in the carotid atherosclerotic plaque indicates a high-risk lesion. The aim of this multicenter cross-sectional study was to establish the characteristics of lesions that may precede IPH and/or FCR. We further sought to construct a CAS that stratifies carotid disease severity.Three hundred forty-four individuals from 4 imaging centers with 16%-99% carotid stenosis by duplex sonography underwent carotid MR imaging. In approximately 60% of the study sample (training group), multivariate analysis was used to determine factors associated with IPH and FCR. Statistically significant parameters identified during multivariate analysis were used to construct CAS. CAS was then applied to the remaining arteries (40%, test group), and the accuracy of classification for determining the presence versus absence of IPH or, separately, FCR was determined by ROC analysis and calculation of the AUC.The maximum proportion of the arterial wall occupied by the LRNC was the strongest predictor of IPH (P.001) and FCR (P.001) during multivariate analysis of the training group. The subsequently derived CAS applied to the test group was an accurate classifier of IPH (AUC = 0.91) and FCR (AUC = 0.93). Compared with MRA stenosis, CAS was a stronger classifier of both IPH and FCR.LRNC quantification may be an effective complementary strategy to stenosis for classifying carotid atherosclerotic disease severity. CAS forms the foundation for a simple imaging-based risk-stratification system in the carotid artery to classify severity of atherosclerotic disease.

In this study, we have aimed to evaluate the relationship between the shape and location of superficial calcification and the presence of fibrous cap rupture and intraplaque hemorrhage in atherosclerotic carotid plaque. Sixty-three patients with carotid stenosis underwent contrast-enhanced high resolution MR examinations with a 3-T MR scanner and 226 slices with superficial calcification were evaluated in the study. The shape of superficial calcification was categorized as the irregular type (dotted/arcuated) and patchy type and the location of superficial calcification was categorized as the marginal type and central type. Intraplaque hemorrhage and fibrous cap rupture depicted on the same slice as superficial calcification were identified. The chi-squared test was used for statistical analysis. A total of 149 slices (65.9%) with intraplaque hemorrhage and 107 slices(47.3%)with fibrous cap rupture were detected. There were 191 slices with irregular type (dotted/arcuated) calcification and 166 slices with marginal type calcification. Irregular superficial calcification was found more frequently accompanied with intraplaque hemorrhage as compared to the patchy type (73.8 vs. 22.9%, P0.0001); there was a significant difference between the marginal type and the central type for the accompaniment of intraplaque hemorrhage (72.9 vs. 46.7%, P0.05). However, there was no significant difference between different shapes and locations of superficial calcification that accompanied with fibrous cap rupture (P0.05). This study showed that superficial calcification is an important factor for determination of instability of atherosclerotic carotid plaque. The shape and location of superficial calcification are important features associated with the occurrence of intraplaque hemorrhage.

It has been demonstrated that hydrogen can selectively reduce hydroxyl and peroxynitrite in vitro. Since most of the ionizing radiation-induced cellular damage is caused by hydroxyl radicals, this study was designed to test the hypothesis that hydrogen may be an effective radioprotective agent. This paper demonstrates that treating cells with hydrogen before irradiation could significantly inhibit ionizing irradiation(IR)-induced Human Lymphocyte AHH-1 cells apoptosis and increase cells viability in vitro. This paper also shows that hydrogen can protect gastrointestinal endothelia from radiation-induced injury, decrease plasma malondialdehyde (MDA) intestinal 8-hydroxydeoxyguanosine (8-OHDG) levels and increase plasma endogenous antioxidants in vivo. It is suggested that hydrogen has a potential as an effective and safe radioprotective agent.

Molecular hydrogen (H2) has been previously reported playing an important role in ameliorating damage caused by acute radiation. In this study, we investigated the effects ofH2on the alterations induced by low-dose long-term radiation (LDLTR). All the mice in hydrogen-treated or radiation-only groups received 0.1 Gy, 0.5 Gy, 1.0 Gy, and 2.0 Gy whole-body gamma radiation, respectively. After the last time of radiation exposure, all the mice were employed for the determination of the body mass (BM) observation, forced swim test (FST), the open field test (OFT), the chromosome aberration (CA), the peripheral blood cells parameters analysis, the sperm abnormality (SA), the lymphocyte transformation test (LTT), and the histopathological studies. And significant differences between the treatment group and the radiation-only groups were observed, showing thatH2could diminish the detriment induced by LDLTR and suggesting the protective efficacy ofH2in multiple systems in mice against LDLTR.

We have demonstrated that grape seed proanthocyanidins (GSPs) could effectively scavenge hydroxyl radical (•OH) in a dose-dependent manner. Since most of the ionizing radiation- (IR-) induced injuries were caused by•OH, this study was to investigate whether GSPs would mitigate IR-induced injuries in vitro and in vivo. We demonstrated that GSPs could significantly reduce IR-induced DNA strand breaks (DSBs) and apoptosis of human lymphocyte AHH-1 cells. This study also showed that GSPs could protect white blood cells (WBC) from IR-induced injuries, speed up the weight of mice back, and decrease plasma malondialdehyde (MDA), thus improving the survival rates of mice after ionizing radiation. It is suggested that GSPs have a potential as an effective and safe radioprotective agent.

The purpose of this in vivo MRI study was to quantify changes in atherosclerotic plaque morphology prospectively and to identify factors that may alter the rate of progression in plaque burden. Sixty-eight asymptomatic subjects with >or=50% stenosis, underwent serial carotid MRI examinations over an 18-month period. Clinical risk factors for atherosclerosis, and medications were documented prospectively. The wall and total vessel areas, matched across time-points, were measured from cross-sectional images. The normalized wall index (NWI=wall area/total vessel area), as a marker of disease severity, was documented at baseline and at 18 months. Multiple regression analysis was used to correlate risk factors and morphological features of the plaque with the rate of progression/regression. On average, the wall area increased by 2.2% per year (P=0.001). Multiple regression analysis demonstrated that statin therapy (P=0.01) and a normalized wall index >0.64 (P=0.001) were associated with a significantly reduced rate of progression in mean wall area. All other documented risk factors were not significantly associated with changes in wall area. Findings from this study suggest that increased normalized wall index and the use of statin therapy are associated with reduced rates of plaque progression amongst individuals with advanced, asymptomatic carotid atherosclerosis.

Changes in plaque tissue components such as lipid-rich necrotic core (LRNC) and fibrous tissue with long-term statin treatment or discontinuation have not been studied.LRNC and fibrous tissue by magnetic resonance imaging were evaluated in subjects who continued and discontinued statin therapy for 2 years after a prospective study.The Rosuvastatin Evaluation of Atherosclerotic Chinese Patients study in 32 lipid treatment naïve subjects showed a significant reduction in LRNC during 24 months of rosuvastatin therapy. After Rosuvastatin Evaluation of Atherosclerotic Chinese Patients was completed, 15 subjects continued taking statins and 17 discontinued despite receiving an instruction to continue statin therapy. LRNC and fibrous tissue were compared between 24 and 48 months within each group and between the 2 groups.At 48 months, LRNC volume and composition decreased significantly compared with that at 24 months in the statin-continued group (101 ± 76 vs 76 ± 65 mm(3); P = .001 and 17.3 ± 11.9% vs 12.6 ± 7.6%; P = .04), whereas fibrous tissue increased significantly in both volume (337 ± 160 vs 357 ± 169 mm(3); P .001) and composition (76.3 ± 10.5% vs 83.1 ± 10.1%, P = .002). Such changes were not seen in subjects who discontinued statin. Furthermore, the changes in LRNC volume and composition and fibrous tissue composition from 24 to 48 months were significantly different between the statin-continued and -discontinued groups (-25 ± 18 vs 9 ± 14 mm(3); P .001) and (-4.6 ± 8.2% vs 1.3 ± 2.8%; P = .009) and (6.9 ± 6.8% vs 1.3 ± 5.4%, P = .018).Continued statin therapy leads to continued decrease in LRNC and increase in fibrous tissue, which indicates improved plaque stability and supports long-term statin therapy.

To retrospectively determine if in vivo magnetic resonance (MR) imaging can simultaneously depict differences between symptomatic and asymptomatic carotid atherosclerotic plaque.Institutional review board approval and informed consent were obtained for this HIPAA-compliant study. Twenty-three patients (21 men, two women; mean age, 66.1 years +/- 11.0 [standard deviation]) with unilateral symptomatic carotid disease underwent 1.5-T time-of-flight MR angiography and 1.5-T T1-, intermediate-, and T2-weighted MR imaging. Both carotid arteries were reviewed. One observer recorded quantitative and morphologic information, which included measurement of the area of the lumen, artery wall, and main plaque components; fibrous cap status (thick, thin, or ruptured); American Heart Association (AHA) lesion type (types I-VIII); and location (juxtaluminal vs intraplaque) and type of hemorrhage. Plaques associated with neurologic symptoms and asymptomatic plaques were compared with Wilcoxon signed rank and McNemar tests.Compared with asymptomatic plaques, symptomatic plaques had a higher incidence of fibrous cap rupture (P = .007), juxtaluminal hemorrhage or thrombus (P = .039), type I hemorrhage (P = .021), and complicated AHA type VI lesions (P = .004) and a lower incidence of uncomplicated AHA type IV and V lesions (P = .005). Symptomatic plaques also had larger hemorrhage (P = .003) and loose matrix (P = .014) areas and a smaller lumen area (P = .008). No significant differences between symptomatic and asymptomatic plaques were found for quantitative measurements of the lipid-rich necrotic core, calcification, and the vessel wall or for the occurrence of intraplaque hemorrhage or type II hemorrhage.This study revealed significant differences between symptomatic and asymptomatic plaques in the same patient.

Background— Previous studies with contrast-enhanced magnetic resonance imaging (CEMRI) have shown that the fibrous cap (FC) in atherosclerotic carotid plaques enhances with gadolinium-based contrast agents. Conversely, the lipid-rich necrotic core (LR-NC), lacking both vasculature and matrix, shows no or only slight enhancement. The goal of this study was to assess whether CEMRI can be used to accurately measure the dimensions of the intact FC and LR-NC. Methods and Results— Twenty-one patients scheduled for carotid endarterectomy were imaged with a 1.5-T scanner. Precontrast images and CEMRI were obtained. One hundred eight locations with an intact FC were matched between MRI and the excised histology specimens. Quantitative measurements of FC length along the lumen circumference, FC area, and LR-NC area were collected from CEMRI images and histology sections. Blinded comparison of corresponding MR images and histology slices showed moderate to good correlation for length ( r =0.73, P r =0.80, P r =0.87, P Conclusions— In vivo high-resolution CEMRI is capable of quantitatively measuring the dimensions of the intact FC and LR-NC. These new parameters may be useful to evaluate plaque vulnerability and provide continuous variables for characterizing the intact FC and LR-NC in progression and regression studies.

The miR-200c has recently been implicated in the epithelial to mesenchymal transition (EMT) process by directly target the EMT related transcriptional factors ZEB1 and ZEB2. The expression of this miRNA is inversely correlated with tumorgenecity and invasiveness in several human cancers. However, little is known about the expression and targets of the miR-200c in radiation carcinogenesis. Here in this study, using a split radiation induced thymic lymphoma (RITL) model in BALB/c mice, we found that miR-200c is down-regulated in RITL samples. Cell death and apoptosis in lymphoma cells was induced by miR-200c mimic while decreased by miR-200c inhibitor. Computational analysis found a putative target site of miR-200c in the 3'UTR of one of the polycomb group (PcG) protein BMI1 mRNA, which was verified by a luciferase reporter assay. Forced over-expression of miR-200c decreased the level of BMI1 protein and moreover, over-expression of BMI1 rescued the biological effects of miR-200c, indicating BMI1 is a direct mediator of miR-200c functions. Furthermore, the BMI1 expression level was up-regulated and inversely correlated with miR-200c in RITL samples. Finally, our data also indicates that Adenovirus over-expression of pre-miR-200c reduced tumorgenesis in vivo. Taken together, we conclude that down-regulated expression of miR-200c and up-regulation of its direct target BMI1 in radiation-induced thymic lymphoma, which may indicate a novel therapeutic method for RITL through induction of miR-200c or inhibition of BMI1.

Background the bone marrow and the intestine are the major sites of ionizing radiation (IR)-induced injury. Our previous study demonstrated that CpG-oligodeoxynucleotide (ODN) treatment mitigated IR-induced bone marrow injury, but its effect on the intestine is not known. In this study, we sought to determine if CpG-ODN have protective effect on IR-induced intestine injury, and if so, to determine the mechanism of its effect. Methods and Findings Mice were treated with CpG-ODN after IR. The body weight and survival were daily monitored for 30 days consecutively after exposure. The number of surviving intestinal crypt was assessed by the microcolony survival assay. The number and the distribution of proliferating cell in crypt were evaluated by TUNEL assay and BrdU assay. The expression of Bcl-2, Bax and caspase-3 in crypt were analyzed by Immunohistochemistry assay. The findings showed that the treatment for irradiated mice with CpG-ODN diminished body weight loss, improved 30 days survival, enhanced intestinal crypts survival and maintained proliferating cell population and regeneration in crypt. The reason might involve that CpG-ODN up-regulated the expression of Bcl-2 protein and down-regulated the expression of Bax protein and caspase-3 protein. Conclusion CpG-ODN was effective in protection of IR-induced intestine injury by enhancing intestinal crypts survival and maintaining proliferating cell population and regeneration in crypt. The mechanism might be that CpG-ODN inhibits proliferating cell apoptosis through regulating the expression of apoptosis-related protein, such as Bax, Bcl-2 and caspase-3.

To assess the value of high-resolution three-dimensional black-blood magnetic resonance imaging (3D-BB-MRI) in quantitative measurement of carotid atherosclerotic plaque by comparison with two-dimensional black-blood magnetic resonance imaging (2D-BB-MRI).Forty patients were scanned with routine 2D and oblique-sagittal 3D-BB-MRI. The original oblique-sagittal 3D images were reformatted to an axial 2D-like dataset. Two experienced radiologists identified the interested slice in consensus for every patient (unilateral carotid artery) in 2D-BB-MRI images and matched the axial reformatted 3D images with 2D black-blood images. Plaque thickness (PT), lumen area (LA) and total vessel area (TVA) were measured, and lumen stenosis (LS) and normalized wall index (NWI) were calculated.There was no measurement difference between 2D-BB-MRI and reformatted 3D-BB-MRI (P0.05), and these two methods had a good correlation (r0.9). The Bland-Altman chart showed that 2D-BB-MRI and 3D-BB-MRI were in good agreement in the measurement of PT, LA and TVA.3D-BB-MRI and 2D-BB-MRI have no obvious difference in quantitative measurement of the carotid plaques. 3D-BB-MRI can demonstrate the vessels and plaques by multiplanar reconstruction and thus have better performance in evaluating carotid atherosclerosis compared with 2D-BB-MRI.